Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits

The economic benefits of reducing physical inactivity: an Australian example

Background: Physical inactivity has major impacts on health and productivity. Our aim was to estimate the health and economic benefits of reducing the prevalence of physical inactivity in the 2008 Australian adult population. The economic benefits were estimated as &lsquo;opportunity cost savings&rsquo;, which represent resources utilized in the treatment of preventable disease that are potentially available for re-direction to another purpose from fewer incident cases of disease occurring in communities.Methods: Simulation models were developed to show the effect of a 10% feasible, reduction target for physical inactivity from current Australian levels (70%). Lifetime cohort health benefits were estimated as fewer incident cases of inactivity-related diseases; deaths; and Disability Adjusted Life Years (DALYs) by age and sex. Opportunity costs were estimated as health sector cost impacts, as well as paid and unpaid production gains and leisure impacts from fewer disease events associated with reduced physical inactivity. Workforce production gains were estimated by comparing surveyed participation and absenteeism rates of physically active and inactive adults, and valued using the friction cost approach. The impact of an improvement in health status on unpaid household production and leisure time were modeled from time use survey data, as applied to the exposed and non-exposed population subgroups and valued by suitable proxy. Potential costs associated with interventions to increase physical activity were not included. Multivariable uncertainty analyses and univariate sensitivity analyses were undertaken to provide information on the strength of the conclusions.Results: A 10% reduction in physical inactivity would result in 6,000 fewer incident cases of disease, 2,000 fewer deaths, 25,000 fewer DALYs and provide gains in working days (114,000), days of home-based production (180,000) while conferring a AUD96 million reduction in health sector costs. Lifetime potential opportunity cost savings in workforce production (AUD12 million), home-based production (AUD71 million) and leisure-based production (AUD79 million) was estimated (total AUD162 million 95% uncertainty interval AUD136 million, AUD196 million).Conclusions: Opportunity cost savings and health benefits conservatively estimated from a reduction in population-level physical inactivity may be substantial. The largest savings will benefit individuals in the form of unpaid production and leisure gains, followed by the health sector, business and government.<br /

A Modelling Study of Indoor Air Chemistry: The Surface Interactions of Ozone and Hydrogen Peroxide

Indoor surfaces play a key role in indoor chemistry, including modification of indoor oxidant concentrations. This study utilises the INdoor CHEmical Model in Python (INCHEM-Py) to investigate the impact of surface transformations and their impact on indoor gas-phase chemistry. INCHEM-Py has been developed to simulate the surface deposition of ozone and hydrogen peroxide onto nine and six individual surfaces respectively in a typical bedroom, kitchen and office for normal indoor concentrations in the absence of household activities. The results show that 91 to 96% of these oxidants are deposited onto indoor surfaces under our simulated conditions. In the bedroom, 38 to 44% of indoor ozone and hydrogen peroxide is deposited onto soft fabric surfaces, with 41 to 54% of ozone deposition occurring on plastic surfaces in the kitchen and office. Total indoor concentrations of straight-chained aldehydes (C1-C10) ranged from 4 to 5 ppb, with nonanal having the highest individual concentration (1.7, 1.6 and 1.5 ppb in the bedroom, kitchen and office respectively), primarily as a result of emissions from plastics following ozone deposition. Aldehyde concentrations following hydrogen peroxide deposition were often less than 0.01 ppb. Understanding how reactions and deposition on different indoor surfaces impact indoor air chemistry will enable internal surface selection with a view to improving overall indoor air quality

The health and economic benefits of reducing intimate partner violence: an Australian example.

BACKGROUND: Intimate partner violence (IPV) has important impacts on the health of women in society. Our aim was to estimate the health and economic benefits of reducing the prevalence of IPV in the 2008 Australian female adult population. METHODS: Simulation models were developed to show the effect of a 5 percentage point absolute feasible reduction target in the prevalence of IPV from current Australian levels (27%). IPV is not measured in national surveys. Levels of psychological distress were used as a proxy for exposure to IPV since psychological conditions represent three-quarters of the disease burden from IPV. Lifetime cohort health benefits for females were estimated as fewer incident cases of violence-related disease and injury; deaths; and Disability Adjusted Life Years (DALYs). Opportunity cost savings were estimated for the health sector, paid and unpaid production and leisure from reduced incidence of IPV-related disease and deaths. Workforce production gains were estimated by comparing surveyed participation and absenteeism rates of females with moderate psychological distress (lifetime IPV exposure) against high or very high distress (current IPV exposure), and valued using the friction cost approach (FCA). The impact of improved health status on unpaid household production and leisure time were modelled from time use survey data. Potential costs associated with interventions to reduce IPV were not considered. Multivariable uncertainty analyses and univariable sensitivity analyses were undertaken. RESULTS: A 5 percentage point absolute reduction in the lifetime prevalence of IPV in the 2008 Australian female population was estimated to produce 6000 fewer incident cases of disease/injury, 74 fewer deaths, 5000 fewer DALYs lost and provide gains of 926,000 working days, 371,000 days of home-based production and 428,000 leisure days. Overall, AUD371 million in opportunity cost savings could be achievable. The greatest economic savings would be home-based production (AUD147 million), followed by leisure time (AUD98 million), workforce production (AUD94 million) and reduced health sector costs (AUD38 million). CONCLUSIONS: This study contributes new knowledge about the economic impact of IPV in females. The findings provide evidence of large potential opportunity cost savings from reducing the prevalence of IPV and reinforce the need to reduce IPV in Australia, and elsewhere

2017 GJMPP Monograph Series: Grace Jordan McFadden Professors Program

The Grace Jordan McFadden Professors Program (GJMPP), formerly the African American Professors Program (AAPP)/Carolina Diversity Professors Program (CDPP) at the University of South Carolina, is honored to publish its sixteenth edition of this annual monograph series. AAPP recognizes the significance of offering its scholars a venue through which to engage actively in research and to publish their refereed papers that continually contribute to their respective fields of study. Parallel with the publication of their manuscripts is the opportunity to gain visibility among colleagues throughout postsecondary institutions at national and international levels. Scholars who have contributed papers for this monograph are acknowledged for embracing the value of including this responsibility within their academic milieu. Writing across disciplines adds broadly to the intellectual diversity of these manuscripts. From neophytes to quite experienced individuals, the chapters have been researched and written in depth. Founded in 1997 through the Department of Educational Leadership and Policies in the College of Education, AAPP was designed originally to address the under-representation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored historically by the University of South Carolina, the W. K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits doctoral students for disciplines in which African Americans currently are underrepresented among faculty in higher education. The continuation of this monograph series is seen as responding to a window of opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, at the same time, to allow for the dissemination of products of scholarship to a broader community. The importance of this series has been voiced by one of our 2002 AAPP graduates, Dr. Shundelle LaTjuan Dogan, formerly an Administrative Fellow at Harvard University, a Program Officer for the Southern Education Foundation, and a Program Officer for the Arthur M. Blank Foundation in Atlanta, Georgia. She is currently a Corporate Citizenship and Corporate Affairs Manager for IBM-International Business Machines in Atlanta, Georgia and has written an impressive Foreword for the 2014 monograph. Dr. Dogan wrote: “One thing in particular that I want to thank you for is having the African American Professors Program scholars publish articles for the monograph. I have to admit that writing the articles seemed like extra work at the time. However, in my recent interview process, organizations have asked me for samples of my writing. Including an article from a published monograph helped to make my portfolio much more impressive. You were ‘right on target’ in having us do the monograph series” (AAPP 2003 Monograph, p. xi). The Grace Jordan McFadden Professors Program purports to advance the tradition of spearheading international scholarship in higher education as evidenced through inspiration from this group of interdisciplinary manuscripts. I hope that you will envision these published papers for serving as an invaluable contribution to your own professional and career enhancement. John McFadden, PhD The Benjamin Elijah Mays Distinguished Professor Emeritus Director, Grace Jordan McFadden Professors Program University of South Carolina Columbia, South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1004/thumbnail.jp

Diamond Line - Fall 2020

In following up the premier issue of The Diamond Line, the fall 2020 editorial staff had big shoes to fill. We took on the challenge of creating something that would uphold the framework of Issue 1 while simultaneously branching out from its margins. Like the editors before us, we had a vision, but ours took a new form — bright, warm colors. Sunset colors. Moons. Playful lines. Isolation and introspection. A stroll through an art gallery. A coming-of-age story bound between two groovy orange bookends. While Issue 2 does not have an overarching theme, we chose the cover art, “Pandemic Prom” by Autumn Blaylock, because it beautifully encompassed the pages within and the vision we were working toward

INCHEM-Py v1.2 : A community box model for indoor air chemistry

The Indoor CHEMical model in Python, INCHEM-Py, is an open-source and accessible box model for the simulation of the indoor atmosphere, and is a refactor and significant development of the INdoor Detailed Chemical Model (INDCM). INCHEM-Py creates and solves a system of coupled ordinary differential equations that include gas-phase chemistry, surface deposition, indoor/outdoor air change, indoor photolysis processes and gas-to-particle partitioning for three common terpenes. It is optimised for ease of installation and simple modification for inexperienced users, while also providing unfettered access to customise the physical and chemical processes for more advanced users. A detailed user manual is included with the model and updated with each version release. In this paper, INCHEM-Py v1.2 is introduced, the modelled processes are described in detail, with benchmarking between simulated data and published experimental results presented, alongside discussion of the parameters and assumptions used. It is shown that INCHEM-Py achieves excellent agreement with measurements from two experimental campaigns which investigate the effects of people and different surfaces on the concentrations of different indoor air pollutants. In addition, INCHEM-Py shows closer agreement to experimental data than INDCM. This is due to the increased functionality of INCHEM-Py to model additional processes, such as deposition-induced surface emissions. Published community use-cases of INCHEM-Py are also presented to show the variety of applications for which this model is valuable to further our understanding of indoor air chemistry

INCHEM-Py v1.2: a community box model for indoor air chemistry

The Indoor CHEMical model in Python, INCHEM-Py, is an open-source and accessible box model for the simulation of the indoor atmosphere, and is a refactor and significant development of the INdoor Detailed Chemical Model (INDCM). INCHEM-Py creates and solves a system of coupled ordinary differential equations that include gas-phase chemistry, surface deposition, indoor/outdoor air change, indoor photolysis processes and gas-to-particle partitioning for three common terpenes. It is optimised for ease of installation and simple modification for inexperienced users, while also providing unfettered access to customise the physical and chemical processes for more advanced users. A detailed user manual is included with the model and updated with each version release. In this paper, INCHEM-Py v1.2 is introduced, the modelled processes are described in detail, with benchmarking between simulated data and published experimental results presented, alongside discussion of the parameters and assumptions used. It is shown that INCHEM-Py achieves excellent agreement with measurements from two experimental campaigns which investigate the effects of people and different surfaces on the concentrations of different indoor air pollutants. In addition, INCHEM-Py shows closer agreement to experimental data than INDCM. This is due to the increased functionality of INCHEM-Py to model additional processes, such as deposition-induced surface emissions. Published community use-cases of INCHEM-Py are also presented to show the variety of applications for which this model is valuable to further our understanding of indoor air chemistry

A numerical approach to finding general stationary vacuum black holes

The Harmonic Einstein equation is the vacuum Einstein equation supplemented by a gauge fixing term which we take to be that of DeTurck. For static black holes analytically continued to Riemannian manifolds without boundary at the horizon this equation has previously been shown to be elliptic, and Ricci flow and Newton's method provide good numerical algorithms to solve it. Here we extend these techniques to the arbitrary cohomogeneity stationary case which must be treated in Lorentzian signature. For stationary spacetimes with globally timelike Killing vector the Harmonic Einstein equation is elliptic. In the presence of horizons and ergo-regions it is less obviously so. Motivated by the Rigidity theorem we study a class of stationary black hole spacetimes, considered previously by Harmark, general enough to include the asymptotically flat case in higher dimensions. We argue the Harmonic Einstein equation consistently truncates to this class of spacetimes giving an elliptic problem. The Killing horizons and axes of rotational symmetry are boundaries for this problem and we determine boundary conditions there. As a simple example we numerically construct 4D rotating black holes in a cavity using Anderson's boundary conditions. We demonstrate both Newton's method and Ricci flow to find these Lorentzian solutions.Comment: 43 pages, 7 figure