Optimal control of HCV transmission under liquoring.

Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases and both are recognized as major causes of liver disease worldwide. Each poses a major public and economic burden to society, and when the two co-exist they appear to have a synergistic effect in the progression of chronic liver disease. In this research, we developed a SIRS model of transmission of the hepatitis C virus (HCV) under effect of liquoring in six compartments: Susceptible, Low liquoring, High liquoring, Acute, Chronic and Recovered Individuals. The system of non-linear ordinary differential equations is formulated. Basic reproduction number R0 is computed using the next generation matrix approach. The stability of the model is worked out at the equilibrium point. Model analysis shows that the disease-free equilibrium point is both locally and globally asymptotically stable. Sensitivity analysis with respect to key parameters of R0 indicates that control strategies should target reduction of the amount of alcohol use amongst people with HCV as it prevents or delays HCV disease progression. The control in our model is in terms of rehabilitation center which helps people to divert from high liquoring to low liquoring. Numerical simulation has been carried out to show the impact of control on different compartment. This research shows the positive impact of rehabilitation on liquoring habits and subsequently on HCV transmission.

Theoretical investigations of a platinum-water interface using quantum-mechanics-molecular-mechanics based molecular dynamics simulations.

Pt-water interfaces have been of immense interest in the field of energy storage and conversion. Studying this interface using both experimental and theoretical tools is challenging. On the theoretical front, typically one uses classical molecular dynamics (MD) simulations to handle large system sizes or time scales while for a more accurate quantum mechanical description Born Oppenheimer MD (BOMD) is typically used. The latter is limited to smaller system sizes and time-scales. In this study using quantum-mechanics-molecular-mechanics (QMMM), we have performed atomistic MD simulations to have a microscopic understanding of the structure of the Pt-water interface using a system size that is much larger than that accessible when using BOMD simulations. In contrast to recent reports using BOMD simulations, our study reveals that the water molecules typically form two distinct layers above the Pt-surface before they form bulk like structures. Further, we also find that a significant fraction of the water molecules at the interface are pointed towards the surface thereby disrupting the H-bond network. Consistent with this observation, the layer resolved oxygen-oxygen radial distribution function for the water molecules belonging to the solvating water layer shows a high density liquid like behaviour even though the overall water behaves like a low density liquid. A charge transfer analysis reveals that this solvating water layer donates electrons to the Pt atoms in contact with it thereby resulting in the formation of an interface dipole that is pointing towards the surface. Our results suggest that, using QMMM-MD, on one hand it is possible to study more realistic models of solid-liquid interfaces that are inaccessible with BOMD, while on the other hand one also has access to information about such systems that are not obtained from conventional classical MD simulations.

In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex.

We performed bedaquiline broth microdilution susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) guidelines on 103 respiratory isolates of Mycobacterium avium complex (MAC), including multidrug-resistant isolates. Approximately 90% of isolates had bedaquiline MICs of ≤0.008 µg/ml, and 102/103 isolates had MICs of ≤0.015 µg/ml. Bedaquiline has excellent potential for use in patients with MAC infections, although for reasons of its metabolism by the cytochrome P450 system, it should not be given with rifampin.

Laterally structured ripple and square phases with one and two dimensional thickness modulations in a model bilayer system.

Molecular dynamics simulations of bilayers in a surfactant/co-surfactant/water system with explicit solvent molecules show formation of topologically distinct gel phases depending upon the bilayer composition. At low temperatures, the bilayers transform from the tilted gel phase, Lß', to the one dimensional (1D) rippled, Pß' phase as the surfactant concentration is increased. More interestingly, we observe a two dimensional (2D) square phase at higher surfactant concentration which, upon heating, transforms to the gel Lß' phase. The thickness modulations in the 1D rippled and square phases are asymmetric in two surfactant leaflets and the bilayer thickness varies by a factor of ∼2 between maximum and minimum. The 1D ripple consists of a thinner interdigitated region of smaller extent alternating with a thicker non-interdigitated region. The 2D ripple phase is made up of two superimposed square lattices of maximum and minimum thicknesses with molecules of high tilt forming a square lattice translated from the lattice formed with the thickness minima. Using Voronoi diagrams we analyze the intricate interplay between the area-per-head-group, height modulations and chain tilt for the different ripple symmetries. Our simulations indicate that composition plays an important role in controlling the formation of low temperature gel phase symmetries and rippling accommodates the increased area-per-head-group of the surfactant molecules.

Melting and mechanical properties of polymer grafted lipid bilayer membranes.

The influence of polymer grafting on the phase behavior and elastic properties of two tail lipid bilayers have been investigated using dissipative particle dynamics simulations. For the range of polymer lengths studied, the L(c) to L(α) transition temperature is not significantly affected for grafting fractions, G(f) between 0.16 and 0.25. A decrease in the transition temperature is observed at a relatively high grafting fraction, G(f) = 0.36. At low temperatures, a small increase in the area per head group, a(h), at high G(f) leads to an increase in the chain tilt, inducing order in the bilayer and the solvent. The onset of the phase transition occurs with the nucleation of small patches of thinned membrane which grow and form continuous domains as the temperature increases. This region is the co-existence region between the L(ß)(thick) and the L(α)(thin) phases. The simulation results for the membrane area expansion as a function of the grafting density conform extremely well to the scalings predicted by self-consistent mean field theories. We find that the bending modulus shows a small decrease for short polymers (number of beads, N(p) = 10) and low G(f), where the influence of polymer is reduced when compared to the effect of the increased a(h). For longer polymers (N(p) > 15), the bending modulus increases monotonically with increase in grafted polymer. Using the results from mean field theory, we partition the contributions to the bending modulus from the membrane and the polymer and show that the dominant contribution to the increased bending modulus arises from the grafted polymer.

Exosome secretome and mediated signaling in breast cancer patients with nontuberculous mycobacterial disease.

Bronchiectasis Nontuberculous mycobacterium (NTMnb) infection is an emerging health problem in breast cancer (BCa) patients. We measured sera exosome proteome in BCa-NTMnb subjects and controls by Mass Spectroscopy. Extracellular matrix protein 1 (ECM1) was detected exclusively in the circulating exosomes of 82% of the BCa-NTMnb cases. Co-culture of ECM1+ exosomes with normal human mammary epithelial cells induced epithelial to mesenchymal transition accompanied by increased Vimentin/CDH1 expression ratio and Glutamate production. Co-culture of the ECM1+ exosomes with normal human T cells modulated their cytokine production. The ECM1+ exosomes were markedly higher in sera obtained from BCa-NTMnb subjects. Exclusive expression of APN, APOC4 and AZGP1 was evident in the circulating exosomes of these BCa-NTMnb cases, which predicts disease prevalence independent of the body max index in concert with ECM1. Monitoring ECM1, APN, APOC4 and AZGP1 in the circulating exosomes could be beneficial for risk assessment, monitoring and surveillance of BCa-NTMnb.

A Comparison of Classical Force-Fields for Molecular Dynamics Simulations of Lubricants.

For the successful development and application of lubricants, a full understanding of their complex nanoscale behavior under a wide range of external conditions is required, but this is difficult to obtain experimentally. Nonequilibrium molecular dynamics (NEMD) simulations can be used to yield unique insights into the atomic-scale structure and friction of lubricants and additives; however, the accuracy of the results depend on the chosen force-field. In this study, we demonstrate that the use of an accurate, all-atom force-field is critical in order to; (i) accurately predict important properties of long-chain, linear molecules; and (ii) reproduce experimental friction behavior of multi-component tribological systems. In particular, we focus on n-hexadecane, an important model lubricant with a wide range of industrial applications. Moreover, simulating conditions common in tribological systems, i.e., high temperatures and pressures (HTHP), allows the limits of the selected force-fields to be tested. In the first section, a large number of united-atom and all-atom force-fields are benchmarked in terms of their density and viscosity prediction accuracy of n-hexadecane using equilibrium molecular dynamics (EMD) simulations at ambient and HTHP conditions. Whilst united-atom force-fields accurately reproduce experimental density, the viscosity is significantly under-predicted compared to all-atom force-fields and experiments. Moreover, some all-atom force-fields yield elevated melting points, leading to significant overestimation of both the density and viscosity. In the second section, the most accurate united-atom and all-atom force-field are compared in confined NEMD simulations which probe the structure and friction of stearic acid adsorbed on iron oxide and separated by a thin layer of n-hexadecane. The united-atom force-field provides an accurate representation of the structure of the confined stearic acid film; however, friction coefficients are consistently under-predicted and the friction-coverage and friction-velocity behavior deviates from that observed using all-atom force-fields and experimentally. This has important implications regarding force-field selection for NEMD simulations of systems containing long-chain, linear molecules; specifically, it is recommended that accurate all-atom potentials, such as L-OPLS-AA, are employed.

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease.

BACKGROUND: Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease. METHODS: We describe a case series of off-label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. The 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). The patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline. RESULTS: Common side effects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG findings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months. After 6 months of therapy, 60% of patients (six of 10) had a microbiologic response, with 50% (five of 10) having one or more negative cultures. CONCLUSIONS: This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but the findings require confirmation with larger studies.

Investigations on the melting and bending modulus of polymer grafted bilayers using dissipative particle dynamics.

Understanding the influence of polymer grafted bilayers on the physicomechanical properties of lipid membranes is important while developing liposomal based drug delivery systems. The melting characteristics and bending moduli of polymer grafted bilayers are investigated using dissipative particle dynamics simulations as a function of the amount of grafted polymer and lipid tail length. Simulations are carried out using a modified Andersen barostat, whereby the membrane is maintained in a tensionless state. For lipids made up of four to six tail beads, the transition from the low temperature L(ß) phase to the L(α) phase is lowered only above a grafting fraction of G(f)=0.12 for polymers made up of 20 beads. Below G(f)=0.12 small changes are observed only for the HT(4) bilayer. The bending modulus of the bilayers is obtained as a function of G(f) from a Fourier analysis of the height fluctuations. Using the theory developed by Marsh et al. [Biochim. Biophys. Acta 1615, 33 (2003)] for polymer grafted membranes, the contributions to the bending modulus due to changes arising from the grafted polymer and bilayer thinning are partitioned. The contributions to the changes in κ from bilayer thinning were found to lie within 11% for the lipids with four to six tail beads, increasing to 15% for the lipids containing nine tail beads. The changes in the area stretch modulus were also assessed and were found to have a small influence on the overall contribution from membrane thinning. The increase in the area per head group of the lipids was found to be consistent with the scalings predicted by self-consistent mean field results.

Effect of polymer grafting on the bilayer gel to liquid-crystalline transition.

Grafted polymers on the surface of lipid membranes have potential applications in liposome-based drug delivery and supported membrane systems. The effect of polymer grafting on the phase behavior of bilayers made up of single-tail lipids is investigated using dissipative particle dynamics. The bilayer is maintained in a tensionless state using a barostat. Simulations are carried out by varying the grafting fraction, G(f), defined as the ratio of the number of polymer molecules to the number of lipid molecules, and the length of the lipid tails. At low G(f), the bilayer shows a sharp transition from the gel (L(beta)) to the liquid-crystalline (L(alpha)) phase. This main melting transition temperature is lowered as G(f) is increased, and above a critical value of G(f), the interdigitated L(betaI) phase is observed prior to the main transition. The temperature range over which the intermediate phases are observed is a function of the lipid tail length and G(f). At higher grafting fractions, the presence of the L(betaI) phase is attributed to the increase in the area per head group due to the lateral pressure exerted by the polymer brush. The areal expansion and decrease in the melting temperatures as a function of G(f) were found to follow the scalings predicted by the self-consistent mean field theories for grafted polymer membranes. Our study shows that the grafted polymer density can be used to effectively control the temperature range and occurrence of a given bilayer phase.