CHRONIC LOW INTENSITY CONTINUOUS AND INTERVAL TRAINING PREVENT HEART FAILURE-RELATED CORONARY ARTERY STIFFNESS

Heart failure (HF) induced by aortic pressure over-load is associated with increased coronary artery stiffness. Perivascular adipose tissue (PVAT) and advanced glycation end products (AGE) both promote arterial stiffness. However, the mechanisms by which coronary PVAT promotes arterial stiffness and the efficacy of exercise to prevent coronary stiffness are unknown. The present study hypothesized both chronic continuous and interval exercise training would prevent coronary artery stiffness associated with inhibition of PVAT secreted AGE. Yucatan mininature swine were divided into four groups: control-sedentary (CON), aortic-banded sedentary heart failure (HF), aortic-banded HF continuous exercise trained (HF+CONT), and aortic-banded HF interval exercise trained (HF+IT). Coronary artery stiffness was assessed by ex vivo mechanical testing and coronary artery elastin, collagen and AGE-related proteins were assessed by immunohistochemistry. HF promoted coronary artery stiffness with reduced elastin content and greater AGE accumulation which was prevented by chronic continuous and interval exercise training. HF PVAT secreted higher AGE compared with CON and was prevented in the HF+CONT and HF+IT groups. Young healthy mouse aortas cultured in HF PVAT conditioned media had increased stiffness, lower elastin content and AGE accumulation compared with CON, which was prevented by PVAT from the HF+CONT and HF+IT groups. HF coronary PVAT secreted greater interleukin-6 (IL-6) and IL-8 compared to CON which was prevented by both continuous and interval exercise training regimens. We conclude chronic continuous and interval exercise is a potential therapeutic strategy to prevent coronary artery stiffness via inhibition of PVAT-derived AGE secretion in a pre-clinical mini-swine model of pressure overload-induced HF

Performance Analysis of a Dual-Hop Cooperative Relay Network with Co-Channel Interference

This paper analyzes the performance of a dual-hop amplify-and-forward (AF) cooperative relay network in the presence of direct link between the source and destination and multiple co-channel interferences (CCIs) at the relay. Specifically, we derive the new analytical expressions for the moment generating function (MGF) of the output signal-to-interference-plus-noise ratio (SINR) and the average symbol error rate (ASER) of the relay network. Computer simulations are given to confirm the validity of the analytical results and show the effects of direct link and interference on the considered AF relay network

Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission

Background: Recently, a number of antibodies capable of broadly neutralizing HIV have been isolated from HIV infected patients, stimulating efforts to develop vaccines capable of eliciting their production in naive individuals. As an alternative to vaccination, we recently described vectored immunoprophylaxis (VIP) as an approach capable of generating high serum concentrations of a desired monoclonal antibody in mice following a single intramuscular injection of a specialized adeno associated viral vector (AAV). Mice that received VIP encoding b12 and VRC01 antibodies demonstrated long-term circulating antibody expression in serum, and VIP-treated humanized mice exhibited remarkable protection against high dose, intravenous challenge with CXCR4-tropic HIV. However, most human infections are initiated by transmission of CCR5- tropic strains through mucosal tissues. Methods: To measure the efficacy of VIP against clinically relevant strains, we humanized VIP-treated mice by adoptive transfer of peripheral blood mononuclear cells (PBMC) and challenged these animals with CCR5-tropic HIV strains including JR-CSF, as well as REJO.c, a transmitted molecular founder. To determine the ability of VIP to prevent mucosal transmission of HIV, we developed a repetitive intravaginal challenge model in VIP-treated BLT humanized mice that were challenged weekly with JR-CSF and monitored for infection. Results: PBMC humanized mice expressing either b12 or VRC01 were protected from intravenous challenge with JR-CSF. In contrast, the b12-resistant REJO.c strain readily infected PBMC humanized mice expressing b12 antibody, while mice expressing VRC01 demonstrated nearly complete protection following challenge. Intravaginally challenged BLT animals expressing a luciferase negative control protein all became infected over the study period while a majority of animals expressing VRC01 had no detectable HIV infection despite fourteen intravaginal challenges with JR-CSF. Conclusion: VIP is capable of protecting humanized mice from challenge by diverse HIV strains and can substantially inhibit mucosal transmission. These findings warrant continued development of VIP as a novel approach for HIV prevention in humans

Positioning, Planning and Operation of Emergency Response Resources and Coordination between Jurisdictions

Railroad related rail incidents, particularly those involving hazardous material (hazmat), cause severe consequences and pose significant threats to safety, public health and the environment. Rail safety is a huge issue in Midwestern states such as Illinois, Wisconsin, and Minnesota. This project aims at strategically positioning and allocating emergency responders and resources in anticipation of potential accidents in a region that may be impacted by rail incidents. Mathematical models and solution techniques are developed to enable systematic analysis of the emergency response system associated with railroad incidents; e.g., to strategically position and allocate emergency responders and resources in anticipation of potential accidents along spatially distributed railroad networks. We consider the added complexity due to vulnerability of the emergency response system itself, such as the risk of disruptions to the transportation network for first-responders (e.g., blockage of railroad crossings). The outcomes from these tasks will provide fundamental understanding, operational guidelines, and practical tools to policy makers (e.g., federal and state agencies) to induce socio-economically favorable system that support safe and efficient railroad industry operations

Durable Suppression of Established Transmitted Founder Replication in Infected BLT Humanized Mice by Vectored Immuno Therapy

Recent reports in humanized mice and monkeys have found that broadly neutralizing antibodies (bNAbs) can suppress the replication of laboratory strains of HIV and SHIV while bNAb concentration remains high. Vectored ImmunoProphylaxis (VIP) results in long-lived bNAb expression following a single intramuscular {IM) injection of a specialized viral vector, and this approach has been demonstrated as a means of durably suppressing viral load. However, previous reports of VIP-delivered bNAbs for HIV therapy required prior antiretroviral drug therapy to reduce viral load to prevent escape. Methods: Humanized BLT mice were infected IV with the REJO.c transmitted molecular founder strain of HIV. A low dose of combination antiretroviral therapy (ART) was administered to these animals for 5 weeks, followed by a single IM injection of VIP expressing VRC07 or luciferase. Mouse plasma was analyzed by ELISA to determine antibody concentration and by qPCR to determine viral load. Cellular fractions were analyzed by flow cytometry to quantify human CD4 cells over time. After sacrifice, plasma was subjected to a clinically validated ultrasensitive PCR-based viral load assay. Results: We detected viral loads of 10^5 copies/mL in infected mice prior to low-dose ART treatment, which resulted in a transient reduction and rebound to pre-therapy loads. Following VIP administration, we observed a rapid increase in the blood concentration of VRC07. Mice expressing VRC07 exhibited a sharp decline in viral load to undetectable levels and an increase in CD4 cells over four weeks and this effect was sustained for the remaining 8 weeks of the study. In contrast, mice expressing luciferase exhibited increasing viral loads with concomitant decreases in CD4 cells throughout the study. Conclusions: Our results demonstrate that VIP expressing VRC07 is sufficient to suppress actively replicating transmitted founder virus at high viral load and support efforts to move Vectored Immuno Therapy into clinical trials with infected patients