Novel Mechanisms Regulating Dopamine Transporter Endocytic Trafficking: Ack1-Controlled Endocytosis And Retromer-Mediated Recycling

Dopamine transporters (DAT) facilitate high-affinity presynaptic dopamine (DA) reuptake in the central nervous system, and are required to constrain extracellular DA levels and maintain presynaptic DAergic tone. DAT is the primary target for addictive and therapeutic psychostimulants, which require DAT binding to elicit reward. DAT availability at presynaptic terminals ensures its proper function, and is dynamically regulated by endocytic trafficking. My thesis research focused on two fundamental questions: 1) what are the molecular mechanisms that control DAT endocytosis? and 2) what are the mechanism(s) that govern DAT’s post-endocytic fate? Using pharmacological and genetic approaches, I discovered that a non-receptor tyrosine kinase, activated by cdc42 kinase 1 (Ack1), stabilizes DAT plasma membrane expression by negatively regulating DAT endocytosis. I found that stimulated DAT endocytosis absolutely requires Ack1 inactivation. Moreover, I was able to restore normal DAT endocytosis to a trafficking dysregulated DAT coding variant identified in an Attention Deficit Hyperactivity Disorder (ADHD) patient via constitutively activating Ack1. To address what mechanisms govern DAT’s post-endocytic fate, I took advantage of a small molecule labeling approach to directly couple fluorophore to the DAT surface population, and subsequently tracked DAT’s temporal-spatial post-endocytic itinerary in immortalized mesencephalic cells. Using this approach, I discovered that the retromer complex mediates DAT recycling and is required to maintain DAT surface levels via a DAT C-terminal PDZ-binding motif. Taken together, these findings shed considerable new light on DAT trafficking mechanisms, and pave the way for future studies examining the role of regulated DAT trafficking in neuropsychiatric disorders

Minimum profile Hellinger distance estimation for a semiparametric mixture model

In this paper, we propose a new effective estimator for a class of semiparametric mixture models where one component has known distribution with possibly unknown parameters while the other component density and the mixing proportion are unknown. Such semiparametric mixture models have been often used in multiple hypothesis testing and the sequential clustering algorithm. The proposed estimator is based on the minimum profile Hellinger distance (MPHD), and its theoretical properties are investigated. In addition, we use simulation studies to illustrate the finite sample performance of the MPHD estimator and compare it with some other existing approaches. The empirical studies demonstrate that the new method outperforms existing estimators when data are generated under contamination and works comparably to existing estimators when data are not contaminated. Applications to two real data sets are also provided to illustrate the effectiveness of the new methodology

GIS-based Economic Cost Estimation of Traffic Accidents in St. Louis, Missouri

AbstractThe economic loss due to total traffic accidents in St. Louis remains high every year. This paper presents an effective approach to spatially identifying potential casualty areas and their economic losses. In this study, five years of traffic accident data, from 2007 to 2011, collected in the City of St. Louis and the adjacent counties, is used. Using Geographic Information System (GIS)-based techniques, e.g. Kernel Density Estimation (KDE), two maps are generated and compared: 1) traffic accident rate map based on the number of traffic accidents per year and 2) the economic costs map. The locations with high economic costs but with low accident rates are identified and shown in a 3-D visualization format. The results can be used as a foundation for the traffic accident cost estimation related research and serves as a guideline for practitioners to investigate the areas with high traffic accident severity levels

Sound Perception of Blind Older Adults in Nursing Homes

The number of blind older adults is gradually increasing with the aging of world’s population, and their needs and perception of sound are specific. This study investigated the behavioral activities of blind older adults and the dominant sound sources through on-site observation of an all-blind nursing home in China, and it used semi-structured interviews to obtain the sound perceptions of blind older adults. The findings showed that the daily behavioral activities can be categorized into basic living activity, leisure activity, social activity; and physical activity. The dominant sound sources included human, equipment, informational, and environmental sounds. This study developed a sound perception model of blind older adults in nursing homes, which takes three levels: sound requirements, acoustic environment, and sound cognition. Firstly, the blind older adults have a basic understanding of sound from the perspective of their living needs, then they feel the sound environment from the perspective of the living environment, and finally, they perceive the acoustic environment from the dimension of sound cognition in conjunction with contextual memory. This study sheds a light on the aural diversity of older adults, which is expected to support the inclusive design of nursing homes for older adults with visual impairments

Pharmaceutical approaches for COVID-19: An update on current therapeutic opportunities

SARS-CoV-2, a newly discovered coronavirus, has been linked to the COVID-19 pandemic and is currently an important public health issue. Despite all the work done to date around the world, there is still no viable treatment for COVID-19. This study examined the most recent evidence on the efficacy and safety of several therapeutic options available including natural substances, synthetic drugs and vaccines in the treatment of COVID-19. Various natural compounds such as sarsapogenin, lycorine, biscoclaurine, vitamin B12, glycyrrhizic acid, riboflavin, resveratrol and kaempferol, various vaccines and drugs such as AZD1222, mRNA-1273, BNT162b2, Sputnik V, and remdesivir, lopinavir, favipiravir, darunavir, oseltamivir, and umifenovir, resp., have been discussed comprehensively. We attempted to provide exhaustive information regarding the various prospective therapeutic approaches available in order to assist researchers and physicians in treating COVID-19 patients

Understanding Contextual Differences in Residential LTC Provision for Cross-National Research : Identifying Internationally Relevant CDEs

Long-term care (LTC) reflects a growing emphasis on person-centered care (PCC), with services oriented around individuals' needs and preferences. Addressing contextual and cultural differences across countries offers important insight into factors that facilitate or hinder application of PCC practices within and across countries. This article takes an international lens to consider country-specific contexts of LTC, describing preliminary steps to develop common data elements that capture contextual differences across LTC settings globally. Through an iterative series of online, telephone, and in-person sessions, we engaged in in-depth discussions with 11 colleague experts in residential LTC and coauthors from six countries (China and Hong Kong, England, Sweden, Thailand, Trinidad and Tobago, and the United States). Our discussions yielded rich narrative describing a vast range in types of LTC settings, leading to our development of a working definition of residential LTC. Scope of services, funding, ownership, and regulations varied greatly across countries and across different residential LTC settings within countries. Moving forward, we recommend expanding our activities to countries that reflect different stages of residential LTC development. Our goal is to contribute to a larger initiative underway by the WE-THRIVE consortium to establish a global research measurement infrastructure that advances PCC internationally.Peer reviewe

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant

The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or endocytic brake, controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA-mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC-stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation

Searching for Radio Outflows from M31* with VLBI Observations

As one of the nearest and most dormant supermassive black holes (SMBHs), M31* provides a rare but promising opportunity for studying the physics of black hole accretion and feedback at the quiescent state. Previous Karl G. Jansky Very Large Array (VLA) observations with an arcsec resolution have detected M31* as a compact radio source over centimeter wavelengths, but the steep radio spectrum suggests optically-thin synchrotron radiation from an outflow driven by a hot accretion flow onto the SMBH. Aiming to probe the putative radio outflow, we have conducted milli-arcsec-resolution very long baseline interferometric (VLBI) observations of M31* in 2016, primarily at 5 GHz and combining the Very Long Baseline Array, Tianma-65m and Shanghai-25m Radio Telescopes. Despite the unprecedented simultaneous resolution and sensitivity achieved, no significant ($\gtrsim 3\sigma$) signal is detected at the putative position of M31* given an RMS level of $\rm 5.9~\mu Jy\ beam^{-1}$, thus ruling out a point-like source with a peak flux density comparable to that ($\sim30~\mu Jy\ beam^{-1}$) measured by the VLA observations taken in 2012. We disfavor the possibility that M31* has substantially faded since 2012, in view that a 2017 VLA observation successfully detected M31* at a historically-high peak flux density ($\sim75~\mu Jy\ beam^{-1}$ at 6 GHz). Instead, the non-detection of the VLBI observations is best interpreted as the arcsec-scale core being resolved out at the milli-arcsec-scale, suggesting an intrinsic size of M31* at 5 GHz larger than $\sim300$ times the Schwarzschild radius. Such extended radio emission may originate from a hot wind driven by the weakly accreting SMBH.Comment: 9 pages, 2 figures. Accepted for publication in the Astrophysical Journa

(Section A: Planning Strategies and Design Concepts)

This paper uses four years of ecosystem classification data, from 2000, 2005, 2010 and 2015, to analyse the spatiotemporal variation characteristics of the ecosystems of counties and cities in the Min Delta urban agglomeration over 15 years across four aspects, including changes in the ecosystem area for each period, a transfer matrix of the counties and cities, the comprehensive dynamic ecosystem index, and the forces driving these changes. The results show that: (1) from 2000 to 2015, the total area of farmland, forest and shrub ecosystems in the Min Delta urban agglomeration decreased, while the total area of urban, wetland and grassland ecosystems has increased. There are spatiotemporal differences and patterns in the area change and transfer of various ecosystems. The series of scales and proportion of ecosystem types in the counties and cities of the Min Triangle show that there is a two-way transfer between farmland and urban ecosystems. In addition, there are spatiotemporal differences in the transfer of these two ecosystems. Forest ecosystems are transferred into farmland, urban and grassland ecosystems at different levels. In the eastern part of the Min Triangle, wetlands are mostly transferred to urban ecosystems, and the western regions are mostly transferred to forests and farmland. (2) For the comprehensive dynamic index of the Min Delta urban agglomeration, from 2000 to 2015, the degree of ecosystem dynamics was higher in each period than the previous, and the dynamics in the eastern and central parts were higher than those in the west and south for the same period. From 2000 to 2005, the comprehensive dynamic index was below 0.2%. The dynamic index of Longhai in Xiamen and Zhangzhou increased significantly from 2005 to 2010 from that of the previous period, and their values all exceeded 0.9%. From 2010 to 2015, the area with a large change in the dynamic index expanded to the east and south from the central area of Xiamen. The dynamics in the northwest did not sufficiently increase. (3) The GDP, value of agricultural production, forestry, and fisheries, secondary and tertiary industries, urbanization rate, and permanent residents are important factors influencing ecosystems. The driving effects of these socioeconomic indicators and urban population development have different degrees of significance on farmland, urban, forest and wetland ecosystems during different periods of the Delta\u27s urban agglomeration