Interactions Among Positions in the Third and Fourth Membrane-Associated Domains at the Intersubunit Interface of the N-Methyl-D-Aspartate Receptor Forming Sites of Alcohol Action

The N-methyl-d-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The predicted structure of the NMDA receptor, based on that of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We tested the hypothesis that these positions interact to regulate receptor kinetics and ethanol sensitivity by using dual substitution mutants. In single-substitution mutants, we found that a position in both subunits adjacent to one previously identified, GluN1(Gly-638) and GluN2A(Phe-636), can strongly regulate ethanol sensitivity. Significant interactions affecting ethanol inhibition and receptor deactivation were observed at four pairs of positions in GluN1/GluN2A: Gly-638/Met-823, Phe-639/Leu-824, Met-818/Phe-636, and Leu-819/Phe-637; the latter pair also interacted with respect to desensitization. Two interactions involved a position in M4 of both subunits, GluN1(Met-818) and GluN2A(Leu-824), that does not by itself alter ethanol sensitivity, whereas a previously identified ethanol-sensitive position, GluN2A(Ala-825), did not unequivocally interact with any other position tested. These results also indicate a shift by one position of the predicted alignment of the GluN1 M4 domain. These findings have allowed for the refinement of the NMDA receptor M domain structure, demonstrate that this region can influence apparent agonist affinity, and support the existence of four sites of alcohol action on the NMDA receptor, each consisting of five amino acids at the M3-M4 domain intersubunit interfaces

Two Adjacent Phenylalanines In the NMDA Receptor GluN2A Subunit M3 Domain Interactively Regulate Alcohol Sensitivity and Ion Channel Gating

The N-methyl-d-aspartate (NMDA) receptor is a key target of ethanol action in the central nervous system. Alcohol inhibition of NMDA receptor function involves small clusters of residues in the third and fourth membrane-associated (M) domains. Previous results from this laboratory have shown that two adjacent positions in the M3 domain, F636 and F637, can powerfully regulate alcohol sensitivity and ion channel gating. In this study, we report that these positions interact with one another in the regulation of both NMDA receptor gating and alcohol action. Using dual mutant cycle analysis, we detected interactions among various substitution mutants at these positions with respect to regulation of glutamate EC50, steady-state to peak current ratios (Iss:Ip), mean open time, and ethanol IC50. This interaction apparently involves a balancing of forces on the M3 helix, such that the disruption of function due to a substitution at one position can be reversed by a similar substitution at the other position. For example, tryptophan substitution at F636 or F637 increased or decreased channel mean open time, respectively, but tryptophan substitution at both positions did not alter open time. Interestingly, the effects of a number of mutations on receptor kinetics and ethanol sensitivity appeared to depend upon subtle structural differences, such as those between the isomeric amino acids leucine and isoleucine, as they could not be explained on the basis of sidechain molecular volume or hydrophilicity

Pea-barley intercrop N dynamics in farmers fields

Knowledge about crop performances in farmers’ fields provides a link between on-farm practice and re-search. Thereby scientists may improve their ability to understand and suggest solutions for the problems facing those who have the responsibility of making sound agricultural decisions. Nitrogen (N) availability is known to be highly heterogeneous in terrestrial plant communities (Stevenson and van Kessel, 1997), a heterogeneity that in natural systems is often associated with variation in the distri-bution of plant species. In intercropping systems the relative proportion of component crops is influenced by the distribution of growth factors such as N in both time and space (Jensen, 1996). In pea-barley intercrops, an increase in the N supply promotes the growth of barley thereby decreasing the N accumulation of pea and giving rise to changes in the relative proportions of the intercropped components (Jensen, 1996). The pres-sure of weeds may, however, significantly change the dynamics in intercrops (Hauggaard-Nielsen et al., 2001). Data from farmers’ fields may provide direct, spatially explicit information for evaluating the poten-tials of improving the utilisation of field variability by intercrops

Functional Interactions of Alcohol-sensitive Sites in the \u3cem\u3eN\u3c/em\u3e-Methyl-d-aspartate Receptor M3 and M4 Domains

The N-methyl-d-aspartate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Previous studies have demonstrated sites in the third and fourth membrane-associated (M) domains of the N-methyl-d-aspartate receptor NR2A subunit that influence alcohol sensitivity and ion channel gating. We investigated whether two of these sites, Phe-637 in M3 and Met-823 in M4, interactively regulate the ethanol sensitivity of the receptor by testing dual substitution mutants at these positions. A majority of the mutations decreased steady-state glutamate EC50 values and maximal steady-state to peak current ratios (Iss/Ip), whereas only two mutations altered peak glutamate EC50 values. Steady-state glutamate EC50 values were correlated with maximal glutamate Iss/Ip values, suggesting that changes in glutamate potency were attributable to changes in desensitization. In addition, there was a significant interaction between the substituents at positions 637 and 823 with respect to glutamate potency and desensitization. IC50 values for ethanol among the mutants varied over the approximate range 100–325 mm. The sites in M3 and M4 significantly interacted in regulating ethanol sensitivity, although this was apparently dependent upon the presence of methionine in position 823. Molecular dynamics simulations of the NR2A subunit revealed possible binding sites for ethanol near both positions in the M domains. Consistent with this finding, the sum of the molecular volumes of the substituents at the two positions was not correlated with ethanol IC50 values. Thus, there is a functional interaction between Phe-637 and Met-823 with respect to glutamate potency, desensitization, and ethanol sensitivity, but the two positions do not appear to form a unitary site of alcohol action

Games and enculturation: A cross-cultural analysis of games and values in Austronesia

While most animals play, only humans play games. As animal play serves to teach offspring important life-skills in a safe scenario, human games might, in similar ways, teach important culturally relevant skills. Humans in all cultures play games; however, it is not clear whether variation in the characteristics of games across cultural groups is related to group-level attributes. Here we investigate specifically whether the cooperativeness of games covaries with socio-ecological differences across cultural groups. We hypothesize that cultural groups that engage in frequent inter-group conflict, cooperative sustenance acquisition, or that have less stratified social structures, might more frequently play cooperative games as compared to groups that do not share these characteristics. To test these hypotheses, we gathered data from the ethnographic record on 25 ethnolinguistic groups in the Austronesian language family. We show that cultural groups with higher levels of inter-group conflict and cooperative land-based hunting play cooperative games more frequently than other groups. Additionally, cultural groups with higher levels of intra-group conflict play competitive games more frequently than other groups. These findings indicate that games are not randomly distributed among cultures, but rather relate to the socio-ecological settings of the cultural groups that practice them. We argue that games serve as training grounds for group-specific norms and values and thereby have an important function in enculturation during childhood. Moreover, games might server an important role in the maintenance of cultural diversity.Introduction Children’s play Games Possible drivers of cooperative goal structures - Interdependence in foraging. - Intra- and inter-group conflict. Lack of social stratification Methods - Games - Cultural covariate data - Statistical analyses Results - Descriptive statistics - Cultural variables and goal structures Discussion Conclusio

Different Sites of Alcohol Action in the NMDA Receptor GluN2A and GluN2B Subunits

The NMDA receptor is a major target of alcohol action in the CNS, and recent behavioral and cellular studies have pointed to the importance of the GluN2B subunit in alcohol action. We and others have previously characterized four amino acid positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN2A subunit that influence both ion channel gating and alcohol sensitivity. In this study, we found that substitution mutations at two of the four corresponding positions in the GluN2B subunit, F637 and G826, influence ethanol sensitivity and ion channel gating. Because position 826 contains a glycine residue in the native protein, we focused our attention on GluN2B(F637). Substitution mutations at GluN2B(F637) significantly altered ethanol IC50 values, glutamate EC50 values for peak (Ip) and steady-state (Iss) current, and steady-state to peak current ratios (Iss:Ip). Changes in apparent glutamate affinity were not due to agonist trapping in desensitized states, as glutamate Iss EC50 values were not correlated with Iss:Ip values. Ethanol sensitivity was correlated with values of both Ip and Iss glutamate EC50, but not with Iss:Ip. Values of ethanol IC50, glutamate EC50, and Iss:Ip for mutants at GluN2B(F637) were highly correlated with the corresponding values for mutants at GluN2A(F636), consistent with similar functional roles of this position in both subunits. These results demonstrate that GluN2B(Phe637) regulates ethanol action and ion channel function of NMDA receptors. However, despite highly conserved M domain sequences, ethanol\u27s actions on GluN2A and GluN2B subunits differ

The Austronesian game taxonomy: A cross-cultural dataset of historical games

Humans in most cultures around the world play rule-based games, yet research on the content and structure of these games is limited. Previous studies investigating rule-based games across cultures have either focused on a small handful of cultures, thus limiting the generalizability of findings, or used cross-cultural databases from which the raw data are not accessible, thus limiting the transparency, applicability, and replicability of research findings. Furthermore, games have long been defined as competitive interactions, thereby blinding researchers to the cross-cultural variation in the cooperativeness of rule-based games. The current dataset provides ethnographic, historic information on games played in cultural groups in the Austronesian language family. These game descriptions (Ngames = 907) are available and codeable for researchers interested in games. We also develop a unique typology of the cooperativeness of the goal structure of games and apply this typology to the dataset. Researchers are encouraged to use this dataset to examine cross-cultural variation in the cooperativeness of games and further our understanding of human cultural behaviour on a larger scale.Background and summary Methods - Defining games. - Defining the goal structure of games Search criteria and methodology - eHRAF - Pulotu - American Anthropologist - The Journal of the Polynesian Society - Additional sources Data records - Variable definitions - Descriptive statistics of games Technical validation - Cultural group identifiers - Record linkage - Filtering and coding of games - Austronesian language phylogeny Research opportunitie

Rock Hill Banking Collection - Accession 1361

This collection consists mostly of materials associated with the Rock Hill National Banks including the People’s National Bank (founded in 1906) and the C & S National Bank; the rest of the collection consists of entries that are linked, either directly or indirectly, with the Banking systems of Rock Hill. The collection consists of mainly of photographs of unknown employees and patrons of People’s National Bank and C & S National Bank, photos of events either attended by members or sponsored by the People’s National Bank and C & S National Bank, photos of employees or customers, a photo of C & S employees serving free drinks to Winthrop students during registration, and photos of the city of Rock Hill, it’s railway system, and Winthrop. The collection also includes a history of the of the Peoples national Bank of Rock Hill and The Peoples Trust Company, correspondence, brochures, posters, certificates, and newspaper articles and clippings.https://digitalcommons.winthrop.edu/manuscriptcollection_findingaids/2659/thumbnail.jp

Why are fish oil supplements apparently failing to reproduce fish consumption epidemiology in RCT for cardiovascular disease?

Abstract of a presentation