Identification of potentially critical genes in the development of heart failure after ST-segment elevation myocardial infarction (STEMI)

Heart failure (HF) remains a common complication after acute ST-segment elevation myocardial infarction (STEMI). Here, we aim to identify critical genes related to the developed HF in patients with STEMI using bioinformatics analysis. The microarray data of GSE59867, including peripheral blood samples from nine patients with post-infarct HF and eight patients without post-infarct HF, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HF and non-HF groups were screened by LIMMA package. Functional enrichment analyses of DEGs were conducted, followed by construction of a protein-protein interaction (PPI) network. The dynamic messenger RNA (mRNA) level of the hub genes during the follow-up was analyzed to further elucidate their role in HF development. A total of 58 upregulated and 75 downregulated DEGs were screen out. They were mainly enriched in biological processes about inflammatory response, extracellular matrix organization, response to cAMP, immune response, and positive regulation of cytosolic calcium ion concentration. Pathway analysis revealed that the DEGs were also involved in hematopoietic cell lineage, pathways in cancer, and extracellular matrix-receptor interaction. In the PPI network consisting of 58 nodes and 72 interactions, CXCL8 (degree = 15), THBS1 (degree = 8), FOS (degree = 7), and ITGA2B (degree = 6) were identified as the hub genes. In the comparison of patients with and without post-infarct HF, the mRNA level of these hub genes were all higher within 30 days but reached similar at 6 months after STEMI. In conclusion, CXCL8, THBS1, FOS, and ITGA2B may play important roles in the development of HF after acute STEMI.     

Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin

Glutathione peroxidase 4 (GPX4) has been confirmed to inhibit ferroptosis in cancer cells, however, whether GPX4 serves as an oncogene is not clear. In this study, the expression of GPX4 and its influence to survival of patients with cancer were analyzed via public databases. Furthermore, the epigenetic regulation of GPX4 and the relation between GPX4 and chemoresistance of different anticancer drugs was also detected. Most importantly, cytological assays were performed to investigate the function of GPX4 in cancer cells. The results showed that GPX4 was higher expressed in cancer tissues than normal and was negatively associated with prognosis of patients. Furthermore, at upstream of GPX4 there was low DNA methylation sites and enhanced level of H3K4me3 and H3K27ac, indicating that high level of GPX4 in cancer may resulted from epigenetic regulation. Moreover, GPX4 was positively related to chemoresistance of anticancer drugs L-685458, lapatinib, palbociclib, and topotecan. In addition, GPX4 may potentially be involved in translation of protein, mitochondrial respiratory chain complex I assembly, electron transport oxidative phosphorylation, nonalcoholic fatty liver disease, and metabolic pathways. Finally, we detected that GPX4 inhibited ferroptosis in cancer cells, the inhibition of GPX4 via RSL3 could enhance the anticancer effect of cisplatin in vitro and in vivo. In conclusion, GPX4 acts as an oncogene and inhibits ferroptosis in cancer cells, the anticancer effect of cisplatin can be enhanced by GPX4 inhibition.     

Stochastic Sensitivity Analysis and Kernel Inference via Distributional Data

Cellular processes are noisy due to the stochastic nature of biochemical reactions. As such, it is impossible to predict the exact quantity of a molecule or other attributes at the single-cell level. However, the distribution of a molecule over a population is often deterministic and is governed by the underlying regulatory networks relevant to the cellular functionality of interest. Recent studies have started to exploit this property to infer network states. To facilitate the analysis of distributional data in a general experimental setting, we introduce a computational framework to efficiently characterize the sensitivity of distributional output to changes in external stimuli. Further, we establish a probability-divergence-based kernel regression model to accurately infer signal level based on distribution measurements. Our methodology is applicable to any biological system subject to stochastic dynamics and can be used to elucidate how population-based information processing may contribute to organism-level functionality. It also lays the foundation for engineering synthetic biological systems that exploit population decoding to more robustly perform various biocomputation tasks, such as disease diagnostics and environmental-pollutant sensing.     

Responses of Crop Water Use Efficiency to Climate Change and Agronomic Measures in the Semiarid Area of Northern China

It has long been concerned how crop water use efficiency (WUE) responds to climate change. Most of existing researches have emphasized the impact of single climate factor but have paid less attention to the effect of developed agronomic measures on crop WUE. Based on the long-term field observations/experiments data, we investigated the changing responses of crop WUE to climate variables (temperature and precipitation) and agronomic practices (fertilization and cropping patterns) in the semi-arid area of northern China (SAC) during two periods, 1983–1999 and 2000–2010 (drier and warmer). Our results suggest that crop WUE was an intrinsical system sensitive to climate change and agronomic measures. Crops tend to reach the maximum WUE (WUEmax) in warm-dry environment while reach the stable minimum WUE (WUEmin) in warm-wet environment, with a difference between WUEmax and WUEmin ranging from 29.0%-55.5%. Changes in temperature and precipitation in the past three decades jointly enhanced crop WUE by 8.1%-30.6%. Elevated fertilizer and rotation cropping would increase crop WUE by 5.6–11.0% and 19.5–92.9%, respectively. These results indicate crop has the resilience by adjusting WUE, which is not only able to respond to subsequent periods of favorable water balance but also to tolerate the drought stress, and reasonable agronomic practices could enhance this resilience. However, this capacity would break down under impact of climate changes and unconscionable agronomic practices (e.g. excessive N/P/K fertilizer or traditional continuous cropping). Based on the findings in this study, a conceptual crop WUE model is constructed to indicate the threshold of crop resilience, which could help the farmer develop appropriate strategies in adapting the adverse impacts of climate warming.     

Endocytosis of superoxide dismutase by rat liver.

We have investigated the endocytosis by rat liver of superoxide dismutase (SOD) labelled with 125I. (125I) SOD is quickly taken up by the liver where it remains in significant amounts for at least 150 min. Adsorptive endocytosis is probably involved. Distribution of radioactivity was established after differential and isopycnic centrifugation and compared with that of cathepsin C, a lysosomal enzyme. Results show that the behavior of radioactivity is similar to that of the hydrolase. SOD activity is only marginally affected by incubation in the presence of a purified lysosome extract; moreover, when (125I) SOD is treated in the same conditions, only a few percent of radioactivity becomes acidosoluble. These observations indicate that SOD taken up by the liver accumulates in lysosomes where it can stay for a relatively long time owing to its relative resistance to lysosomal hydrolases.     

Information for targeting to the chloroplastic inner envelope membrane is contained in the mature region of the maize Bt1-encoded protein.

Based on the protein sequence deduced from a cDNA clone, it has been proposed that the maize bt1 locus encodes an amyloplast membrane metabolite translocator protein (Sullivan, T. D., Strelow, L. I., Illingworth, C. A., Phillips, R. L., and Nelson, O. E., Jr. (1991) Plant Cell 3, 1337-1348). The present work provides further evidence for this hypothesis by showing that the gene product of Bt1 could be imported into chloroplasts in vitro and processed to lower molecular weight mature proteins. More importantly, the imported mature proteins were localized to the inner envelope membrane, where metabolite translocators are located in plastids. In addition, the location of information for targeting to the inner membrane was investigated by constructing and analyzing the import of chimeric precursor proteins. A chimeric protein with the transit peptide of the precursor to the small subunit of ribulose-1,5-bisphosphate carboxylase fused to the mature region of the Bt1-encoded protein was targeted to the inner envelope membrane of chloroplasts. Moreover, a chimeric protein with the transit peptide of the Bt1-encoded protein fused to the mature protein of the light-harvesting chlorophyll a/b binding protein was targeted to the thylakoid. These results indicate that the transit peptide of the Bt1-encoded protein functions primarily as a stromal targeting sequence. The information for targeting to the chloroplastic inner envelope membrane is contained in the mature region of the protein.