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

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

Boundary -work in United States psychology: A study of three interdisciplinary programs

Between 1970 and 2000 scientists from three interdisciplinary programs---evolutionary psychology, cognitive science, and chaos theory---contributed to changing U.S. psychology\u27s disciplinary boundaries. These interdisciplinary scientists brought about this change through their conceptual, material, and social practices. Psychologists used boundary-work as a means to control the influx of these various practices. Boundary-work connotes activities that promote scientists\u27 epistemic authority in society. Boundary-work also serves to demarcate a science\u27s particular collection of knowledge from other collections. Through their boundary-work activities, various psychologists resisted some of the practices of these interdisciplinary scientists while making accommodations for other types of practices. These resistances and accommodations illustrate the ways in which psychologists conveyed their epistemic authority and demarcated their discipline\u27s boundaries between these three decades. The purpose of my dissertation is to describe psychologists\u27 boundary-work in reaction to the introduction of these interdisciplinary programs\u27 practices between 1970 and 2000. First, I present an overview of psychology\u27s complex disciplinary boundaries. I then use the history of psychology and sociology of scientific knowledge literature to describe the nature of boundary-work activities. Next, I present the foundational components and a brief history of each interdisciplinary program. Fourth, I outline each program\u27s conceptual, material, and social practices. Lastly, I discuss psychologists\u27 resistances and accommodations to each interdisciplinary program\u27s practices with reference to how they affected psychology\u27s disciplinary boundaries. My results indicate that certain psychologists most often resisted evolutionary psychologists\u27, cognitive scientists\u27, and chaos theorists\u27 conceptual practices. Psychologists\u27 resistances seemed ineffective in preventing these conceptual practices from entering the discipline and did not stop other psychologists from using them. Accommodations occurred for all types of practices for all three programs, indicating that psychology\u27s disciplinary boundaries are relatively permeable. I argue that psychologists made accommodations for these practices to increase their epistemic authority within the scientific community and throughout society. Finally, I discuss the advantages of writing psychology\u27s history through an examination of psychologists\u27 boundary-work

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

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