Development and Validation of a Liquid-Liquid Phase Separation-Related Gene Signature as Prognostic Biomarker for Low-Grade Gliomas.

Aim: To explore whether the liquid-liquid phase separation- (LLPS-) related genes were potential prognostic markers that could contribute to the further classification of low-grade gliomas (LGGs). Methods: The LLPS-related genes were subjected to functional enrichment analysis. The univariable, least absolute shrinkage and selection operator, and multivariable stepwise Cox regression analyses were performed to develop an LLPS-related gene signature (GS) in the discovery data set. The biological characteristics of the high-risk LGG were explored using gene set enrichment analysis. Two independent external data sets were used to validate the LLPS-related GS. Results: LLPS-related genes are involved in multiple important cancer-related biological processes and pathways in LGG. Nine LLPS-related genes were identified to construct the LLPS-related GS, which was significantly associated with the prognosis of LGG patients. The LLPS-related GS could successfully divide patients with LGG into high- and low-risk groups, and the high-risk group showed a poorer prognosis than the low-risk group. Furthermore, the LLPS-related GS was independent of IDH and 1p19q status. Several cancer-related pathways may be more active in high-risk LGGs, such as IL6 JAK STAT3 signaling pathway. The LLPS-related GS was successfully validated with two independent external data sets. Conclusion: We developed and validated a novel LLPS-related GS for risk stratification of LGG. Our findings may provide more precise management for LGGs and a useful reference for LLPS mechanism to link LGG studies.

An Approach for Predicting the Low-Cycle-Fatigue Crack Initiation Life of Ultrafine-Grained Aluminum Alloy Considering Inhomogeneous Deformation and Microscale Multiaxial Strain.

In this paper, a low-cycle-fatigue (LCF) crack initiation life prediction approach that explicitly distinguishes nucleation and small crack propagation regimes is presented for ultrafine-grained (UFG) aluminum alloy by introducing two fatigue indicator parameters (FIPs) at the grain level. These two characterization parameters, the deformation inhomogeneity measured by the standard deviation of the dot product of normal stress and longitudinal strain and the microscale multiaxial strain considering the non-proportional cyclic additional hardening and mean strain effect, were proposed and respectively regarded as the driving forces for fatigue nucleation and small crack propagation. Then, the nucleation and small crack propagation lives were predicted by correlating these FIPs with statistical variables and cyclic J-integrals, respectively. By constructing a microstructure-based 3D polycrystalline finite element model with a free surface, a crystal plasticity finite element-based numerical simulation was carried out to quantify FIPs and clarify the role of crystallographic anisotropy in fatigue crack initiation. The numerical results reveal the following: (1) Nucleation is prone to occur on the surface of a material as a result of it having a higher inhomogeneous deformation than the interior of the material. (2) Compared with the experimental data, the LCF initiation life of UFG 6061 aluminum alloy could be predicted using the new parameters as FIPs. (3) The predicted results confirm the importance of considering the fatigue behavior of nucleation and small crack propagation with different deformation mechanisms for improving the fatigue crack initiation life prediction accuracy.

Pramipexole Protects Against Traumatic Brain Injury-Induced Blood-Brain Barrier (BBB) Dysfunction.

Traumatic brain injury (TBI) is a severe disease of brain damage accompanied by blood-brain barrier (BBB) dysfunction. The BBB is composed of brain microvascular endothelial cells (BMECs), astrocyte terminus, pericytes, and a basement membrane. Tight junction proteins expressed by BMECs play important roles in preserving BBB integrity. Pramipexole is a selective dopamine agonist applied for treating Parkinson's disease and has been recently claimed with neuroprotective capacity. This study will further explore the impact of Pramipexole on tight junctions and BBB integrity to provide the potential treatment strategy for TBI-induced BBB damage. The TBI model was established in mice and was identified by the promoted brain water content, declined Garcia scores, reduced latency of the rotarod test, aggravated pathological changes in the brain cortex, and excessively released inflammatory factors. After treatment with Pramipexole, the neurofunctional deficits, behavioral disability, and aggravated pathological changes were dramatically reversed, accompanied by the alleviated BBB permeability, and upregulated occludin, an important tight junction protein. TBI model cells were established by the scratching bEnd.3 cells method. Cells were stimulated with 10 and 20 µM Pramipexole, followed by exposure to TBI. Increased fluorescence intensity of FITC-dextran, reduced value of TEER, and downregulated occludin and KLF2 were observed in TBI-exposed cells, all of which were greatly reversed by 10 and 20 µM Pramipexole. Furthermore, in KLF2-silenced bEnd.3 cells, the protective ability of Pramipexole against endothelial permeability and the expression level of occludin were dramatically abolished. Collectively, our results suggest that Pramipexole protected against TBI-induced BBB dysfunction by mediating KLF2.

Circular RNA Circ-0003006 Promotes Hepatocellular Carcinoma Proliferation and Metastasis Through Sponging miR-542-3p and Regulating HIF-1A.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one most common cancer types among gastrointestinal cancer over the world, while its underlying mechanisms remain unclear. CircRNA has been revealed to participate in multiple biological functions and contribute to various diseases' progression. METHODS: Bioinformatic analysis of the differently expressed circRNAs in the HCC tissues, then verified by real-time quantitative PCR (RT-qPCR) assay. We found that circ-0003006 was upregulated in the HCC tissues, the cell fractionation assay and RNA fluorescence in situ hybridization (FISH) were performed to confirm the cell location of circ-0003006. shRNA silence assay was used to knock down the expression of circ-0003006 in the HCC cells. RESULTS: Cell account kit 8 (CCK-8) and transwell assay were revealed that circ-0003006 knockdown inhibited the proliferation and metastasis in HCC cells. The target miR­542­3p and target gene HIF-1A were predicted by bioinformatics analysis, then verified through biotinylated RNA pull-down and dual-luciferase reporter assays. The mechanism, circ-0003006, probably acted as a sponge of miR­542­3p and regulated HIF-1A levels in hepatocellular carcinoma cells. Moreover, HIF-1A overexpression abolished the effect of circ-0003006 inhibition on the progression of hepatocellular carcinoma cells. The subcutaneous tumor formation experiment indicated that circ-0003006 knockdown inhibited the HCC cell growth in vivo. CONCLUSION: Circ-0003006 was demonstrated to promote HCC progression in vitro and in vivo by sponging miR­542­3p to release the inhibition on HIF-1A.

RPLP1 is highly expressed in hepatocellular carcinoma tissues and promotes proliferation, invasion and migration of human hepatocellular carcinoma Hep3b cells.

Hepatocellular carcinoma (HCC) is a common primary malignant tumor with a high mortality rate. Increasing evidence suggests that ribosomal protein LP1 (RPLP1) is involved in the progression of different types of cancer. Thus, the present study aimed to investigate the underlying molecular mechanism of RPLP1 in HCC progression. The cellular behaviors of Hep3b cells were assessed via Cell Counting Kit-8, colony formation, wound healing and Transwell assays. Western blot analysis was performed to detect protein expression levels, while reverse transcription-quantitative PCR analysis was performed to detect mRNA expression levels. The results demonstrated that RPLP1 was highly expressed in HCC tissues and cells, and the overexpression of RPLP1 was associated with a less favorable prognosis of patients with HCC. Notably, downregulation of RPLP1 significantly suppressed the proliferation, migration and invasion of Hep3b cells. Taken together, the results of the present study suggested that RPLP1 acts as an oncogene in HCC, and thus may be used to treat patients with HCC.