Physical Education 2

Exam paper for first semester 201

Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning

Experience with confirmatory measurements at the Savannah River Plant

Confirmatory measurements are performed on all category I and II plutonium shipments to the Savannah River Plant (SRP). The primary technique employed has been neutron coincidence counting using three instruments; two slab counters, and a well counter. These measurements have provided the required safeguards features to support the physical security measures already in place for inter-site shipments of special nuclear material (SNM). Similar confirmatory measurements have also been performed on a variety of scrap mixed-oxide materials stored at SRP for later processing. The data handling and results for several categories of material will be examined in addition to planned uses of the Rocky Flats Plant (RFP)/SRP Confirmatory Measurements Counter (CMC). 2 refs., 4 figs

Wall-Modeled Lattice Boltzmann and Navier-Stokes Approaches for Separated Flows

Lattice Boltzmann (LB) and hybrid Reynolds-averaged Navier-Stokes/large eddy simulation (RANS/LES) methods within the Launch Ascent and Vehicle Aerodynamics (LAVA) solver framework are applied to NASA's Revolutionary Computational Aerosciences (RCA) standard test cases for separated flows. A detailed comparison between the performance and accuracy of the two emerging numerical methodologies for turbulence resolving simulations, i.e. the LB and hybrid RANS/LES methods will be presented. This contribution addresses the RCA technical challenge to identify and down-select critical turbulence, transition, and numerical method technologies for 40% reduction in predictive error for standard turbulence separated flow test cases. Results for the 2D NASA wall-mounted hump and the axisymmetric transonic bump including time-averaged pressure coefficient, skin friction, and velocity pro les, as well as resolved and modeled Reynolds stresses for both numerical approaches will be presented and differences between LB and hybrid RANS/LES will be discussed

Prophage induction reduces Shiga toxin producing \u3ci\u3eEscherichia coli\u3c/i\u3e (STEC) and Salmonella enterica on tomatoes and spinach: A model study

Fresh produce is increasingly implicated in foodborne outbreaks and most fresh produce is consumed raw, emphasizing the need to develop non-thermal methods to control foodborne pathogens. This study investigates bacterial cell lysis through induction of prophages as a novel approach to control foodborne bacterial pathogens on fresh produce. Shiga toxin producing Escherichia coli (STEC) and Salmonella enterica isolates were exposed to different prophage inducers (i.e. mitomycin C or streptonigrin) and growth of the cells was monitored by measuring the optical density (OD600) during incubation at 37C. Beginning at three hours after addition of the inducer, all concentrations (0.5, 1, 2 mg/mL) of mitomycin C, or 2 mg/mL streptonigrin significantly reduced the OD600 in broth cultures, in a concentration dependent manner, relative to cultures where no inducer was added. PCR confirmed bacterial release of induced bacteriophages and demonstrated that a single compound could successfully induce multiple types of prophages. The ability of mitomycin C to induce prophages in STEC O157:H7 and in S. enterica (serovars Typhimurium and Newport) on fresh produce was evaluated by inoculating red greenhouse tomatoes or spinach leaves with 5 x 107 and 5 x 108 colony forming units, respectively. After allowing time for the inoculum to dry on the fresh produce samples, 6 mg/mL mitomycin C was sprayed onto each sample, while control samples were sprayed with water. Following overnight incubation at 4C, the bacterial cells were recovered and plate counts were performed. A 3 log reduction in STEC O157:H7 cells was observed on tomatoes sprayed with mitomycin C compared to those sprayed with water, while a 1 log reduction was obtained on spinach. Similarly, spraying mitomycin C on tomatoes and spinach inoculated with S. enterica isolates resulted in a 1-1.5 log and 2 log reduction, respectively. These findings serve as a proof of concept that prophage induction can effectively control bacterial foodborne pathogens on fresh produce

Hallmarks of cancer-the new testament.

Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles' heel that can be targeted in effective therapies. Throughout history, this endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories-from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal 'Hallmarks of Cancer' reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically

Characterizing planetary systems with SPIRou: M-dwarf planet-search survey and the multiplanet systems GJ 876 and GJ 1148

SPIRou is a near-infrared spectropolarimeter and a high-precision velocimeter. The SPIRou Legacy Survey collected data from February 2019 to June 2022, half of the time devoted to a blind search for exoplanets around nearby cool stars. The aim of this paper is to present this program and an overview of its properties, and to revisit the radial velocity (RV) data of two multiplanet systems, including new visits with SPIRou. From SPIRou data, we can extract precise RVs using efficient telluric correction and line-by-line measurement techniques, and we can reconstruct stellar magnetic fields from the collection of polarized spectra using the Zeeman-Doppler imaging method. The stellar sample of our blind search in the solar neighborhood, the observing strategy, the RV noise estimates, chromatic behavior, and current limitations of SPIRou RV measurements on bright M dwarfs are described. In addition, SPIRou data over a 2.5-year time span allow us to revisit the known multiplanet systems GJ~876 and GJ~1148. For GJ~876, the new dynamical analysis including the four planets is consistent with previous models and confirms that this system is deep in the Laplace resonance and likely chaotic. The large-scale magnetic map of GJ~876 over two consecutive observing seasons is obtained and shows a dominant dipolar field with a polar strength of 30~G, which defines the magnetic environment in which the inner planet with a period of 1.94~d is embedded. For GJ~1148, we refine the known two-planet model.Comment: accepted in A&

Wapiti\texttt{Wapiti}: a data-driven approach to correct for systematics in RV data -- Application to SPIRou data of the planet-hosting M dwarf GJ 251

Context: Recent advances in the development of precise radial velocity (RV) instruments in the near-infrared (nIR) domain, such as SPIRou, have facilitated the study of M-type stars to more effectively characterize planetary systems. However, the nIR presents unique challenges in exoplanet detection due to various sources of planet-independent signals which can result in systematic errors in the RV data. Aims: In order to address the challenges posed by the detection of exoplanetary systems around M-type stars using nIR observations, we introduce a new data-driven approach for correcting systematic errors in RV data. The effectiveness of this method is demonstrated through its application to the star GJ 251. Methods: Our proposed method, referred to as $\texttt{Wapiti}$ (Weighted principAl comPonent analysIs reconsTructIon), uses a dataset of per-line RV time-series generated by the line-by-line (LBL) algorithm and employs a weighted principal component analysis (wPCA) to reconstruct the original RV time-series. A multi-step process is employed to determine the appropriate number of components, with the ultimate goal of subtracting the wPCA reconstruction of the per-line RV time-series from the original data in order to correct systematic errors. Results: The application of $\texttt{Wapiti}$ to GJ 251 successfully eliminates spurious signals from the RV time-series and enables the first detection in the nIR of GJ 251b, a known temperate super-Earth with an orbital period of 14.2 days. This demonstrates that, even when systematics in SPIRou data are unidentified, it is still possible to effectively address them and fully realize the instrument's capability for exoplanet detection. Additionally, in contrast to the use of optical RVs, this detection did not require to filter out stellar activity, highlighting a key advantage of nIR RV measurements.Comment: Submitted to A&A. For the publicly available Wapiti code, see https://github.com/HkmMerwan/wapit