Slepton Flavor Physics at Linear Colliders

If low energy supersymmetry is realized in nature it is possible that a first generation linear collider will only have access to some of the superpartners with electroweak quantum numbers. Among these, sleptons can provide sensitive probes for lepton flavor violation through potentially dramatic lepton violating signals. Theoretical proposals to understand the absence of low energy quark and lepton flavor changing neutral currents are surveyed and many are found to predict observable slepton flavor violating signals at linear colliders. The observation or absence of such sflavor violation will thus provide important indirect clues to very high energy physics. Previous analyses of slepton flavor oscillations are also extended to include the effects of finite width and mass differences.Comment: 7 pages, no figures, uses RevTeX4. Contribution to Snowmass 200

A Theory of Non-Local Mixing Length Convection. III. Comparing Theory and Numerical Experiment

We solve the nonlocal convection equations. The solutions for four model problems are compared with results of GSPH simulations. In each case we test two closure schemes: 1) where third moments are defined by the diffusion approximation; and 2) where the full third moment equations are used and fourth moments are defined by a modified form of the quasi-normal approximation. In overshooting models, the convective flux becomes negative shortly after the stability boundary. The negative amplitude remains small, and the temperature gradient in the overshooting zone has nearly the radiative value. Turbulent velocities decay by a factor of $e$ after $0.5$--$1.5\ell$, depending on the model, where $\ell$ is the mixing length. Turbulent viscosity is more important than negative buoyancy in decelerating overshooting fluid blobs. These predictions are consistent with helioseismology.Comment: 36 pages, plain TeX, email for figures, submitted to MNRA

Double-Diffusive Mixing-Length Theory, Semiconvection, and Massive Star Evolution

Double-diffusive convection refers to mixing where the effects of thermal and composition gradients compete to determine the stability of a fluid. In addition to the familiar fast convective instability, such fluids exhibit the slow, direct salt finger instability and the slow, overstable semiconvective instability. Previous approaches to this subject usually have been based on linear stability analyses. We develop here the nonlinear mixing-length theory (MLT) of double-diffusive convection, in analogy to the more familiar MLT for a fluid of homogeneous composition. We present approximate solutions for the mixing rate in the various regimes, and show that the familiar Schwarzschild and Ledoux stability criteria are good approximations to the precise criteria in stellar interiors. We have implemented the self-consistent computation of the temperature gradient and turbulent mixing rate in a stellar evolution code and solved a diffusion equation to mix composition at the appropriate rate. We have evolved 15\msun and 30\msun stars from the zero-age main sequence to the end of core He-burning. Semiconvective mixing is fast enough to alter stellar composition profiles on relevant time scales, but not so fast that instantaneous readjustment is appropriate.Comment: 17 pages, 6 postscript figures, to appear in MNRA

Novel approaches to tackling antimicrobial resistance: the design, synthesis and evaluation of quorum sensing inhibitors in Pseudomonas aeruginosa

The bacterium Pseudomonas aeruginosa is a nosocomial pathogen, which causes infection in immunocompromised patients. Its high levels of antibiotic resistance make P. aeruginosa infections difficult to treat, and examples of pan-resistant P. aeruginosa have been observed. P. aeruginosa contains three intertwined quorum sensing (QS) systems, which aid in the onset and continuation of infection through community-wide communication. The las, rhl and pqs systems, which are controlled by their respective transcriptional regulators LasR, RhlR and PqsR, regulate the production and detection of signal molecules, as well as other virulence factors such as the toxins pyocyanin and HCN. Therefore, inhibition of QS circuits can lead to therapeutic benefits and shows promise as a method of decreasing the occurrence of drug-resistant microorganisms. A series of tri-substituted ureas, bearing a phenyl, benzyl and thiazoline moiety were developed in order to target inhibition of the transcriptional regulator of the rhl system, RhlR. In total 24 compounds were synthesised, including resynthesizing a hit compound identified through virtual and in vitro screening of an in-house compound library. The hit compound was found to inhibit RhlR with an IC50 value of 33.5 micromolar in a whole cell, luminescence-based bioreporter assay of strain PAO1-L rhlI mCTX::rhlI-luxCDABE. Aside from this compound, only one other compound in the series showed any activity, with an IC50 value of 25.9 micromolar. However, due to an overall lack of activity across the whole series, the work was not continued any further. A further high-throughput screening of the library identified a quinazolinone bearing a thiazole moiety as an inhibitor of PqsR, with an IC50 value of 1.6 micromolar in a whole cell, luminescence-based bioreporter assay of strain PAO1-L mCTX::PpqsA-luxCDABE. A structure-activity relationship (SAR) study enabled optimisation of this scaffold to generate two lead compounds bearing linear alkyl chains in place of the isopropyl unit, showing activities of 343 nM and 265 nM in an analogous bioreporter assay using the clinically relevant strain PA14. X-ray crystallography studies produced crystal structures of the original hit compound, in addition to both lead compounds and a further compound in the series bearing a tert-butyl group, where each compound differed in the alkyl chain at the thiazole 2-position. Moreover, the lead compounds were shown to significantly reduce the production of the toxin pyocyanin, and both displayed an excellent therapeutic window, with minimal cytotoxicity against the A549 lung epithelial cell line up to 100 micromolar. An attempt was made to evolve these PqsR inhibitors further, by developing them into dual inhibitors against PqsR and an epigenetic target, histone deacetylases (HDAC), which are implicated in P. aeruginosa’s ability to modulate host immunity. One target compound was successfully synthesised through addition of a 2-fluorophenone group to the terminus of the alkyl chain (Figure iii), and was shown to be a potent PqsR inhibitor (IC50 in PA14 = 122 nM), but showed no HDAC inhibitory properties. No dual PqsR/HDAC inhibitors were successfully synthesised, though possible modifications to elicit this effect include replacing the ketone with an amide, and the fluoro group with an aniline. The thiazole group could also be removed for synthetic tractability

Quantification of total fetal brain volume using 3D MR imaging data acquired in utero.

Objective: Interpretation of magnetic resonance (MR) imaging of the fetal brain in utero is primarily undertaken using 2D images to provide anatomical information about structural abnormalities. It is now possible to obtain 3D image acquisitions that allow measurement of fetal brain volumes that are potentially useful clinically. The aim of our current work is to provide reference values of total brain volumes obtained from a cohort of low risk fetuses with no abnormalities on ante-natal ultrasonography and in utero MR imaging. Method: Images from volume MR acquisitions of 132 fetuses were used to extract brain volumes by manual segmentation. Reproducibility and reliability were assessed by analysis of the results of two subgroups who had repeated measurements made by the primary and a secondary observer. Results: Intra-observer and inter-observer agreement was high with no statistically significant differences between and within observers (p = 0.476 and p = 0.427, respectively). The results of the brain volume assessments are presented graphically with mean and 95% prediction limits alongside estimates of normal growth rates. Conclusion: We have shown that fetal brain volumes can be reliably extracted from in utero MR (iuMR) imaging 3D datasets with a high degree of reproducibility. The resultant data could potentially be used as a reference tool in the clinical setting

Tackling antimicrobial resistance through two novel methods: repurposing vanoxerine as a novel anti-tubercular drug; and silencing virulence in Pseudomonas aeruginosa through inhibition of PqsR

The antimicrobial resistance crisis is one which will persist and worsen without intervention. This thesis looks to explore two innovative research areas in order to develop new antibiotics and stem the rise in antibiotic resistance. The first project looked at the potential to repurpose the former central nervous system (CNS) drug candidate vanoxerine into an anti-tubercular compound. Previous work has suggested that vanoxerine acts as a prodrug in mycobacteria and interacts with the monooxygenase enzymes Rv0565c and Rv3518c of Mycobacterium tuberculosis (Mtb). In this work a MIC50 assay was utilised to complete a structure-activity relationship (SAR) study and prove that vanoxerine is hydroxylated in vivo to its active form. Further to this, a global lipid analysis was completed suggesting that when treated with analogues of vanoxerine a lipid biosynthetic pathway was halted, though the lipid itself could not be identified. Although mass spectrometry was employed to identify changes in lipid concentrations at varying concentrations of drug, no trends were clear. However, the mass spectrometry data did indicate that analogues of vanoxerine were also hydroxylated in vivo, furthering the original hypothesis. A further novel method for targeting antimicrobial resistance is the targeting of virulence systems. By inhibiting virulence but not affecting cell viability, no selection pressures are put on the pathogenic population. This enables the immune system to clear the infection without the host cells from being harmed by the release of toxins whilst preventing resistant subpopulations from dominating. In this work, a series of compounds were synthesised to act as antagonists to the protein PqsR, the autoinductive regulator of the quorum sensing system pqs in Pseudomonas aeruginosa. This system is associated with a range of effects including the synthesis of the toxin pyocyanin and the biofilm formation. Therefore, interference with these pathways may attenuate P. aeruginosa without encouraging selection of resistant bacteria. A biosensor reporter assay provided semiquantitative data suggesting that the majority of synthesised compounds reduced expression of the pqs system. Moreover, IC50 testing has been initiated, providing quantitative data on the potency of the synthesised series

Novel approaches to tackling antimicrobial resistance: the design, synthesis and evaluation of quorum sensing inhibitors in Pseudomonas aeruginosa

The bacterium Pseudomonas aeruginosa is a nosocomial pathogen, which causes infection in immunocompromised patients. Its high levels of antibiotic resistance make P. aeruginosa infections difficult to treat, and examples of pan-resistant P. aeruginosa have been observed. P. aeruginosa contains three intertwined quorum sensing (QS) systems, which aid in the onset and continuation of infection through community-wide communication. The las, rhl and pqs systems, which are controlled by their respective transcriptional regulators LasR, RhlR and PqsR, regulate the production and detection of signal molecules, as well as other virulence factors such as the toxins pyocyanin and HCN. Therefore, inhibition of QS circuits can lead to therapeutic benefits and shows promise as a method of decreasing the occurrence of drug-resistant microorganisms. A series of tri-substituted ureas, bearing a phenyl, benzyl and thiazoline moiety were developed in order to target inhibition of the transcriptional regulator of the rhl system, RhlR. In total 24 compounds were synthesised, including resynthesizing a hit compound identified through virtual and in vitro screening of an in-house compound library. The hit compound was found to inhibit RhlR with an IC50 value of 33.5 micromolar in a whole cell, luminescence-based bioreporter assay of strain PAO1-L rhlI mCTX::rhlI-luxCDABE. Aside from this compound, only one other compound in the series showed any activity, with an IC50 value of 25.9 micromolar. However, due to an overall lack of activity across the whole series, the work was not continued any further. A further high-throughput screening of the library identified a quinazolinone bearing a thiazole moiety as an inhibitor of PqsR, with an IC50 value of 1.6 micromolar in a whole cell, luminescence-based bioreporter assay of strain PAO1-L mCTX::PpqsA-luxCDABE. A structure-activity relationship (SAR) study enabled optimisation of this scaffold to generate two lead compounds bearing linear alkyl chains in place of the isopropyl unit, showing activities of 343 nM and 265 nM in an analogous bioreporter assay using the clinically relevant strain PA14. X-ray crystallography studies produced crystal structures of the original hit compound, in addition to both lead compounds and a further compound in the series bearing a tert-butyl group, where each compound differed in the alkyl chain at the thiazole 2-position. Moreover, the lead compounds were shown to significantly reduce the production of the toxin pyocyanin, and both displayed an excellent therapeutic window, with minimal cytotoxicity against the A549 lung epithelial cell line up to 100 micromolar. An attempt was made to evolve these PqsR inhibitors further, by developing them into dual inhibitors against PqsR and an epigenetic target, histone deacetylases (HDAC), which are implicated in P. aeruginosa’s ability to modulate host immunity. One target compound was successfully synthesised through addition of a 2-fluorophenone group to the terminus of the alkyl chain (Figure iii), and was shown to be a potent PqsR inhibitor (IC50 in PA14 = 122 nM), but showed no HDAC inhibitory properties. No dual PqsR/HDAC inhibitors were successfully synthesised, though possible modifications to elicit this effect include replacing the ketone with an amide, and the fluoro group with an aniline. The thiazole group could also be removed for synthetic tractability

How to project a bipartite network?

The one-mode projecting is extensively used to compress the bipartite networks. Since the one-mode projection is always less informative than the bipartite representation, a proper weighting method is required to better retain the original information. In this article, inspired by the network-based resource-allocation dynamics, we raise a weighting method, which can be directly applied in extracting the hidden information of networks, with remarkably better performance than the widely used global ranking method as well as collaborative filtering. This work not only provides a creditable method in compressing bipartite networks, but also highlights a possible way for the better solution of a long-standing challenge in modern information science: How to do personal recommendation?Comment: 7 pages, 4 figure