Pharmacological analysis of transmission activation of two aphid-vectored plant viruses, turnip mosaic virus and cauliflower mosaic virus

Turnip mosaic virus (TuMV, family Potyviridae) and cauliflower mosaic virus (CaMV, family Caulimoviridae) are transmitted by aphid vectors. They are the only viruses shown so far to undergo transmission activation (TA) immediately preceding plant-to-plant propagation. TA is a recently described phenomenon where viruses respond to the presence of vectors on the host by rapidly and transiently forming transmissible complexes that are efficiently acquired and transmitted. Very little is known about the mechanisms of TA and on whether such mechanisms are alike or distinct in different viral species. We use here a pharmacological approach to initiate the comparison of TA of TuMV and CaMV. Our results show that both viruses rely on calcium signaling and reactive oxygen species (ROS) for TA. However, whereas application of the thiol-reactive compound N-ethylmaleimide (NEM) inhibited, as previously shown, TuMV transmission it did not alter CaMV transmission. On the other hand, sodium azide, which boosts CaMV transmission, strongly inhibited TuMV transmission. Finally, wounding stress inhibited CaMV transmission and increased TuMV transmission. Taken together, the results suggest that transmission activation of TuMV and CaMV depends on initial calcium and ROS signaling that are generated during the plant's immediate responses to aphid manifestation. Interestingly, downstream events in TA of each virus appear to diverge, as shown by the differential effects of NEM, azide and wounding on TuMV and CaMV transmission, suggesting that these two viruses have evolved analogous TA mechanisms

Cellular Postconditioning: Allogeneic Cardiosphere-Derived Cells Reduce Infarct Size and Attenuate Microvascular Obstruction When Administered After Reperfusion in Pigs With Acute Myocardial Infarction

Intracoronary (IC) delivery of cardiosphere-derived cells (CDCs) has been demonstrated to be safe and effective in porcine and human chronic myocardial infarction (MI). However, IC delivery of CDCs after reperfusion in acute MI has never been assessed in a clinically-relevant large animal model. We tested CDCs as adjunctive therapy to reperfusion in a porcine model of MI

Cardiosphere-Derived Cells Reverse Heart Failure With Preserved Ejection Fraction in Rats by Decreasing Fibrosis and Inflammation

The pathogenesis of heart failure with a preserved ejection fraction (HFpEF) is unclear. Myocardial fibrosis, inflammation, and cardiac hypertrophy have been suggested to contribute to the pathogenesis of HFpEF. Cardiosphere-derived cells (CDCs) are heart-derived cell products with antifibrotic and anti-inflammatory properties. This study tested whether rat CDCs were sufficient to decrease manifestations of HFpEF in hypertensive rats. Starting at 7 weeks of age, Dahl salt-sensitive rats were fed a high-salt diet for 6 to 7 weeks and randomized to receive intracoronary CDCs or placebo. Dahl rats fed normal chow served as controls. High-salt rats developed hypertension, left ventricular (LV) hypertrophy, and diastolic dysfunction, without impairment of ejection fraction. Four weeks after treatment, diastolic dysfunction resolved in CDC-treated rats but not in placebo. The improved LV relaxation was associated with lower LV end-diastolic pressure, decreased lung congestion, and enhanced survival in CDC-treated rats. Histology and echocardiography revealed no decrease in cardiac hypertrophy after CDC treatment, consistent with the finding of sustained, equally-elevated blood pressure in CDC- and placebo-treated rats. Nevertheless, CDC treatment decreased LV fibrosis and inflammatory infiltrates. Serum inflammatory cytokines were likewise decreased after CDC treatment. Whole-transcriptome analysis revealed that CDCs reversed changes in numerous transcripts associated with HFpEF, including many involved in inflammation and/or fibrosis. These studies suggest that CDCs normalized LV relaxation and LV diastolic pressure while improving survival in a rat model of HFpEF. The benefits of CDCs occurred despite persistent hypertension and cardiac hypertrophy. By selectively reversing inflammation and fibrosis, CDCs may be beneficial in the treatment of HFpEF

Phenotypic plasticity in evolutionary rescue experiments

Population persistence in a new and stressful environment can be influenced by the plastic phenotypic responses of individuals to this environment, and by the genetic evolution of plasticity itself. This process has recently been investigated theoretically, but testing the quantitative predictions in the wild is challenging because (i) there are usually not enough population replicates to deal with the stochasticity of the evolutionary process, (ii) environmental conditions are not controlled, and (iii) measuring selection and the inheritance of traits affecting fitness is difficult in natural populations. As an alternative, predictions from theory can be tested in the laboratory with controlled experiments. To illustrate the feasibility of this approach, we briefly review the literature on the experimental evolution of plasticity, and on evolutionary rescue in the laboratory, paying particular attention to differences and similarities between microbes and multicellular eukaryotes. We then highlight a set of questions that could be addressed using this framework, which would enable testing the robustness of theoretical predictions, and provide new insights into areas that have received little theoretical attention to date

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies. Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDC-treated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

BACKGROUND: Infusion of allogeneic cardiosphere‐derived cells (allo‐CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long‐term effects of allo‐CDCs have not been assessed. We performed a placebo‐controlled pivotal study for long‐term evaluation, as well as shorter‐term mechanistic studies. METHODS AND RESULTS: Minipigs underwent 1.5‐hour mid‐left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo‐CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC‐treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo‐CDC infusion. In addition, allo‐CDCs improved regional function and decreased hypertrophy 2 months post‐treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo‐CDC‐treated pigs at 2 months. Allo‐CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short‐term experiments designed to probe mechanism revealed antiapoptotic effects of allo‐CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. CONCLUSIONS: Allo‐CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits

Cellular Postconditioning

BackgroundIntracoronary delivery of cardiosphere-derived cells (CDCs) has been demonstrated to be safe and effective in porcine and human chronic myocardial infarction. However, intracoronary delivery of CDCs after reperfusion in acute myocardial infarction has never been assessed in a clinically-relevant large animal model. We tested CDCs as adjunctive therapy to reperfusion in a porcine model of myocardial infarction.Methods and resultsFirst, escalating doses (5, 7.5, and 10 million cells) of allogeneic CDCs were administered intracoronary 30 minutes after reperfusion. Forty-eight hours later, left ventriculography was performed and animals euthanized to measure area at risk, infarct size (IS), and microvascular obstruction. Second, identical end points were measured in a pivotal study of minipigs (n=14) that received 8.5 to 9 million allogeneic CDCs, placebo solution, or sham. Multiple indicators of cardioprotection were observed with 7.5 and 10 million allogeneic CDCs, but not 5 million CDCs, relative to control. In the pivotal study, IS, microvascular obstruction, cardiomyocyte apoptosis, and adverse left ventricular remodeling were all smaller in the CDC group than in sham or placebo groups. In addition, serum troponin I level at 24 hours was lower after CDC infusion than that in the placebo or sham groups, consistent with the histologically-demonstrated reduction in IS.ConclusionsIntracoronary delivery of allogeneic CDCs is safe, feasible, and effective in cardioprotection, reducing IS, preventing microvascular obstruction, and attenuating adverse acute remodeling. This novel cardioprotective effect, which we call cellular postconditioning, differs from previous strategies to reduce IS in that it works even when initiated with significant delay after reflow