Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.

High-damage-threshold mid-infrared saturable absorber enabled by tantalum carbide nanoparticles.

A stable mid-infrared saturable absorber with a high damage threshold is urgently required for high-performance optical modulation in the mid-infrared regime. Here, we demonstrate stable mid-infrared erbium-doped fiber laser generation modulated by tantalum carbide nanoparticles (TaC NPs) experimentally. The TaC NPs show high physicochemical stability, obvious nonlinear optical absorption, and a high damage threshold. By introducing the TaC-based saturable absorber into an erbium-doped fiber laser, stable nanosecond pulses can be successfully delivered with a minimum pulse duration of 575 ns and signal-to-noise ratio of over 40 dB. The experimental results show that TaC NPs can act as a stable mid-infrared pulse modulator, and may make inroads for developing highly stable broadband optoelectronic devices.

Potent NKT cell ligands overcome SARS-CoV-2 immune evasion to mitigate viral pathogenesis in mouse models.

One of the major pathogenesis mechanisms of SARS-CoV-2 is its potent suppression of innate immunity, including blocking the production of type I interferons. However, it is unknown whether and how the virus interacts with different innate-like T cells, including NKT, MAIT and γδ T cells. Here we reported that upon SARS-CoV-2 infection, invariant NKT (iNKT) cells rapidly trafficked to infected lung tissues from the periphery. We discovered that the envelope (E) protein of SARS-CoV-2 efficiently down-regulated the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein is a small membrane protein and a viroporin that plays important roles in virion packaging and envelopment during viral morphogenesis. We showed that the transmembrane domain of E protein was responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and led to their degradation. Point mutations demonstrated that the putative ion channel function was required for suppression of CD1d expression and inhibition of the ion channel function using small chemicals rescued the CD1d expression. Importantly, we discovered that among seven human coronaviruses, only E proteins from highly pathogenic coronaviruses including SARS-CoV-2, SARS-CoV and MERS suppressed CD1d expression, whereas the E proteins of human common cold coronaviruses, HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1, did not. These results suggested that E protein-mediated evasion of NKT cell function was likely an important pathogenesis factor, enhancing the virulence of these highly pathogenic coronaviruses. Remarkably, activation of iNKT cells with their glycolipid ligands, both prophylactically and therapeutically, overcame the putative viral immune evasion, significantly mitigated viral pathogenesis and improved host survival in mice. Our results suggested a novel NKT cell-based anti-SARS-CoV-2 therapeutic approach.

The roles of long noncoding RNAs in the regulation of OCT4 expression.

OCT4 is a major transcription factor that maintains the pluripotency of stem cells, including embryonic stem cells, induced pluripotent stem cells and cancer stem cells. An increasing number of long noncoding RNAs have been reported to participate in the regulation of OCT4 expression through various mechanisms, including binding with the OCT4 gene promoter to regulate local methylation; promoting chromosomal spatial folding to form an inner ring, thereby aggregating OCT4 cis-acting elements scattered in discontinuous sites of the chromosome; competitively binding microRNAs with OCT4 to upregulate OCT4 expression at the posttranscriptional level; and sharing a promoter with OCT4. Moreover, the transcription of some long noncoding RNAs is regulated by OCT4, and certain long noncoding RNAs form feedback regulatory loops with OCT4. In this review, we summarized the research progress of the long noncoding RNAs involved in the regulation of OCT4 expression.

Class C1 decoy oligodeoxynucleotide inhibits profibrotic genes expression in rat hepatic stellate cells.

The aim of the present study was to investigate whether class C1 decoy oligodeoxynucleotides (ODNs) can inhibit the expression of pro­fibrotic genes associated with rat hepatic stellate cell (HSC) activation and hepatic fibrosis. Luciferase reporter assays were performed to test the promoter activities of transforming growth factor (TGF)­ß and its downstream target genes following transfection of decoy ODNs and plasmids into HSC­T6 cells, and western blot assays were performed to measure the protein expression of those genes following decoy ODN transfection. Class C1 decoy ODNs were confirmed to inhibit the promoter activity of TGF­ß and its downstream target genes, such as type 1 collagen (COLI)α1, tissue inhibitor of metalloproteinases (TIMP)1 and α­smooth muscle actin by Gaussia luciferase reporter assay, and to further downregulate the expression of TGF­ß, SMAD3, COLIα1 and TIMP1 by western blotting in activated HSC­T6 cells. In conclusion, class C1 decoy ODNs inhibited pro­fibrotic gene expression in rat HSCS by downregulating TGF­ß signaling.

Hydrophilic Flexible Ether Containing, Cross-Linked Anion-Exchange Membrane Quaternized with DABCO.

Anion-exchange membranes (AEM) with high ion content usually suffer from excessive water absorption and dilution effects that impair conductivity and mechanical properties. We herein report a novel ether containing a cross-linking strategy without adopting high ion-exchange capacity (IEC). The ether-containing cross-links and the quaternized structure are created simultaneously by introducing an ether-containing flexible hydrophilic spacer between two 1,4-diazabicyclo[2,2,2,2]octane or DABCO molecules; the resultant bi-DABCO structure was further employed to react with chloromethylated polysulfone. The long spacer with the ether moiety may benefit the hydroxide ion transport, and the cross-links will control the swelling and water absorption of the AEM. The two ether groups in the long spacer of the cross-links will also shield the DABCO cation from OH- attack due to an electron-donating effect. The prepared membranes exhibited an improved conductivity of 31 mS/cm (at 25 °C) at a comparatively low IEC (1.08 mmol/g) with a rational water absorption and low swelling ratio (95.0 and 27.1%, respectively); they also displayed an enhanced alkaline stability in 1 M NaOH aqueous solution at 80 °C for 150 h. The density functional theory study and physical characterization after the alkaline treatment further confirm the better chemical stability of the cross-linked membrane over its counterpart. Our work presents an effective strategy to balance AEM conductivity and robustness.