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

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

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

What Are the Transmission Mechanisms of Influenza A Viruses in Wild Mammals?

Some influenza A viruses (IAVs) represent serious potential threats to public and agricultural health, with 3 notable examples from the past decade. During 2009, a novel H1N1 IAV (A[H1N1]pdm09), which was first detected in the United States, spread rapidly throughout many regions of the world. In the United States alone, the Centers for Disease Control and Prevention estimated that \u3e60 million human cases were associated with this emergent and pandemic virus. During 2013, a novel H7N9 avian-origin IAV (Asian lineage avian influenza A[H7N9] virus) was first detected in China. This virus not only cost the poultry industry more than $1 billion through culling and market closures, it also proved to be detrimental to public health, as this virus is readily transmitted to humans and can cause moderate-to-high rates of mortality. More recently, a highly pathogenic clade 2.3.4.4 avian IAV was first detected in North America during 2014. Ultimately, the introduction of this virus (and subsequent reassortant viruses) elicited the most expensive highly pathogenic IAV outbreak in US history, with total losses estimated to be billions of dollars. These 3 examples exemplify the enormous burdens that some IAVs can place on public and agricultural health systems and suggest that a diversity of studies need to be conducted to address the complex epidemiology of these virushost systems

Linearized inverse scattering based on seismic Reverse Time Migration

In this paper we study the linearized inverse problem associated with imaging of reflection seismic data. We introduce an inverse scattering transform derived from reverse-time migration (RTM). In the process, the explicit evaluation of the so-called normal operator is avoided, while other differential and pseudodifferential operator factors are introduced. We prove that, under certain conditions, the transform yields a partial inverse, and support this with numerical simulations. In addition, we explain the recently discussed 'low-frequency artifacts' in RTM, which are naturally removed by the new method

Influenza A Viruses in Peridomestic Mammals

During recent years, serological evidence has shown that a number of peridomestic mammals (e.g., those commonly found in or around human structures) are naturally exposed to influenza A viruses (IAVs). In addition, experimental studies have demonstrated that many of these species can successfully replicate several different IAVs, including IAVs of high consequence to public or agricultural health. The replication of some IAVs within this group of mammals could have implications for biosecurity associated with poultry production and live bird markets in some regions of the world. Given this evidence, the need for further study and understanding of the role that peridomestic mammals may play in IAV dynamics is increasingly being recognized. This chapter will provide a general overview on IAV associations in peridomestic mammals, especially as they pertain to avian IAVs, and provide some general views and guidelines for sampling these species in various situations

Monitoring and manipulating the human brain: new neuroscience technologies and their ethical implications

Discusses the use of new neuroscience technologies in monitoring and manipulating brain function, as of May 2004. History of modern brain imaging; Implications of neuroimaging for medical ethics; Factors that contributed to brain enhancement