Blood transcriptome responses to PFOA and GenX treatment in the marsupial biomedical model Monodelphis domestica

Introduction: Perfluoroalkyl and poly-fluoroalkyl substances (PFASs) are widely used in industrial and consumer products. Due to their environmental persistence and bioaccumulation, PFASs can be found in the blood of humans and wild animals all over the world. Various fluorinated alternatives such as GenX have been developed to replace the long-chain PFASs, but there is limited information about their potential toxicity. Methods:The current study developed blood culture protocols to assess the response to toxic compounds in the marsupial, Monodelphis domestica. After whole-blood culture conditions were tested and optimized, changes in gene expression in response to PFOA and GenX treatment were assessed. Results: More than 10,000 genes were expressed in the blood transcriptomes with and without treatment. Both PFOA and GenX treatment led to significant changes in the whole blood culture transcriptomes. A total of 578 and 148 differentially expressed genes (DEGs) were detected in the PFOA and GenX treatment groups, 32 of which overlapped. Pathway enrichment analysis revealed that DEGs involved in developmental processes were upregulated after PFOA exposure, while those enriched for metabolic and immune system processes were downregulated. GenX exposure upregulated genes associated with fatty acid transport pathways and inflammatory processes, which is consistent with previous studies using rodent models. Discussion: To our knowledge, this study is the first to investigate the effect of PFASs in a marsupial model. The findings provide supportive evidence for significant transcriptomic alterations, suggesting that this mammalian model may provide a mechanism for exploring the potential toxicity of PFOA and GenX

The GPS Space Service Volume

Prior to the advent of artificial satellites, the concept of navigating in space and the desire to understand and validate the laws of planetary and satellite motion dates back centuries. At the initiation of orbital flight in 1957, space navigation was dominated by inertial and groundbased tracking methods, underpinned by the laws of planetary motion. It was early in the 1980s that GPS was first explored as a system useful for refining the position, velocity, and timing (PVT) of other spacecraft equipped with GPS receivers. As a result, an entirely new GPS utility was developed beyond its original purpose of providing PVT services for land, maritime, and air applications. Spacecraft both above and below the GPS constellation now receive the GPS signals, including the signals that spill over the limb of the Earth. The use of radionavigation satellite services for space navigation in High Earth Orbits is in fact a capability unique to GPS. Support to GPS space applications is being studied and planned as an important improvement to GPS. This paper discusses the formalization of PVT services in space as part of an overall GPS improvement effort. It describes the GPS Space Service Volume (SSV) and compares it to the Terrestrial Service Volume (TSV). It also discusses SSV coverage with the current GPS constellation, coverage characteristics as a function of altitude, expected power levels, and coverage figures of merit

Lymphocyte Levels of GRK2 (βARK1) Mirror Changes in the LVAD-Supported Failing Human Heart: Lower GRK2 Associated With Improved β-Adrenergic Signaling After Mechanical Unloading

Background In human heart failure, increased expression of G protein–coupled receptor kinases (GRKs) causes the loss of β-adrenergic receptor (βAR) signaling and function. Mechanical unloading with a left ventricular assist device (LVAD) promotes reverse remodeling, which includes restoration of βAR responsiveness. We tested the hypothesis that LVAD support of the failing human heart alters the expression and activity of GRKs and we sought to determine whether changes in myocardial GRKs could be tracked in lymphocytes. Methods and Results Paired samples of human LV tissue (n = 12) and blood were obtained at the time of LVAD implantation (heart failure) and subsequent cardiac transplantation (LVAD). βAR signaling was quantified by receptor density and adenylyl cyclase activity. Immunoblotting and real-time reverse transcription polymerase chain reaction were used to measure GRK2 and GRK5 protein and mRNA levels. Rhodopsin phosphorylation was used to assess total GRK activity. Consistent with reverse remodeling, βAR density and signaling were restored to nonfailing levels after LVAD support. GRK2 protein levels were significantly reduced 55% after LVAD support and GRK2 mRNA was similarly reduced. In contrast, GRK5 protein and mRNA levels were unchanged. Total myocardial GRK activity was reduced similar to the drop in GRK2 expression. In lymphocytes, GRK2 protein levels were decreased after LVAD support and there was a significant positive correlation between myocardial and lymphocyte GRK2 levels in both heart failure and LVAD samples. Conclusion The changes in myocardial GRK2 expression and activity that are mirrored in lymphocytes provide a possible mechanism for the restoration of βAR signaling and reverse remodeling after mechanical unloading in the failing heart. Moreover, lymphocytes may provide a surrogate marker of myocardial GRK2 in these patients

A novel protective effect of erythropoietin in the infarcted heart

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart