Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report ...that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1
and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.
A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.
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Vanadium (V) is sensitive to minute quantity of oxygen interstitials, which induce pronounced hardening and embrittlement. Here, we utilize oxygen to synthesize V solid solutions in order to reveal ...the mechanism of oxygen solutes induced hardening. With increasing of oxygen solute concentrations, the fracture modes of V samples transform from dimple, to a mixture of dimple and cleavage, and to a fully transgranular cleavage. High density of dislocations and dislocation debris are produced in strained samples. The mobility of screw dislocations is reduced and the dislocation cross-slip events are promoted by oxygen solutes. In addition to oxygen solution hardening, the generation of high density of oxygen-vacancy complexes plays a dominant role in the strengthening. High quantity of loop-shaped dislocation debris are direct evidence for the formation of oxygen-vacancy complexes. Profuse oxygen-vacancy complexes trap dislocations, promote cross-slips and assist dislocation storage, thus give rise to a superior combination of strengthening, strain hardening, and ductility in V with 1.0 at% of oxygen. Once beyond a critical oxygen concentration (>1.6 at%), V shows catastrophic brittle failure due to the exceptional high density of oxygen-vacancy complexes. These findings provide insight to design high performance refractory metals utilizing oxygen solutes.
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Charcot‐Marie‐Tooth disease (CMT) is one of the most common inherited neurodegenerative disorders with an increasing number of CMT‐associated variants identified as causative factors, however, there ...has been no effective therapy for CMT to date. Aminoacyl‐tRNA synthetases (aaRS) are essential enzymes in translation by charging amino acids onto their cognate tRNAs during protein synthesis. Dominant monoallelic variants of aaRSs have been largely implicated in CMT. Some aaRSs variants affect enzymatic activity, demonstrating a loss‐of‐function property. In contrast, loss of aminoacylation activity is neither necessary nor sufficient for some aaRSs variants to cause CMT. Instead, accumulating evidence from CMT patient samples, animal genetic studies or protein conformational analysis has pinpointed toxic gain‐of‐function of aaRSs variants in CMT, suggesting complicated mechanisms underlying the pathogenesis of CMT. In this review, we summarize the latest advances in studies on CMT‐linked aaRSs, with a particular focus on their functions. The current challenges, future direction and the promising candidates for potential treatment of CMT are also discussed.
Variants of some aminoacyl‐tRNA synthetases (aaRS) are strongly associated with Charcot–Marie–Tooth disease (CMT), one of the most common inherited neuromuscular disorders. Some variants affect enzymatic activity, showing loss‐of‐function effects. In contrast, evidence from CMT patient samples, animal genetic studies or protein conformational analysis has confirmed toxic gain‐of‐function of some aaRSs variants in CMT outside of aminoacylation. In this review, we will discuss the latest advances in studies on CMT‐associated aaRSs, with a particular focus on the complicated mechanisms in the pathogenesis of CMT.
Body-centered cubic metals including steels and refractory metals suffer from an abrupt ductile-to-brittle transition (DBT) at a critical temperature, hampering their performance and applications. ...Temperature-dependent dislocation mobility and dislocation nucleation have been proposed as the potential factors responsible for the DBT. However, the origin of this sudden switch from toughness to brittleness still remains a mystery. Here, we discover that the ratio of screw dislocation velocity to edge dislocation velocity is a controlling factor responsible for the DBT. A physical model was conceived to correlate the efficiency of Frank-Read dislocation source with the relative mobility of screw versus edge dislocations. A sufficiently high relative mobility is a prerequisite for the coordinated movement of screw and edge segments to sustain dislocation multiplication. Nanoindentation experiments found that DBT in chromium requires a critical mobility ratio of 0.7, above which the dislocation sources transition from disposable to regeneratable ones. The proposed model is also supported by the experimental results of iron, tungsten, and aluminum.
Abstract
Zirconium alloys are widely used structural materials of choice in the nuclear industry due to their exceptional radiation and corrosion resistance. However long-time exposure to irradiation ...eventually results in undesirable shape changes, irradiation growth, that limit the service life of the component. Crystal defects called loops, routinely seen no smaller than 13 nm in diameter, are the source of the problem. How they form remains a matter of debate. Here, using transmission electron microscopy, we reveal the existence of a novel defect, nanoscale triangle-shaped vacancy plates. Energy considerations suggest that the collapse of the atomically thick triangle-shaped vacancy platelets can directly produce dislocation loops. This mechanism agrees with experiment and implies a characteristic incubation period for the formation of dislocation loops in zirconium alloys.
The plasticity of body-centered cubic (BCC) metals is sensitive to interstitial trace impurities. Owing to high oxygen affinity, vanadium (V) shows a tendency of embrittlement with increasing oxygen ...concentration. However, how oxygen solutes affect the ductile-to-brittle transition (DBT) behavior of V remains unclear. In this study, we investigate the DBT behavior of V with different oxygen solute concentrations using small-punch test. As oxygen content increases, the DBT temperature (DBTT) rises incrementally accompanied by a widening of the semi-brittle transition zone. The reduction of the lower fracture energy plateaus indicates a classical low-temperature embrittlement, while the rising of the upper fracture energy plateaus manifests a remarkable high-temperature toughening. Below DBTT, owing to the strong pinning effect of oxygen-vacancy complexes on dislocations, only a limited number of slip systems were activated with very low dislocation density, and all screw dislocations are immobile. Above DBTT, owing to the intensive interactions between dislocation and oxygen-vacancy complexes, frequent dislocation cross-slips trigger multiple slip systems and accelerate dislocation multiplication and storage, all of which contribute to the high-temperature toughness. These findings clarify the effect of oxygen solute on the DBT of V and guide the design of high-performance refractory metals.
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In this work, we employ transmission electron microscopy and helium ion irradiation to study the response of biphase interfaces to radiation induced point defect fluxes from the two adjoining phases. ...Analysis of interface-affected defect accumulation was carried out over a wide range of radiation damage levels from near zero displacement per atom (dpa) to 16 dpa and helium concentrations of 0 at.% to 8 at.%. Results show a strong interface density dependence in which Cu/Ag interfaces in the nanolayered regions spaced <500 nm were remarkably microstructural stable over the entire range without accumulating micro-scale defects, while those spaced >1 μm apart were destroyed. We report the concomitant development of a bubble-free zone in Cu that was independent of defect levels and interface-contacting bubbles zone in Ag. This finding is explained by bias segregation to the interface of interstitials from Ag and vacancies to misfit dislocation nodes in the interface from Cu. The point defect transfer across the interface can be explained by the spatial variation in interface pressure within the interface and gradient in pressure across the interface, both originating from the lattice mismatch and surface energy difference between the two crystals.
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Zirconium (Zr) hydrides threaten the reliability of fuel assembly and have repeatedly induced failures in cladding tubes and pressure vessels. Thus, they attract a broad range of research interests. ...For example, delayed hydride cracking induced a severe fracture and failure in a Zircaloy-2 pressure tube in 1983, causing the emergency shutdown of the Pickering nuclear reactor. Hydride has high hardness and very low toughness, and it tends to aggregate toward cooler or tensile regions, which initiates localized hydride precipitation and results in delayed hydride cracking. Notably, hydride reorientation under tensile stress substantially decreases the fracture toughness and increases the ductile-to-brittle transition temperature of Zr alloys, which reduces the safety of the long-term storage of spent nuclear fuel. Therefore, improving our knowledge of Zr hydrides is useful for effectively controlling hydride embrittlement in fuel assembly. The aim of this review is to reorganize the mechanisms of hydride nucleation and growth behaviors, hydride reorientation under external stress, and hydride-induced embrittlement. We revisit important examples of progress of research in this field and emphasize the key future aspects of research on Zr hydrides.
The inherent ductile-to-brittle transition (DBT) behavior of body-centered cubic (BCC) metals severely limits their applications, and leads to low-temperature brittleness. To enhance the low ...temperature toughness of BCC metals, we take chromium as an example and design a fine-grained structure with average grain size of 5 μm, which shows a substantial decrease of DBT temperature to -36 °C. Compared with other samples with larger average grain sizes (45–135 μm), the fine-grained chromium still exhibits excellent toughness at -20 °C, and has the highest fracture energy and the yielding load. Our results reveal that numerous grain boundaries act as dislocation sources to emit easy glide edge dislocations at low temperature and also effectively slow down crack propagation, all together toughen ambient brittle chromium.
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Abstract
Motivation
The large-scale multidimensional omics data in the Genomic Data Commons (GDC) provides opportunities to investigate the crosstalk among different RNA species and their regulatory ...mechanisms in cancers. Easy-to-use bioinformatics pipelines are needed to facilitate such studies.
Results
We have developed a user-friendly R/Bioconductor package, named GDCRNATools, for downloading, organizing and analyzing RNA data in GDC with an emphasis on deciphering the lncRNA-mRNA related competing endogenous RNAs regulatory network in cancers. Many widely used bioinformatics tools and databases are utilized in our package. Users can easily pack preferred downstream analysis pipelines or integrate their own pipelines into the workflow. Interactive shiny web apps built in GDCRNATools greatly improve visualization of results from the analysis.
Availability and implementation
GDCRNATools is an R/Bioconductor package that is freely available at Bioconductor (http://bioconductor.org/packages/devel/bioc/html/GDCRNATools.html). Detailed instructions, manual and example code are also available in Github (https://github.com/Jialab-UCR/GDCRNATools).
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