Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors.

The homotrimeric HIV-1 envelope glycoprotein (Env) undergoes receptor-triggered structural changes that mediate viral entry through membrane fusion. This process is inhibited by chemokine receptor antagonists (CoRAs) that block Env-receptor interactions and by fusion inhibitors (FIs) that disrupt Env conformational transitions. Synergy between CoRAs and FIs has been attributed to a CoRA-dependent decrease in the rate of viral membrane fusion that extends the lifetime of the intermediate state targeted by FIs. Here, we demonstrated that the magnitude of CoRA/FI synergy unexpectedly depends on FI-binding affinity and the stoichiometry of chemokine receptor binding to trimeric Env. For C-peptide FIs (clinically represented by enfuvirtide), synergy waned as binding strength decreased until inhibitor combinations behaved additively. Curiously, this affinity dependence on synergy was absent for 5-Helix-type FIs. We linked this complex behavior to the CoRA dependence of Env deactivation following FI binding. For both FI classes, reducing chemokine receptor levels on target cells or eliminating competent chemokine receptor-binding sites on Env trimers resulted in a loss of synergistic activity. These data imply that the stoichiometry required for CoRA/FI synergy exceeds that required for HIV-1 entry. Our analysis suggests two distinct roles for chemokine receptor binding, one to trigger formation of the FI-sensitive intermediate state and another to facilitate subsequent conformational transitions. Together, our results could explain the wide variety of previously reported activities for CoRA/FI combinations. These findings also have implications for the combined use of CoRAs and FIs in antiviral therapies and point to a multifaceted role for chemokine receptor binding in promoting HIV-1 entry

Wafer level reliability for high-performance VLSI design

As very large scale integration architecture requires higher package density, reliability of these devices has approached a critical level. Previous processing techniques allowed a large window for varying reliability. However, as scaling and higher current densities push reliability to its limit, tighter control and instant feedback becomes critical. Several test structures developed to monitor reliability at the wafer level are described. For example, a test structure was developed to monitor metal integrity in seconds as opposed to weeks or months for conventional testing. Another structure monitors mobile ion contamination at critical steps in the process. Thus the reliability jeopardy can be assessed during fabrication preventing defective devices from ever being placed in the field. Most importantly, the reliability can be assessed on each wafer as opposed to an occasional sample

Large transport landing characteristics as simulated in flight and on the ground

Comparison of theoretical and simulated low speed landing characteristics for large transport aircraft

Investigations in space communications theory, including topics related to random processes, filtering, telemetry Semiannual status report, 1 Oct. 1966 - 31 Mar. 1967

Random processes, filtering, and telemetry problems in space communications theor

Internal visual workmanship standard for microelectronic devices /NASA STD XX-2/ and training manual, volume 2

Internal visual workmanship standards for monolithic microelectronic devices - training manua

Ethane-xenon mixtures under shock conditions

Mixtures of light elements with heavy elements are important in inertial confinement fusion and planetary science. We explore the physics of molecular scale mixing through a validation study of equation of state (EOS) properties. Density functional theory molecular dynamics (DFT-MD) at elevated-temperature and pressure is used to obtain the thermodynamic state properties of pure xenon, ethane, and various compressed mixture compositions along their principal Hugoniots. To validate these simulations, we have performed shock compression experiments using the Sandia Z-Machine. A bond tracking analysis correlates the sharp rise in the Hugoniot curve with the completion of dissociation in ethane. The DFT-based simulation results compare well with the experimental data along the principal Hugoniots and are used to provide insight into the dissociation and temperature along the Hugoniots as a function of mixture composition

Asymmetric deactivation of HIV-1 gp41 following fusion inhibitor binding.

Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that influence the antiviral potency of two such gp41 inhibitors, C37 and 5-Helix. Employing a series of C37 and 5-Helix variants, we investigated the physical properties of gp41 inhibition, including the ability of inhibitor-bound gp41 to recover its fusion activity once inhibitor was removed from solution. Our results indicated that antiviral activity critically depended upon irreversible deactivation of inhibitor-bound gp41. For C37, which targets the N-terminal region of the gp41 ectodomain, deactivation was a slow process that depended on chemokine receptor binding to Env. For 5-Helix, which targets the C-terminal region of the gp41 ectodomain, deactivation occurred rapidly following inhibitor binding and was independent of chemokine receptor levels. Due to this kinetic disparity, C37 inhibition was largely reversible, while 5-Helix inhibition was functionally irreversible. The fundamental difference in deactivation mechanism points to an unappreciated asymmetry in gp41 following inhibitor binding and impacts the development of improved fusion inhibitors and HIV-1 vaccines. The results also demonstrate how the activities of intermediate state inhibitors critically depend upon the final disposition of inhibitor-bound states

Introducing the concept of Potential Aerosol Mass (PAM)

International audiencePotential Aerosol Mass (PAM) can be defined as the maximum aerosol mass that the oxidation of precursor gases produces. In the measurement, all precursor gases are rapidly oxidized with extreme amounts of oxidants to low volatility compounds, resulting in the aerosol formation. Oxidation occurs in a small, simple, flow-through chamber that has a short residence time and is irradiated with ultraviolet light. The amount of the oxidants ozone (O3), hydroxyl (OH), and hydroperoxyl (HO2) were measured directly and can be controlled by varying the UV light and the relative humidity. Maximum values were 40 ppmv for O3, 500 pptv for OH, and 4 ppbv for HO2. The oxidant amounts are 100 to 1000 times troposphere values, but the ratios OH/O3 and HO2/OH are similar to troposphere values. The aerosol production mechanism and the aerosol mass yield were studied for several controlling variables, such as temperature, relative humidity, oxidant concentration, presence of nitrogen oxides (NOx), precursor gas composition and amount, and the presence of acidic seed aerosol. The measured secondary organic aerosol (SOA) yield of several natural and anthropogenic volatile organic compounds and a mixture of hydrocarbons in the PAM chamber were similar to those obtained in large, batch-style environmental chambers. This PAM method is being developed for measuring potential aerosol mass in the atmosphere, but is also useful for examining SOA processes in the laboratory and in environmental chambers

Dallas with balls: televized sport, soap opera and male and female pleasures

Two of the most popular of television genres, soap opera and sports coverage have been very much differentiated along gender lines in terms of their audiences. Soap opera has been regarded very much as a 'gynocentric' genre with a large female viewing audience while the audiences for television sport have been predominantly male. Gender differentiation between the genres has had implications for the popular image of each. Soap opera has been perceived as inferior; as mere fantasy and escapism for women while television sports has been perceived as a legitimate, even edifying experience for men. In this article the authors challenge the view that soap opera and television sport are radically different and argue that they are, in fact, very similar in a number of significant ways. They suggest that both genres invoke similar structures of feeling and sensibility in their respective audiences and that television sport is a 'male soap opera'. They consider the ways in which the viewing context of each genre is related to domestic life and leisure, the ways in which the textual structure and conventions of each genre invoke emotional identification, and finally, the ways in which both genres re-affirm gender identities