Structural characterization and selective drug targeting of higher-order DNA G-quadruplex systems.

There is now substantial evidence that guanine-rich regions of DNA form non-B DNA structures known as G-quadruplexes in cells. G-quadruplexes (G4s) are tetraplex DNA structures that form amid four runs of guanines which are stabilized via Hoogsteen hydrogen bonding to form stacked tetrads. DNA G4s have roles in key genomic functions such as regulating gene expression, replication, and telomere homeostasis. Because of their apparent role in disease, G4s are now viewed as important molecular targets for anticancer therapeutics. To date, the structures of many important G4 systems have been solved by NMR or X-ray crystallographic techniques. Small molecules developed to target these structures have shown promising results in treating cancer in vitro and in vivo, however, these compounds commonly lack the selectivity required for clinical success. There is now evidence that long single-stranded G-rich regions can stack or otherwise interact intramolecularly to form G4-multimers, opening a new avenue for rational drug design. For a variety of reasons, G4 multimers are not amenable to NMR or X-ray crystallography. In the current dissertation, I apply a variety of biophysical techniques in an integrative structural biology (ISB) approach to determine the primary conformation of two disputed higher-order G4 systems: (1) the extended human telomere G-quadruplex and (2) the G4-multimer formed within the human telomerase reverse transcriptase (hTERT) gene core promoter. Using the higher-order human telomere structure in virtual drug discovery approaches I demonstrate that novel small molecule scaffolds can be identified which bind to this sequence in vitro. I subsequently summarize the current state of G-quadruplex focused virtual drug discovery in a review that highlights successes and pitfalls of in silico drug screens. I then present the results of a massive virtual drug discovery campaign targeting the hTERT core promoter G4 multimer and show that discovering selective small molecules that target its loops and grooves is feasible. Lastly, I demonstrate that one of these small molecules is effective in down-regulating hTERT transcription in breast cancer cells. Taken together, I present here a rigorous ISB platform that allows for the characterization of higher-order DNA G-quadruplex structures as unique targets for anticancer therapeutic discovery

Engines of Environmental Innovation: Reflections on the Role of States in the U.S. Regulatory System

This article focuses on the role that states play in environmental regulation. Specifically, this article offers examples of the central part in the evolution of United States environmental regulation states played in the past, continue to play today, and will play in the future. First, this article explores the history of state environmental regulation, demonstrating that despite a lack of resources, states were actively engaged in environmental regulation before the advent of the modern era of federal environmental regulation in the 1970s. This article relates not only the regulatory efforts of states, but also the practical benefits of state regulation. Further, this article discusses the ways in which state environmental regulations were used to form the first federal environmental laws, demonstrating that states have been environmental innovators from the outset. Second, this article describes the current environmental regulatory scheme, often referred to as cooperative federalism, which demonstrates the states\u27 major role in carrying out the nation\u27s system of environmental statutes and regulation. Third, this article provides several examples of states\u27 continuing role as environmental innovators, highlighting several state efforts to establish programs and regulatory approaches that exceed the minimum level of environmental regulation established by the federal government. While acknowledging that some states adopt the federal minimum environmental standards as maximum regulatory approaches in their borders, this article nonetheless asserts that states\u27 actions as innovators is powerful and necessary, as evidenced by their ability to influence the market using their own environmental regulations, their ability to partner with other organizations to create new federal standards, and their ongoing efforts to work with the federal government to improve on the collaborative federalism model. This article concludes that this nation must move to an era of true environmental partnership between states and the federal government to achieve meaningful environmental progress--and to deliver the clean and healthy environment all Americans have come to expect and demand. To do this, we must continue to fuel states with political, fiscal, and public support, so that they may continue their important role as engines of environmental innovation

Lifetime measurement of the ^3P_2 metastable state of strontium atoms

We have measured the lifetime of the 5s5p ^3P_2 metastable state of strontium atoms by magneto-optically trapping the decayed atoms to the ground state, which allowed sensitive detection of the rare decay events. We found that the blackbody radiation-induced decay was the dominant decay channel for the state at T = 300 K. The lifetime was determined to be 500^{+280}_{-130} s in the limit of zero temperature.Comment: 4 pages, 3 figures, submitted to Physical Review Letter

Talpa: Or the Chronicles of a Clay Farm

Dialecto Literario. -- Surrey. -- Pertenece a la colección LD del Corpus de Salamanca. -- Chandos Wren Hoskyns, 1812-1876. -- Talpa: Or the Chronicles of a Clay Farm. -- 1854.[ES] Colección de artículos sobre agricultura que contiene dialecto de Surrey. [EN] Collection of articles on agriculture that contains Surrey dialect

Study of spin-scan imaging for outer planets missions

The constraints that are imposed on the Outer Planet Missions (OPM) imager design are of critical importance. Imager system modeling analyses define important parameters and systematic means for trade-offs applied to specific Jupiter orbiter missions. Possible image sequence plans for Jupiter missions are discussed in detail. Considered is a series of orbits that allow repeated near encounters with three of the Jovian satellites. The data handling involved in the image processing is discussed, and it is shown that only minimal processing is required for the majority of images for a Jupiter orbiter mission

Effects of temperature on swimming performance of three Gila congenerics: G. cypha, G. elegans and G. robusta

The Colorado River Basin (CRB) is an environmentally complex aquatic network, with historically large annual variations in discharge, sediment loads, and water temperatures, that pose significant ecological and physiological challenges to its native ichthyofauna (Schmidt et al., 1998; Kammerer, 2005). Effects of climate change within the CRB are likely to produce a drier and warmer regional climate, more frequent droughts, as well as changes in variability, frequency, and amount of precipitation (Meehl et al., 2010; Xie et al, 2010; Pielke et al., 1999). Water temperatures within the CRB could increase by 5.6° C over the next century, which will affect the aquatic food web structure, biodiversity, and the endemic native fishes of this region, and it is uncertain how this ecosystem and its organisms will respond (Wrona et al., 2006; IPCC, 2007; Arismendi et al., 2014). Among the native species which will be affected by this water temperature increase, Gila elegans, G. cypha, and G. robusta offer a unique opportunity to examine how the swimming performance of these species will be affected by climate change due to their close phylogenetic relationships, shared ecology, and distinctive morphologies. (Minckley & Marsh, 2009). This study examined the effects of temperature on the swimming performance of juvenile G. elegans, G. cypha, and G. robusta acclimated to one test temperature (10°C, 16°C, 20°C, or 30°C) for 7 days. Results of this study demonstrated that these three species are affected uniformly by temperature, that temperature and species affects the swimming performance, and yet the results do not support an interaction of these two variables as having an effect of swimming performance. Of these three species, G. cypha demonstrated the greatest swimming performance while G. elegans and G. robusta demonstrated indistinguishable differences in swimming performance. The swimming performance for G. cypha increases as temperature is increased from 10°C to 20°C, however there is no difference between the swimming performance at 20°C and 30°C. Size, temperature, and the interaction of these two response variables was shown to influence the swimming performance of juvenile G. elegans

Study of spin-scan imaging for outer planets missions: Executive summary

The development and characteristics of spin-scan imagers for interplanetary exploration are discussed. The spin-scan imaging photopolarimeter instruments of Pioneer 10 and 11 are described. In addition to the imaging function, the instruments are also used in a faint-light mode to take sky maps in both radiance and polarization. The performance of a visible-infrared spin-scan radiometer (VISSR), which operates in both visible and infrared wavelengths, is reported