Prediction of Protein-Protein Interaction Sites by Multifeature Fusion and RF with mRMR and IFS.

Prediction of protein-protein interaction (PPI) sites is one of the most perplexing problems in drug discovery and computational biology. Although significant progress has been made by combining different machine learning techniques with a variety of distinct characteristics, the problem still remains unresolved. In this study, a technique for PPI sites is presented using a random forest (RF) algorithm followed by the minimum redundancy maximal relevance (mRMR) approach, and the method of incremental feature selection (IFS). Physicochemical properties of proteins and the features of the residual disorder, sequence conservation, secondary structure, and solvent accessibility are incorporated. Five 3D structural characteristics are also used to predict PPI sites. Analysis of features shows that 3D structural features such as relative solvent-accessible surface area (RASA) and surface curvature (SC) help in the prediction of PPI sites. Results show that the performance of the proposed predictor is superior to several other state-of-the-art predictors, whose average prediction accuracy is 81.44%, sensitivity is 82.17%, and specificity is 80.71%, respectively. The proposed predictor is expected to become a helpful tool for finding PPI sites, and the feature analysis presented in this study will give useful insights into protein interaction mechanisms.

Effectiveness of a nurse-led online educational programme based on basic insulin therapy in patients with diabetes mellitus: A quasi-experimental trial.

AIMS AND OBJECTIVES: To evaluate the effectiveness of a nurse-led online educational programme based on patients with diabetes mellitus treated with initial basal insulin therapy. BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) need to be treated with insulin to control hyperglycaemia and reduce the risk of diabetic complications when oral hypoglycaemic drugs are not effective or contraindicated. Current practices emphasise the leading role of nurses in patients treated with initial basal insulin therapy after discharge. The introduction of nurse-led online education within this area is a relatively new programme. DESIGN: This study was a quasi-experimental, nonequivalent, two-group, comparison group design. METHODS: The study selected 800 patients with T2DM hospitalised in the Department of Endocrinology at a Chinese hospital from July 2018 to June 2020 who were initially treated with insulin. According to the time sequence, 400 patients from July 2018 to June 2019 were divided into the control group and 400 patients from July 2019 to June 2020 into the intervention group. The control group received routine health education and doctor-led follow-up based on routine health education. The intervention group received systematic health education and online insulin injection activities led by nurses. The effects were evaluated after 3 and 6 months of intervention. The TREND checklist was followed to ensure rigour in the study. RESULTS: In total, 339 patients were enrolled in the intervention group and 333 patients within the control group. According to the analysis, 3 months after the intervention, the compliance rate of fasting blood glucose (FBG) (rate difference: 0.078, 95% CI: 0.006-1.150, p < .05) and HbA1c (%) (rate difference: 0.070, 95% CI: 0.001-0.137, p < .05) between the intervention and control groups were statistically significant; 6 months after the intervention, the compliance rate of FBG (rate difference: 0.077, 95% CI: 0.007-0.14, p < .05) and HbA1c (%) (rate difference: 0.106, 95% CI: 0.324-0.180, p < .01) between the intervention and the control groups were statistically significant. The total score of the 'My Opinion on Insulin' scale in the intervention group was (80.18 ± 6.68), and in the control group was (71.15 ± 8.17), there was a significant difference in the scale between the two groups (mean difference: 9.03, 95% CI: 7.900-10.160, p < .01). Through a multivariable regression model, in order to correct the important baseline characteristics, the daily insulin dosage, and the total score of the 'My Opinion on Insulin' scale after 6 months of intervention were independent risk factors for the two intervention methods in diabetic patients treated with initial basal insulin therapy (p < .05). CONCLUSIONS: A nurse-led online programme was feasible and effective for patients with diabetes mellitus treated with initial basal insulin therapy. This programme could effectively be used to reduce the patient's daily insulin dose, as well as improve the patients' compliance using insulin therapy. RELEVANCE TO CLINICAL PRACTICE: Nurse-led online education has a role in implementing a safe, standardised, and sustained approach to patients with diabetes mellitus treated with initial basal insulin therapy during follow-up after discharge.

Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis.

Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells.

Both mitochondrial morphology and the level of cytosolic calcium [Ca2+]c are actively changed and play critical roles in a number of malignancies. However, whether communications existed between these two processes to ingeniously control the malignant phenotype are far from clear. We investigated the reciprocal regulation between mitochondrial fission and cytosolic calcium signaling in human hepatocellular carcinoma (HCC) cells. Furthermore, the underlying molecular mechanisms and the synergistic effect on autophagy were explored. Our results showed that mitochondrial fission increased the [Ca2+]c and calcium oscillation in HCC cells. We further found that mitochondrial fission-mediated calcium signaling was dependent on ROS-activated NF-κB pathways, which facilitated the expression of STIM1 and subsequent store-operated calciumentry. Additionally, we also demonstrated that increase in [Ca2+]c promoted mitochondrial fission by up-regulating expression of Drp1 and FIS1 via transcription factors NFATC2 and c-Myc, respectively. Moreover, the positive feedback loop significantly promoted HCC cell global autophagy by Ca2+/CAMKK/AMPK pathway. Our data demonstrate a positive feedback loop between mitochondrial fission and cytosolic calcium signaling and their promoting role in autophagy of HCC cells, which provides evidence for this loop as a potential drug target in tumor treatment.

SETDB1 plays an essential role in maintenance of gonocyte survival in pigs.

Histone methyltransferase SETDB1 suppresses gene expression and modulates heterochromatin formation through H3K9me2/3. Previous studies have revealed that SETDB1 catalyzes lysine 9 of histone H3 tri-methylation and plays essential roles in maintaining the survival of embryonic stem cells and spermatogonial stem cells in mice. However, the function of SETDB1 in porcine male germ cells remains unclear. The aim of the present study was to reveal the expression profile and function of SETDB1 in porcine germ cells. SETDB1 expression gradually increased during testis development. SETDB1 was strongly localized in gonocytes. Knockdown of SETDB1 gene expression led to gonocyte apoptosis and a decrease in H3K27me3, but no significant change in H3K9me3. These observations suggested that SETDB1 is a novel epigenetic regulator of porcine male germ cells, and contributes to the maintenance of gonocyte survival in pigs, probably due to the regulation of H3K27me3 rather than H3K9me3. These findings will provide a theoretical basis for the future study of epigenetic regulation of spermatogenesis.

Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma.

Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Recently, we have reported that increased mitochondrial fission promotes autophagy and apoptosis resistance in hepatocellular carcinoma (HCC) cell through ROS-mediated coordinated regulation of NF-κB and p53 pathways. However, little is known about the roles of mitochondrial dynamics in HCC cell proliferation, another key feature of cancer cells. In this study, we systematically investigated the functional role of mitochondrial fission in the regulation of HCC cell proliferation. Furthermore, the underlying molecular mechanisms were deeply explored. We found that, increased mitochondrial fission by forced expression of Drp1 promoted the proliferation of HCC cells both in vitro and in vivo mainly by facilitating G1/S phase transition of cell cycle. Whereas, Drp1 knockdown or treatment with mitochondrial division inhibitor-1 induced significant G1 phase arrest in HCC cells and reduced tumor growth in the xenotransplantation model. We further demonstrated that the proliferation-promoting role of Drp1-mediated mitochondrial fission was mediated via p53/p21 and NF-κB/cyclins pathways. Moreover, the crosstalk between p53 and NF-κB pathways was proved to be involved in the regulation of mitochondrial fission-mediated cell proliferation. In conclusion, our findings demonstrate that Drp1-mediated mitochondrial fission plays a critical role in the regulation of cell cycle progression and HCC cell proliferation. Thus, targeting Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing tumor growth of HCC.

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.