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

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

Portable Simulator for On-Board International Space Station Emergency Training

The crew on-board the International Space Station (ISS) have to be prepared for any possible emergency. The emergencies of most concern are a fire, depressurization or a toxic atmosphere. The crew members train on the ground before launch but also need to practice their emergency response skills while they are on orbit for 6 months. On-Board Training (OBT) events for emergency response proficiency used to require the crew and ground teams to use paper "scripts" that showed the path through the emergency procedures. This was not very realistic since the participants could read ahead and never deviate from this scripted path. The new OBT emergency simulator allows the crew to view dynamic information on an iPad only when it would become available during an event. The simulator interface allows the crew member to indicate hatch closures, don and doff masks, read pressures, and sample smoke or atmosphere levels. As the crew executes their actions using the on-board simulator, the ground teams are able to monitor those actions via ground display data flowing through the ISS Ku Band communication system which syncs the on-board simulator software with a ground simulator which is accessible in all the control centers. The OBT Working Group (OBT WG), led by the Chief Training Office (CTO) at Johnson Space center is a Multilateral working group with partners in Russia, Japan, Germany and U.S.A. The OBTWG worked together to create a simulator based on these principles: (a) Create a dynamic simulation that gives real-time data feedback; (b) Maintain real-time interface between Mission Control Centers and crew during OBTs; (c) Provide flexibility for decision making during drill execution; (d) Materially reduce Instructor and Flight Control Team man-hour costs involved with developing, updating, and maintaining emergency OBT cases/scenarios; and (e) Introduce an element of surprise to emergency scenarios so the team can't tell the outcome of the case by reading ahead in a paper script. This paper details some of the background as the project evolved with the International Partners. It also provides more details on how the simulator information for the crew is also shared with the ground teams. Finally, the paper will discuss how this remote simulator concept can be useful for future, longer term space missions

Are “New Urban” Neighborhood Design Characteristics Associated with Greater Levels of Social Capital within Neighborhoods? : Evidence from Greenville, South Carolina

Proponents of “new urbanism” suggest that “new urban” neighborhood design characteristics promote social interaction within the neighborhood. In this paper we formally analyze the relationship between “new urban” neighborhood characteristics (e.g., grid street patterns, green space, mixed commercial and residential land use) and social capital formation. We conducted a survey in order to determine the presence of new urban characteristics in neighborhoods and levels of neighborhood-specific social capital in Greenville, South Carolina. We then constructed a social capital index, which we regressed against a set of new urban and control variables. We find that new urban characteristics which facilitate personal interactions are correlated with the social capital index, as are the “youthfulness” of the neighborhood, homeownership rates, fewer hours worked, and the presence of children 18 and under in the household. These results suggest that some aspects of new urbanism may help promote the development of social capital within neighborhoods

An Examination of the use of Effects to Convey Narrative in Nikita Koshkin’s the Prince’s Toys Suite and Francis Kleynjans’ A L’aube Du Dernier Jour

Programmatic music conveys an extramusical narrative or idea. In pieces of this nature, it is common for a compositional device known as “tone-painting” to be used, in which elements of the narrative or idea the work is based on are reflected in the music. Sometimes this can be quite vivid, giving the impression of events occurring within a story. Examples of this imitative tone-painting can be referred to as “effects.”The guitar is capable of producing a great variety of sounds, and therefore many effects. After an introduction discussing the concept of effects and programmatic music, the author will give an overview of the use of effects in classical guitar repertoire. A detailed description of the use of effects in Nikita Koshkin’s The Prince’s Toys Suite and Francis Kleynjans’ A l’Aube du Dernier Jour will follow. These works are unique in classical guitar literature, in that they use effects to convey detailed narratives. The author seeks to provide a clear explanation of how Koshkin and Kleynjans were able to use effects in this manner

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

C34, a Membrane Fusion Inhibitor, Blocks HIV Infection of Langerhans Cells and Viral Transmission to T Cells

Development of topical microbicides that prevent sexual transmission of HIV is an active area of investigation. The purpose of this study was to test the ability of the potent membrane fusion inhibitor C34, an HIV gp41 antagonist, to block HIV infection of human Langerhans cells (LCs) in an epithelial environment that mimics a major route of HIV infection. We incubated freshly isolated epidermal explants containing LCs with various doses of C34 before, during, and after exposing explants to HIV. Although C34 only partially blocked HIV infection of LCs when pre-incubated with skin, it displayed full, dose-dependent inhibition when present during and after viral exposure. The poor protection from HIV infectivity in pre-incubated samples is consistent with mechanism of C34 inhibition and starkly contrasts to the full protection provided by PSC-RANTES, an entry inhibitor that prevents HIV gp120 interaction with its co-receptor CCR5. Real-time PCR confirmed that C34 blocked HIV infection of LCs before reverse transcription and inhibited LC-mediated transfer of virus to T cells. We conclude that C34, if used topically at susceptible mucosal sites, and if continually present, has the potential to block sexual transmission of HIV

Somebody\u27s Watching Me: FCPA Monitorships and How They Can Work Better

This article explores the rise of the corporate compliance monitor as a condition for settling violations of the U.S. Foreign Corrupt Practices Act (“FCPA”) — a setting in which federal prosecutors routinely impose monitors. If U.S. enforcement authorities maintain their current approach, the reality is that companies facing liability for violating the FCPA are likely to have a monitor imposed on them as part of a settlement agreement. From the U.S. government’s perspective, monitorships make sense for companies that violate anti-bribery laws, making it important for offending corporations to learn how to deal with monitors. Pulling from the authors’ extensive experience with three major FCPA compliance monitorships, as well as their work assisting clients operating under an FCPA monitorship, this article aids in that process. It also hopes to help monitors themselves, as well as the prosecutors who appoint them, in making the monitorship a more constructive feature of an FCPA settlement

Somebody\u27s Watching Me: FCPA Monitorships and How They Can Work Better

This article explores the rise of the corporate compliance monitor as a condition for settling violations of the U.S. Foreign Corrupt Practices Act (“FCPA”) — a setting in which federal prosecutors routinely impose monitors. If U.S. enforcement authorities maintain their current approach, the reality is that companies facing liability for violating the FCPA are likely to have a monitor imposed on them as part of a settlement agreement. From the U.S. government’s perspective, monitorships make sense for companies that violate anti-bribery laws, making it important for offending corporations to learn how to deal with monitors. Pulling from the authors’ extensive experience with three major FCPA compliance monitorships, as well as their work assisting clients operating under an FCPA monitorship, this article aids in that process. It also hopes to help monitors themselves, as well as the prosecutors who appoint them, in making the monitorship a more constructive feature of an FCPA settlement