Analyzing Machupo virus-receptor binding by molecular dynamics simulations

In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein-protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non-alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host-virus protein-protein interface. We use steered molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second, although the static co-crystal structure shows two large hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate that one of them may not be important for tight binding. Third, one viral site known to be critical for infection may mark an important evolutionary suppressor site for infection-resistant hTfR1 mutants. Finally, our approach provides a framework to compare the effects of multiple mutations, individually and jointly, on protein-protein interactions.Comment: 33 pages, 8 figures, 5 table

Phase Diagram of Metal-Insulator Transition in System with Anderson-Hubbard Centers

The model of a strongly correlated system in which periodically spaced Anderson-Hubbard centers are introduced into narrow-band metal is considered. Besides the interactions between localized magnetic moments and strong on-site Coulomb interaction, the model takes into account the hybridization of localized and band states. To study the efect of the lattice deformation on the electrical properties of the system the phonon term and elastic energy have been taken into account. Green functions for band and localized electrons have been found. On this base, the energy spectrum has been investigated as function of model parameters, temperature and external pressure. The criterion of metal-insulator transition for integer value of electron concentration has been derived and the phase diagram of the metal-insulator transition has been built.Comment: presented at 12 International Simposium on Physics of Materials, Prague 4-8.09.201

A Reanalysis of the Carbon Abundance in the Translucent Cloud toward HD 24534

We have reanalyzed the Goddard High Resolution Spectrograph data set presented by Snow et al. which contains the interstellar intersystem C II] 2325A line through the translucent cloud toward HD 24534 (X Persei). In contrast to the results of Snow et al., we clearly detect the C II] feature at the 3-sigma confidence level and measure a C^+ column density of 2.7 +/- 0.8 x 10^17 cm^-2. Accounting for the C I column density along the line of sight, we find 10^6 C/H = 106 +/- 38 in the interstellar gas toward this star. This gas-phase carbon-to-hydrogen ratio suggests that slightly more carbon depletion may be occurring in translucent as compared to diffuse clouds. The average diffuse-cloud C/H, however, is within the 1-sigma uncertainty of the measurement toward HD 24534. We therefore cannot rule out the possibility that the two cloud types have comparable gas-phase C/H, and therefore comparable depletions of carbon.Comment: 9 pages, 3 figures, to appear in the Astrophysical Journal Letter

Direct current driven by ac electric field in quantum wells

It is shown that the excitation of charge carriers by ac electric field with zero average driving leads to a direct electric current in quantum well structures. The current emerges for both linear and circular polarization of the ac electric field and depends on the field polarization and frequency. We present a micoscopic model and an analytical theory of such a nonlinear electron transport in quantum wells with structure inversion asymmetry. In such systems, dc current is induced by ac electric field which has both the in-plane and out-of-plane components. The ac field polarized in the interface plane gives rise to a direct current if the quantum well is subjected to an in-plane static magnetic field.Comment: 6 pages, 3 figure

Noise radiated from a periodically stiffened cylindrical shell excited by a turbulent boundary layer

© 2019 Elsevier Ltd This work proposes a semi-analytical method to model the vibroacoustic behavior of submerged cylindrical shells periodically stiffened by axisymmetric frames and excited by a homogeneous and fully developed turbulent boundary layer (TBL). The process requires the computation of the TBL wall-pressure cross spectral density function and the sensitivity functions for stiffened cylindrical shells. The former is deduced from an existent TBL model and the latter are derived from a wavenumber-point reciprocity principle and a spectral formulation of the problem. The stiffeners' dynamic behavior is introduced in the formulation through circumferential admittances that are computed by a standard finite element code using shell elements. Four degrees of freedom are taken into account for the coupling between the shell and the stiffeners: three translation directions and one tangential rotation. To investigate the effect of the stiffeners on the radiated noise, two case studies are considered. The first one examines a fluid-loaded cylindrical shell with regularly spaced simple supports. The influence of Bloch-Floquet waves and the support spacing on the noise radiation are highlighted. The second case study inspects the fluid-loaded cylindrical shell with two different periodic ring stiffeners, namely stiffeners with T-shaped and I-shaped cross-sections. Their influence on the vibroacoustics of the shell is thoroughly analyzed

Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease

There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gall-stone formation and mitigate biliary pain in gall-stone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gall-bladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 × 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05±0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94±0.27 versus 0.93±0.32 mg/ml) or total protein (5.8±0.9 versus 6.4±1.3 mg/ml), cholesterol saturation (1.3±0.2 versus 1.5±0.2), or nucleation time (2.0±3.0 versus 1.5±2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9±0.6 versus 5.6±1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content. Since mucus glycoproteins are major determinants of bile viscosity, an alteration in mucin macromolecular composition may conceivably cause the indomethacin-induced decrease in biliary viscosity and explain the beneficial effects of nonsteroidal anti-inflammatory drugs in gallstone disease