The inefficiency of re-weighted sampling and the curse of system size in high order path integration

Computing averages over a target probability density by statistical re-weighting of a set of samples with a different distribution is a strategy which is commonly adopted in fields as diverse as atomistic simulation and finance. Here we present a very general analysis of the accuracy and efficiency of this approach, highlighting some of its weaknesses. We then give an example of how our results can be used, specifically to assess the feasibility of high-order path integral methods. We demonstrate that the most promising of these techniques -- which is based on re-weighted sampling -- is bound to fail as the size of the system is increased, because of the exponential growth of the statistical uncertainty in the re-weighted average

Regulation of CFTR ion channel gating by MgATP

AbstractSingle channel currents of wild-type CFTR reconstituted in lipid bilayers were recorded to study the temperature dependence of channel gating between +20°C and +40°C. The opening of the channel was highly temperature dependent and required an activation energy of about 100 kJ/mol. Closing of the channel was only weakly temperature dependent with an activation energy close to that of diffusion in water. We found no significant difference in the free energy between the open and closed states. Most of the excess energy needed to activate channel opening is used to diminish the entropy of the open state. This structural reorganization is initiated by ATP binding followed by interconversion to the open channel structure as the CFTR-ATP-Mg complex passes to the transition state for hydrolysis. The energy of the CFTR-ATP-Mg interaction in the transition state is responsible for the CFTR ion channel opening rather than the energy of ATP hydrolysis. Channel closing is a diffusion limited process and does not require additional ATP binding

Voltage-dependent Block of the Cystic Fibrosis Transmembrane Conductance Regulator Cl- Channel by Two Closely Related Arylaminobenzoates

The gene defective in cystic fibrosis encodes a Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is blocked by diphenylamine-2-carboxylate (DPC) when applied extracellularly at millimolar concentrations. We studied the block of CFTR expressed in Xenopus oocytes by DPC or by a closely related molecule, flufenamic acid (FFA). Block of whole-cell CFTR currents by bath-applied DPC or by FFA, both at 200 µM, requires several minutes to reach full effect. Blockade is voltage dependent, suggesting open-channel block: currents at positive potentials are not affected but currents at negative potentials are reduced. The binding site for both drugs senses ~40% of the electric field across the membrane, measured from the inside. In single-channel recordings from excised patches without blockers, the conductance was 8.0 ± 0.4 pS in symmetric 150 mM Cl^-. A subconductance state, measuring ~60% of the main conductance, was often observed. Bursts to the full open state lasting up to tens of seconds were uninterrupted at depolarizing membrane voltages. At hyperpolarizing voltages, bursts were interrupted by brief closures. Either DPC or FFA (50 µM) applied to the cytoplasmic or extracellular face of the channel led to an increase in flicker at V_m =-100 mV and not at V_m = +100 mV, in agreement with whole-cell experiments. DPC induced a higher frequency of flickers from the cytoplasmic side than the extracellular side. FFA produced longer closures than DPC; the FFA closed time was roughly equal (~ 1.2 ms) at -100 mV with application from either side. In cell-attached patch recordings with DPC or FFA applied to the bath, there was flickery block at V_m = -100 mV, confirming that the drugs permeate through the membrane to reach the binding site. The data are consistent with the presence of a single binding site for both drugs, reached from either end of the channel. Open-channel block by DPC or FFA may offer tools for use with site-directed mutagenesis to describe the permeation pathway

A conceptual model of suicide in rural areas

Context: Suicide is an important public health issue among rural communities although there is no single pattern of suicide in rural areas. Despite this, there are common themes in much of the research evidence on suicide in rural areas. From the published research in the area, a conceptual model of rural suicide has been developed which can be used by clinical and public health services when considering possible routes of intervention.Issue: A conceptual model can be defined as 'a type of diagram which shows a set of relationships between factors that are believed to impact or lead to a target condition'. The model presented here uses the 'Cry of pain/ Entrapment' model of suicide risk to build a framework of factors which are associated with suicide in rural areas. Cross-setting factors associated with suicide rates include gender, poverty, mental illness, substance use, biological factors including apparent genetic risk, coping skills and media coverage of suicide. There are, however, other factors that appear to have particular importance in rural areas. These include rural stressors, such as isolation and political and social exclusion; factors affecting support, including social support, cultural norms on help-seeking, stigma associated with mental illness service availability; factors affecting the decision to self-harm, including modelling and cultural views on self-harm, and issues affecting the likelihood of self-harm resulting in death, including method availability, norms on methods of self-harm and treatment availability after harm occurs. Identifying which of these areas are the greatest local priorities helps to target activity.Lessons learned: This model provides a way of considering suicide in rural areas. Local staff can use it to consider which issues are most relevant to their area. It allows classification of existing interventions, and deciding which other areas of work might be of local value. For researchers and service planners, it provides a way of classifying interventions and describing projects

Dual Effects of Adp and Adenylylimidodiphosphate on Cftr Channel Kinetics Show Binding to Two Different Nucleotide Binding Sites

The CFTR chloride channel is regulated by phosphorylation by protein kinases, especially PKA, and by nucleotides interacting with the two nucleotide binding domains, NBD-A and NBD-B. Giant excised inside-out membrane patches from Xenopus oocytes expressing human epithelial cystic fibrosis transmembrane conductance regulator (CFTR) were tested for their chloride conductance in response to the application of PKA and nucleotides. Rapid changes in the concentration of ATP, its nonhydrolyzable analogue adenylylimidodiphosphate (AMP-PNP), its photolabile derivative ATP-P3-[1-(2-nitrophenyl)ethyl]ester, or ADP led to changes in chloride conductance with characteristic time constants, which reflected interaction of CFTR with these nucleotides. The conductance changes of strongly phosphorylated channels were slower than those of partially phosphorylated CFTR. AMP-PNP decelerated relaxations of conductance increase and decay, whereas ATP-P3-[1-(2-nitrophenyl)ethyl]ester only decelerated the conductance increase upon ATP addition. ADP decelerated the conductance increase upon ATP addition and accelerated the conductance decay upon ATP withdrawal. The results present the first direct evidence that AMP-PNP binds to two sites on the CFTR. The effects of ADP also suggest two different binding sites because of the two different modes of inhibition observed: it competes with ATP for binding (to NBD-A) on the closed channel, but it also binds to channels opened by ATP, which might either reflect binding to NBD-A (i.e., product inhibition in the hydrolysis cycle) or allosteric binding to NBD-B, which accelerates the hydrolysis cycle at NBD-A

Nunalleq, Stories from the Village of Our Ancestors:Co-designing a multivocal educational resource based on an archaeological excavation

This work was funded by the UK-based Arts and Humanities Research Council through grants (AH/K006029/1) and (AH/R014523/1), a University of Aberdeen IKEC Award with additional support for travel and subsistence from the University of Dundee, DJCAD Research Committee RS2 project funding. Thank you to the many people who contributed their support, knowledge, feedback, voices and faces throughout the project, this list includes members of the local community, colleagues, specialists, students, and volunteers. If we have missed out any names we apologize but know that your help was appreciated. Jimmy Anaver, John Anderson, Alice Bailey, Kieran Baxter, Pauline Beebe, Ellinor Berggren, Dawn Biddison, Joshua Branstetter, Brendan Body, Lise Bos, Michael Broderick, Sarah Brown, Crystal Carter, Joseph Carter, Lucy Carter, Sally Carter, Ben Charles, Mary Church, Willard Church, Daniele Clementi, Annie Cleveland, Emily Cleveland, Joshua Cleveland, Aron Crowell, Neil Curtis, Angie Demma, Annie Don, Julia Farley, Veronique Forbes, Patti Fredericks, Tricia Gillam, Sean Gleason, Sven Haakanson, Cheryl Heitman, Grace Hill, Diana Hunter, Joel Isaak, Warren Jones, Stephan Jones, Ana Jorge, Solveig Junglas, Melia Knecht, Rick Knecht, Erika Larsen, Paul Ledger, Jonathan Lim Soon, Amber Lincoln, Steve Luke, Francis Lukezic, Eva Malvich, Pauline Matthews, Roy Mark, Edouard Masson-MacLean, Julie Masson-MacLean, Mhairi Maxwell, Chuna Mcintyre, Drew Michael, Amanda Mina, Anna Mossolova, Carl Nicolai Jr, Chris Niskanen, Molly Odell, Tom Paxton, Lauren Phillips, Lucy Qin, Charlie Roberts, Chris Rowe, Rufus Rowe,Chris Rowland, John Rundall, Melissa Shaginoff, Monica Shah, Anna Sloan, Darryl Small Jr, John Smith, Mike Smith, Joey Sparaga, Hannah Strehlau, Dora Strunk, Larissa Strunk, Lonny Strunk, Larry Strunk, Robbie Strunk, Sandra Toloczko, Richard Vanderhoek, the Qanirtuuq Incorporated Board, the Quinhagak Dance Group and the staff at Kuinerrarmiut Elitnaurviat. We also extend our thanks to three anonymous reviewers for their valuable comments on our paper.Peer reviewedPublisher PD

The structure of quotients of the Onsager algebra by closed ideals

We study the Onsager algebra from the ideal theoretic point of view. A complete classification of closed ideals and the structure of quotient algebras are obtained. We also discuss the solvable algebra aspect of the Onsager algebra through the use of formal Lie algebras.Comment: 33 pages, Latex, small topos corrected-Journal versio

Asymptotic Expansions for the Conditional Sojourn Time Distribution in the M/M/1M/M/1-PS Queue

We consider the $M/M/1$ queue with processor sharing. We study the conditional sojourn time distribution, conditioned on the customer's service requirement, in various asymptotic limits. These include large time and/or large service request, and heavy traffic, where the arrival rate is only slightly less than the service rate. The asymptotic formulas relate to, and extend, some results of Morrison \cite{MO} and Flatto \cite{FL}.Comment: 30 pages, 3 figures and 1 tabl

Statistical Properties of the Final State in One-dimensional Ballistic Aggregation

We investigate the long time behaviour of the one-dimensional ballistic aggregation model that represents a sticky gas of N particles with random initial positions and velocities, moving deterministically, and forming aggregates when they collide. We obtain a closed formula for the stationary measure of the system which allows us to analyze some remarkable features of the final `fan' state. In particular, we identify universal properties which are independent of the initial position and velocity distributions of the particles. We study cluster distributions and derive exact results for extreme value statistics (because of correlations these distributions do not belong to the Gumbel-Frechet-Weibull universality classes). We also derive the energy distribution in the final state. This model generates dynamically many different scales and can be viewed as one of the simplest exactly solvable model of N-body dissipative dynamics.Comment: 19 pages, 5 figures include