Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding Site for general anesthetics

[Image: see text] Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure–activity relationships that are necessary for anesthetic binding

DEVELOPING AN ASSESSMENT SYSTEM FOR DOD DEMAND REDUCTION INITIATIVES

The DOD developed a new Joint Warfighting Concept (JWC) to address how the United States will confront the nation’s most pressing national security challenges. The focus of the JWC was the importance of logistics during combat operations and the ability to sustain a large force over strategic distances. The DOD’s shift of focus to near-peer threats requires sustainment demand reduction across the services. Many demand reduction initiatives (DRI) are under consideration to lessen the burden of logistics at the strategic, operational, and tactical levels. Due to the relative newness of the JWC, the LOG FCB does not have a quantitative, credible, repeatable process to effectively assess, compare, and prioritize implementation of demand reduction initiatives. This study implemented several systems engineering (SE) concepts that include the completion of stakeholder analysis, functional analysis, mapping of function to form, creating a top-level and detailed systems design, the use of value modeling, and the application of sensitivity analysis. The use of these SE tools and processes resulted in the development of a DRI Assessment System which includes instructions for use of the system, questionnaire for data collection, Excel calculation sheets, and the metrics and definitions for the selected attributes. These products provide the logistics functional capability board (LOG FCB) the capability to objectively prioritize current and future DRIs to implement across the DOD.Major, United States ArmyMajor, United States ArmyCaptain, United States ArmyMajor, United States ArmyApproved for public release. Distribution is unlimited

Site-site memory equation approach in study of density/pressure dependence of translational diffusion coefficient and rotational relaxation time of polar molecular solutions: acetonitrile in water, methanol in water, and methanol in acetonitrile

We present results of theoretical study and numerical calculation of the dynamics of molecular liquids based on combination of the memory equation formalism and the reference interaction site model - RISM. Memory equations for the site-site intermediate scattering functions are studied in the mode-coupling approximation for the first order memory kernels, while equilibrium properties such as site-site static structure factors are deduced from RISM. The results include the temperature-density(pressure) dependence of translational diffusion coefficients D and orientational relaxation times t for acetonitrile in water, methanol in water and methanol in acetonitrile, all in the limit of infinite dilution. Calculations are performed over the range of temperatures and densities employing the SPC/E model for water and optimized site-site potentials for acetonitrile and methanol. The theory is able to reproduce qualitatively all main features of temperature and density dependences of D and t observed in real and computer experiments. In particular, anomalous behavior, i.e. the increase in mobility with density, is observed for D and t of methanol in water, while acetonitrile in water and methanol in acetonitrile do not show deviations from the ordinary behavior. The variety exhibited by the different solute-solvent systems in the density dependence of the mobility is interpreted in terms of the two competing origins of friction, which interplay with each other as density increases: the collisional and dielectric frictions which, respectively, increase and decrease with increasing density.Comment: 13 pages, 8 eps-figures, 3 tables, RevTeX4-forma

Common datastream permutations of animal social network data are not appropriate for hypothesis testing using regression models

1. Social network methods have become a key tool for describing, modelling and testing hypotheses about the social structures of animals. However, due to the non-independence of network data and the presence of confounds, specialised statistical techniques are often needed to test hypotheses in these networks. Datastream permutations, originally developed to test the null hypothesis of random social structure, have become a popular tool for testing a wide array of null hypotheses in animal social networks. In particular, they have been used to test whether exogenous factors are related to network structure by interfacing these permutations with regression models.2. Here, we show that these datastream permutations typically do not represent the null hypothesis of interest to researchers interfacing animal social network analysis with regression modelling, and use simulations to demonstrate the potential pitfalls of using this methodology.3. Our simulations show that, if used to indicate whether a relationship exists between network structure and a covariate, datastream permutations can result in extremely high type I error rates, in some cases approaching 50%. In the same set of simulations, traditional node-label permutations produced appropriate type I error rates (~5%).4. Our analysis shows that datastream permutations do not represent the appropriate null hypothesis for these analyses. We suggest that potential alternatives to this procedure may be found in regarding the problems of non-independence of network data and unreliability of observations separately. If biases introduced during data collection can be corrected, either prior to model fitting or within the model itself, node-label permutations then serve as a useful test for interfacing animal social network analysis with regression modelling

Why do house-hunting ants recruit in both directions?

To perform tasks, organisms often use multiple procedures. Explaining the breadth of such behavioural repertoires is not always straightforward. During house hunting, colonies of Temnothorax albipennis ants use a range of behaviours to organise their emigrations. In particular, the ants use tandem running to recruit naïve ants to potential nest sites. Initially, they use forward tandem runs (FTRs) in which one leader takes a single follower along the route from the old nest to the new one. Later, they use reverse tandem runs (RTRs) in the opposite direction. Tandem runs are used to teach active ants the route between the nests, so that they can be involved quickly in nest evaluation and subsequent recruitment. When a quorum of decision-makers at the new nest is reached, they switch to carrying nestmates. This is three times faster than tandem running. As a rule, having more FTRs early should thus mean faster emigrations, thereby reducing the colony’s vulnerability. So why do ants use RTRs, which are both slow and late? It would seem quicker and simpler for the ants to use more FTRs (and higher quorums) to have enough knowledgeable ants to do all the carrying. In this study, we present the first testable theoretical explanation for the role of RTRs. We set out to find the theoretically fastest emigration strategy for a set of emigration conditions. We conclude that RTRs can have a positive effect on emigration speed if FTRs are limited. In these cases, low quorums together with lots of reverse tandem running give the fastest emigration

Destabilising conventions using temporary interventions

Conventions are an important concept in multi-agent systems as they allow increased coordination amongst agents and hence a more efficient system. Encouraging and directing convention emergence has been the focus of much research, particularly through the use of fixed strategy agents. In this paper we apply temporary interventions using fixed strategy agents to destabilise an established convention by (i) replacing it with another convention of our choosing, and (ii) allowing it to destabilise in such a way that no other convention explicitly replaces it. We show that these interventions are effective and investigate the minimum level of intervention needed

The Dynamics of the Southwest Monsoon Current in 2016 from High-Resolution In Situ Observations and Models

The strong stratification of the Bay of Bengal (BoB) causes rapid variations in sea surface temperature (SST) that influence the development of monsoon rainfall systems. This stratification is driven by the salinity difference between the fresh surface waters of the northern bay and the supply of warm, salty water by the Southwest Monsoon Current (SMC). Despite the influence of the SMC on monsoon dynamics, observations of this current during the monsoon are sparse. Using data from high-resolution in situ measurements along an east–west section at 8°N in the southern BoB, we calculate that the northward transport during July 2016 was between 16.7 and 24.5 Sv (1 Sv ≡ 106 m3 s−1), although up to ⅔ of this transport is associated with persistent recirculating eddies, including the Sri Lanka Dome. Comparison with climatology suggests the SMC in early July was close to the average annual maximum strength. The NEMO 1/12° ocean model with data assimilation is found to faithfully represent the variability of the SMC and associated water masses. We show how the variability in SMC strength and position is driven by the complex interplay between local forcing (wind stress curl over the Sri Lanka Dome) and remote forcing (Kelvin and Rossby wave propagation). Thus, various modes of climatic variability will influence SMC strength and location on time scales from weeks to years. Idealized one-dimensional ocean model experiments show that subsurface water masses advected by the SMC significantly alter the evolution of SST and salinity, potentially impacting Indian monsoon rainfall