Synthetic lethality is the synthesis of mutations leading to cell death. Tumor‐specific synthetic lethality has been targeted in research to improve cancer therapy. With the advances of techniques in ...molecular biology, such as RNAi and CRISPR/Cas9 gene editing, efforts have been made to systematically identify synthetic lethal interactions, especially for frequently mutated genes in cancers. However, elucidating the mechanism of synthetic lethality remains a challenge because of the complexity of its influencing conditions. In this study, we proposed a new computational method to identify critical functional features that can accurately predict synthetic lethal interactions. This method incorporates several machine learning algorithms and encodes protein‐coding genes by an enrichment system derived from gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways to represent their functional features. We built a random forest‐based prediction engine by using 2120 selected features and obtained a Matthews correlation coefficient of 0.532. We examined the top 15 features and found that most of them have potential roles in synthetic lethality according to previous studies. These results demonstrate the ability of our proposed method to predict synthetic lethal interactions and provide a basis for further characterization of these particular genetic combinations.
A computational analysis of synthetic lethality was performed in this study. Synthetic lethality gene pairs were encoded via enrichment theory of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Advanced computational methods were adopted to build an optimal prediction model and extract important features.
Abstract
Heterochromatin, a transcriptionally silenced chromatin domain, is important for genome stability and gene expression. Histone 3 lysine 9 methylation (H3K9me) and histone hypoacetylation are ...conserved epigenetic hallmarks of heterochromatin. In fission yeast, RNA interference (RNAi) plays a key role in H3K9 methylation and heterochromatin silencing. However, how RNAi machinery and histone deacetylases (HDACs) are coordinated to ensure proper heterochromatin assembly is still unclear. Previously, we showed that Dpb4, a conserved DNA polymerase epsilon subunit, plays a key role in the recruitment of HDACs to heterochromatin during S phase. Here, we identified a novel RNA-binding protein Dri1 that interacts with Dpb4. GFP-tagged Dri1 forms distinct foci mostly in the nucleus, showing a high degree of colocalization with Swi6/Heterochromatin Protein 1. Deletion of dri1+ leads to defects in silencing, H3K9me, and heterochromatic siRNA generation. We also showed that Dri1 physically associates with heterochromatic transcripts, and is required for the recruitment of the RNA-induced transcriptional silencing (RITS) complex via interacting with the complex. Furthermore, loss of Dri1 decreases the association of the Sir2 HDAC with heterochromatin. We further demonstrated that the C-terminus of Dri1 that includes an intrinsically disordered (IDR) region and three zinc fingers is crucial for its role in silencing. Together, our evidences suggest that Dri1 facilitates heterochromatin assembly via the RNAi pathway and HDAC.
Long noncoding RNAs (lncRNAs) evolve more rapidly than mRNAs. Whether conserved lncRNAs undergo conserved processing, localization, and function remains unexplored. We report differing subcellular ...localization of lncRNAs in human and mouse embryonic stem cells (ESCs). A significantly higher fraction of lncRNAs is localized in the cytoplasm of hESCs than in mESCs. This turns out to be important for hESC pluripotency. FAST is a positionally conserved lncRNA but is not conserved in its processing and localization. In hESCs, cytoplasm-localized hFAST binds to the WD40 domain of the E3 ubiquitin ligase β-TrCP and blocks its interaction with phosphorylated β-catenin to prevent degradation, leading to activated WNT signaling, required for pluripotency. In contrast, mFast is nuclear retained in mESCs, and its processing is suppressed by the splicing factor PPIE, which is highly expressed in mESCs but not hESCs. These findings reveal that lncRNA processing and localization are previously under-appreciated contributors to the rapid evolution of function.
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•Subcellular localization of conserved lncRNAs is different in hESCs and mESCs•Cytoplasmic hFAST but not nuclear mFast promotes WNT signaling in hESC pluripotency•PPIE regulates distinct FAST processing in hESCs and mESCs•RNA processing and localization contribute to lncRNA functional evolution
A pair of lncRNA orthologs exhibits different subcellular localization in human and murine ESCs because of differential RNA processing, which, in turn, leads to their functional divergence in the context of pluripotency regulation. The findings highlight how conserved lncRNAs may achieve functional evolution through non-conserved RNA processing.
This work investigated the metastable pitting corrosion mechanism of laser powder bed fusion (LPBF) produced Ti–6Al–4V. The passive films of samples were produced by potentiostatic polarization in ...NaCl solutions with different concentrations, and electrochemical measurements were employed to understand the influence of Cl- on the characteristics of passive films. The frequency of pitting nucleation and the pit dimension increase with increased Cl- concentration. The attack of Cl- promotes the dissolution of passive films. A higher density of oxygen vacancies is produced in passive film because of the ingressive Cl-, resulting in the condensation of voids and pitting corrosion.
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•A Ti-6Al-4V alloy was fabricated by laser powder bed fusion (LPBF) method.•Metastable pitting corrosion of the samples was investigated in NaCl solutions.•Cl- suppresses the formation of passive film formed on LPBF-produced sample.•The passive film has higher flux of oxygen vacancies in 10 wt% NaCl solution.•The condensation of cation-anion-vacancy associations triggers voids and pitting.
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•A universal strategy was adopted to produce defective Zr-MOFs like NH2-UiO-66.•The defective SS-NH2-UiO-66-X originated from the missing linker and Zr-O clusters.•SS-NH2-UiO-66-X ...displayed effective and selective adsorption toward Pb(II).
Within this work, a green and facile approach was proposed to modulate NH2-UiO-66 for purpose of obtaining SS-NH2-UiO-66-X (“X” implied the dosage of used SS) using seignette salt (SS). The generation of abundant vacancies with the formation of hierarchical pores boosted their sorption performance for lead (Pb(II)), which strengthened the mass transfer of Pb(II) in SS-NH2-UiO-66-X interior. Particularly, the optimal SS-NH2-UiO-66-5 exhibited good adsorption capacity toward Pb(II) (186.14 mg g−1) and fast diffusion rate (32.1 mg g−1·min0.5) at 25 °C and initial pH = 5.46, which were about 34.2 and 66.9 times higher than those of the pristine NH2-UiO-66, respectively. SS-NH2-UiO-66-5 could selectively capture the Pb(II) from simulated wastewater containing different co-existing ions. The mechanism was proposed that the defect sites played a significant role in boosting the Pb(II) capture performance, which was further affirmed by X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectra (XPS). The density functional theory calculations (DFT calculations) illustrated that the hierarchical pores and rich vacancies enhanced the Pb(II) mobility toward the adsorption active sites and reduced the adsorption energy between SS-NH2-UiO-66-X and Pb(II). This defect engineering approach could be introduced to modulate other Zr-MOFs like MOF-801, UiO-66 and MOF-808, which presented a general strategy to fabricate defective Zr-MOFs for the boosted adsorption performance toward pollutants removal from wastewater.
Objective
Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m) with OLP lesions, dysplastic features and ...squamous cell carcinoma (OSCC).
Materials and Methods
This is a case–control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High‐risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups.
Results
OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high‐risk habits exhibited significantly higher ZNF582m than those without high‐risk habits. However, ZNF582m in OLP patients was not affected by those high‐risk habits.
Conclusions
OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC.
Fibrillar centers (FCs) and dense fibrillar components (DFCs) are essential morphologically distinct sub-regions of mammalian cell nucleoli for rDNA transcription and pre-rRNA processing. Here, we ...report that a human nucleolus consists of several dozen FC/DFC units, each containing 2–3 transcriptionally active rDNAs at the FC/DFC border. Pre-rRNA processing factors, such as fibrillarin (FBL), form 18–24 clusters that further assemble into the DFC surrounding the FC. Mechanistically, the 5′ end of nascent 47S pre-rRNA binds co-transcriptionally to the RNA-binding domain of FBL. FBL diffuses to the DFC, where local self-association via its glycine- and arginine-rich (GAR) domain forms phase-separated clusters to immobilize FBL-interacting pre-rRNA, thus promoting directional traffic of nascent pre-rRNA while facilitating pre-rRNA processing and DFC formation. These results unveil FC/DFC ultrastructures in nucleoli and suggest a conceptual framework for considering nascent RNA sorting using multivalent interactions of their binding proteins.
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•Visualizing the ultrastructure of FC/DFC and rDNA arrangements in human nucleoli•Processing factors, such as FBL, form protein clusters and then assemble into a DFC•Self-association of GAR in FBL ensures sorting and processing of nascent 47S pre-rRNA•Nascent pre-rRNA sorting via a phase-separation mechanism promotes DFC assembly
Yao et al. unveil the FC/DFC ultrastructure and rDNA arrangements in human nucleoli and show that a phase-separation mechanism promotes nascent pre-rRNA sorting and processing and the assembly of the DFC sub-nucleolar region.
Breast cancer is regarded worldwide as a severe human disease. Various genetic variations, including hereditary and somatic mutations, contribute to the initiation and progression of this disease. ...The diagnostic parameters of breast cancer are not limited to the conventional protein content and can include newly discovered genetic variants and even genetic modification patterns such as methylation and microRNA. In addition, breast cancer detection extends to detailed breast cancer stratifications to provide subtype-specific indications for further personalized treatment. One genome-wide expression-methylation quantitative trait loci analysis confirmed that different breast cancer subtypes have various methylation patterns. However, recognizing clinically applied (methylation) biomarkers is difficult due to the large number of differentially methylated genes. In this study, we attempted to re-screen a small group of functional biomarkers for the identification and distinction of different breast cancer subtypes with advanced machine learning methods. The findings may contribute to biomarker identification for different breast cancer subtypes and provide a new perspective for differential pathogenesis in breast cancer subtypes.
Compared with green and red perovskite light‐emitting diodes (PeLEDs), the development of blue PeLEDs has been lagging due to high defect density and inferior carrier transport. Herein, a novel ...defect‐passivation strategy is proposed to fabricate efficient sky‐blue PeLEDs by using isocyanate molecules. This strategy not only significantly reduces the nonradiative recombination loss caused by defects but also improves the injection and transport capacities of carriers by reducing the confinement effect. Benefiting from the passivation engineering and the reduction of confinement effect, the prepared sky‐blue PeLEDs present a significantly improved external quantum efficiency of 12.5% at 489 nm, which is 1.5 times higher than that of the control device. Meanwhile, the universality of isocyanate‐based passivators to improve the performance of PeLEDs is also demonstrated. The finding of this study provides a new reference for the selection of novel passivation agents to construct highly efficient blue PeLEDs.
An isocyanate molecule, 2,4‐toluene diisocyanate (2,4‐TDI), is introduced into perovskite to fabricate sky‐blue perovskite light‐emitting diodes (PeLEDs). Benefiting from the passivation engineering and reduced confinement effect by 2,4‐TDI molecules, an efficient sky‐blue PeLED at 489 nm with a significantly improved external quantum efficiency of 12.5%, which is 1.5 times that of the control device is successfully fabricated.
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