Diversity oriented synthesis : substitution at C5 in unreactive pyrimidines by Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4 in pteridines and pyrido[2,3-d]pyrimidines

Diversity oriented synthesis of fused pyrimidines leads to scaffolds with many biological activities. In the case of the preparation of pyrido[2,3-d]pyrimidines from 2-alkylthiopyrimidines, the formation of a new carbon-carbon bond at C5 is required, a reaction that is very limited in scope. However Claisen type rearrangement of simple 4-allylic ethers affords C5 substituted pyrimidines readily; in cases with an ester substituent, rearrangement occurs at room temperature. Subsequent cyclisation to afford 6-methylpyrido[2,3-d]pyrimidin-7(8H)-ones was achieved in high yield. Using allylic ethers derived from 3-chloromethyl-4-arylbut-3-en-2-ones as substrates, a new titanium[IV]chloride catalysed reaction affording 6-arylmethyl-7-methylpyrido[2,3-d]pyrimidines was discovered. In contrast, 2-alkylthiopteridines are readily available. In both cases, substitution at C2 and C4 to generate diversity has been carried out and the reactivity compared; yields of substitution products were generally higher with pteridine substrates. In biological assays unexpected hits were found for activity against the Gram positive bacterium, Nocardia farcinia, and against the parasite Trypanosoma brucei brucei, illustrating the value of diversity oriented synthesis in the discovery of biologically active compound

The local dayside reconnection rate for oblique interplanetary magnetic fields

We present an analysis of local properties of magnetic reconnection at the dayside magnetopause for various interplanetary magnetic field (IMF) orientations in global magnetospheric simulations. This has heretofore not been practical because it is difficult to locate where reconnection occurs for oblique IMF, but new techniques make this possible. The approach is to identify magnetic separators, the curves separating four regions of differing magnetic topology, which map the reconnection X-line. The electric field parallel to the X-line is the local reconnection rate. We compare results to a simple model of local two-dimensional asymmetric reconnection. To do so, we find the plasma parameters that locally drive reconnection in the magnetosheath and magnetosphere in planes perpendicular to the X-line at a large number of points along the X-line. The global magnetohydrodynamic simulations are from the three-dimensional Block-Adaptive, Tree Solarwind Roe-type Upwind Scheme (BATS-R-US) code with a uniform resistivity, although the techniques described here are extensible to any global magnetospheric simulation model. We find that the predicted local reconnection rates scale well with the measured values for all simulations, being nearly exact for due southward IMF. However, the absolute predictions differ by an undetermined constant of proportionality, whose magnitude increases as the IMF clock angle changes from southward to northward. We also show similar scaling agreement in a simulation with oblique southward IMF and a dipole tilt. The present results will be an important component of a full understanding of the local and global properties of dayside reconnection.Comment: 12 pages, 7 figures, 1 table, Submitted to Journal Geophysical Research Space Physics February 12, 2016; Revised April 28, 201

Ensemble Transport Adaptive Importance Sampling

Markov chain Monte Carlo methods are a powerful and commonly used family of numerical methods for sampling from complex probability distributions. As applications of these methods increase in size and complexity, the need for efficient methods increases. In this paper, we present a particle ensemble algorithm. At each iteration, an importance sampling proposal distribution is formed using an ensemble of particles. A stratified sample is taken from this distribution and weighted under the posterior, a state-of-the-art ensemble transport resampling method is then used to create an evenly weighted sample ready for the next iteration. We demonstrate that this ensemble transport adaptive importance sampling (ETAIS) method outperforms MCMC methods with equivalent proposal distributions for low dimensional problems, and in fact shows better than linear improvements in convergence rates with respect to the number of ensemble members. We also introduce a new resampling strategy, multinomial transformation (MT), which while not as accurate as the ensemble transport resampler, is substantially less costly for large ensemble sizes, and can then be used in conjunction with ETAIS for complex problems. We also focus on how algorithmic parameters regarding the mixture proposal can be quickly tuned to optimise performance. In particular, we demonstrate this methodology's superior sampling for multimodal problems, such as those arising from inference for mixture models, and for problems with expensive likelihoods requiring the solution of a differential equation, for which speed-ups of orders of magnitude are demonstrated. Likelihood evaluations of the ensemble could be computed in a distributed manner, suggesting that this methodology is a good candidate for parallel Bayesian computations

Canonical singularities of orders over surfaces

We classify the possible ramification data and etale local structure of orders over surfaces with canonical singularities.Comment: This contains major revisions, primarily to help introduce the reader to the minimal model program for orders on surface

Bioengineering Lantibiotics for Therapeutic Success

peer-reviewedSeveral examples of highly modified antimicrobial peptides have been described. While many such peptides are non-ribosomally synthesized, ribosomally synthesized equivalents are being discovered with increased frequency. Of the latter group, the lantibiotics continue to attract most attention. In the present review, we discuss the implementation of in vivo and in vitro engineering systems to alter, and even enhance, the antimicrobial activity, antibacterial spectrum and physico-chemical properties, including heat stability, solubility, diffusion and protease resistance, of these compounds. Additionally, we discuss the potential applications of these lantibiotics for use as therapeutics.DF,CH,PC,RR are supported by the Irish Government under the National Development Plan, through a Science Foundation Ireland (SFI) Technology and Innovation Development Award (TIDA14/TIDA/2286) to DF, a SFI Investigator awards to CH and RR (10/IN.1/B3027),SFI-PIfunding(11/PI/1137) to PDC and the Alimentary Pharmabiotic Centre under Grant Number SFI/12/RC/2273