Tibetan Pilgrimage Guides to Bhaktapur

This paper explores the phenomenon of a single devotional image identified with multiple deities by drawing from both premodern and modern Tibetan guidebook literature and ethnographic work. It engages the Tibetan-Newar Buddhist interface in the Kathmandu Valley with a focus on the Mūl Dīpaṃkara Buddha of Bhaktapur (alias Speaking Tārā, Sgrol ma gsung byon). The essay provides the first chronology of relevant literature and traces what has historically been of interest to Tibetan Buddhist pilgrims in Bhaktapur. The contemporary Dīpaṃkara/Speaking Tārā identification appears to supervene an older conflation occurring until the 18th century, when Tibetan pilgrims identified the Hindu Tantric goddess Taleju, the tutelary deity of the Malla kings who resides in Bhaktapur’s Royal Palace, as Speaking Tārā. The paper offers a preliminary investigation of this development and reflects on spatialized shifts in Tibetan pilgrimage practices

Streptococcal virulence and the coagulation system.

This thesis explores streptococcal virulence from both mechanistic and evolutionary perspectives, where the mechanistic studies focus on interactions with the human coagulation system. We describe interactions between streptococcal surface proteins and components of the intrinsic pathway of coagulation and the kallikrein-kinin system in human plasma, as well as to how these surface proteins are produced in different growth phases. The interactions involve activation of the kallikrein-kinin system and inhibition of its antibacterial effects. Inspired by these results, we review the literature, and develop a general model of streptococcal virulence. According to this model, the bacteria have two strategies, which we call asymptomatic colonization and superficial symptomatic infection, respectively, and they are adaptive under different epidemiological conditions. We propose that the bacteria's ability to cause invasive infections, which are the best studied, because they are the most severe, is a side effect of traits that evolved as adaptations for superficial symptomatic infections. This implies that many virulence mechanisms that have been described in invasive infections should have their functions in superficial symptomatic infections. We therefore investigate one such mechanism–the activation of host plasminogen–in conditions simulating pharyngitis, a very common superficial streptococcal infection. Pharyngitis is characterized by the exudation of plasma into an environment with saliva. We find that saliva affects the initiating enzymes of the intrinsic pathway of coagulation, and that this results in the formation of clots that entrap the bacteria. The bacteria escape the clots by activating host plasminogen, a finding that is in concordance with the model. As a whole this thesis underscores the utility of evolutionary analysis for interpreting and guiding mechanistic studies in infection biology, and conversely, the usefulness of mechanistic input for evolutionary theorizing

The Gramine Route to Pyrido[4,3-b]indol-3-ones – Identification of a New Cytotoxic Lead

A novel approach to 3-oxo-γ-carbolines was worked out starting from methyl indol-2-ylacetate via a gramine derivative. After quaternization, ammonia and 4-methoxybenzylamine could be inserted giving appropriate 3-oxo-γ-carbolines. Condensation with 2-chlorobenzaldehyde under microwave irradiation gave a 4-(2-chlorobenzyl)-3-oxo-γ-carboline. N-methylation lead to a product with very promising antifungal and cytotoxic activities

Evolving antibiotics against resistance : a potential platform for natural product development?

To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. However, the complex functions performed by antibiotics—combining, e.g., penetration of membranes, counteraction of resistance mechanisms, and interaction with molecular targets— have proven hard to achieve with current methods for drug development, including target-based screening and rational design. Here, we argue that we can meet the evolution of resistance in the clinic with evolution of antibiotics in the laboratory. On the basis of the results of experimental evolution studies of microbes in general and antibiotic production in Actinobacteria in particular, we propose methodology for evolving antibiotics to circumvent mechanisms of resistance. This exploits the ability of evolution to find solutions to complex problems without a need for design. We review evolutionary theory critical to this approach and argue that it is feasible and has important advantages over current methods for antibiotic discovery