Intercepting Cyclic Dinucleotide Signaling with Small Molecules

Bacterial infections, especially the ones that are caused by multidrug-resistant strains, are becoming increasingly difficult to treat and put enormous stress on healthcare systems. Recently President Obama announced a new initiative to combat the growing problem of antibiotic resistance. New types of antibiotic drugs are always in need to catch up with the rapid speed of bacterial drug-resistance acquisition. Bacterial second messengers, cyclic dinucleotides, play important roles in signal transduction and therefore are currently generating great buzz in the microbiology community because it is believed that small molecules that inhibit cyclic dinucleotide signaling could become next-generation antibacterial agents. The first identified cyclic dinucleotide, c-di-GMP, has now been shown to regulate a large number of processes, such as virulence, biofilm formation, cell cycle, quorum sensing, etc. Recently, another cyclic dinucleotide, c-di-AMP, has emerged as a regulator of key processes in Gram-positive and mycobacteria. C-di-AMP is now known to regulate DNA damage sensing, fatty acid synthesis, potassium ion transport, cell wall homeostasis and host type I interferon response induction. Due to the central roles that cyclic dinucleotides play in bacteria, we are interested in small molecules that intercept cyclic dinucleotide signaling with the hope that these molecules would help us learn more details about cyclic dinucleotide signaling or could be used to inhibit bacterial viability or virulence. This dissertation documents the development of several small molecule inhibitors of a cyclic dinucleotide synthase (DisA from B. subtilis) and phosphodiesterases (RocR from P. aeruginosa and CdnP from M. tuberculosis). We also demonstrate that an inhibitor of RocR PDE can inhibit bacterial swarming motility, which is a virulence factor.

School Development in Urbanizing Areas

Good schools are essential for building thriving urban areas. They are important for preparing the future human resource and directly contribute to social and economic development of a place. They not only act as magnets for prospective residents, but also are necessary for retaining current population. As public infrastructure, schools mirror their neighborhood. “Their location, design and physical condition are important determinants of neighborhood quality, regional growth and change, and quality of life.”2 They impact housing development and utility requirements among many things. Hence, planning for schools along with other infrastructure in an area is essential. Schools are very challenging to plan, especially in urbanizing areas with changing demographic dynamics, where the development market and housing development can shift drastically a number of times. In such places projecting the future school enrollments is very difficult and in case of large population influx, school development can be unable to catch up with population growth which results in overcrowding. Typical is the case of Arlington County VA. In the past two decades the County has changed dramatically from a collection of bedroom communities in Washington DC Metro Region to a thriving urban area. Its metro accessible urban corridors are among most desired locations for development in the region. However, converting single family neighborhoods into high density areas has put a lot of pressure on its school facilities and has resulted in overcrowded schools. Its public school enrollment has grown by 19% from 2009 to 2014.3 While the percentage of population under 5 years age has increased in last 10 years, those in the 5-19 age group have decreased4. Hence, there is more pressure on the elementary school facilities than others in the County. Design-wise, elementary schools, due to their size, can be imagined as a community component. There are a number of strategies that can be used to develop elementary school in urbanizing areas as a part of the neighborhood. Experimenting with space planning and building on partnership and mixed-use opportunities can help produce better designs for new schools in future. This thesis is an attempt to develop elementary school models for urbanizing areas of Arlington County. The school models will be designed keeping in mind the shifting nature of population and resulting student enrollments in these areas. They will also aim to be efficient and sustainable, and lead to the next generation design for elementary school education. The overall purpose of the project is to address barriers to elementary school development in urbanizing areas through creative design and planning strategies. To test above mentioned ideas, the Joint-Use School typology of housing +school design has been identified for elementary school development in urbanizing areas in this thesis project. The development is based on the Arlington Public School’s Program guidelines (catering to 600 students). The site selected for this project is Clarendon West (part of Red Top Cab Properties) in Clarendon, Arlington County VA.