Isolation and Characterisation of a Human-Like Antibody Fragment (scFv) That Inactivates VEEV In Vitro and In Vivo

Venezuelan equine encephalitis virus (VEEV) belongs to the Alphavirus genus and several species of this family are pathogenic to humans. The viruses are classified as potential agents of biological warfare and terrorism and sensitive detection as well as effective prophylaxis and antiviral therapies are required

Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections

The role of justice in negotiation

This chapter discusses the role of justice in negotiation between rival parties and the durability of peace agreements. It draws on research about group negotiation processes and agreements to end civil wars, mostly during the early 1990s. Hypothesized relationships between the presence and importance of distributive justice (DJ) in the agreements, and their durability, were first explored with multiple methods (see also the chapter by Koeszegi and Vetschera, this volume). The difficulty of the conflict environment was shown to have the strongest impact on durability. However, the DJ principle of equality was found to reduce the negative impact of difficult environments. An emphasis on equality was also associated with more forward-looking agreements, which were found to be more durable than those that were backward looking. (See also the chapters by Nurmi, Klamber, Kilgour and Hipel, Turel, and Yuan, this volume for modeling approaches to issues of justice and fairness.) Next, the presence and importance of procedural justice (PJ) were examined in the negotiation processes that led to the signing of the peace agreements. Significantly more durable agreements occurred when a process based on PJ led to agreements that emphasized equality. This focus on process is similar to the analyses conducted by the authors chapters (See also the chapter by Koeszegi and Vetschera, Kersten and Lai, this volume). A close examination of how the equality principle was applied revealed that agreements based on provisions of equal treatment and/or equal shares were particularly durable. The chapter concludes with a discussion of tactics used by third parties to produce durable agreements, and lessons for policy

Effects of MIld cold shock (25°C) followed by warming up a 37°C on the cellular stress response.

Temperature variations in cells, tissues and organs may occur in a number of circumstances. We report here that reducing temperature of cells in culture to 25°C for 5 days followed by a rewarming to 37°C affects cell biology and induces a cellular stress response. Cell proliferation was almost arrested during mild hypothermia and not restored upon returning to 37°C. The expression of cold shock genes, CIRBP and RBM3, was increased at 25°C and returned to basal level upon rewarming while that of heat shock protein HSP70 was inversely regulated. An activation of pro-apoptotic pathways was evidenced by FACS analysis and increased Bax/Bcl2 and BclXS/L ratios. Concomitant increased expression of the autophagosome-associated protein LC3II and AKT phosphorylation suggested a simultaneous activation of autophagy and pro-survival pathways. However, a large proportion of cells were dying 24 hours after rewarming. The occurrence of DNA damage was evidenced by the increased phosphorylation of p53 and H2AX, a hallmark of DNA breaks. The latter process, as well as apoptosis, was strongly reduced by the radical oxygen species (ROS) scavenger, N-acetylcysteine, indicating a causal relationship between ROS, DNA damage and cell death during mild cold shock and rewarming. These data bring new insights into the potential deleterious effects of mild hypothermia and rewarming used in various research and therapeutical fields