Identification and Functional Analysis of ThADH1 and ThADH4 Genes Involved in Tolerance to Waterlogging Stress in Taxodium hybrid ‘Zhongshanshan 406’

The Taxodium hybrid ‘Zhongshanshan 406’ (T. hybrid ‘Zhongshanshan 406’) [Taxodium mucronatum Tenore × Taxodium distichum (L.). Rich] has an outstanding advantage in flooding tolerance and thus has been widely used in wetland afforestation in China. Alcohol dehydrogenase genes (ADHs) played key roles in ethanol metabolism to maintain energy supply for plants in low-oxygen conditions. Two ADH genes were isolated and characterized—ThADH1 and ThADH4 (GenBank ID: AWL83216 and AWL83217—basing on the transcriptome data of T. hybrid ‘Zhongshanshan 406’ grown under waterlogging stress. Then the functions of these two genes were investigated through transient expression and overexpression. The results showed that the ThADH1 and ThADH4 proteins both fall under ADH III subfamily. ThADH1 was localized in the cytoplasm and nucleus, whereas ThADH4 was only localized in the cytoplasm. The expression of the two genes was stimulated by waterlogging and the expression level in roots was significantly higher than those in stems and leaves. The respective overexpression of ThADH1 and ThADH4 in Populus caused the opposite phenotype, while waterlogging tolerance of the two transgenic Populus significantly improved. Collectively, these results indicated that genes ThADH1 and ThADH4 were involved in the tolerance and adaptation to anaerobic conditions in T. hybrid ‘Zhongshanshan 406’

Estrogen induces global reorganization of chromatin structure in human breast cancer cells

In the cell nucleus, each chromosome is confined to a chromosome territory. This spatial organization of chromosomes plays a crucial role in gene regulation and genome stability. An additional level of organization has been discovered at the chromosome scale: the spatial segregation into open and closed chromatins to form two genome-wide compartments. Although considerable progress has been made in our knowledge of chromatin organization, a fundamental issue remains the understanding of its dynamics, especially in cancer. To address this issue, we performed genome-wide mapping of chromatin interactions (Hi-C) over the time after estrogen stimulation of breast cancer cells. To biologically interpret these interactions, we integrated with estrogen receptor α (ERα) binding events, gene expression and epigenetic marks. We show that gene-rich chromosomes as well as areas of open and highly transcribed chromatins are rearranged to greater spatial proximity, thus enabling genes to share transcriptional machinery and regulatory elements. At a smaller scale, differentially interacting loci are enriched for cancer proliferation and estrogen-related genes. Moreover, these loci are correlated with higher ERα binding events and gene expression. Taken together these results reveal the role of a hormone--estrogen--on genome organization, and its effect on gene regulation in cancer

Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish

SummaryMolecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis

A Functional Data Analysis Approach for Circadian Patterns of Activity of Teenage Girls

Background: Longitudinal or time-dependent activity data are useful to characterize the circadian activity patterns and to identify physical activity differences among multiple samples. Statistical methods designed to analyze multiple activity sample data are desired, and related software is needed to perform data analysis. Methods: This paper introduces a functional data analysis (fda) approach to perform a functional analysis of variance (fANOVA) for longitudinal circadian activity count data and to investigate the association of covariates such as weight or body mass index (BMI) on physical activity. For multiple age group adolescent school girls, the fANOVA approach is developed to study and to characterize activity patterns. The fANOVA is applied to analyze the physical activity data of three grade adolescent girls (i.e., grades 10, 11, and 12) from the NEXT Generation Health Study 2009–2013. To test if there are activity differences among girls of the three grades, a functional version of the univariate F-statistic is used to analyze the data. To investigate if there is a longitudinal (or time-dependent activity count) difference between two samples, functional t-tests are utilized to test: (1) activity differences between grade pairs; (2) activity differences between low-BMI girls and high-BMI girls of the NEXT study. Results: Statistically significant differences existed among the physical activity patterns for adolescent school girls in different grades. Girls in grade 10 tended to be less active than girls in grades 11 & 12 between 5:30 and 9:30. Significant differences in physical activity were detected between low-BMI and high-BMI groups from 8:00 to 11:30 for grade 10 girls, and low-BMI group girls in grade 10 tended to be more active. Conclusions: The fda approach is useful in characterizing time-dependent patterns of actigraphy data. For two-sample data defined by weight or BMI values, fda can identify differences between the two time-dependent samples of activity data. Similarly, fda can identify differences among multiple physical activity time-dependent datasets. These analyses can be performed readily using the fda R program

Machine Learning in Cardio-Oncology: New Insights from an Emerging Discipline

A growing body of evidence on a wide spectrum of adverse cardiac events following oncologic therapies has led to the emergence of cardio-oncology as an increasingly relevant interdisciplinary specialty. This also calls for better risk-stratification for patients undergoing cancer treatment. Machine learning (ML), a popular branch discipline of artificial intelligence that tackles complex big data problems by identifying interaction patterns among variables, has seen increasing usage in cardio-oncology studies for risk stratification. The objective of this comprehensive review is to outline the application of ML approaches in cardio-oncology, including deep learning, artificial neural networks, random forest and summarize the cardiotoxicity identified by ML. The current literature shows that ML has been applied for the prediction, diagnosis and treatment of cardiotoxicity in cancer patients. In addition, role of ML in gender and racial disparities for cardiac outcomes and potential future directions of cardio-oncology are discussed. It is essential to establish dedicated multidisciplinary teams in the hospital and educate medical professionals to become familiar and proficient in ML in the future.</p

Denervation as a Common Mechanism Underlying Different Pulmonary Vein Isolation Strategies for Paroxysmal Atrial Fibrillation: Evidenced by Heart Rate Variability after Ablation

Backgrounds. Segmental and circumferential pulmonary vein isolations (SPVI and CPVI) have been demonstrated to be effective therapies for paroxysmal atrial fibrillation (PAF). PVI is well established as the endpoint of different ablation techniques, whereas it may not completely account for the long-term success. Methods. 181 drug-refractory symptomatic PAF patients were referred for segmental or circumferential PVI (SPVI = 67; CPVI = 114). Heart rate variability (HRV) was assessed before and after the final ablation. Results. After following up for 62.23±12.75 months, patients underwent 1.41±0.68 procedures in average, and the success rates in SPVI and CPVI groups were comparable. 119 patients were free from AF recurrence (SPVI-S, n=43; CPVI-S, n=76). 56 patients had recurrent episodes (SPVI-R, n=21; CPVI-R, n=35). Either ablation technique decreased HRV significantly. Postablation SDNN and rMSSD were significantly lower in SPVI-S and CPVI-S subgroups than in SPVI-R and CPVI-R subgroups (SPVI-S versus SPVI-R: SDNN 91.8±32.6 versus 111.5±36.2 ms, rMSSD 47.4±32.3 versus 55.2±35.2 ms; CPVI-S versus CPVI-R: SDNN 83.0±35.6 versus 101.0±40.7 ms, rMSSD 41.1±22.9 versus 59.2±44.8 ms; all P<0.05). Attenuation of SDNN and rMSSD remained for 12 months in SPVI-S and CPVI-S subgroups, whereas it recovered earlier in SPVI-R and CPVI-R subgroups. Multivariate logistic regression analysis identified SDNN as the only predictor of long-term success. Conclusions. Beyond PVI, denervation may be a common mechanism underlying different ablation strategies for PAF

ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future