Identification of an RNA-binding perturbing characteristic for thiopurine drugs and their derivatives to disrupt CELF1-RNA interaction.

RNA-binding proteins (RBPs) are attractive targets in human pathologies. Despite a number of efforts to target RBPs with small molecules, it is still difficult to develop RBP inhibitors, asking for a deeper understanding of how to chemically perturb RNA-binding activity. In this study, we found that the thiopurine drugs (6-mercaptopurine and 6-thioguanine) effectively disrupt CELF1-RNA interaction. The disrupting activity relies on the formation of disulfide bonds between the thiopurine drugs and CELF1. Mutating the cysteine residue proximal to the RNA recognition motifs (RRMs), or adding reducing agents, abolishes the disrupting activity. Furthermore, the 1,2,4-triazole-3-thione, a thiopurine analogue, was identified with 20-fold higher disrupting activity. Based on this analogue, we found that compound 9 disrupts CELF1-RNA interaction in living cells and ameliorates CELF1-mediated myogenesis deficiency. In summary, we identified a thiol-mediated binding mechanism for thiopurine drugs and their derivatives to perturb protein-RNA interaction, which provides novel insight for developing RBP inhibitors. Additionally, this work may benefit the pharmacological and toxicity research of thiopurine drugs.

Hypoxia is fine-tuned by Hif-1α and regulates mesendoderm differentiation through the Wnt/ß-Catenin pathway.

BACKGROUND: Hypoxia naturally happens in embryogenesis and thus serves as an important environmental factor affecting embryo development. Hif-1α, an essential hypoxia response factor, was mostly considered to mediate or synergistically regulate the effect of hypoxia on stem cells. However, the function and relationship of hypoxia and Hif-1α in regulating mesendoderm differentiation remains controversial. RESULTS: We here discovered that hypoxia dramatically suppressed the mesendoderm differentiation and promoted the ectoderm differentiation of mouse embryonic stem cells (mESCs). However, hypoxia treatment after mesendoderm was established promoted the downstream differentiation of mesendoderm-derived lineages. These effects of hypoxia were mediated by the repression of the Wnt/ß-Catenin pathway and the Wnt/ß-Catenin pathway was at least partially regulated by the Akt/Gsk3ß axis. Blocking the Wnt/ß-Catenin pathway under normoxia using IWP2 mimicked the effects of hypoxia while activating the Wnt/ß-Catenin pathway with CHIR99021 fully rescued the mesendoderm differentiation suppression caused by hypoxia. Unexpectedly, Hif-1α overexpression, in contrast to hypoxia, promoted mesendoderm differentiation and suppressed ectoderm differentiation. Knockdown of Hif-1α under normoxia and hypoxia both inhibited the mesendoderm differentiation. Moreover, hypoxia even suppressed the mesendoderm differentiation of Hif-1α knockdown mESCs, further implying that the effects of hypoxia on the mesendoderm differentiation were Hif-1α independent. Consistently, the Wnt/ß-Catenin pathway was enhanced by Hif-1α overexpression and inhibited by Hif-1α knockdown. As shown by RNA-seq, unlike hypoxia, the effect of Hif-1α was relatively mild and selectively regulated part of hypoxia response genes, which fine-tuned the effect of hypoxia on mESC differentiation. CONCLUSIONS: This study revealed that hypoxia is fine-tuned by Hif-1α and regulates the mesendoderm and ectoderm differentiation by manipulating the Wnt/ß-Catenin pathway, which contributed to the understanding of hypoxia-mediated regulation of development.

Mutagenesis and Resistance Development of Bacteria Challenged by Silver Nanoparticles.

Because of their extremely broad spectrum and strong biocidal power, nanoparticles of metals, especially silver (AgNPs), have been widely applied as effective antimicrobial agents against bacteria, fungi, and so on. However, the mutagenic effects of AgNPs and resistance mechanisms of target cells remain controversial. In this study, we discover that AgNPs do not speed up resistance mutation generation by accelerating genome-wide mutation rate of the target bacterium Escherichia coli. AgNPs-treated bacteria also show decreased expression in quorum sensing (QS), one of the major mechanisms leading to population-level drug resistance in microbes. Nonetheless, these nanomaterials are not immune to resistance development by bacteria. Gene expression analysis, experimental evolution in response to sublethal or bactericidal AgNPs treatments, and gene editing reveal that bacteria acquire resistance mainly through two-component regulatory systems, especially those involved in metal detoxification, osmoregulation, and energy metabolism. Although these findings imply low mutagenic risks of nanomaterial-based antimicrobial agents, they also highlight the capacity for bacteria to evolve resistance.

Observation and control of pseudospin switching in a finite-width topological photonic crystal.

Finite-size effect plays a significant role in topology photonics not to mention in reality all experimental setups are in finite-size. A photonic bandgap is opened in the topological edge state dispersion if a topological photonic crystal with finite width is considered, and the bandgap size relies on the finite-size effect. Pseudospin-preserving and pseudospin-flipping processes can be realized when a selectively switch of the pseudospin of edge states are customized by our designs. Our microwave experiments also successfully demonstrate pseudospin switch-on and -off behaviors in a finite-width photonic crystal. By combining photonic crystals with finite widths, a multi-tunneling proposal of topological photonic crystals can also be achieved. Our study of the finite-size effect will provide new approaches and thoughts to improve the development of topological photonic devices in the future.

Theoretical Study on the High HER/OER Electrocatalytic Activities of 2D GeSi, SnSi, and SnGe Monolayers and Further Improvement by Imposing Biaxial Strain or Doping Heteroatoms.

Under the DFT calculations, two-dimensional (2D) GeSi, SnSi, and SnGe monolayers, considered as the structural analogues of famous graphene, are confirmed to be dynamically, mechanically and thermodynamically stable, and all of them can also possess good conductivity. Furthermore, we systematically investigate their electrocatalytic activities in overall water splitting. The SnSi monolayer can show good HER catalytic activity, while the SnGe monolayer can display remarkable OER catalytic activity. In particular, the GeSi monolayer can even exhibit excellent bifunctional HER/OER electrocatalytic activities. In addition, applying the biaxial strain or doping heteroatoms (especially P atom) can be regarded as the effective strategies to further improve the HER activities of these three 2D monolayers. The doped GeSi and SnSi systems can usually exhibit higher HER activity than the doped SnGe systems. The correlative catalytic mechanisms are also analyzed. This work could open up a new avenue for the development of non-noble-metal-based HER/OER electrocatalysts.

Broadband and switchable terahertz polarization converter based on graphene metasurfaces.

In this work, we propose broadband and switchable terahertz (THz) polarization converters based on either graphene patch metasurface (GPMS) or its complementary structure (graphene hole metasurface, GHMS). The patch and hole are simply cross-shaped, composed of two orthogonal arms, along which plasmonic resonances mediated by Fabry-Perot cavity play a key role in polarization conversion (PC). An incidence of linear polarization will be converted to its cross-polarization (LTL) or circular polarization (LTC), as the reflected wave in the direction of two arms owning the same amplitude and π phase difference (LTL), or ±π/2 phase difference (LTC). Such requirements can be met by optimizing the width and length of two arms, thickness of dielectric layer, and Fermi level EF of graphene. By using GPMS, LTL PC of polarization conversion ratio (PCR) over 90% is achieved in the frequency range of 2.92 THz to 6.26 THz, and by using GHMS, LTC PC of ellipticity χ ≤ -0.9 at the frequencies from 4.45 THz to 6.47 THz. By varying the Fermi level, the operating frequency can be actively tuned, and the functionality can be switched without structural modulation; for instance, GPMS supports LTL PC as EF = 0.6 eV and LTC PC of χ ≥ 0.9 as EF = 1.0 eV, in the frequency range of 2.69 THz to 4.19 THz. Moreover, GHMS can be optimized to sustain LTL PC and LTC PC of |χ| ≥ 0.9, in the frequency range of 4.96 THz to 6.52 THz, which indicates that the handedness of circular polarization can be further specified. The proposed polarization converters of broad bandwidth, active tunability, and switchable functionality will essentially make a significant progress in THz technology and device applications, and can be widely utilized in THz communications, sensing and spectroscopy.

Splitting spoof surface plasmon polaritons to different directions with high efficiency in ultra-wideband frequencies.

An efficient method to split spoof surface plasmon polaritons (SSPPs) to different directions is proposed by designing a low-loss SSPP waveguide in an ultrawide frequency band. For this purpose, a coplanar-waveguide-based SSPP structure with double-row hole arrays etched on its middle line is first studied, which can be easily used to split the SSPP waves. Based on this method, a Y-shaped -3 dB SSPP power divider and its application on a Mach-Zehnder interferometer are presented. The experiment demonstrates that the proposed method splits the SSPP waves to different directions effectively in ultrawide frequencies (2.5-39.7 GHz) with good isolations, indicating that the proposed SSPP power divider can have good application on a Mach-Zehnder interferometer and plasmonic integrated circuits.

Visualization of Higher-Order Topological Insulating Phases in Two-Dimensional Dielectric Photonic Crystals.

The studies of topological phases of matter have been developed from condensed matter physics to photonic systems, resulting in fascinating designs of robust photonic devices. Recently, higher-order topological insulators have been investigated as a novel topological phase of matter beyond the conventional bulk-boundary correspondence. Previous studies of higher-order topological insulators have been mainly focused on the topological multipole systems with negative coupling between lattice sites. Here we experimentally demonstrate that second-order topological insulating phases without negative coupling can be realized in two-dimensional dielectric photonic crystals. We visualize both one-dimensional topological edge states and zero-dimensional topological corner states by using the near-field scanning technique. Our findings open new research frontiers for photonic topological phases and provide a new mechanism for light manipulating in a hierarchical way.

Magnetoplasmon excitation and hybridization in gyroelectric cylinders.

We investigate magnetoplasmon resonances and their coupling effects in gyroelectric cylinders. In individual cylinders, the dipole plasmon can be excited by plane wave illumination, and the dipole plasmon splits into lower energy and higher energy rotational magnetoplasmons in the presence of an external magnetic field. With respect to the external magnetic field, the two magnetoplasmons carry either right-handed chirality or left-handed chirality. In addition, originally dark plasmons can also be excited as the magnetic field increases. They are lower-order bulk plasmons (such as the radial breathing mode). In cylindrical dimers, the optically bright modes are combinations of magnetoplasmons with the same chirality. If the magnetic fields are antiparallel, the absorption spectra will be different for light incident from two opposite directions. This asymmetry can be well understood by carrying out eigenstate analysis, where the eigenstate does not possess mirror symmetry respecting the dimer axis. The dark modes engineering and asymmetrical optical behavior could have potential for terahertz device applications.

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification.

Understanding the mechanisms of early cardiac fate determination may lead to better approaches in promoting heart regeneration. We used a mesoderm posterior 1 (Mesp1)-Cre/Rosa26-EYFP reporter system to identify microRNAs (miRNAs) enriched in early cardiac progenitor cells. Most of these miRNA genes bear MESP1-binding sites and active histone signatures. In a calcium transient-based screening assay, we identified miRNAs that may promote the cardiomyocyte program. An X-chromosome miRNA cluster, miR-322/-503, is the most enriched in the Mesp1 lineage and is the most potent in the screening assay. It is specifically expressed in the looping heart. Ectopic miR-322/-503 mimicking the endogenous temporal patterns specifically drives a cardiomyocyte program while inhibiting neural lineages, likely by targeting the RNA-binding protein CUG-binding protein Elav-like family member 1 (Celf1). Thus, early miRNAs in lineage-committed cells may play powerful roles in cell-fate determination by cross-suppressing other lineages. miRNAs identified in this study, especially miR-322/-503, are potent regulators of early cardiac fate.

Flexibly designed spoof surface plasmon waveguide array for topological zero-mode realization.

We propose a flexibly designed photonic system based on ultrathin corrugated metallic "H-bar" waveguide that supports spoof surface plasmon polariton (SPP) at microwave frequencies. Five designs were presented, in order to demonstrate flexibility according to varying height, period, core width, rotation, and shifting on the "H-bar" unit of the waveguide. The propagation constant between two hybrid designs of period and height structure was then shown in order to study the coupling effect. Next, we constructed a coupled waveguide array that followed the Su-Schrieffer-Heeger (SSH) model. This model was constructed by a hybrid design with the identical propagation constant of each waveguide, except it had dimerized spacing. The propagation feature of topological zero mode was then observed as theoretically expected in the dimerized array. Our proposed spoof SPP waveguide array has great flexibility to be used as a powerful experiment platform, particularly in photonic simulation of the quantum or topological phenomena described by Schrödinger equation in condensed matters.

A theoretical study on the structures and electronic and magnetic properties of new boron nitride composite nanosystems by depositing superhalogen Al13 on the surface of nanosheets/nanoribbons.

Inorganic boron nitride (BN) nanomaterials possess outstanding physical and chemical characteristics, and can be considered as an excellent building block to construct new composite nanomaterials. In this work, on the basis of the first-principles computations, a new type of composite nanostructure can be constructed by depositing superhalogen Al13 on the surface of low-dimensional BN monolayer or nanoribbons (BNML/BNNRs). All these Al13-modified BN nanosystems can possess large adsorption energies, indicating that superhalogen Al13 can be stably adsorbed on the surface of these BN materials. In particular, it is revealed that independent of the chirality, ribbon width and adsorption site, introducing superhalogen Al13 can endow the BN-based composite systems with a magnetic ground state with a magnetic moment of about 1.00 µB, and effectively narrow their robust wide band gaps. These new superhalogen-Al13@BN composite nanostructures, with magnetism and an appropriate band gap, can be very promising to be applied in multifunctional nanodevices in the near future.

Highly Active, Nonprecious Electrocatalyst Comprising Borophene Subunits for the Hydrogen Evolution Reaction.

Developing nonprecious hydrogen evolution electrocatalysts that can work well at large current densities (e.g., at 1000 mA/cm2: a value that is relevant for practical, large-scale applications) is of great importance for realizing a viable water-splitting technology. Herein we present a combined theoretical and experimental study that leads to the identification of α-phase molybdenum diboride (α-MoB2) comprising borophene subunits as a noble metal-free, superefficient electrocatalyst for the hydrogen evolution reaction (HER). Our theoretical finding indicates, unlike the surfaces of Pt- and MoS2-based catalysts, those of α-MoB2 can maintain high catalytic activity for HER even at very high hydrogen coverage and attain a high density of efficient catalytic active sites. Experiments confirm α-MoB2 can deliver large current densities in the order of 1000 mA/cm2, and also has excellent catalytic stability during HER. The theoretical and experimental results show α-MoB2's catalytic activity, especially at large current densities, is due to its high conductivity, large density of efficient catalytic active sites and good mass transport property.

Adsorbing the 3d-transition metal atoms to effectively modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons.

On the basis of first-principles computations, we propose a simple and effective strategy through surface-adsorbing 3d-transition metal (TM) atoms, including Ti, Cr, Mn, Fe and Co, to modulate the electronic and magnetic behaviors of zigzag SiC nanoribbons (zSiCNRs), in view of the unique d electronic structures and intrinsic magnetic moments of TM atoms. It is revealed that like applying an electric field, the adsorption of these transition metal atoms can induce an evident change in the electrostatic potential of the substrate zSiCNRs owing to the electron transfer from the TM atom to the substrate. This can break the magnetic degeneracy of zSiCNRs and solely ferromagnetic (FM) or antiferromagnetic (AFM) metallicity and even intriguing FM or AFM half-metallicity can be observed in the TM-modified zSiCNR systems. Moreover, all these modified systems can exhibit considerably large adsorption energies ranging from -0.872 eV to -4.304 eV, indicating their considerably high structural stabilities. These intriguing findings will be advantageous for promoting excellent SiC-based nanomaterials in the practical application of spintronics and multifunctional nanodevices in the near future.

Celf1 regulates cell cycle and is partially responsible for defective myoblast differentiation in myotonic dystrophy RNA toxicity.

Myotonic dystrophy is a neuromuscular disease of RNA toxicity. The disease gene DMPK harbors expanded CTG trinucleotide repeats on its 3'-UTR. The transcripts of this mutant DMPK led to misregulation of RNA-binding proteins including MBNL1 and Celf1. In myoblasts, CUG-expansion impaired terminal differentiation. In this study, we formally tested how the abundance of Celf1 regulates normal myocyte differentiation, and how Celf1 expression level mediates CUG-expansion RNA toxicity-triggered impairment of myocyte differentiation. As the results, overexpression of Celf1 largely recapitulated the defects of myocytes with CUG-expansion, by increasing myocyte cycling. Knockdown of endogenous Celf1 level led to precocious myotube formation, supporting a negative connection between Celf1 abundance and myocyte terminal differentiation. Finally, knockdown of Celf1 in myocyte with CUG-expansion led to partial rescue, by promoting cell cycle exit. Our results suggest that Celf1 plays a distinctive and negative role in terminal myocyte differentiation, which partially contribute to DM1 RNA toxicity. Targeting Celf1 may be a valid strategy in correcting DM1 muscle phenotypes, especially for congenital cases.

Realizing diverse electronic and magnetic properties in hybrid zigzag BNC nanoribbons via hydrogenation.

By means of first-principles DFT computations, we systematically investigate the geometries, stabilities, electronic and magnetic properties of fully and partially hydrogenated zigzag BNC nanoribbons (fH-zBNCNRs and pH-zBNCNRs) with interfacial N-C or B-C connections. It is revealed that in the lowest-lying configuration of hybrid fH-zBNCNRs, the constituent C and BN segments can possess respective chair and boat conformations and both of them are connected by the chair mode, independent of the N-C/B-C interface. Changing the ribbon width and the ratio of BN to C can endow these fH-zBNCNR systems with abundant electronic and magnetic properties involving nonmagnetic (NM) semiconductivity, ferromagnetic (FM) metallicity, antiferromagnetic (AFM) metallicity as well as AFM half-metallicity. Besides, manipulating the hydrogenation pattern and ratio can also result in rich electronic and magnetic behaviors in pH-zBNCNRs, where NM semiconductivity, AFM semiconductivity, AFM metallicity and even AFM spin gapless semiconductor are observed. Additionally, the origin of the magnetism in these hydrogenated zBNCNRs is analyzed in detail. Finally, all of these hydrogenated BNC structures can possess a favorable formation energy, large binding energy per hydrogen atom and high thermal stability, indicating the great possibility of their experimental realization by hydrogenating pristine zBNCNRs. These valuable insights can be advantageous for promoting hybrid BNC-based nanomaterials in the applications of spintronics and multifunctional nanodevices.

Conformal surface plasmons propagating on ultrathin and flexible films.

Surface plasmon polaritons (SPPs) are localized surface electromagnetic waves that propagate along the interface between a metal and a dielectric. Owing to their inherent subwavelength confinement, SPPs have a strong potential to become building blocks of a type of photonic circuitry built up on 2D metal surfaces; however, SPPs are difficult to control on curved surfaces conformably and flexibly to produce advanced functional devices. Here we propose the concept of conformal surface plasmons (CSPs), surface plasmon waves that can propagate on ultrathin and flexible films to long distances in a wide broadband range from microwave to mid-infrared frequencies. We present the experimental realization of these CSPs in the microwave regime on paper-like dielectric films with a thickness 600-fold smaller than the operating wavelength. The flexible paper-like films can be bent, folded, and even twisted to mold the flow of CSPs.

Trapping surface plasmon polaritons on ultrathin corrugated metallic strips in microwave frequencies.

It has been demonstrated that an ultrathin uniformly corrugated metallic strip is a good plasmonic waveguide in microwave and terahertz frequencies to propagate spoof surface plasmon polaritons (SPPs) with well confinement and small loss (Shen et al., PNAS 110, 40-45, 2013). Here, we propose a simple method to trap SPP waves on the ultrathin corrugated metallic strips in broad band in the microwave frequencies. By properly designing non-uniform corrugations with gradient-depth grooves, we show that the SPP waves are slowed down gradually and then reflected at pre-designed positions along the ultrathin metallic strip when the frequency varies. We design and fabricate the ultrathin gradient-corrugation metallic strip on a thin dielectric film. Both numerical simulation and measurement results validate the efficient trapping of SPP waves in broadband from 9 to 14 GHz. This proposal is a promising candidate for slow-wave devices in both microwave and terahertz regimes.

Multiple Fano resonances in spoof localized surface plasmons.

We present the occurrence of bright modes and dark modes in spoof localized surface plasmons (LSPs) generated by ultrathin corrugated metallic disks. As two such disks with asymmetric geometries are placed in close proximity, we find that dark modes (in multipoles) of one disk emerge by coupling with the bright modes (in dipoles) of the other disk. Then we further observe multiple Fano resonances due to destructive interferences of dark modes with the overlapping and broadened bright modes. These Fano line-shapes clearly exhibit the strong polarization dependence. We design and fabricate the ultrathin corrugated bi-disk structure in the microwave frequency, and the measurement results show reasonable agreement with theoretical predictions and numerical simulations. Such multiple Fano resonances could be exploited for the plasmonic devices at lower frequencies.

PHD2 safeguards modest mesendoderm development.

PHD2 is essential in modulating HIF-1α levels upon oxygen fluctuations. Hypoxia, a hallmark of uterus, and HIF-1α have recently emerged as opposing regulators of mesendoderm specification, suggesting a role for PHD2 therein. We found that PHD2 expression initially covered the epiblast and gradually receded from the primitive streak, which was identical to hypoxia and exclusive to HIF-1α. The investigations performed in mESCs, embryoids, and mouse embryos together demonstrated that PHD2 negatively regulated mesendoderm specification. Single-cell RNA sequencing revealed that PHD2 governed the transition from epiblast to mesendoderm. The downstream effect of PHD2 relied on the HIF-1α regulated Wnt/ß-catenin pathway, while it was regulated upstream by miR-429. In summary, our research highlights PHD2's essential role in mesendoderm specification and its interactions with hypoxia and HIF-1α.