Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the α6 subtype

Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at α6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure–activity relationship are discussed in the context of the design of small molecules targeting smoking cessation

Structural differences determine the relative selectivity of nicotinic compounds for native α4β2^*-, α6β2^*-, α3β4^*- and α7-nicotine acetylcholine receptors

Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, α4β2^* and α6β2^*-nAChR have the highest affinity for nicotine (where ^* indicates possibility of other subunits). The α4β2^*-nAChRs are widely distributed, while α6β2^*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. α4β2^*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics.We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compoundswere screened usingmembrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing hα7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, α4β2^*, α6β2^*, α7 and α3β4^*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at α4b2^* and α6β2^*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for α6β2^*-nAChR

α6* Nicotinic Acetylcholine Receptor Expression and Function in a Visual Salience Circuit

Nicotinic acetylcholine receptors (nAChRs) containing α6 subunits are expressed in only a few brain areas, including midbrain dopamine (DA) neurons, noradrenergic neurons of the locus ceruleus, and retinal ganglion cells. To better understand the regional and subcellular expression pattern of α6-containing nAChRs, we created and studied transgenic mice expressing a variant α6 subunit with green fluorescent protein (GFP) fused in-frame in the M3-M4 intracellular loop. In α6-GFP transgenic mice, α6-dependent synaptosomal DA release and radioligand binding experiments confirmed correct expression and function in vivo. In addition to strong α6* nAChR expression in glutamatergic retinal axons, which terminate in superficial superior colliculus (sSC), we also found α6 subunit expression in a subset of GABAergic cell bodies in this brain area. In patch-clamp recordings from sSC neurons in brain slices from mice expressing hypersensitive α6* nAChRs, we confirmed functional, postsynaptic α6* nAChR expression. Further, sSC GABAergic neurons expressing α6* nAChRs exhibit a tonic conductance mediated by standing activation of hypersensitive α6* nAChRs by ACh. α6* nAChRs also appear in a subpopulation of SC neurons in output layers. Finally, selective activation of α6* nAChRs in vivo induced sSC neuronal activation as measured with c-Fos expression. Together, these results demonstrate that α6* nAChRs are uniquely situated to mediate cholinergic modulation of glutamate and GABA release in SC. The SC has emerged as a potential key brain area responsible for transmitting short-latency salience signals to thalamus and midbrain DA neurons, and these results suggest that α6* nAChRs may be important for nicotinic cholinergic sensitization of this pathway

THE ROLE OF INTERDEPENDENCE IN THE MICRO-FOUNDATIONS OF ORGANIZATION DESIGN: TASK, GOAL, AND KNOWLEDGE INTERDEPENDENCE

Interdependence is a core concept in organization design, yet one that has remained consistently understudied. Current notions of interdependence remain rooted in seminal works, produced at a time when managers’ near-perfect understanding of the task at hand drove the organization design process. In this context, task interdependence was rightly assumed to be exogenously determined by characteristics of the work and the technology. We no longer live in that world, yet our view of interdependence has remained exceedingly task-centric and our treatment of interdependence overly deterministic. As organizations face increasingly unpredictable workstreams and workers co-design the organization alongside managers, our field requires a more comprehensive toolbox that incorporates aspects of agent-based interdependence. In this paper, we synthesize research in organization design, organizational behavior, and other related literatures to examine three types of interdependence that characterize organizations’ workflows: task, goal, and knowledge interdependence. We offer clear definitions for each construct, analyze how each arises endogenously in the design process, explore their interrelations, and pose questions to guide future research

Asymptotic solutions for the asymmetric flow in a channel with porous retractable walls under a transverse magnetic field

The self-similarity solutions of the Navier-Stokes equations are constructed for an incompressible laminar flow through a uniformly porous channel with retractable walls under a transverse magnetic field. The flow is driven by the expanding or contracting walls with different permeability. The velocities of the asymmetric flow at the upper and lower walls are different in not only the magnitude but also the direction. The asymptotic solutions are well constructed with the method of boundary layer correction in two cases with large Reynolds numbers, i.e., both walls of the channel are with suction, and one of the walls is with injection while the other one is with suction. For small Reynolds number cases, the double perturbation method is used to construct the asymptotic solution. All the asymptotic results are finally verified by numerical results.</p

Facing differences with an open mind: Openness to Experience, salience of intra-group differences, and performance of diverse groups.

This study examined how the performance of diverse teams is affected by member openness to experience and the extent to which team reward structure emphasizes intragroup differences. Fifty-eight heterogeneous four-person teams engaged in an interactive task. Teams in which reward structure converged with diversity (i.e., "faultline" teams) performed more poorly than teams in which reward structure cut across differences between group members or pointed to a "superordinate identity." High openness to experience positively influenced teams in which differences were salient (i.e., faultline and "cross-categorized" teams) but not teams with a superordinate identity. This effect was mediated by information elaboration

What an Agile Leader Does: The Group Dynamics Perspective

When large industrial organizations change to (or start with) an agile approach to operations, managers and some employees are supposed to be “agile leaders” often without being given a clear definition of what that comprises when building agile teams. An inductive thematic analysis was used to investigate what 15 appointed leaders actually do and perceive as challenges regarding group dynamics working with an agile approach. Team maturity, Team design, and Culture and mindset were all categories of challenges related to group dynamics that the practitioners face and manage in their work-life that are not explicitly mentioned in the more process-focused agile transformation frameworks. The results suggest that leader mitigation of these three aspects of group dynamics is essential to the success of an agile transformation

Individual Conditions for Co-production of a Social Innovation in a Living Lab: Case Sunshine PopUp Park

Participative processes and the empowerment of citizens are seen as central aspects of social innovation, which involves collaborative activities between the private, public and third sectors. It is important to identify the factors influencing citizen involvement, and we therefore investigate how people can be encouraged to contribute to improving societal well-being and to enhance partnerships between citizens, regions and, also, the profit and non-profit sectors. In particular, we investigate the motivation of citizens involved in the co-production of social innovation. We also provide descriptions of specific citizen- and public authority-related outcomes of the co-production process, which are missing from most previous studies (Voorberg et al., Public Management Review, 17(9), 1333–1357, 2015). We also identify actions that might facilitate the co-production of social innovation. In this study, we report a successful case of co-produced social innovation and derive findings from it.Post-print / Final draf

Job Crafting via Decreasing Hindrance Demands:The Motivating Role of Interdependence Misfit and the Facilitating Role of Autonomy

Job crafting theory suggests that misalignment between an employee’s preferred and actual amount of job characteristics acts as a motivational trigger for job crafting. We test this unexplored, yet key proposition underlying job crafting theory. To do so, however, we take a more comprehensive misfit perspective than previously applied, evaluating person-job undersupply and oversupply. We propose that task interdependence misfit motivates a reductive form of job crafting, decreasing hindrance demands. We also propose that low autonomy mitigates the misfit to decreasing hindrance demands relationship. To empirically evaluate this direction, we employ moderated polynomial regression and response surface analysis. Study 1 (N = 159 English-speaking respondents) findings suggest that task interdependence misfit (both undersupply and oversupply) is positively related to decreasing hindrance demands. Study 2 (N = 363 Dutch-speaking respondents) findings replicate and support our misfit hypothesis. Further, as expected, low levels of autonomy neutralize the relationship between task interdependence misfit and decreasing hindrance demands. Theoretical and practical implications regarding the misfit-as-motivation hypothesis, and the simultaneous investigation of job crafting facilitators (i.e., autonomy) and motivators (i.e., misfit) are discussed

Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior

Firing rates of dopamine (DA) neurons in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) control DA release in target structures such as striatum and prefrontal cortex. DA neuron firing in the soma and release probability at axon terminals are tightly regulated by cholinergic transmission and nicotinic acetylcholine receptors (nAChRs). To understand the role of α6* nAChRs in DA transmission, we studied several strains of mice expressing differing levels of mutant, hypersensitive (leucine 9′ to serine [L9′S]) α6 subunits. α6 L9′S mice harboring six or more copies of the hypersensitive α6 gene exhibited spontaneous home-cage hyperactivity and novelty-induced locomotor activity, whereas mice with an equal number of WT and L9′S α6 genes had locomotor activity resembling that of control mice. α6-dependent, nicotine-stimulated locomotor activation was also more robust in high-copy α6 L9′S mice versus low-copy mice. In wheel-running experiments, results were also bi-modal; high-copy α6 L9′S animals exhibited blunted total wheel rotations during each day of a 9-day experiment, but low-copy α6 L9′S mice ran normally on the wheel. Reduced wheel running in hyperactive strains of α6 L9′S mice was attributable to a reduction in both overall running time and velocity. ACh and nicotine-stimulated DA release from striatal synaptosomes in α6 L9′S mice was well-correlated with behavioral phenotypes, supporting the hypothesis that augmented DA release mediates the altered behavior of α6 L9′S mice. This study highlights the precise control that the nicotinic cholinergic system exerts on DA transmission and provides further insights into the mechanisms and consequences of enhanced DA release