Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact

Following its evoked release, DA signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DAT. DAT surface availability is dynamically regulated by endocytic trafficking, and direct PKC activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals, or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation, and that the DAT N-terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization, and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What’s to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment

A qualitative exploration of facilitators and barriers of adherence to time-restricted eating

Time-restricted eating (TRE), a dietary strategy that involves limiting daily energy intake to a window of ≤12 h is appealing for weight management and metabolic health due to its relative simplicity and the ability to consume ad libitum diet during eating windows. Despite the potential utility of TRE for improving health and reducing disease, the feasibility of adherence depends upon a variety of multilevel factors which are largely unexplored. The primary aim of our study was to explore facilitators and barriers of adherence to TRE among community-dwelling individuals. Semi-structured qualitative interviews were conducted among 24 individuals (50% male; M age: 34, range: 18-57; 58% overweight/obese) who currently or formerly practiced TRE. Thematic analysis identified facilitators of and barriers to TRE adherence at multiple levels of influence (i.e., biological, behavioral, psychosocial, environmental). Key facilitators of adherence included improvements in physical health and energy levels, alignment with other aspects of diet, exercise and sleep patterns, self-monitoring and positive psychological impacts, social support, and busy or regular schedules. Key barriers included negative physical health effects, feelings of hunger and sluggishness, difficulty in skipping valued baseline eating routines or inadequate diet quality during the eating window, misalignment of TRE with 24-h activity behaviors, difficulties with self-monitoring, the need to mitigate negative feelings, social situations that discourage TRE, and irregular or idle schedules. Results illustrate that key drivers of adherence differ across individuals and their unique settings and that multiple drivers of behavior should be considered in the successful implementation of TRE. Findings may inform interventions seeking to tailor TRE schedules to fit individuals\u27 diverse behavioral patterns and preferences, thereby optimizing adherence

Local vanadium release from a calcium sulfate carrier accelerates fracture healing.

This study evaluated the efficacy of using calcium sulfate (CaSO4 ) as a carrier for intramedullary delivery of an organic vanadium salt, vanadyl acetylacetonate (VAC) after femoral fracture. VAC can act as an insulin-mimetic and can be used to accelerate fracture healing in rats. A heterogenous mixture of VAC and CaSO4 was delivered to the fracture site of BB Wistar rats, and mechanical testing, histomorphometry, micro-computed tomography (micro-CT) were performed to measure healing. At 4 weeks after fracture, maximum torque to failure, effective shear modulus, and effective shear stress were all significantly higher (p \u3c 0.05) in rats treated with 0.25 mg/kg VAC-CaSO4 as compared to carrier control rats. Histomorphometry found a 71% increase in percent cartilage matrix (p \u3c 0.05) and a 64% decrease in percent mineralized tissue (p \u3c 0.05) at 2 weeks after fracture in rats treated with 0.25 mg/kg of VAC-CaSO4 . Micro-CT analyses at 4 weeks found a more organized callus structure and higher trending maximum connected z-ray. fraction for VAC-CaSO4 groups. Evaluation of radiographs and serial histological sections at 12 weeks did not show any evidence of ectopic bone formation. As compared to previous studies, CaSO4 was an effective carrier for reducing the dose of VAC required to accelerate femoral fracture healing in rats

Trends in diabetes incidence among 7 million insured adults, 2006-2011: the SUPREME-DM project

An observational cohort analysis was conducted within the Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) DataLink, a consortium of 11 integrated health-care delivery systems with electronic health records in 10 US states. Among nearly 7 million adults aged 20 years or older, we estimated annual diabetes incidence per 1,000 persons overall and by age, sex, race/ethnicity, and body mass index. We identified 289,050 incident cases of diabetes. Age- and sex-adjusted population incidence was stable between 2006 and 2010, ranging from 10.3 per 1,000 adults (95% confidence interval (CI): 9.8, 10.7) to 11.3 per 1,000 adults (95% CI: 11.0, 11.7). Adjusted incidence was significantly higher in 2011 (11.5, 95% CI: 10.9, 12.0) than in the 2 years with the lowest incidence. A similar pattern was observed in most prespecified subgroups, but only the differences for persons who were not white were significant. In 2006, 56% of incident cases had a glycated hemoglobin (hemoglobin A1c) test as one of the pair of events identifying diabetes. By 2011, that number was 74%. In conclusion, overall diabetes incidence in this population did not significantly increase between 2006 and 2010, but increases in hemoglobin A1c testing may have contributed to rising diabetes incidence among nonwhites in 2011

Prevalence of chronic kidney disease among individuals with diabetes in the SUPREME-DM Project, 2005-2011

AIMS: Diabetes is a leading cause of chronic kidney disease (CKD). Different methods of CKD ascertainment may impact prevalence estimates. We used data from 11 integrated health systems in the United States to estimate CKD prevalence in adults with diabetes (2005-2011), and compare the effect of different ascertainment methods on prevalence estimates. METHODS: We used the SUPREME-DM DataLink (n = 879,312) to estimate annual CKD prevalence. Methods of CKD ascertainment included: diagnosis codes alone, impaired estimated glomerular filtration rate (eGFR) alone (eGFR \u3c 60 mL/min/1.73 m(2)), albuminuria alone (spot urine albumin creatinine ratio \u3e 30 mg/g or equivalent), and combinations of these approaches. RESULTS: CKD prevalence was 20.0% using diagnosis codes, 17.7% using impaired eGFR, 11.9% using albuminuria, and 32.7% when one or more method suggested CKD. The criteria had poor concordance. After age- and sex-standardization to the 2010 U.S. Census population, prevalence using diagnosis codes increased from 10.7% in 2005 to 14.3% in 2011 (P \u3c 0.001). The prevalence using eGFR decreased from 9.7% in 2005 to 8.6% in 2011 (P \u3c 0.001). CONCLUSIONS: Our data indicate that CKD prevalence and prevalence trends differ according to the CKD ascertainment method, highlighting the necessity for multiple sources of data to accurately estimate and track CKD prevalence

Incidence Rates of Childhood Asthma with Recurrent Exacerbations in the U.S. Environmental influences on Child Health Outcomes (ECHO) Program

BACKGROUND: Descriptive epidemiological data on incidence rates (IRs) of asthma with recurrent exacerbations (ARE) are sparse. OBJECTIVE: We hypothesized that IRs for ARE would vary by time, geography, age, race and ethnicity, irrespective of parental asthma history. METHODS: We leveraged data from 17246 children born after 1990 enrolled in 59 U.S. and one Puerto Rican cohort in the Environmental Influences on Child Health Outcomes consortium to estimate IRs for AREs. RESULTS: The overall crude IR for ARE was 6.07/1000 person-years (95% confidence intervals (CI) 5.63, 6.51) and was highest for children age 2-4 years, for Hispanic and non-Hispanic Black children and for those with a parental history of asthma. ARE IRs were higher for 2-4 year olds in each race and ethnicity category and for both sexes. Multi-variable analysis confirmed higher adjusted ARE IRs (aIRR) for children born 2000-2009 compared to 1990-1999 and 2010-2017, 2-4 versus 10-19 years old (aIRR=15.36; CI 12.09, 2.99), and for males versus females (aIRR=1.34; CI 1.16, 1.55). Black children (non-Hispanic and Hispanic) had higher rates than non-Hispanic White children (aIRR=2.51; CI 2.10, 2.99 and aIRR=2.04; CI 1.22, 3.39, respectively). Children born in the Midwest, Northeast and South had higher rates than the West (p\u3c0.01 for each comparison). Children with a parental history of asthma had rates nearly three times higher than those without such history (aIRR=2.90; CI 2.43-3.46). CONCLUSIONS: Factors associated with time, geography, age, race and ethnicity, sex and parental history appear to influence the inception of ARE among children and adolescents