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Soft biological tissues demonstrate strong time-dependent mechanical behavior, arising from their intrinsic viscoelasticity and fluid flow-induced poroelasticity. It is increasingly recognized that time-dependent mechanical properties of soft tissues influence their physiological functions and are linked to several pathological processes. Nevertheless, soft tissue time-dependent characteristics, especially their micromechanical variation with tissue composition and location, remain poorly understood. Nanoindentation is a well-established technique to measure local elastic properties but has not been fully explored to determine micro-scale time-dependent properties of soft tissues. Here, a nanoindentation-based experimental strategy is implemented to characterize the micro-scale poroelastic and viscoelastic behavior of mouse heart, kidney, and liver tissues. It is demonstrated that heart tissue exhibits substantial mechanical heterogeneity where the elastic modulus varies spatially from 1 to 30 kPa. In contrast, both kidney and liver tissues show relatively homogeneous response with elastic modulus 0.5-3 kPa. All three tissues demonstrate marked load relaxation under constant indentation, where the relaxation behavior is observed to be largely dominated by tissue viscoelasticity. Intrinsic permeability varies among different tissues, where heart tissue is found to be less permeable compared to kidney and liver tissues. Overall, the results presented herein provide key insights into the time-dependent micromechanical behavior of different tissues and can therefore contribute to studies of tissue pathology and tissue engineering applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Myocardial tissue damage that occurs during an ischemic event leads to a spiraling deterioration of cardiac muscle structural and functional integrity. Reperfusion is the only known efficacious strategy and is the most commonly used treatment to reduce injury and prevent remodeling. However, timing is critical, and the procedure is not always feasible for a variety of reasons. The complex molecular basis for cardioprotection has been studied for decades but formulation of a viable therapeutic that can significantly attenuate myocardial injury remains elusive. In this review, we address barriers to the development of a fruitful approach that will substantially improve the prognosis of those suffering from this widespread and largely unmitigated disease. Furthermore, we proffer that ephrinA1, a candidate molecule that satisfies many of the important criteria discussed, possesses robust potential to overcome these hurdles and thus offers protection that surpasses the limitations currently observed.

EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.

Background: We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI., Methods: Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05., Results: Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed., Conclusions: We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing.

Gingivitis and periodontitis are among the most common diseases known to man. Although bacterial plaque is generally accepted as the primary etiologic agent, little information is available concerning the influence that host genetic factors have on these diseases. The purpose of the present study was to examine the relative contribution of environmental and host genetic factors to clinical measures of periodontal disease through the study of both reared-together twins and monozygous twins reared apart. Probing depth, clinical attachment loss, gingivitis, and plaque were assessed from the Ramfjord teeth in 110 pairs of adult twins (mean age 40.3 years), including 63 monozygous and 33 dizygous twin pairs reared together and 14 monozygous twin pairs reared apart. Bootstrap sampling was used to estimate and provide confidence limits of between-pair and within-pair variances, intraclass correlations and heritability. Based on ratios of within-pair variances or heritability estimates, a significant (P less than 0.05) genetic component was identified for gingivitis, probing depth, attachment loss and plaque. Heritability estimates indicated that between 38% to 82% of the population variance for these periodontal measures of disease may be attributed to genetic factors. While there is general agreement that bacteria are important in the pathogenesis of the periodontal diseases, future etiologic studies should consider the role of host genetic influences.