Kinetic Partitioning Modulates Human Telomere DNA G-Quadruplex Structural Polymorphism

Telomeres are specialized chromatin structures found at the end of chromosomes and are crucial to the maintenance of eukaryotic genome stability. Human telomere DNA is comprised of the repeating sequence (T₂AG₃)_n, which is predominantly double-stranded but terminates with a 3’ single-stranded tail. The guanine-rich tail can fold into secondary structures known as a G-quadruplexes (GQs) that may exist as a polymorphic mixture of anti-parallel, parallel, and several hybrid topological isomers. Using single-molecule Förster resonance energy transfer (smFRET), we have reconstructed distributions of telomere DNA GQ conformations generated by an in situ refolding protocol commonly employed in single-molecule studies of GQ structure, or using a slow cooling DNA annealing protocol typically used in the preparation of GQ samples for ensemble biophysical analyses. We find the choice of GQ folding protocol has a marked impact on the observed distributions of DNA conformations under otherwise identical buffer conditions. A detailed analysis of the kinetics of GQ folding over timescales ranging from minutes to hours revealed the distribution of GQ structures generated by in situ refolding gradually equilibrates to resemble the distribution generated by the slow cooling DNA annealing protocol. Interestingly, conditions of low ionic strength, which promote transient GQ unfolding, permit the fraction of folded DNA molecules to partition into a distribution that more closely approximates the thermodynamic folding equilibrium. Our results are consistent with a model in which kinetic partitioning occurs during in situ folding at room temperature in the presence of K⁺ ions, producing a long-lived non-equilibrium distribution of GQ structures in which the parallel conformation predominates on the timescale of minutes. These results suggest that telomere DNA GQ folding kinetics, and not just thermodynamic stability, likely contributes to the physiological ensemble GQ structures.     

Improved Working Memory Performance through Self-Regulation of Dorsal Lateral Prefrontal Cortex Activation Using Real-Time fMRI

Working memory is important for a wide range of high-level cognitive activities. Previous studies have shown that the dorsal lateral prefrontal cortex (DLPFC) plays a critical role in working memory and that behavioral training of working memory can alter the activity of DLPFC. However, it is unclear whether the activation in the DLPFC can be self-regulated and whether any self-regulation can affect working memory behavior. The recently emerged real-time functional magnetic resonance imaging (rtfMRI) technique enables the individuals to acquire self-control of localized brain activation, potentially inducing desirable behavioral changes. In the present study, we employed the rtfMRI technique to train subjects to up-regulate the activation in the left DLPFC, which is linked to verbal working memory. After two rtfMRI training sessions, activation in the left DLPFC was significantly increased, whereas the control group that received sham feedback did not show any increase in DLPFC activation. Pre- and post-training behavioral tests indicated that performance of the digit span and letter memory task was significantly improved in the experimental group. Between-group comparison of behavioral changes showed that the increase of digit span in the experimental group was significantly greater than that in the control group. These findings provide preliminary evidence that working memory performance can be improved through learned regulation of activation in associated brain regions using rtfMRI.     

Autophagic Protein Beclin 1 Serves as an Independent Positive Prognostic Biomarker for Non-Small Cell Lung Cancer

Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients’ clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future.     

Exogenous Spermidine Promotes Somatic Embryogenesis of <i>Cunninghamia lanceolata</i> by Altering the Endogenous Phytohormone Content

In order to study how exogenous hormones in C. lanceolata (gymnosperm) regulate somatic embryogenesis, we measured the endogenous phytohormones of two genotypes with different somatic embryogenesis efficiency and found that an increase in endogenous concentrations of IAA and ABA may be correlated to more efficient somatic embryogenesis. By applying exogenous spermidine, we found that exogenous hormones may affect somatic embryogenesis efficiency through affecting the endogenous phytohormone content. Based on these results, further studies can be conducted whereby the concentration of exogenous hormones or the levels of endogenous phytohormones by molecular methods are regulated to promote somatic embryogenesis. Our research may benefit the long-term economic output of the forestry industry and lays the foundation to studying the molecular mechanism that controls somatic embryogenesis efficiency.     

The effects of soil phosphorus on aboveground biomass are mediated by functional diversity in a tropical cloud forest

Plant and Soil - Soil phosphorus is a key driver of plant biodiversity and aboveground biomass (AGB) in tropical forests. A plant community’s ability to exploit such limiting resources may be...     

Selenium-Alleviated Hepatocyte Necrosis and DNA Damage in Cyclophosphamide-Treated Geese by Mitigating Oxidative Stress

Biological Trace Element Research - Selenium (Se) has been well recognized as an immune-enhancing agent with antioxidant and anti-tumor properties. The commonly used chemotherapy drug,...     

Variable Spontaneous Mutation and Loss of Heterozygosity among Heterozygous Genomes in Yeast

Mutation and recombination are the primary sources of genetic variation. To better understand the evolution of genetic variation, it is crucial to comprehensively investigate the processes involving mutation accumulation and recombination. In this study, we performed mutation accumulation experiments on four heterozygous diploid yeast species in the Saccharomycodaceae family to determine spontaneous mutation rates, mutation spectra, and losses of heterozygosity (LOH). We observed substantial variation in mutation rates and mutation spectra. We also observed high LOH rates (1.65–11.07×10⁻⁶ events per heterozygous site per cell division). Biases in spontaneous mutation and LOH together with selection ultimately shape the variable genome-wide nucleotide landscape in yeast species.     

LINC00205 modulates the expression of EPHX1 through the inhibition of miR-184 in hepatocellular carcinoma as a ceRNA

Several studies have shown that low expression of epoxide hydrolase 1 (EPHX1) is closely associated with varying human cancers, including hepatocellular carcinoma (HCC). This study aims to explore the potential mechanism of EPHX1 silencing and revealed a novel regulatory pathway in the pathogenesis of HCC. In this study, micro ribonucleic acid (miR)-184 was predicted and validated to be a regulator of EPHX1 through experiments, and its expression was negatively correlated with the messenger RNA (mRNA) levels of EPHX1 in primary tumors. Elevation of EPHX1 suppressed cell proliferation and migration as well as cell cycle progression, and induced apoptosis, while downregulation of miR-184 exhibited the opposite effect on cellular processes. Moreover, LINC00205 interacted with miR-184 and was markedly downregulated in tumors. The effects of the miR-184 inhibitor on cell proliferation, apoptosis, and migration were reversed in part by the transfection with LINC00205 small interfering RNAs. In addition, LINC00205 acted as a molecular sponge to positively regulate the mRNA and protein levels of EPHX1 via regulating miR-184. The tumorigenicity of HCC cells was enhanced by LINC00205 shRNA but diminished by overexpression of EPHX1 in vivo. Clinically, the EPHX1 expression in patients with HCC was markedly downregulated. Taken together, the results of this study suggest that as a competing endogenous RNA, LINC00205 may regulate EPHX1 by inhibiting miR-184 in the progression of HCC and that targeting the LINC00205/miR-184/EPHX1 axis may provide a treatment protocol for patients.