Model of Transcriptional Activation by MarA in Escherichia coli

We have developed a mathematical model of transcriptional activation by MarA in Escherichia coli, and used the model to analyze measurements of MarA-dependent activity of the marRAB, sodA, and micF promoters in mar-rob- cells. The model rationalizes an unexpected poor correlation between the mid-point of in vivo promoter activity profiles and in vitro equilibrium constants for MarA binding to promoter sequences. Analysis of the promoter activity data using the model yielded the following predictions regarding activation mechanisms: (1) MarA activation of the marRAB, sodA, and micF promoters involves a net acceleration of the kinetics of transitions after RNA polymerase binding, up to and including promoter escape and message elongation; (2) RNA polymerase binds to these promoters with nearly unit occupancy in the absence of MarA, making recruitment of polymerase an insignificant factor in activation of these promoters; and (3) instead of recruitment, activation of the micF promoter might involve a repulsion of polymerase combined with a large acceleration of the kinetics of polymerase activity. These predictions are consistent with published chromatin immunoprecipitation assays of interactions between polymerase and the E. coli chromosome. A lack of recruitment in transcriptional activation represents an exception to the textbook description of activation of bacterial sigma-70 promoters. However, use of accelerated polymerase kinetics instead of recruitment might confer a competitive advantage to E. coli by decreasing latency in gene regulation.Comment: 30 pages, 2 figure

Conceptualizing Cancer Drugs as Classifiers

Cancer and healthy cells have distinct distributions of molecular properties and thus respond differently to drugs. Cancer drugs ideally kill cancer cells while limiting harm to healthy cells. However, the inherent variance among cells in both cancer and healthy cell populations increases the difficulty of selective drug action. Here we formalize a classification framework based on the idea that an ideal cancer drug should maximally discriminate between cancer and healthy cells. More specifically, this discrimination should be performed on the basis of measurable cell markers. We divide the problem into three parts which we explore with examples. First, molecular markers should discriminate cancer cells from healthy cells at the single-cell level. Second, the effects of drugs should be statistically predicted by these molecular markers. Third, drugs should be optimized for classification performance. We find that expression levels of a handful of genes suffice to discriminate well between individual cells in cancer and healthy tissue. We also find that gene expression predicts the efficacy of some cancer drugs, suggesting that these cancer drugs act as suboptimal classifiers using gene profiles. Finally, we formulate a framework that defines an optimal drug, and predicts drug cocktails that may target cancer more accurately than the individual drugs alone. Conceptualizing cancer drugs as solving a discrimination problem in the high-dimensional space of molecular markers promises to inform the design of new cancer drugs and drug cocktails.</p

An Analysis of B_s Decays in the Left-Right-Symmetric Model with Spontaneous CP Violation

Non-leptonic B_s decays into CP eigenstates that are caused by \bar b -> \bar cc\bar s quark-level transitions, such as B_s -> D_s^+D^-_s, J/psi eta^(') or J/psi phi, provide a powerful tool to search for ``new physics'', as the CP-violating effects in these modes are tiny in the Standard Model. We explore these effects for a particular scenario of new physics, the left-right-symmetric model with spontaneous CP violation. In our analysis, we take into account all presently available experimental constraints on the parameters of this model, i.e. those implied by K- and B-decay observables; we find that CP asymmetries as large as O(40%) may arise in the B_s channels, whereas the left-right-symmetric model favours a small CP asymmetry in the ``gold-plated'' mode B_d -> J/psi K_S. Such a pattern would be in favour of B-physics experiments at hadron machines, where the B_s modes are very accessible.Comment: 12 pages, 5 figure

An Ex-Ante Method to Verify Commercial U.S. Nuclear Power Plant Decommissioning Cost Estimates

There are billions of dollars at stake in the US nuclear power plant decommissioning market. Approximately 100 nuclear power plants are still operating but will come offline and need to be decommissioned over the next few decades. The US Nuclear Regulatory Commission (NRC) mandates that the operators of these plants set money aside in segregated funds to finance decommissioning work. However, it is hard for external stakeholders to verify the cost estimations, which ultimately determine how much operators are required to save. In this paper, we develop a method to validate the existing cost models and calculate a contingency empirically for these models. We extend Reference Class Forecasting methods using adaptive kernel fitting and the Wilks' formula. Based on this method, and assuming a social tolerance for potential cost overruns of 20%, we calculate a new contingency of 48% of the estimated radiological decommissioning cost. After a "stress test" of the current decommissioning trust funds of operating reactor sites, we find that 48% of reactors we considered have sufficient funding-in many cases substantially more than required-and could therefore finance the potential scale of overrun. However, we find that 28 plants (52%) would fall short on average $211 million. Still, overruns at every plant are not a foregone conclusion because-while overruns are probable, based on past experience-the actual scale and frequency is not known. Nevertheless, our results add further evidence to the mounting call for the NRC to revise its cost models in light of new information

Solar astronomy

An overview is given of modern solar physics. Topics covered include the solar interior, the solar surface, the solar atmosphere, the Large Earth-based Solar Telescope (LEST), the Orbiting Solar Laboratory, the High Energy Solar Physics mission, the Space Exploration Initiative, solar-terrestrial physics, and adaptive optics. Policy and related programmatic recommendations are given for university research and education, facilitating solar research, and integrated support for solar research

Temperature and Emission-Measure Profiles Along Long-Lived Solar Coronal Loops Observed with TRACE

We report an initial study of temperature and emission measure distributions along four steady loops observed with the Transition Region and Coronal Explorer (TRACE) at the limb of the Sun. The temperature diagnostic is the filter ratio of the extreme-ultraviolet 171-angstrom and 195-angstrom passbands. The emission measure diagnostic is the count rate in the 171-angstrom passband. We find essentially no temperature variation along the loops. We compare the observed loop structure with theoretical isothermal and nonisothermal static loop structure.Comment: 10 pages, 3 postscript figures (LaTeX, uses aaspp4.sty). Accepted by ApJ Letter