Random Fixed Point Theorems of Random Comparable Operators and an Application

We introduce the new concept of random comparable operators as a generalization of random monotone operators and prove several random fixed point theorems for such a class of operators in partially ordered Banach spaces. Part of the presented results generalize and extend some known results of random monotone operators. Finally, as an application, we consider the existence of the solution of a random Hammerstein integral equation

ErbB2 is required for cardiomyocyte proliferation in murine neonatal hearts

It has been long recognized that the mammalian heart loses its proliferative capacity soon after birth, yet, the molecular basis of this loss of cardiac proliferation postnatally is largely unknown. In this study, we found that cardiac ErbB2, a member of the epidermal growth factor receptor family, exhibits a rapid and dramatic decline in expression at the neonatal stage. We further demonstrate that conditional ablation of ErbB2 in the ventricular myocardium results in upregulation of negative cell cycle regulators and a significant reduction in cardiomyocyte proliferation during the narrow neonatal proliferative time window. Together, our data reveal a positive correlation between the expression levels of ErbB2 with neonatal cardiomyocyte proliferation and suggest that reduction in cardiac ErbB2 expression may contribute to the loss of postnatal cardiomyocyte proliferative capacity

The Potential Use of DCE-MRI Texture Analysis to Predict HER2 2+ Status

Purpose: To evaluate the ability of texture analysis of breast dynamic contrast enhancement-magnetic resonance (DCE-MR) images in differentiating human epidermal growth factor receptor 2 (HER2) 2+ status of breast tumors.Methods: A total of 73 cases were retrospectively selected. HER2 2+ status was confirmed by fluorescence in situ hybridization. For each case, 279 textural features were derived. A student's t-test or Mann-Whitney U test was used to select features with statistically significant differences between HER2 2+ positive and negative groups. A principal component analysis was applied to eliminate feature correlation. Three machine learning classifiers, logistic regression (LR), quadratic discriminant analysis (QDA), and a support vector machine (SVM), were trained and tested using a leave-one-out cross-validation method. The area under a receiver operating characteristic curve (AUC) was measured to assess the classifier's performance.Results: The AUCs for the different classifiers were satisfactory, ranging from 0.808 to 0.865. The classification methods derived with LR and SVM demonstrated similarly high performances, and the accuracy levels were 81.06 and 81.18%, respectively. The AUC for the classifier derived with SVM was the highest (0.865), and a marked specificity (88.90%) was presented. For the classifier with LR, the AUC was 0.851, and the corresponding sensitivity (94.44%) was the highest.Conclusion: The texture analysis for breast DCE-MRI proposed in this study demonstrated potential utility in HER2 2+ status discrimination

Improved Generation of Induced Cardiomyocytes Using a Polycistronic Construct Expressing Optimal Ratio of Gata4, Mef2c and Tbx5

Direct conversion of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) holds great potential for regenerative medicine by offering alternative strategies for treatment of heart disease. This conversion has been achieved by forced expression of defined factors such as Gata4 (G), Mef2c (M) and Tbx5 (T). Traditionally, iCMs are generated by a cocktail of viruses expressing these individual factors. However, reprogramming efficiency is relatively low and most of the in vitro G,M,T-transduced fibroblasts do not become fully reprogrammed, making it difficult to study the reprogramming mechanisms. We recently have shown that the stoichiometry of G,M,T is crucial for efficient iCM reprogramming. An optimal stoichiometry of G,M,T with relative high level of M and low levels of G and T achieved by using our polycistronic MGT vector (hereafter referred to as MGT) significantly increased reprogramming efficiency and improved iCM quality in vitro. Here we provide a detailed description of the methodology used to generate iCMs with MGT construct from cardiac fibroblasts. Isolation of cardiac fibroblasts, generation of virus for reprogramming and evaluation of the reprogramming process are also included to provide a platform for efficient and reproducible generation of iCMs

Generation of an inducible fibroblast cell line for studying direct cardiac reprogramming: Inducible Cell Line for iCM Reprogramming

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) through forced expression of cardiac lineage-specific transcription factors holds promise as an alternative strategy for cardiac regeneration. To facilitate research in iCM reprogramming, we generated a suite of new tools. We developed a transformed cell line derived from mouse embryonic fibroblasts (MEF). This fibroblast cell line (MEF-T) harbors an αMHC-eGFP reporter transgene for rapid detection of newly derived iCMs. The MEF-T cell line is highly proliferative and easily transfected and transduced, making it an ideal tool for transgene expression and genetic manipulation. Additionally, we generated a Tet-On inducible polycistronic iCM reprogramming construct for the temporal regulation of reprogramming factor expression. Furthermore, we introduced this construct into MEF-T and created an inducible reprogrammable fibroblast cell line. These tools will facilitate future research in cell fate reprogramming by enabling the temporal control of reprogramming factor expression as well as high throughput screening using libraries of small molecules, non-coding RNAs and siRNAs

Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming

Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM reprogramming and found that reducing levels of the polycomb complex gene Bmi1 significantly enhanced induction of beating iCMs from neonatal and adult mouse fibroblasts. The inhibitory role of Bmi1 in iCM reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. Reduced Bmi1 expression corresponded with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK119ub at cardiogenic loci, and de-repression of cardiogenic gene expression during iCM conversion. Furthermore, Bmi1 deletion could substitute for Gata4 during iCM reprogramming. Thus, Bmi1 acts as a critical epigenetic barrier to iCM production. Bypassing this barrier simplifies iCM generation and increases yield, potentially streamlining iCM production for therapeutic purposes

Climatic impact of the Millennium eruption of Changbaishan volcano in China: New insights from high-precision radiocarbon wiggle-match dating

Changbaishan volcano in northeast China, previously dated to have erupted around the mid-10th century A.D., is renowned for producing one of the largest eruptions in history (magnitude 6.8) and thus speculated to have substantial climatic impact. Here we report a new high-precision 14C wiggle-match age of A.D. 946 ± 3 obtained from a 264 year old tree trunk (with bark) killed during the eruption, using the OxCal's Bayesian modeling approach with 27 sequentially sampled annual rings of decadal intervals. The new chronology conforms well to the calendar date of A.D. 946 for the eruption inferred from historical documentary evidence. We find no stratospherically loaded sulfate spike that might be associated with the A.D. 946 eruption in the global volcanism record from the GISP2 ice core, suggesting the stratospheric sulfate aerosols produced during the eruption were not transported to the arctic region, due probably to its relatively low stratospheric sulfur emission and the seasonal effects of the atmospheric circulation at the time of the eruption that likely occurred in the winter of A.D. 946–947. Since the stratospheric volcanic sulfates are the main cause of large-scale climate perturbations, this finding indicates that the Millennium eruption of Changbaishan volcano might have limited regional climatic effects, rather than global or hemispheric impact as implied by its magnitude