A Steered Molecular Dynamics Study of Binding and Translocation Processes in the GABA Transporter

The entire substrate translocation pathway in the human GABA transporter (GAT-1) was explored for the endogenous substrate GABA and the anti-convulsive drug tiagabine. Following a steered molecular dynamics (SMD) approach, in which a harmonic restraining potential is applied to the ligand, dissociation and re-association of ligands were simulated revealing events leading to substrate (GABA) translocation and inhibitor (tiagabine) mechanism of action. We succeeded in turning the transporter from the outward facing occluded to the open-to-out conformation, and also to reorient the transporter to the open-to-in conformation. The simulations are validated by literature data and provide a substrate pathway fingerprint in terms of which, how, and in which sequence specific residues are interacted with. They reveal the essential functional roles of specific residues, e.g. the role of charged residues in the extracellular vestibule including two lysines (K76 (TM1) and K448 (TM10)) and a TM6-triad (D281, E283, and D287) in attracting and relocating substrates towards the secondary/interim substrate-binding site (S2). Likewise, E101 is highlighted as essential for the relocation of the substrate from the primary substrate-binding site (S1) towards the cytoplasm

Experimental evaluation of the usage of ad hoc networks as stubs for multiservice networks

This paper describes an experimental evaluation of a multiservice ad hoc network, aimed to be interconnected with an infrastructure, operator-managed network. This network supports the efficient delivery of services, unicast and multicast, legacy and multimedia, to users connected in the ad hoc network. It contains the following functionalities: routing and delivery of unicast and multicast services; distributed QoS mechanisms to support service differentiation and resource control responsive to node mobility; security, charging, and rewarding mechanisms to ensure the correct behaviour of the users in the ad hoc network. This paper experimentally evaluates the performance of multiple mechanisms, and the influence and performance penalty introduced in the network, with the incremental inclusion of new functionalities. The performance results obtained in the different real scenarios may question the real usage of ad-hoc networks for more than a minimal number of hops with such a large number of functionalities deployed

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

ABSTRACT: Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults

Avian movements in a modern world - cognitive challenges

Different movement patterns have evolved as a response to predictable and unpredictable variation in the environment with migration being an adaptation to predictable environments, nomadism to unpredictable environments and partial migration to a mixture of predictable and unpredictable conditions. Along different movement patterns different cognitive abilities have evolved which are reviewed and discussed in relation to an organism’s ability to respond to largely unpredictable environmental change due to climate and human-induced change and linked to population trends. In brief, migrants have a combination of reliance on memory, low propensity to explore and high avoidance of environmental change that in combination with overall small brain sizes results in low flexibility to respond to unpredictable environmental change. In line with this, many migrants have negative population trends. In contrast, while nomads may use their memory to find suitable habitats they can counteract negative effects of finding such habitats disturbed by large-scale exploratory movements and paying attention to environmental cues. They are also little avoidant of environmental change. Population trends are largely stable or increasing indicating their ability to cope with climate and human-induced change. Cognitive abilities in partial migrants are little investigated but indicate attention to environmental cues coupled with high exploratory tendencies that allow them a flexible response to unpredictable environmental change. Indeed, their population trends are mainly stable or increasing. In conclusion, cognitive abilities have evolved in conjunction with different movement patterns and affect an organism’s ability to adapt to rapidly human-induced changes in the environment

Cold spells in the Nordic Seas during the early Eocene Greenhouse

Abstract The early Eocene (c. 56 - 48 million years ago) experienced some of the highest global temperatures in Earth’s history since the Mesozoic, with no polar ice. Reports of contradictory ice-rafted erratics and cold water glendonites in the higher latitudes have been largely dismissed due to ambiguity of the significance of these purported cold-climate indicators. Here we apply clumped isotope paleothermometry to a traditionally qualitative abiotic proxy, glendonite calcite, to generate quantitative temperature estimates for northern mid-latitude bottom waters. Our data show that the glendonites of the Danish Basin formed in waters below 5 °C, at water depths of &lt;300 m. Such near-freezing temperatures have not previously been reconstructed from proxy data for anywhere on the early Eocene Earth, and these data therefore suggest that regionalised cool episodes punctuated the background warmth of the early Eocene, likely linked to eruptive phases of the North Atlantic Igneous Province.</jats:p