👤 Alaa El-Din Sallam

Although a giant Egyptian domestic non-migratory duck breed is phenotypically identical to the migratory Mallard, yet it is three times larger. The current study sought to determine the genetic and metabolic differences between this duck and Mallard, which arrives in Egypt in September for wintering and departs in March. Mitochondrial DNA control region (D-loop) was extracted, amplified, sequenced, and analyzed in both ducks. Both ducks were given a high-fat diet (HFD) for 6 weeks to assess their metabolic response to this diet. Polymorphism results indicated that the D-loop is highly variable and both populations expansion is balanced. The hierarchical analysis of molecular variants (AMOVA) and interpopulation difference parameters revealed significant genetic differentiation and minimal gene flow between migrant and resident populations. Phylogeny and Network analyses revealed that domestic ducks are a distinct group that separated from mallards. Physiologically, domestic duck blood and adipose tissue had a higher level of triglycerides and adipocyte volume than that of the depleting arriving migratory Mallard ducks, while leaving Mallard parameters were the highest, suggesting a high level of preparatory fat deposition and utilization before starting the trip. In response to HFD, the expression of FA uptake genes cd36, fabp1 was upregulated similarly in livers of domestic and migratory Mallard ducks, while the expression of lipid accumulation genes dgat2 and plin2 was higher in domestic than in migratory Mallards. However, the highest body mass and adipocytes volume gain was observed in the arriving migratory Mallards. In pectoral muscle, the expression of cd36 and fabp3 was higher in domestic than in leaving ducks, while in arriving Mallards, both genes were not upregulated in response to HFD. Dgat2 was upregulated only in domestic muscle, while lipid oxidation genes cpt1, lpl, and the controlling ppara were more upregulated in leaving Mallard. In conclusion, both ducks can be genetically and metabolically differentiated. Migratory mallards are more flexible and efficient in lipid metabolism than domestic ducks. Show less

Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery. In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload. In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs. Show less