Design and Analysis of the Dual-Band Far-Field Super-Resolution Metalens with Large Aperture.

The resolving power of metalens telescopes rely on their aperture size. Flat telescopes are advancing with the research on super-resolution confocal metalenses with large aperture. However, the aperture sizes of metalenses are usually bound within hundreds of micrometers due to computational and fabrication challenges, limiting their usage on practical optical devices like telescopes. In this work, we demonstrated a two-step designing method for the design of dual-band far-field super-resolution metalens with aperture sizes from the micro-scale to macro-scale. By utilizing two types of inserted unit cells, the phase profile of a dual-wavelength metalens with a small aperture of 100 µm was constructed. Through numerical simulation, the measured FWHM values of the focal spots of 5.81 µm and 6.81 µm at working wavelengths of 632.8 nm and 1265.6 nm were found to all be slightly smaller than the values of 0.61 λ/NA, demonstrating the super-resolution imaging of the designed metalens. By measuring the optical power ratio of the focal plane and the incident plane, the focusing efficiencies were 76% at 632.8 nm and 64% at 1265.6 nm. Based on the design method for small-aperture metalens, far-field imaging properties through the macro metalens with an aperture of 40 mm were simulated by using the Huygens-Fresnel principle. The simulation results demonstrate confocal far-field imaging behavior at the target wavelengths of 632.8 nm and 1265.6 nm, with a focal length of 200 mm. The design method for dual-band far-field super-resolution metalens with a large aperture opens a door towards the practical applications in the dual-band space telescope system.

FBXO30 functions as a tumor suppressor and an E3 ubiquitin ligase for hZIP1­mediated HIF­1α degradation in renal cell carcinoma.

Studies on clear cell renal cell carcinoma (ccRCC) are gaining momentum due to its high malignancy and potential to metastasize. F­box protein 30 (FBXO30) is a member of the F­box protein family; however, its role and mechanism in cancer remains to be fully elucidated. Western blotting, reverse transcription­quantitative PCR and immunohistochemsitry were performed to detect the expression levels of FBXO30 in ccRCC tissues and adjacent normal tissues. Tumor biological function assays and animal experiments were conducted to clarify the inhibitory effect of FBXO30 on the progression and metastasis of ccRCC. Protein half­life assay, MG132 inhibition assay, immunofluorescence assay and co­immunoprecipitation assay were performed to explore the ubiquitination mechanism of FBXO30 and HIF­1α. Zinc supplementation assay was used to verify the regulatory relationship between human ZRT, IRT­like protein 1 (hZIP1), FBXO30 and HIF­1α. The present study revealed that the expression levels of FBXO30 were lower in ccRCC tissues compared with those in normal adjacent tissues. In addition, FBXO30 inhibited the tumorigenesis and metastatic capacity of ccRCC cells in vivo and in vitro. FBXO30 mediated the ubiquitination and degradation of hypoxia­inducible factor­1α (HIF­1α) in ccRCC cells under normoxia, thereby inhibiting the oncogenic effect of HIF­1α. Notably, hZIP1 served as an upstream regulator of FBXO30, regulating the expression of FBXO30 and HIF­1α by recruiting Zn2+. In conclusion, the present data suggested that FBXO30 is a novel E3 ubiquitination ligase that can function as a tumor suppressor in ccRCC, and the hZIP1/Zn2+/FBXO30/HIF­1α axis may provide potential biomarkers or therapeutic targets for ccRCC.

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer.

BACKGROUND: Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. METHODS: We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. RESULTS: Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. CONCLUSIONS: In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

Recent advancements in understanding the self-assembly of macroions in solution via molecular modeling.

Macroionic solutions behave quite differently from small ions in solution or colloids in suspension, representing a previously missing and very important transitional stage, and can further be connected to solutions of polyelectrolytes, including proteins and DNA (e.g., similarities between "blackberry" formation and virus capsid formation). While synthesis and characterization have produced an immense database regarding the self-assembly behavior of macroions in solution resulting in many empirical rules and guidelines, theory and simulations are sorely needed to connect these disparate threads into a cohesive and coherent narrative of macroionic solution theory and to provide guidance for future work. We recently developed a versatile coarse-grained model specifically designed for modelling the self-assembly of macroions in solution and have answered some of the most outstanding questions about the solution behavior of macroions including the source of the attractive force between like-charged macroions and how they self-assemble into a 2D monolayer structure.

METTL14-mediated N6-methyladenosine modification of ITGB4 mRNA inhibits metastasis of clear cell renal cell carcinoma.

BACKGROUND: Integrin ß4 (ITGB4) participates in tumorigenesis and progression of several malignancies, but its role and related mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were used to detect mRNA and protein levels of relevant genes. Biological functions of ITGB4 and methyltransferase-like 14 (METTL14) were determined by in vitro and in vivo experiments. The levels of N6-methyladenosine (m6A) in ccRCC tissues and adjacent normal tissues were calculated via total RNA m6A quantification assay. The m6A modification of ITGB4 was demonstrated via m6A RNA immunoprecipitation (MeRIP), RIP and luciferase reporter assays. RESULTS: ITGB4 was significantly overexpressed in ccRCC tissues and high level of ITGB4 predicted poor prognosis as well as metastasis. Functionally, ITGB4 stimulated ccRCC cell migration and invasion in vitro and metastasis in vivo with epithelial-mesenchymal transition (EMT) strengthened. Mechanically, the total levels of m6A were reduced in ccRCC tissues. METTL14, a favorable factor for ccRCC patients' prognosis, facilitated m6A modification on ITGB4 3'UTR and subsequently accelerated ITGB4 mRNA degradation, leading to its declined expression. Furthermore, the METTL14-mediated inhibition of ITGB4 expression was dependent on the YTH domain family protein 2 (YTHDF2), which acted as an m6A reader to bind to ITGB4 mRNA and to promote its decay. In addition, we demonstrated that knockdown of METTL14 promoted ccRCC cell migration, invasiveness and metastasis as well as stimulating the EMT process and the PI3K/AKT signal by overexpressing ITGB4. CONCLUSION: Our study reveals that METTL14 inhibits ITGB4 expression via m6A modification to attenuate metastasis and EMT of ccRCC cells, suggesting the METTL14/ITGB4 axis as a potential prognostic biomarker and therapeutic target for ccRCC. Video Abstract.

Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2.

Dysregulation of deubiquitination has been reported to contribute to carcinogenesis. However, the function and mechanism of deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of ovarian cancer (OV), the deadliest gynecological cancer, still remains to be characterized. The present study demonstrated that PSMD14 was overexpressed in OV tissues and its higher levels correlated with a higher International Federation of Gynecology and Obstetrics (FIGO) stage in OV patients. A high level of PSMD14 expression was related to poor survival in OV patients. Knockdown and overexpression experiments elucidated that PSMD14 stimulated OV cell proliferation, invasion, and migration in vitro. Repression of PSMD14 suppressed OV tumor growth in vivo. PSMD14 inhibitor O-phenanthroline (OPA) effectively attenuated malignant behaviors of OV cells in vitro and OV tumor growth in vivo. Mechanistically, we uncovered that PSMD14 was involved in post-translational regulation of pyruvate kinase M2 isoform (PKM2). PSMD14 decreased K63-linked ubiquitination on PKM2, downregulated the ratio of PKM2 tetramers to dimers and monomers, and subsequently diminished pyruvate kinase activity and induced nuclear translocation of PKM2, contributing to aerobic glycolysis in OV cells. Collectively, our findings highlight the potential roles of PSMD14 as a biomarker and therapeutic candidate for OV.

METTL13 inhibits progression of clear cell renal cell carcinoma with repression on PI3K/AKT/mTOR/HIF-1α pathway and c-Myc expression.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported. METHODS: qRT-PCR, western blotting and immunohistochemistry were used to detect METTL13's expression in tissues. The effects of METTL13 on ccRCC cells' growth and metastasis were determined by both functional experiments and animal experiments. Weighted gene co-expression network analysis (WGCNA) was performed to annotate METTL13's functions and co-immunoprecipitation (co-IP) was used to determine the interaction between METTL13 and c-Myc. RESULTS: METTL13 was underexpressed in ccRCC tissues compared to normal kidney tissues and its low expression predicted poor prognosis for ccRCC patients. The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells' proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT). The in vivo experiment demonstrated the inhibitory effect that METTL13 had on ccRCC cells' growth and metastasis. Bioinformatic analyses showed various biological functions and pathways METTL13 was involved in. In ccRCC cells, we observed that METTL13 could negatively regulate PI3K/AKT/mTOR/HIF-1α pathway and that it combined to c-Myc and inhibited c-Myc protein expression. CONCLUSIONS: In general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients. Meanwhile, METTL13 can inhibit growth and metastasis of ccRCC cells with participation in multiple potential molecular mechanisms. Therefore, we suggest METTL13 can be a new diagnostic and therapeutic target for ccRCC in the future.

TMEM119 facilitates ovarian cancer cell proliferation, invasion, and migration via the PDGFRB/PI3K/AKT signaling pathway.

BACKGROUND: Ovarian cancer (OV) is the deadliest gynecological cancer. Transmembrane protein 119 (TMEM119) has been reported as oncogene in several human cancers. However, the function of TMEM119 in OV is still poorly known. METHODS: Western blot and qRT-PCR were used to analyze TMEM119 levels. Transwell assays, wound healing assays, CCK-8 assays and EdU cell proliferation assays were designed to explore the function and potential mechanism of TMEM119 in malignant biological behaviors in OV. RESULTS: TMEM119 was observed to be overexpressed in OV tissues and associated with poor survival in OV patients. Knockdown and overexpression experiments demonstrated that TMEM119 promoted proliferation, invasion, and migration in OV cells in vitro. TMEM119 mRNA expression was related to the pathways of focal adhesion according to Gene Set Enrichment Analyses and was correlated with the mRNA expression level of platelet-derived growth factor receptor beta (PDGFRB). TMEM119 exerted oncogenic effects partially by regulating the expression of PDGFRB and by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Collectively, our findings highlight the potential role of TMEM119 in the malignant biological behavior of OV, which may serve as a potential biomarker and a therapeutic candidate for OV.

An 18-gene signature based on glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer.

BACKGROUND: Glucose metabolism and DNA methylation play important roles in cancers. We aimed to identify glucose metabolism-related genes that were DNA methylation associated to establish a prognostic signature of bladder cancer (BLCA). METHODS: With BLCA sample transcriptome data from The Cancer Genome Atlas (TCGA) and methylation data from TCGA 450 K microarray, glucose metabolism-related genes associated to prognosis and DNA methylation were identified and a prognostic signature was established. GSEA and WGCNA analysis were performed and two genes, UCHL1 and PYCR1, were selected for functional validations. RESULTS: 18 target genes were identified and the signature based on them was considered an effective and independent prognostic factor. Several pathways were enriched in the high-risk group by GSEA and three modules of genes were identified by WGCNA. UCHL1 and PYCR1 proliferated proliferation, migration and invasion ability of bladder cancer cells. CONCLUSIONS: The 18-gene signature is an independent prognostic factor for bladder cancer patients.

The role of ubiquitination and deubiquitination in cancer metabolism.

Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

SLC7A2 serves as a potential biomarker and therapeutic target for ovarian cancer.

The solute carrier (SLC) family is the largest group of membrane transporters, but their functions in ovarian cancer (OV) remain unclear. We analyzed SLC family members with amino acids-transporting functions in OV. The mRNA expression levels and prognostic values of SLCs in OV were analyzed in the Gene Expression Profiling Interactive Analysis and Kaplan-Meier Plotter database. Solute carrier family 7 member 2 (SLC7A2), which showed differential expression and the most significant prognostic value, was selected for further analyses. The cBioPortal database, Gene Set Enrichment Analysis and Weighted Correlation Network Analysis were used to explore the potential functions and molecular mechanisms of SLC7A2 in OV. Validations in our own samples and in Gene Expression Omnibus datasets were conducted. Functional validation in OV cell lines was carried out. In total, 73 SLC family members were analyzed. Seven members were upregulated while 11 members were downregulated in OV and 15 members were protective factors for prognosis while 12 members were risk factors. SLC7A2 was downregulated in OV, and it was positively associated with prognosis. Knockdown of SLC7A2 promoted viability, invasion and migration of OV cells. These SLC family members and in particular SLC7A2 represented novel biomarkers for diagnosis and treatment for OV.

Unique Symmetry-Breaking Phenomenon during the Self-assembly of Macroions Elucidated by Simulation.

Various soluble hydrophilic macroions can self-assemble into hollow, spherical, monolayered supramolecular "blackberry"-type structures, despite their like-charged nature. However, how the 3-D symmetrical macroions prefer to form 2-D monolayers in bulk solution, especially for the highly symmetrical "Keplerate" polyoxometalates and functionalized C60 macroions has been a mystery. Through molecular dynamics simulations, using a model specifically designed for macroions in solution, the mechanism of this intriguing symmetry-breaking process is found to be related to the apparently asymmetric charge distribution on the surface of macroions in the equatorial belt area (the area which can be effectively involved in the counterion-mediated attraction). As a result, the electric field lines around macroions during the self-assembly process clearly show that the symmetry-breaking happens at the dimer level effectively defining the plane of the self-assembly. These findings are expected to contribute to our fundamental knowledge of complex solution systems that are found in many fields from materials science to biological phenomena.

Illustrating the Molecular Origin of Mechanical Stress in Ductile Deformation of Polymer Glasses.

New experiments show that tensile stress vanishes shortly after preyield deformation of polymer glasses while tensile stress after postyield deformation stays high and relaxes on much longer time scales, thus hinting at a specific molecular origin of stress in ductile cold drawing: chain tension rather than intersegmental interactions. Molecular dynamics simulation based on a coarse-grained model for polystyrene confirms the conclusion that the chain network plays an essential role, causing the glassy state to yield and to respond with a high level of intrachain retractive stress. This identification sheds light on the future development regarding an improved theoretical account for molecular mechanics of polymer glasses and the molecular design of stronger polymeric materials to enhance their mechanical performance.

Cation Translocation around Single Polyoxometalate-Organic Hybrid Cluster Regulated by Electrostatic and Cation-π Interactions.

We report herein an interesting dynamic translocation process of countercations around one polyoxometalate(POM)-organic hybrid anionic cluster at various concentrations and temperatures. It was found that both electrostatic interactions and cation-π interactions regulate the position of small countercations around single clusters. The dynamic geometry and the symmetry of the hybrid macroions are largely affected by the type of counterions, as shown by nuclear magnetic resonance (NMR) spectroscopy studies and all-atom molecular dynamics simulation. It is also shown that electrostatic interactions dominate over cation-π interactions in determining the locations of the counterions in the current system.

Carbon Nanotube Based Groundwater Remediation: The Case of Trichloroethylene.

Adsorption of chlorinated organic contaminants (COCs) on carbon nanotubes (CNTs) has been gaining ground as a remedial platform for groundwater treatment. Applications depend on our mechanistic understanding of COC adsorption on CNTs. This paper lays out the nature of competing interactions at play in hybrid, membrane, and pure CNT based systems and presents results with the perspective of existing gaps in design strategies. First, current remediation approaches to trichloroethylene (TCE), the most ubiquitous of the COCs, is presented along with examination of forces contributing to adsorption of analogous contaminants at the molecular level. Second, we present results on TCE adsorption and remediation on pure and hybrid CNT systems with a stress on the specific nature of substrate and molecular architecture that would contribute to competitive adsorption. The delineation of intermolecular interactions that contribute to efficient remediation is needed for custom, scalable field design of purification systems for a wide range of contaminants.

Elucidating the Origin of the Attractive Force among Hydrophilic Macroions.

Coarse-grained simulation approach is applied to provide a general understanding of various soluble, hydrophilic macroionic solutions, especially the strong attractions among the like-charged soluble macroions and the consequent spontaneous, reversible formation of blackberry structures with tunable sizes. This model captures essential molecular details of the macroions and their interactions in polar solvents. Results using this model provide consistent conclusions to the experimental observations, from the nature of the attractive force among macroions (counterion-mediated attraction), to the blackberry formation mechanism. The conclusions can be applied to various macroionic solutions from inorganic molecular clusters to dendrimers and biomacromolecules.