A Molecular Mechanism for Endocytic Recycling of the M5 Muscarinic Acetylcholine Receptor

Muscarinic acetylcholine receptors (MRs), a family of five G protein-coupled receptors (GPCRs), play an essential role in the regulation of mammalian physiology. In the brain, MR-mediated neurotransmission is required for the control of movement and motivated behavior by the basal ganglia, and MR dysfunction may contribute to schizophrenia, Alzheimerʼs disease, and motor disorders. Functional studies of the muscarinic receptors have been hampered by a lack of selective pharmacology, poor receptor immunoreactivity and a wide, overlapping pattern of expression. MRs are characterized by the presence of a large third intracellular loop domain (i3), the sequence of which is divergent between MR subtypes. The i3 is known to determine signaling and trafficking characteristics of GPCRs by binding to defined subsets of regulatory and effector proteins. In an effort to discover novel, subtype-specific muscarinic receptor regulatory mechanisms, we performed yeast two-hybrid proteinprotein interaction screens with the five MR i3 regions. An interaction between M5 and the Arf GAP protein AGAP1 was detected, and was observed to be specific to the M5 subtype. This interaction was confirmed in vitro, and was shown to mediate the binding of the AP-3 adaptor complex to the M5 i3. Immunocytochemical and live cell imaging of primary rat hippocampal neurons revealed co-localization of M5 and AGAP1- or AP-3- positive vesicles after treatment with a muscarinic agonist. Activity-induced receptor trafficking studies demonstrated that interaction with AGAP1 and activity of AP-3 were required for the endocytic recycling of M5 in neurons, the lack of which resulted in downregulation of cell surface receptor density. M5 has been shown to be expressed in the dopaminergic neurons of the ventral midbrain and to function in the presynaptic modulation of dopamine release in the striatum. Results from dopamine release studies suggest that the abrogation of AGAP1-mediated recycling decreases the magnitude of presynaptic M5-mediated release potentiation. Our study demonstrates a novel, neuronspecific trafficking function for AGAP1 and AP-3, and suggests the presence of a previously unknown receptor recycling pathway that may underlie mechanisms of sustained sensitivity of GPCRs

Loss of α-Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons.

Increased α-synuclein (αsyn) and mitochondrial dysfunction play central roles in the pathogenesis of Parkinson's disease (PD), and lowering αsyn is under intensive investigation as a therapeutic strategy for PD. Increased αsyn levels disrupt mitochondria and impair respiration, while reduced αsyn protects against mitochondrial toxins, suggesting that interactions between αsyn and mitochondria influences the pathologic and physiologic functions of αsyn. However, we do not know if αsyn affects normal mitochondrial function or if lowering αsyn levels impacts bioenergetic function, especially at the nerve terminal where αsyn is enriched. To determine if αsyn is required for normal mitochondrial function in neurons, we comprehensively evaluated how lowering αsyn affects mitochondrial function. We found that αsyn knockout (KO) does not affect the respiration of cultured hippocampal neurons or cortical and dopaminergic synaptosomes, and that neither loss of αsyn nor all three (α, β and γ) syn isoforms decreased mitochondria-derived ATP levels at the synapse. Similarly, neither αsyn KO nor knockdown altered the capacity of synaptic mitochondria to meet the energy requirements of synaptic vesicle cycling or influenced the localization of mitochondria to dopamine (DA) synapses in vivo. Finally, αsyn KO did not affect overall energy metabolism in mice assessed with a Comprehensive Lab Animal Monitoring System. These studies suggest either that αsyn has little or no significant physiological effect on mitochondrial bioenergetic function, or that any such functions are fully compensated for when lost. These results implicate that αsyn levels can be reduced in neurons without impairing (or improving) mitochondrial bioenergetics or distribution

Assessing the size and growth of the US wetland and stream compensatory mitigation industry

Interest has focused on quantifying the size and scope of environmental markets, particularly those that offset ecosystem impacts or restore natural infrastructure to improve habitat or promote clean air and water. In this paper, we focus on the US wetland and stream compensatory mitigation market, asking: what types of firms make up the mitigation “industry”? What are the economic impacts–i.e., the “size”–of the mitigation industry? How has this industry changed over time? We present the results of a national survey of mitigation firms and construct an input-output model of the industry’s economic impacts and employment. We also develop a comparative, 2014 model of the industry using data from a previous study of the broader, ecological restoration economy. Our findings suggest that the (2019, pre-COVID) mitigation industry collects annual revenues (direct economic impacts) in excess of $3.5 billion, which, along with additional indirect (supply chain) and induced (spillover) economic impacts, combine to over$9.6 billion in total output and support over 53,000 total jobs. We estimate 2014–2019 growth of ~35.2 percent in revenues, ~32.6 percent in total economic impacts, and a compound annual growth rate (CAGR) of 5.25%. This places the mitigation industry within the range of other, well-established industries within the technical services sector. We suggest establishing North American Industry Classification System (NAICS) codes specifically for ecological restoration and mitigation firms, an essential step in generating accurate and consistent employment estimates in the future, particularly at sub-national geographic scales

A plume-in-grid approach to characterize air quality impacts of aircraft emissions at the Hartsfield-Jackson Atlanta International Airport

This study examined the impacts of aircraft emissions during the landing and takeoff cycle on PM2.5 concentrations during the months of June 2002 and July 2002 at the Hartsfield-Jackson Atlanta International Airport. Primary and secondary pollutants were modeled using the Advanced Modeling System for Transport, Emissions, Reactions, and Deposition of Atmospheric Matter (AMSTERDAM). AMSTERDAM is a modified version of the Community Multiscale Air Quality (CMAQ) model that incorporates a plume-in-grid process to simulate emissions sources of interest at a finer scale than can be achieved using CMAQ's model grid. Three fundamental issues were investigated: the effects of aircraft on PM2.5 concentrations throughout northern Georgia, the differences resulting from use of AMSTERDAM's plume-in-grid process rather than a traditional CMAQ simulation, and the concentrations observed in aircraft plumes at sub-grid scales. Comparison of model results with an air quality monitor located in the vicinity of the airport found that normalized mean bias ranges from -77.5% to 6.2% and normalized mean error ranges from 40.4% to 77.5%, varying by species. Aircraft influence average PM2.5 concentrations by up to 0.232 μg m-3 near the airport and by 0.001-0.007 μg m-3 throughout the Atlanta metro area. The plume-in-grid process increases concentrations of secondary PM pollutants by 0.005-0.020 μg m-3 (compared to the traditional grid-based treatment) but reduces the concentration of non-reactive primary PM pollutants by up to 0.010 μg m-3, with changes concentrated near the airport. Examination of sub-grid scale results indicates that puffs within 20 km of the airport often have average PM2.5 concentrations one order of magnitude higher than aircraft contribution to the grid cells containing those puffs, and within 1-4 km of emitters, puffs may have PM2.5 concentrations 3 orders of magnitude greater than the aircraft contribution to their grid cells. 21% of all aircraft-related puffs from the Atlanta airport have at least 0.1 μg m-3 PM2.5 concentrations. Median daily puff concentrations vary between 0.017 and 0.134 μg m-3, while maximum daily puff concentrations vary between 6.1 and 42.1 μg m-3 during the 2-month period. In contrast, median daily grid concentrations vary between 0.015 and 0.091 μg m-3, while maximum daily grid concentrations vary between 0.751 and 2.55 μg m-3. Future researchers may consider using AMSTERDAM to understand the impacts of aircraft emissions at other airports, for proposed future airports, for airport expansion projects under various future scenarios, and for other national-scale studies specifically when the maximum impacts at fine scales are of interest

In and Out of Equilibrium II: Evolution in Repeated Games with Discounting and Complexity Costs

We explore evolutionary dynamics for repeated games with small, but positive complexity costs. To understand the dynamics, we extend a folk theorem result by Cooper (1996) to continuation probabilities, or discount rates, smaller than 1. While this result delineates which payoffs can be supported by neutrally stable strategies, the only strategy that is evolutionarily stable, and has a uniform invasion barrier, is All D. However, with sufficiently small complexity costs, indirect invasions - but now through 'almost neutral' mutants - become an important ingredient of the dynamics. These indirect invasions include stepping stone paths out of full defection

Cooperation, Norms, and Revolutions: A Unified Game-Theoretical Approach

Cooperation is of utmost importance to society as a whole, but is often challenged by individual self-interests. While game theory has studied this problem extensively, there is little work on interactions within and across groups with different preferences or beliefs. Yet, people from different social or cultural backgrounds often meet and interact. This can yield conflict, since behavior that is considered cooperative by one population might be perceived as non-cooperative from the viewpoint of another. To understand the dynamics and outcome of the competitive interactions within and between groups, we study game-dynamical replicator equations for multiple populations with incompatible interests and different power (be this due to different population sizes, material resources, social capital, or other factors). These equations allow us to address various important questions: For example, can cooperation in the prisoner's dilemma be promoted, when two interacting groups have different preferences? Under what conditions can costly punishment, or other mechanisms, foster the evolution of norms? When does cooperation fail, leading to antagonistic behavior, conflict, or even revolutions? And what incentives are needed to reach peaceful agreements between groups with conflicting interests? Our detailed quantitative analysis reveals a large variety of interesting results, which are relevant for society, law and economics, and have implications for the evolution of language and culture as well

The Rationality of Prejudices

We model an -player repeated prisoner's dilemma in which players are given traits (e.g., height, age, wealth) which, we assume, affect their behavior. The relationship between traits and behavior is unknown to other players. We then analyze the performance of “prejudiced” strategies—strategies that draw inferences based on the observation of some or all of these traits, and extrapolate the inferred behavior to other carriers of these traits. Such prejudiced strategies have the advantage of learning rapidly, and hence of being well adapted to rapidly changing conditions that might result, for example, from high migration or birth rates. We find that they perform remarkably well, and even systematically outperform both Tit-For-Tat and ALLD when the population changes rapidly

Neuromagnetic Evidence for Early Auditory Restoration of Fundamental Pitch

Background: Understanding the time course of how listeners reconstruct a missing fundamental component in an auditory stimulus remains elusive. We report MEG evidence that the missing fundamental component of a complex auditory stimulus is recovered in auditory cortex within 100 ms post stimulus onset. Methodology: Two outside tones of four-tone complex stimuli were held constant (1200 Hz and 2400 Hz), while two inside tones were systematically modulated (between 1300 Hz and 2300 Hz), such that the restored fundamental (also knows as ‘‘virtual pitch’’) changed from 100 Hz to 600 Hz. Constructing the auditory stimuli in this manner controls for a number of spectral properties known to modulate the neuromagnetic signal. The tone complex stimuli only diverged on the value of the missing fundamental component. Principal Findings: We compared the M100 latencies of these tone complexes to the M100 latencies elicited by their respective pure tone (spectral pitch) counterparts. The M100 latencies for the tone complexes matched their pure sinusoid counterparts, while also replicating the M100 temporal latency response curve found in previous studies. Conclusions: Our findings suggest that listeners are reconstructing the inferred pitch by roughly 100 ms after stimulus onset and are consistent with previous electrophysiological research suggesting that the inferential pitch is perceived i

The emergence of altruism as a social norm

Expectations, exerting influence through social norms, are a very strong candidate to explain how complex societies function. In the Dictator game (DG), people expect generous behavior from others even when they cannot enforce any sharing of the pie. Here we assume that people donate following their expectations, and that they update their expectation after playing a DG by reinforcement learning to construct a model that explains the main experimental results in the DG. Full agreement with the experimental results is reached when some degree of mismatch between expectations and donations is added into the model. These results are robust against the presence of envious agents, but affected if we introduce selfish agents that do not update their expectations. Our results point to social norms being on the basis of the generous behavior observed in the DG and also to the wide applicability of reinforcement learning to explain many strategic interactions

Reconstructing Speech from Human Auditory Cortex

Direct brain recordings from neurosurgical patients listening to speech reveal that the acoustic speech signals can be reconstructed from neural activity in auditory cortex