A local resampling trick for focused molecular dynamics

We describe a method that focuses sampling effort on a user-defined selection of a large system, which can lead to substantial decreases in computational effort by speeding up the calculation of nonbonded interactions. A naive approach can lead to incorrect sampling if the selection depends on the configuration in a way that is not accounted for. We avoid this pitfall by introducing appropriate auxiliary variables. This results in an implementation that is closely related to configurational freezing and elastic barrier dynamical freezing. We implement the method and validate that it can be used to supplement conventional molecular dynamics in free energy calculations (absolute hydration and relative binding)

MICE: The muon ionization cooling experiment. Step I: First measurement of emittance with particle physics detectors

Copyright @ 2011 APSThe Muon Ionization Cooling Experiment (MICE) is a strategic R&D project intended to demonstrate the only practical solution to providing high brilliance beams necessary for a neutrino factory or muon collider. MICE is under development at the Rutherford Appleton Laboratory (RAL) in the United Kingdom. It comprises a dedicated beamline to generate a range of input muon emittances and momenta, with time-of-flight and Cherenkov detectors to ensure a pure muon beam. The emittance of the incoming beam will be measured in the upstream magnetic spectrometer with a scintillating fiber tracker. A cooling cell will then follow, alternating energy loss in Liquid Hydrogen (LH2) absorbers to RF cavity acceleration. A second spectrometer, identical to the first, and a second muon identification system will measure the outgoing emittance. In the 2010 run at RAL the muon beamline and most detectors were fully commissioned and a first measurement of the emittance of the muon beam with particle physics (time-of-flight) detectors was performed. The analysis of these data was recently completed and is discussed in this paper. Future steps for MICE, where beam emittance and emittance reduction (cooling) are to be measured with greater accuracy, are also presented.This work was supported by NSF grant PHY-0842798

Development of Degradable, pH‐Sensitive Star Vectors for Enhancing the Cytoplasmic Delivery of Nucleic Acids

The report describes the synthesis of degradable, pH‐sensitive, membrane‐destabilizing, star‐shaped polymers where copolymers of hydrophobic hexyl methacrylate (HMA) and 2‐(dimethylamino)ethyl methacrylate (DMAEMA) monomers are grafted from the secondary face of a beta‐cyclodextrin (β‐CD) core via acid‐labile hydrazone linkages using atom transfer radical polymerization. The effect of the graft's molecular weight, HMA/DMAEMA molar ratio, and the fraction of DMAEMA converted to cationic N,N,N‐trimethylaminoethyl methacrylate (TMAEMA) monomers on polymer's transfection capacity is systematically investigated. Results show that all star‐shaped polymers condense anti‐GAPDH silencing RNA (siRNA) into nanosized particles at +/‐ ratio ≤ 4:1. Star polymers with shorter (25kDa) P(HMA‐ co ‐DMAEMA‐ co ‐TMAEMA) grafts are more efficient and less cytotoxic than carriers with longer (40kDa) grafts. The results show that increasing the ratio of hydrophobic HMA monomers in graft's composition higher than 50 mole% dramatically reduces polymer's aqueous solubility and abolishes their transfection capacity. Further, retention of DMAEMA monomers in graft's composition provide a buffering capacity that enhanced the endosomal escape and transfection capacity of the polymers. These systematic studies show that β‐CD‐P(HMA‐ co ‐DMAEMA‐ co ‐TMAEMA) 4.8 polymer with a 25 kDa average graft's molecular weight and a 50/25/25 ratio of HMA/DMAEMA/TMAEMA monomers is the most efficient carrier in delivering the siRNA cargo into the cytoplasm of epithelial cancer cells. A series of degradable, pH‐sensitive, membrane‐destabilizing, star‐shaped polymers is synthesized. Star polymers are engineered to “sense” the drop in endosomal pH, which triggers the hydrolysis of acid‐labile hydrazone linkages and release of membrane‐active grafts that rupture the endosomal membrane and release the loaded siRNA cargo into the cytoplasm to produce the desired knockdown of targeted gene expression at both the mRNA and protein levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99666/1/3885_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99666/2/adfm_201203762_sm_suppl.pd

Joined-up places? Social cohesion and neighbourhood regeneration

SIGLEAvailable from British Library Document Supply Centre-DSC:99/22478 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Home owners on new estates in the 1990s

Available from British Library Document Supply Centre-DSC:q97/18117 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Mechanistic Insights into Passive Membrane Permeability of Drug-Like Molecules from a Weighted Ensemble of Trajectories

Passive permeability of a drug-like molecule is a critical assay early in a drug discovery campaign that informs a medicinal chemist how well a compound can traverse biological membranes, such as gastrointestinal epithelial or restrictive organ barriers, so it can perform a specific therapeutic function. However, the challenge that remains is the development of a method, experimental or computational, which can both determine the permeation rate and provide mechanistic insights into the transport process to help with the rational design for any given molecule. Typically, one of three methods are used to measure membrane permeability: (1) experimental permeation assays acting on either artificial or natural membranes; (2) quantitative structure-permeability relationship (QSPR) models that rely on experimental values of permeability or related pharmacokinetic properties of a range of molecules to infer those for new molecules; (3) estimates of permeability from the Smoluchowski equation, where free energy and diffusion profiles along the membrane normal are taken as input from large-scale molecular dynamics simulations. While all these methods provide estimates of permeation coefficients, they provide very little information for guiding rational drug design. In this study, we employ a highly parallelizable weighted ensemble (WE) path sampling strategy, empowered by cloud computing techniques, to generate unbiased permeation pathways and permeability coefficients for a set of drug-like molecules across a neat 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) membrane bilayer. Our WE method predicts permeability coefficients that compare well to experimental values from an MDCK-LE cell line and PAMPA assays for a set of drug-like amines of varying size, shape, and flexibility. Our method also yields a series of continuous permeation pathways weighted and ranked by their associated probabilities. Taken together, the ensemble of reactive permeation pathways, along with the estimate of the permeability coefficient, provides a clearer picture of the microscopic underpinnings of small molecule membrane permeation