A Stereochemical Test of a Proposed Structural Feature of the Nicotinic Acetylcholine Receptor

Understanding the gating mechanism of the nicotinic acetylcholine receptor (nAChR) and similar channels constitutes a significant challenge in chemical neurobiology. In the present work, we use a stereochemical probe to evaluate a proposed pin-into-hydrophobic socket mechanism for the αVal46 side chain of the nAChR. Utilizing nonsense suppression methodology we incorporated isoleucine (Ile), O-methyl threonine (Omt) and threonine (Thr) as well as their side chain epimers (the allo counterparts). Surprisingly, our results indicate that only the pro-S methyl group of the αVal46 side chain is sensitive to changes in hydrophobicity, consistent with the precise geometrical requirements of the pin-into-socket mechanism

Evaluating the influence of lake morphology, trophic status and diagenesis on geochemical profiles in lake sediments

Recent geochemical studies provide evidence that changes in vertical distributions of nutrients in lake sediments are driven by anthropogenic activities, based primarily on trends of increasing concentrations in upper sediment layers. However, we show that vertical concentration profiles of carbon (C), nitrogen (N) and phosphorus (P) in lake sediments can be higher in the upper, most recently deposited sediment strata, driven largely by natural diagenetic processes and not eutrophication alone. We examined sediment cores from 14 different lakes in New Zealand and China ranging from oligotrophic to highly eutrophic and shallow to deep, and found that the shape of vertical profiles of total P, a key nutrient for lake productivity, can be similar in sediments across gradients of widely differing trophic status. We derived and applied empirical and mechanistic diagenesis steady state profile models to describe the vertical distribution of C, N and P in the sediments. These models, which focus on large scale temporal (decades) and spatial (up to 35 cm in the vertical) processes, revealed that density-differentiated burial and biodiffusive mixing, were strongly correlated with vertical concentration gradients of sediment C, N and P content, whereas lake trophic status was not. A sensitivity analysis of parameters included in the diagenetic model further showed that the processes including flux of organic matter to the sediment-water interface, burial (net sedimentation), breakdown of organic matter and biodiffusion all significantly can influence the vertical distribution of sediment P content. We conclude that geochemical studies attempting to evaluate drivers of the vertical distribution of sediment C, N, and P content in lake sediments should also account for the natural diagenetic drivers of vertical concentration gradients, assisted with application of similar models to those presented in this study. This would include quantification of key sediment diagenesis model parameters to separate out the influence of anthropogenic activities

Cation-pi interactions in aromatics of biological and medicinal interest: Electrostatic potential surfaces as a useful qualitative guide

The cation-pi interaction is an important, general force for molecular recognition in biological receptors. Through the sidechains of aromatic amino acids, novel binding sites for cationic ligands such as acetylcholine can be constructed. We report here a number of calculations on prototypical cation-pi systems, emphasizing structures of relevance to biological receptors and prototypical heterocycles of the type often of importance in medicinal chemistry. Trends in the data can be rationalized using a relatively simple model that emphasizes the electrostatic component of the cation-pi interaction. In particular, plots of the electrostatic potential surfaces of the relevant aromatics provide useful guidelines for predicting cation-pi interactions in new systems

Gamma-soft Analog of the Confined Beta-soft Rotor Model

A gamma-soft analog of the confined beta-soft (CBS) rotor model is developed, by using a gamma-independent displaced infinite well beta-potential in the Bohr Hamiltonian, for which exact separation of variables is possible. Level schemes interpolating between the E(5) critical point symmetry (with R(4/2)=E(4)/E(2)= 2.20) and the O(5) gamma-soft rotor (with R(4/2)=2.50) are obtained, exhibiting a crossover of excited 0+ bandheads which leads to agreement with the general trends of first excited 0+ states in this region and is observed experimentally in 128-Xe and 130-Xe.Comment: 10 pages, LaTeX, including 7 eps figure

Dissipative Effects on Quantum Sticking

Using variational mean-field theory, many-body dissipative effects on the threshold law for quantum sticking and reflection of neutral and charged particles are examined. For the case of an ohmic bosonic bath, we study the effects of the infrared divergence on the probability of sticking and obtain a non-perturbative expression for the sticking rate. We find that for weak dissipative coupling $\alpha$, the low energy threshold laws for quantum sticking are modified by an infrared singularity in the bath. The sticking probability for a neutral particle with incident energy $E\to 0$ behaves asymptotically as ${\it s}\sim E^{(1+\alpha)/2(1-\alpha)}$; for a charged particle, we obtain ${\it s}\sim E^{\alpha/2(1-\alpha)}$. Thus, "quantum mirrors" --surfaces that become perfectly reflective to particles with incident energies asymptotically approaching zero-- can also exist for charged particles.Comment: 10 pages, 0 fig

Expression and Circular Dichroism Studies of the Extracellular Domain of the alpha Subunit of the Nicotinic Acetylcholine Receptor

To provide material suitable for structural studies of the nicotinic acetylcholine receptor, we have expressed and purified the NH2-terminal extracellular domain of the mouse muscle alpha subunit. Several constructs were initially investigated using Xenopus oocytes as a convenient small scale expression system. A fusion protein (alpha210GPI) consisting of the 210 NH2-terminal amino acids of the alpha subunit and a glycosylphosphatidylinositol anchorage sequence conferred surface alpha-bungarotoxin binding in oocytes. Coexpression of alpha210GPI with an analogous construct made from the delta subunit showed no evidence of heterodimer formation. The alpha210GPI protein was chosen for large scale expression in transfected Chinese hamster ovary cells. The alpha210GPI protein was cleaved from these cells and purified on an immunoaffinity column. Gel and column chromatography show that the purified protein is processed as expected and exists as a monomer. The purified protein also retains the two distinct, conformation-specific binding sites expected for the correctly folded alpha subunit. Circular dichroism studies of alpha210GPI suggest that this region of the receptor includes considerable beta-sheet secondary structure, with a small proportion of alpha-helix

A Long-Term Hydrologically-Based Data Set of Land Surface Fluxes and States for the Conterminous United States

A frequently encountered difficulty in assessing model-predicted land–atmosphere exchanges of moisture and energy is the absence of comprehensive observations to which model predictions can be compared at the spatial and temporal resolutions at which the models operate. Various methods have been used to evaluate the land surface schemes in coupled models, including comparisons of model-predicted evapotranspiration with values derived from atmospheric water balances, comparison of model-predicted energy and radiative fluxes with tower measurements during periods of intensive observations, comparison of model-predicted runoff with observed streamflow, and comparison of model predictions of soil moisture with spatial averages of point observations. While these approaches have provided useful model diagnostic information, the observation-based products used in the comparisons typically are inconsistent with the model variables with which they are compared—for example, observations are for points or areas much smaller than the model spatial resolution, comparisons are restricted to temporal averages, or the spatial scale is large compared to that resolved by the model. Furthermore, none of the datasets available at present allow an evaluation of the interaction of the water balance components over large regions for long periods. In this study, a model-derived dataset of land surface states and fluxes is presented for the conterminous United States and portions of Canada and Mexico. The dataset spans the period 1950–2000, and is at a 3-h time step with a spatial resolution of ⅛ degree. The data are distinct from reanalysis products in that precipitation is a gridded product derived directly from observations, and both the land surface water and energy budgets balance at every time step. The surface forcings include precipitation and air temperature (both gridded from observations), and derived downward solar and longwave radiation, vapor pressure deficit, and wind. Simulated runoff is shown to match observations quite well over large river basins. On this basis, and given the physically based model parameterizations, it is argued that other terms in the surface water balance (e.g., soil moisture and evapotranspiration) are well represented, at least for the purposes of diagnostic studies such as those in which atmospheric model reanalysis products have been widely used. These characteristics make this dataset useful for a variety of studies, especially where ground observations are lacking

Using Sensor Metadata Streams to Identify Topics of Local Events in the City

In this paper, we study the emerging Information Retrieval (IR) task of local event retrieval using sensor metadata streams. Sensor metadata streams include information such as the crowd density from video processing, audio classifications, and social media activity. We propose to use these metadata streams to identify the topics of local events within a city, where each event topic corresponds to a set of terms representing a type of events such as a concert or a protest. We develop a supervised approach that is capable of mapping sensor metadata observations to an event topic. In addition to using a variety of sensor metadata observations about the current status of the environment as learning features, our approach incorporates additional background features to model cyclic event patterns. Through experimentation with data collected from two locations in a major Spanish city, we show that our approach markedly outperforms an alternative baseline. We also show that modelling background information improves event topic identification