DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.

Tumor Cell-Intrinsic BTLA Receptor Inhibits the Proliferation of Tumor Cells via ERK1/2.

B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that mediates the escape of tumor cells from immunosurveillance. Consequently, BTLA and its ligand herpesvirus entry mediator (HVEM) are potentially immunotherapeutic targets. However, the potential effects of BTLA on tumor cells remain incompletely unknown. Here, we show that BTLA is expressed across a broad range of tumor cells. The depletion of BTLA or HVEM promotes cell proliferation and colony formation, which is reversed by the overexpression of BTLA in BTLA knockout cells. In contrast, overexpression of BTLA or HVEM inhibits tumor cell proliferation and colony formation. Furthermore, the proliferation of a subpopulation with high BTLA was also significantly slower than that of the low BTLA subpopulation. Mechanistically, the coordination of BTLA and HVEM inhibits its major downstream extracellular regulated protein kinase (ERK1/2) signaling pathway, thus preventing tumor cell growth. This study demonstrates that tumor cell-intrinsic BTLA/HVEM is a potential tumor suppressor and is likely to have a potential antagonist for immunotherapy, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry.

After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27-retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.

LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival.

Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.

DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression.

Aberrant N 6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.

Impact of coupling topology upon noise robustness of small optical reservoirs.

In this work, we perform the numerical investigation of the performance of the small optical reservoir computing (RC) systems with four neurons using the commercial software for optical fiber communication system. The small optical RC system consists of the components of the optical fiber communication. The nonlinear function which is required in RC is provided by the erbium-doped optical fiber amplifiers (EDFA). We demonstrate that the EDFA should be operated in the saturated or non-linear regime to obtain a better performance of the small optical RC system. The performance of the small optical RC systems for different topological neuron structures is investigated. The results show that the interconnection between the neurons could offer a better performance than the systems without interconnection between the neurons. Moreover, the input signals with different noise levels are launched into the systems. The results show that the small optical RC system can classify the noisy input optical waveforms even when the signal-to-noise ratio is as low as - 2.55 dB.

Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy.

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

Carrier Transport and Recombination Mechanism in Blue Phosphorescent Organic Light-Emitting Diode with Hosts Consisting of Cabazole- and Triazole-Moiety.

In this study, we demonstrated a blue phosphorescent organic light-emitting diode (BPOLED) based on a host with two carbazole and one trizole (2CbzTAZ) moiety, 9,9'-(2-(4,5-diphenyl-4H-1,2,4-triazol-3-yl)-1,3-phenylene)bis(9H-carbazole), that exhibits bipolar transport characteristics. Compared with the devices with a carbazole host (N,N'-dicarbazolyl-3,5-benzene, (mCP)), triazole host (3-(biphenyl-4-yl)-5-(4-tert-butylphenyl)-4-phenyl-4H-1,2,4-triazole, (TAZ)), or a physical mixture of mCP:TAZ, which exhibit hole, electron, and bipolar transport characteristics, respectively, the BPOLED with the bipolar 2CbzTAZ host exhibited the lowest driving voltage (6.55 V at 10 mA/cm2), the highest efficiencies (maximum current efficiency of 52.25 cd/A and external quantum efficiency of 23.89%), and the lowest efficiency roll-off, when doped with bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium(III) (FIrpic) as blue phosphor. From analyses of light leakage of the emission spectra of electroluminescence, transient electroluminescence, and partially doped OLEDs, it was found that the recombination zone was well confined inside the emitting layer and the recombination rate was most efficient in a 2CbzTAZ-based OLED. For the other cases using mCP, TAZ, and mCP:TAZ as hosts, electrons and holes transported with different routes that resulted in carrier accumulation on different organic molecules and lowered the recombination rate.

WW Domain-Containing Proteins YAP and TAZ in the Hippo Pathway as Key Regulators in Stemness Maintenance, Tissue Homeostasis, and Tumorigenesis.

The Hippo pathway is a conserved signaling pathway originally defined in Drosophila melanogaster two decades ago. Deregulation of the Hippo pathway leads to significant overgrowth in phenotypes and ultimately initiation of tumorigenesis in various tissues. The major WW domain proteins in the Hippo pathway are YAP and TAZ, which regulate embryonic development, organ growth, tissue regeneration, stem cell pluripotency, and tumorigenesis. Recent reports reveal the novel roles of YAP/TAZ in establishing the precise balance of stem cell niches, promoting the production of induced pluripotent stem cells (iPSCs), and provoking signals for regeneration and cancer initiation. Activation of YAP/TAZ, for example, results in the expansion of progenitor cells, which promotes regeneration after tissue damage. YAP is highly expressed in self-renewing pluripotent stem cells. Overexpression of YAP halts stem cell differentiation and yet maintains the inherent stem cell properties. A success in reprograming iPSCs by the transfection of cells with Oct3/4, Sox2, and Yap expression constructs has recently been shown. In this review, we update the current knowledge and the latest progress in the WW domain proteins of the Hippo pathway in relevance to stem cell biology, and provide a thorough understanding in the tissue homeostasis and identification of potential targets to block tumor development. We also provide the regulatory role of tumor suppressor WWOX in the upstream of TGF-ß, Hyal-2, and Wnt signaling that cross talks with the Hippo pathway.

Comparative transcriptome analysis reveals relationship of three major domesticated varieties of Auricularia auricula-judae.

Auricularia auricula-judae is an edible mushroom and a traditional medicine in China as well as the fourth largest cultivated mushroom species in the world. Here for the first time, we present comparative transcriptome analyses of the fruiting bodies of three morphologically distinguishable A. auricula-judae cultivated varieties (Wujin, smooth; Banjin, partially wrinkled; and Quanjin, fully wrinkled) collected from Jilin Province, China. Biological triplicates were performed to determine the expression levels of 13,937 unigenes. Among them, only 13 unigenes were annotated to A. auricula-judae, highlighting the lack of publicly available reference sequences for this economically important species. Principal component analysis (PCA) determined that the gene expression profile of Quanjin was unique when compared to those of Banjin and Wujin. Such relationships were further supported by analyses of annotated and unannotated unigenes, differentially expressed unigenes, gene ontology functions, and the family of peroxidase genes. Using the KEGG database, significant alternations in biological pathways were detected among the three cultivars. This work contributes a large set of A. auricula-judae sequences to public database, establishes the relationships among major cultivars, and provides molecular guidance for breeding and cultivation.

Long non-coding RNA MYU promotes prostate cancer proliferation by mediating the miR-184/c-Myc axis.

Long non-coding RNAs (lncRNAs) play critical roles in tumorigenesis and cancer progression. The c-Myc upregulated lncRNA MYU (VPS9D1 antisense RNA1, annotated as VPS9D1-AS1) has been reported in several common types of human cancers, which has revealed that lncRNA MYU could function as either an oncogene or a tumor-suppressor gene in different cancer types. However, the function of lncRNA MYU in prostate cancer remains unknown. In the present study, we demonstrated that lncRNA MYU is significantly upregulated in prostate cancer tissues. MYU knockdown impaired prostate cancer cell growth and migration as shown from cell viability, colony formation, Transwell and wound healing assays. In contrast, MYU overexpression displayed opposite effects. No correlation was noted between MYU and its cognate VPS9D1 expression level. Moreover, lncRNA MYU did not regulate the expression of VPS9D1 either at the mRNA or protein level as detected using qRT-PCR and western blotting assays. Furthermore, lncRNA MYU was able to be transported into the extracellular milieu by means of exosomes, and then promoted adjacent cell proliferation and migration. Mechanistically, lncRNA MYU upregulated c-Myc by competitively binding miR-184 and then induced the proliferation of prostate cancer. Thus, this study demonstrated that lncRNA MYU functions as an oncogene in prostate cancer at least in part through the miR-184/c-Myc axis, and may serve as a potential diagnostic biomarker and therapeutic target.

The long non-coding RNA PCSEAT exhibits an oncogenic property in prostate cancer and functions as a competing endogenous RNA that associates with EZH2.

Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer deaths in males. Recent studies demonstrate that long non-coding RNAs (lncRNAs) are involved in many aspects of PCa. However, their biological roles in PCa remain imperfectly understood. Here,wecharacterized anlncRNA, PCaspecific expression and EZH2-associatedtranscript (PCSEAT, annotated as PRCAT38), which is specifically overexpressedin PCa. We further demonstrated that knockdown of PCSEAT results in the reduction of PCa cell growth and motility, and overexpression of PCSEAT reverses these phenotypes. Furthermore, bioactive PCSEAT is incorporated into exosomes and transmitted to adjacent cells, thus promoting cell proliferation and motility. Mechanistically, we found that PCSEAT promotes cell proliferation, at least in part by affecting miR-143-3p- and miR-24-2-5p-mediated regulation of EZH2, suggesting that PCSEAT and EZH2 competitively 'sponge' miR-143-3p and miR-24-2-5p.Overall, ourresultsrevealthat PCSEAT is specifically overexpressed in PCa patients and a potential oncogene in PCa cells via mediating EZH2 activity, indicating that PCSEAT may be a potential therapeutic target in PCa.

An oleaginous filamentous microalgae Tribonema minus exhibits high removing potential of industrial phenol contaminants.

Discharge of industrial phenol contaminants could cause great harm on natural environment. Through oleaginous microalgae cultivation in phenolic wastewater, pollutants can be phototrophically biofixed into biomass as feedstock for bioenergy production. It was firstly reported in this study that, an oleaginous filamentous microalgae Tribonema minus exhibited strong environmental phenol removal ability. T. minus filaments showed 449.46mgg-1 of phenol-uptake capacity, obviously higher than those strains with low phenol absorption such as Scenedesmus dimorphus. And phenols could be removed efficiently at the initial phenol concentration up to 700mgL-1. Simultaneously, through T. minus growth, phenol concentration could be decreased from 100mgL-1 to the range of 0.1-0.5mgL-1, which meet industrial discharge need of phenol contaminants in most countries. So Tribonema minus is a potential algal specie to help the construction of integrated process for both oleaginous biomass production and bioremediation of phenol contaminants.

Looking into meta-atoms of plasmonic nanowire metamaterial.

Nanowire-based plasmonic metamaterials exhibit many intriguing properties related to the hyperbolic dispersion, negative refraction, epsilon-near-zero behavior, strong Purcell effect, and nonlinearities. We have experimentally and numerically studied the electromagnetic modes of individual nanowires (meta-atoms) forming the metamaterial. High-resolution, scattering-type near-field optical microscopy has been used to visualize the intensity and phase of the modes. Numerical and analytical modeling of the mode structure is in agreement with the experimental observations and indicates the presence of the nonlocal response associated with cylindrical surface plasmons of nanowires.

Enhancing bright-field image of microorganisms by local plasmon of Ag nanoparticle array.

Inspecting biological cells with bright-field light microscopy often engenders a challenge, owing to their optical transparency. We show that imaging contrast can be greatly enhanced as yeast cells are placed on a silver nanoparticle array. Its near- and far-field traits, revealed by electrodynamic simulations, illustrate that the enhancement is attributed to the sensitivity of its plasmonic characteristics to the attached cells. This study demonstrates that the silver nanoparticle array can serve as the agent for concurrently enhancing Raman scattering and imaging contrast of microorganisms for identification and examination.

Revealing local, enhanced optical field characteristics of Au nanoparticle arrays with 10 nm gap using scattering-type scanning near-field optical microscopy.

Anomalous optical properties displayed by plasmonic structures are commonly attributed to the enhanced, local field within their corrugations. Though theoretical calculations of such field enhancements abound, experimental observations are relatively few, because only few optical microscopic techniques have enough spatial resolution. We used scattering-type scanning near-field optical microscopy to resolve local optical characteristics of a gold nanoparticle array with 10 nm gap between adjacent particles. Subnanometer-resolution measurement of the optical field intensity was achieved by use of etched silicon atomic force microscopy probe tip. The result shows that, with a p-polarized excitation scheme, the induced field is enhanced and the phase undergoes a large change in the gap region. The spatially-resolved signals are attributed to the electromagnetic interaction within an array of vertical dipoles. We show that scattering-type near-field optical microscopy is well-suited to the investigation of field enhancements in plasmon-enhanced sensing and spectroscopy array structures.

Transparent Raman-enhancing substrates for microbiological monitoring and in situ pollutant detection.

Opaque Raman-enhancing substrates made of Ag nanoparticles on incompletely oxidized aluminum templates have been rendered transparent by an ion-drift process to complete the oxidation. The result shows that the transparent substrates exhibit high/uniform surface-enhanced Raman scattering (SERS) capability and good optical transmissivity, allowing for concurrent SERS characterization and high contrast transmission-mode optical imaging of S. aureus bacteria. We also demonstrate that the transparent substrates can used in conjunction with optical fibers as SERS sensors for in situ detection of malachite green down to 10(-9) M.