Background-Familial hypertrophic cardiomyopathy (FHC) is characterized by genetic and clinical heterogeneity. Five percent of FHC families have 2 FHC-causing mutations, which results in earlier disease onset, increased cardiac dysfunction, and a higher incidence of sudden death events. These observations suggest a relationship between the number of gene mutations and phenotype severity in FHC. Methods and Results-We sought to develop, characterize, and investigate the pathogenic mechanisms in a double-mutant murine model of FHC. This model (designated TnI-203/MHC-403) was generated by crossbreeding mice with the Gly203Ser cardiac troponin I (TnI-203) and Arg403Gln ␣-myosin heavy chain (MHC-403) FHC-causing mutations.The mortality rate in TnI-203/MHC-403 mice was 100% by age 21 days. At age 14 days, TnI-203/MHC-403 mice developed a significantly increased ratio of heart weight to body weight, marked interstitial myocardial fibrosis, and increased expression of atrial natriuretic factor and brain natriuretic peptide compared with nontransgenic, TnI-203, and MHC-403 littermates. By age 16 to 18 days, TnI-203/MHC-403 mice rapidly developed a severe dilated cardiomyopathy and heart failure, with inducibility of ventricular arrhythmias, which led to death by 21 days. Downregulation of mRNA levels of key regulators of Ca 2ϩ homeostasis in TnI-203/MHC-403 mice was observed. Increased levels of phosphorylated STAT3 were observed in TnI-203/MHC-403 mice and corresponded with the onset of disease, which suggests a possible cardioprotective response. Conclusions-TnI-203/MHC-403 double-mutant mice develop a severe cardiac phenotype characterized by heart failure and early death. The presence of 2 disease-causing mutations may predispose individuals to a greater risk of developing severe heart failure than human FHC caused by a single gene mutation.

Background Presymptomatic COVID-19 patients have been identified as a major stumbling block in efforts to break the chain of transmission. Studies on temporal dynamics of its shedding suggests it peaks 1–2 days prior to any symptom onset. Therefore, a large proportion of patients are actively spreading the disease unknowingly whilst undetected. However, lengthy lockdowns and isolation leads to a host of socioeconomic issues and are impractical. Conversely, there exists no study describing this group and their clinical significance despite their key role in disease transmission. Methods As a result, we devised a retrospective study to look at the prevalence of presymptomatic patients with COVID-19 from data sourced via our medical records office. Subsequently, we identify early indicators of infection through demographic information, biochemical and radiological abnormalities which would allow early diagnosis and isolation. In addition, we will look into the clinical significance of this group and their outcome; if it differs from asymptomatic or symptomatic patients. Descriptive statistics were used in addition to tabulating the variables and corresponding values for reference. Variables are compared between the presymptomatic group and others via Chi-square testing and Fisher’s exact test, accepting a p value of < 0.05 as significant. Results Our analysis shows a higher proportion of presymptomatic patients with atypical symptoms like chest pain while symptomatic patients commonly present with respiratory symptoms like cough and shortness of breath. Besides that, there were more females presenting as presymptomatic patients compared to males (p = 0.019) and these group of patients were likely to receive treatment (p < 0.001). Otherwise, we were not able to identify other statistically significant markers suggesting a patient is presymptomatic. Conclusion As we have little means of identifying these silent spreaders, it highlights further the importance of general measures implemented to stop COVID-19 transmission like social distancing, face mask, and widespread testing.

Bcl-2 family proteins are crucial regulators of apoptosis. Both pro- and antiapoptotic members exist, and overexpression of the latter facilitates evasion of apoptosis in many cancer types. Bcl-2 homology domain 3 (BH3) mimetics are small molecule inhibitors of antiapoptotic Bcl-2 family members, and these inhibitors are promising anticancer agents. In this study, we report that gamma-tocotrienol (γT3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Treatment of cells with inhibitors of Bax or caspase-9 attenuated the cell death induced by γT3. Simulated docking analysis suggested that γT3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that γT3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that γT3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16 pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16 was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16 were determined by western blot technique. The finding of this study showed that p16 mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16 and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16 and hypophosphorylated-pRb and cyclin D1 protein expressions.