TC up to ∼400 K and saturation magnetization of 0.11 emu g−1 (300 K) can be achieved in graphene by embedding isolated Co atoms with the aid of coordinated N atoms. Extensive structural characterizations show that square-planar Co-N4 moieties were formed in the graphene lattices, where atomically dispersed Co atoms provide local magnetic moments. Detailed electronic structure calculations reveal that the hybridization between the d electrons of Co atoms and delocalized pz electrons of N/C atoms enhances the conduction-electron mediated long-range magnetic coupling. This work provides an effective means to induce room-temperature ferromagnetism in graphene and may open possibilities for developing graphene-based spintronics devices.Graphene is extremely promising for next-generation spintronics applications; however, realizing graphene-based room-temperature magnets remains a great challenge. Here, we demonstrate that robust room-temperature ferromagnetism with  Graphene has shown incredible promise as ideal material for numerous fields; however its use in spintronics has been hampered by the lack of intrinsic magnetism. Here, Hu et al succeed in embedding Cobalt in the graphene lattice, creating robust room-temperature ferromagnetism. It possesses many unique properties such as large specific surface area3, superior mechanical strength4, high intrinsic carrier mobility6, and thermal conductivity7. Great efforts have been devoted to promoting the applications of graphene in a diversity of fields including field-effect transistors8, chemical sensors9, fuel cells10, and so forth. Graphene is also envisaged to be a highly promising material for next-generation spintronic applications, owing to its extraordinary carrier mobility, long spin diffusion length, weak intrinsic spin–orbit coupling, and limited hyperfine interactions12. For practical applications in spintronic devices, the graphene-based material is required to be ferromagnetic above room temperature. Unfortunately, pristine graphene is intrinsically diamagnetic and lacks local magnetic moments14. Therefore, development of effective strategies to induce and manipulate the ferromagnetism of graphene has become a key issue to extend its applications in spintronics.Graphene is a two-dimensional (2D) layered material composed of a one-atom-thick hexagonal network of 15, sp3 functionlization16, chemical doping17, surface adsorption18, and zigzag edges19. However, the magnetic moments induced by point defects or edges are relatively weak and unstable; and consequently the ferromagnetic ordering often collapses at rather low temperatures21. For instance, Grigorieva and colleagues21 produced high-density vacancy defects on graphene with ion beam radiation and realized a macroscopic magnetic moment of 0.001 14 found that S-doped graphene could only maintain ferromagnetic ordering at temperatures below 62 K, and Liu et al.22 demonstrated that only pure diamagnetism can be observed in N-doped graphene at 300 K. To improve the stability of ferromagnetic coupling, the common wisdom is to increase the content of defects so as to shorten the distance between weak local magnetic moments. However, an excessive content of defects would break the π-bonding networks and degrade the electric properties of graphene. In analogous 2D system of graphene like transition metal (TM) dichalcogenides, doping of magnetic TM  has been experimentally demonstrated to be an effective method for inducing stable room-temperature ferromagnetic ordering24. However, direct doping of TM atoms in graphene is impractical because graphene is not an ionic crystal like TM dichalcogenides and its honeycomb networks are maintained by strong C–C covalent bonds. This makes the energy barrier of embedding a single TM atom into pristine graphene lattices very steep. Indeed, previous attempts to produce TM-graphene compositions merely yielded TM atoms or clusters adsorbed on the surface of graphene26, where the magnetism is not intrinsic but mainly contributed by the metal clusters. Meanwhile the adsorbed TM atoms on graphene could be easily dissociated or coagulated at elevated temperatures. For example, graphene with Co atoms attached on the surface can maintain ferromagnetic ordering only below 10 K26. Hence, stable anchoring of magnetic TM atoms on graphene is important for the manufacture of graphene-based room-temperature ferromagnetic materials. Inspired by the metal-nitrogen (M-N) moiety strategies developed recently for atomically dispersed TM catalysts28, we speculate that doping TM with the aid of coordinated N might be a possible way to embed TM atoms into graphene lattices. As the Pauling electronegativity of N (3.0) is significantly higher than that of C (2.5), the TM atoms can be strongly bound by N atoms rather than by C atoms as observed in many TM-N-C systems29. Therefore, the TM-Nx moiety can be doped in graphene and act as the ferromagnetic centers. Previous density functional theory (DFT) simulations confirmed the structural stability of the heavy N-doped graphene at up to 1000 K30, further supporting the feasibility of TM-Nx moiety on building the graphene-based room-temperature ferromagnetic materials.So far, various strategies have been attempted to realize ferromagnetic ordering in graphene, including utilization of atomic vacancies4 moiety doped graphene, which was synthesized via an impregnation-pyrolysis method, and exhibits unprecedented ferromagnetic orderings with Curie temperature (TC) up to ∼400 K. A high saturation magnetization of 0.11 emu g−1 at 300 K (0.73 emu g−1 at 5 K) is obtained at the Co content of 0.4 at.%. Detailed X-ray absorption spectroscopy characterizations and multiple-scattering simulations confirm the embedding of Co atoms in the graphene lattices, via the formation of isolated Co-N4 units. Electronic structure calculations reveal that stable room-temperature ferromagnetic coupling is mediated by carriers and arises from the d-p orbital hybridization between the embedded Co and C/N atoms. Besides the ferromagnetic ordering, the Co-N4 doped graphene possesses unique electronic structure where only one spin channel crosses the Fermi level, which is beneficial for the generation of spin-polarized current in spintronics31. This deliberately designed strategy opens up an avenue for the development of graphene-based spintronic devices.Herein, motivated by the above consideration, we propose a coordination atom assisted strategy by embedding magnetic TM into graphene lattices under the assistance of coordinated N atoms, where stable room-temperature ferromagnetism can be achieved in graphene. This strategy is exemplified by the single-metal-atomic Co-N33. No Co-related second phases were detected. Furthermore, Co K-edge X-ray absorption near edge structure (XANES) spectra  spectra  was prepared through a two-step synthesis strategy consisting of the impregnation and following pyrolysis procedures. For comparison, samples with other Co contents were prepared, denoted as 0.2Co-N/G, 0.5Co-N/G, and 3Co-N/G with 0.2×, 0.5×, and 3× Co precursors during preparation than that of 1Co-N/G sample . According to the X-ray photoelectron spectroscopy (XPS) analysis , pyrrolic (400.0 eV), graphitic (401.2 eV), and oxidized N groups (402.3 eV), there is also a signal from Co-N bonds with the XPS peak at ~399.2 eV34. The formation of Co-N bonds was also confirmed by N K-edge XANES spectra  by comparing the formation energies . The calculation results and structural schematics are given in Fig. x4−Cx/G  moiety was ensured to be the converged configuration after structural optimization  moiety is much more energetic favorable than other CoNx4−Cx/G  compounds. In addition, the simulated Co K-edge XANES spectrum based on the structure model of a square-planar Co-N4/G generated by DFT calculations is presented in Fig. 4 moieties is the most possible structure for Co atoms in the 1Co-N/G nanosheets.In order to explore the bonding configuration of Co atoms in 1Co-N/G nanosheets, we performed XPS, and N and C K-edge XANES measurements. XPS survey spectrum   for 1Co-N/G nanosheets are given in Fig. TC above room temperature (300 K). The magnetization difference (ΔM) between FC and ZFC curves (MFC−MZFC) in the inset shows a decreasing trend but still perfectly positive in the whole temperature range (up to ~400 K). Hence, the possibility of spin glass effects and superparamagnetism can be excluded in the 1Co-N/G nanosheets41. The corresponding M−T curves for 0.2Co-N/G and 0.5Co-N/G under an applied field of 500 Oe are also depicted in Fig. M–H curves at 300 K are given in Supplementary Fig. 17. Seen from Fig. 45. Furthermore, in order to visually show the change of magnetism with Co contents in doped graphene nanosheets, we extracted magnetic signals from the M−H curves for all the samples and plotted them against the Co contents in Supplementary Fig. M−H curves for 1Co-N/G nanosheets exhibit similar ferromagnetism with higher saturation magnetization of ~0.73 emu g−1  with that of Co metal (1.7 μB Co−1), we can estimate that ~24% of the total doped Co atoms should be in the form of clusters. Such a content of Co clusters should be easily detected by TEM and XANES46, which is however contrary to the experimental observations  Fig.  at 300 Kons Fig. . Meanwhi4-graphene system, we performed spin-polarize DFT calculations . The total densities of states (TDOS), projected densities of states (PDOS), energy band structure and spatial distribution of spin density are presented in Fig. E = 0 eV in the DOS)48. In contrast, the TDOS and PDOS of CoN4-graphene system  and antiferromagnetic (AFM) states of different bi-Co-N4 configurations 53. Due to the intense hybridization between Co d and delocalized N/C pz orbits, the long-range magnetic coupling between Co atoms can be attributed to an indirect conduction-electron mediated Ruderman–Kittel–Kasuya–Yosida (RKKY)-like interaction55. Meanwhile, we have also carefully considered other magnetic coupling frameworks including successive spin polarization-based ferromagnetic coupling (SSP-FMC)57 and bound magnetic polaron (BMP)58 that have successfully interpreted the origins of ferromagnetism in many TM-doped system. However, due to the metallic nature, enhanced DOS at Fermi level and spin-polarized π electrons for our CoN4-graphene system, the conduction-electron mediated ferromagnetism is a more reasonable and straightforward explanation for the main origin of ferromagnetism in CoN4-graphene nanosheets. Since the hybridization between the Co-3d, N-2p, and C-2p electronic bands is essential for the development of the ferromagnetic coupling in CoN4-graphene nanosheets, the strong room-temperature ferromagnetism originates from the chemical bonding that embeds Co atoms into the graphene lattice. Hence the DFT simulations lead us to conclude that the Co-N4 moieties are responsible for the observed room-temperature ferromagnetism in the as-synthesized CoN4-graphene nanosheets.To obtain an in-depth understanding on the origin of the room-temperature ferromagnetic coupling in CoNtem Fig.  exhibitsity Fig.  also indp electron, making them an n-type dopant in graphene, which can effectively improve the electric conductivity of graphene and enhance the DOS around the Fermi level to meet the Stoner criterion. (3) In the context of the bipartite nature of graphene, the N atoms induce a bipartite arrangement of magnetic moments of the sublattices where they are. Moreover, it is worth noting that the CoN4-graphene nanosheets have greatly improved performance of spin-polarized current because only one spin channel crosses the Fermi level31.Finally, we summarize the important role of co-doped N atoms in the establishment of graphene magnetism: (1) N atoms serve as a stable anchoring site for Co due to the higher Pauling electronegativity than that of C atoms, which avoids the loss of ferromagnetic Co atoms from graphene lattice. (2) Compared with C atoms, N possess one additional x moieties. A simple and controllable impregnation-pyrolysis process was employed to synthesize the Co-N-graphene system. Comprehensive structural characterizations confirm the existence of square-planar Co-N4 moieties in the graphene lattices at the content of 0.4 at.% (for 1Co-N/G nanosheets), which displays unprecedented stable ferromagnetic ordering with TC up to ∼400 K and saturation magnetization of 0.11 emu g−1 (300 K). No Co-related second phase that may induce extrinsic ferromagnetism is observed. On the one hand, Co-N4 moieties avoid the loss of Co atoms from the graphene lattices, thus providing a strong local magnetic moment; on the other hand, DFT calculation reveals that the long-range ferromagnetic coupling originates from the hybridization between the Co-3d and C/N-2p orbitals through a carrier-mediated magnetic interaction. The stable room-temperature graphene magnets developed in this work will pave the way towards practical graphene-based spintronic applications.In summary, we have explored the possibility of achieving stable room-temperature ferromagnetic ordering in graphene by embedding single magnetic TM atoms in the lattice via the strong chemical bonds in the TM-N59. Then, 50 μl of CoCl2·6H2O solution (3 mg ml–1) and 15 μl of H2O2 solution (30%) were added dropwise into 10 ml of GO suspension (2 mg ml–1) and the mixture was sonicated for 1 h. The obtained suspension was transferred into a stainless steel autoclave and maintained at 180 °C for 6 h, forming a hydrogel. After freeze drying, the Co2+-containing gel was heated in the center of a quartz tube furnace at 900 °C for 1 h under gas flows of 100 sccm Ar and 50 sccm NH3 to obtain 1Co-N/G. For comparison, the N/G nanosheets were prepared with the same procedure with no addition of CoCl2·6H2O.1Co-N/G nanosheets were synthesized through a two-step impregnation-pyrolysis procedure. In the typical procedure, graphene oxide (GO) was firstly prepared by oxidation of powdered flake graphite following a modified Hummers’ method0.2Co-N/G, 0.5Co-N/G, and 3Co-N/G nanosheets were synthesized with a similar procedure to 1Co-N/G except for 0.2×, 0.5×, and 3× Co precursors during preparation, respectively.60 and some calculation results were visualized with VMD software61. The electron exchange-correlation was processed within the framework of generalized gradient approximation (GGA) in the Perdew–Burke–Ernzerhof (PBE) parametrization. The electron-ion interaction was described using the projected augmented wave (PAW) method. The kinetic energy cutoffs of the plane wave and electron density were 80 and 500 Ry. The long-range van der Waals interaction was considered with the DFT-D3 scheme62. A 6 × 6 × 1 k-grid was used for sampling in the Brillouin zone. Energy convergence of ~1.0 × 10−3 meV/atom was ensured during the self-consistent field calculations. And the convergence criteria for the atomic forces was 0.05 eV/Å. Various typical planar and nonplanar configurations have been fully considered during the structure optimizations, as the examples shown in Supplementary Figs. The spin-polarized DFT calculations were performed with Quantum Espresso software package4. A vacuum layer of 15 Å was placed along the z direction to prevent the interlayer interaction.The Co embedded nitrogen-doped graphene nanosheets were modeled based on an 8 × 8 × 1 hexagonal supercell of graphene. Six adjacent carbon atoms were replaced with Co-NxCx4- moieties in graphene were calculated according to the following equation,xCx4- moiety; The formation energies of Co-NKα line (λ = 1.54178 Å) and an ESCALAB MKII equipped with Mg Kα source (һν = 1253.6 eV), respectively. The N K-edge, C K-edge, and Mo L3-edge XANES were obtained at the BL12B beamline of National Synchrotron Radiation Laboratory  under a total electron yield (TEY) mode with vacuum better than 5 × 10−7 Pa. The Co K-edge EXAFS spectra were obtained on the 1W1B beamline of Beijing Synchrotron Radiation Facility  under fluorescence mode. The temperature- and magnetic field-dependent magnetization curves were measured on a superconducting quantum interference device (SQUID) magnetometer.TEM and EDX spectroscopy results were taken on a field emission transmission electron microscope (JEM-2100F) with 200 KV accelerating voltage. The HAADF-STEM images were captured on a JEM-ARM200F instrument at 200 KV. The XRD and XPS patterns were collected on a Philips X’Pert Pro Super diffractometer with Cu Supplementary Information


In this paper, we propose a tunable coordinated multi-band absorber that combines graphene with metal–dielectric–metal structures for the realization of multiple toward perfect absorption. The parametric inversion method is used to extract the equivalent impedance and explain the phenomena of multiple-peak absorption. With the change of the Fermi level, equivalent impedances were extracted, and the peculiarities of the individual multiple absorption peaks to change were determined. By changing the structure parameters of gold rings, we obtain either multiple narrow-band absorption peaks or a broadband absorption peak, with the bandwidth of 0.8 μm where the absorptance is near 100%. Therefore, our results provide new insights into the development of tunable multi-band absorbers and broadband absorbers that can be applied to terahertz imaging in high-performance coordinate sensors and other promising optoelectronic devices. Metamaterials are artificially structured materials that can have negative permittivity or/and permeability, which can be achieved by periodic metal–dielectric arrays ,2,3,4. WGraphene is a relatively new two-dimensional sheet composed of carbon atoms of atomic thickness with unique quantum, thermodynamic , and opt2 is situated, while the top layer represents an array of different sized gold rings (see – 1). The proposed structure is simulated using the commercial finite element method (FEM) solver COMSOL Multiphysics with the purpose of obtaining a number of closely located near-perfect absorption peaks. For reliability purposes, an additional numerical simulation utilizing the method of inverse parameter extraction is carried out to extract effective parameters and explain the phenomenon of multiple absorption peaks. By adjusting the Fermi level of graphene, at least three absorption peaks can be tunable between 8 μm (37.5 THz) and 14 μm (21.4 THz) while the structural changes in parameters of metal rings lead to a single wide absorption peak with an absorptance higher than 80%. The position of the single peak is also Fermi-level adjustable.While the proposed novel, multi-band, and tunable selective absorber utilizes graphene as its key component, its base structure uses gold as a ground plane that reflects electromagnetic waves. Between the ground plane and graphene, a substrate layer of SiOXZ plane by red arrows. The yellow layer and rings represent gold with thicknesses of d1 and d3, respectively. The blue layer represents SiO2 with a thickness of d2. A single layer of graphene between the upper gold rings and the SiO2 substrate is pictured as a honeycomb structure. Within the operating wavelengths, the dispersion of dielectric constant of SiO2 [εSiO2 = 3.9, and the permittivity of gold can be expressed as ε = 1 − (ω2 + iωγ)) using the Drude model [pω = 1.36 × 1016 rad/s and collision frequency γ = 3.33 × 1013 rad/s. The graphene is simulated in COMSOL by setting the surface current density.The three-dimensional structure of the graphene-based selective absorber is proposed in  of SiO2  is neglide model  with theσinter and σintra are expressed as the interband and intraband transition contributions, respectively. Bk, ℏ, and e represent the Boltzmann constant, reduced Plank constant, and electron charge, respectively. ω is the angular frequency of the incident radiation, fE is the graphene Fermi energy level, τ is the electron-phonon relaxation time, and T is the ambient temperature. As we only consider highly doped graphene, we should take into account that fE ≫ BTk and fE ≫ ℏω. Therefore, the Kubo equation can be simplified to a Drude-like equation [τ = fμE/ – rings R, resulting in the green dotted line in R1, resulting in the red dotted line in R2, resulting in the blue dotted line in The black curve in μ1 and ε1, which is surrounded by an outer layer with material parameters μ0 and ε0, as illustrated in Z axis—that is, perpendicular to the surface of the absorber. For simplicity, layers 1 and 3 in An inversion algorithm is applied to extract the normalized impedance of the multiple-peak absorber for explaining the physical mechanism of the phenomenon. The absorber is considered as a uniform layer with material parameters Ex0 = 1. Then, the electromagnetic field strength in medium 1 can be written as:When TM propagates in medium 1, without loss of generality, we set the amplitude Then, the TM wave moves through the interface of medium 1 and medium 2, and the electromagnetic field strength in medium 2 can be written as:k1 = k3 = k0 is the wave number in vacuum, k2 = nk0 is the wave number in the relative medium, Γ1 and Γ2 are the reflection coefficients between medium 1 and medium 2, and medium 2 and medium 3, respectively. τ1 and τ2 are the transmission coefficients between medium 1 and medium 2, and medium 2 and medium 3, respectively.Finally, the TM wave enters the medium 3, and the electromagnetic field strength in medium 3 can be written as:Z = 0. According to the boundary conditions encountered by the electromagnetic wave at the discontinuous interface when Z = 0, we can obtain:Z = d, that is, at the interface between medium 2 and medium 3:We let the interface of medium 1 and medium 2 be the origin—that is, Γ1 = (Z − 1)/(Z + 1). Since we use gold as the reflective layer of the entire absorber, there is no transmission spectrum, so S21 = 0. According to the selection of the sign [According to the above-mentioned boundary conditions that the electromagnetic wave meets on the discontinuous interface, the scattering parameters can be obtained:the sign ,44, we cIn order to minimize reflection, the normalized impedance of the absorber should be close enough to the impedance of free space—that is, the closer the real part of the normalized impedance is to unity and the closer the imaginary part is to vanishing, giving rise to the greater the absorptance of the structure. As is shown in The relationship between the normalized impedance and the energy of Fermi level is investigated in R increasing independently from 1.04 μm to 1.08 μm, R1 increasing independently from 1.11 μm to 1.15 μm, and R2 increasing independently from 1.27 μm to 1.30 μm, the resonance wavelengths of the corresponding absorption peaks are red-shifted by 1.2 μm, 0.4 μm, and 0.4 μm respectively  is the structural constant of graphene, and rλ is the polarization resonance wavelength of graphene. From the above formula, the resonance frequency of the plasmon surface of the graphene can be obtained: rf ∝ (α0fE/(2π2ℏcL))1/2. That is, as the Fermi level increases, the resonant frequency also increases. Since the structure proposed by us lays a layer of graphene, we can adjust the Fermi level of graphene by applying a voltage across the graphene, thereby changing the resonance frequency of the absorption peak. The Fermi level energy g Ef see . Known fR = 1.06 μm, R1 = 1.24 μm, R2 = 1.26 μm, and w = 0.44 μm. In this case, the absorptance greater than 80% occurs between wavelengths 10.51 and 11.31 μm  absorption peaks with an absorptance greater than 80% is achieved. We assume that our findings can potentially be useful in those practical applications relating to adjustable optical filters, splitters, modulators.


Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1—a non-RBP commonly associated with familial ALS (fALS)—exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research. Amyotrophic lateral sclerosis (ALS) is a fatal, incurable, and highly heterogeneous neurodegenerative disease that deteriorates both upper and lower motor neurons (MNs), leading to extensive muscle weakness, atrophy, and paralysis . More thOver the years, the number of neurodegenerative diseases that have been associated with pathological protein aggregates has increased. In ALS, more than 50 genes  have beeInterestingly, both SOD1 and several RNA-binding proteins including TDP-43 and FUS, have also been shown to contain aggregation-promoting prion-like domains that are able to rapidly associate. This property cements these RNA-modifiers as plausible instigators of proteinopathy. Recent studies have also highlighted the interference of pathological TDP-43 and FUS aggregates with normal stress granule formation upon mis-localization to neuronal cytoplasm ,16, whicSeveral miRNAs have also been put forth as potential diagnostic biomarkers for ALS in both the neuron and microglial cells including miR-155, Let-7a, and miR-125b ,18. ResuSOD1 account for 20% of familial ALS and 5% of sporadic disease .,44.43,44Examining this heavily conserved biogenesis ultimately illustrates the extreme degree of regulation of an intricate, essential, multi-step process that emphasizes both the scale of the cumulative effects of miRNA control and the potential for missteps at multiple points along production.TDP-43 is a nuclear protein that shuttles between nucleus and cytoplasm and like FUS, is structurally and functionally similar to the heterogeneous nuclear ribonucleoproteins (hnRNPs), which are involved in RNA processing. TDP-43′s association with over 6000 mRNA targets—almost 30% of the entire human transcriptome—suggests a significant capacity to cause regulatory chaos when this gene becomes dysfunctional . PatholoThis raises the question as to whether mis-localization and subsequent nuclear depletion leads to a reduced supply of the protein for its nuclear role, or if pathology results from toxic cytoplasmic aggregates. In the nucleus, the role of TDP-43 has been implicated in DNA repair , mRNA spTDP-43, therefore plays a clear and essential role as a nuclear protein; pathologically, TDP-43 has a less understood role, as hypothesized to be translocated to the cytoplasm ,59,60,61Although Kawahara and Mieda-Sato revealed the association that TDP-43 and Drosha share, they noted that the interaction was only permitted by certain RNA species, or a direct protein–protein interaction, which occurs through the C-terminal tail (of amino acids 316–401). Treatment with RNase VI, A, or both, elicited a dose-dependent response, highlighting RNA to be crucial in the typical functioning of TDP-43 and Drosha. However, even upon excess RNase treatment and a proven dispensability of the RNA-binding domain of TDP-43 in vitro, some association remained. The study thus concluded that the interaction between TDP-43 and Drosha exists as both RNA-dependent and -independent, although still indispensable for pre-miRNA processing. This raises the question of the role that Dicer complexes without TRBP play: are they simply “floaters” in the bigger picture of miRNA biogenesis, or do they have an unspecified, yet critical role? One possibility may include the existence of a feedback system, where these non-TRBP Dicer complexes assist, should there be a shortage of certain miRNAs. Overall, this study demonstrates the unique function of TDP-43 not only in the nucleus, but also in the cytoplasm, which may have immense relevance in the compartmental shuttling of TDP-43.As evidenced through multiple studies conducted on induced pluripotent stem cell (iPSC)-derived neurons, TDP-43 affects several miRNA expression levels upon downregulation, and it is thus unsurprising that the regulatory effects of TDP-43 extend beyond biogenesis and toward direct associations with produced miRNA such as that of miR-let-7b ,64,65. TConsidering the lack of categorization of miRNAs, and the numerous, yet specific, miRNAs involved in TDP-43 pathology and beyond, perhaps one should consider, at least in the scope of ALS, the grouping of miRNA into “families” of those associated with TDP-43 and at what stage of miRNA biogenesis this effect occurs. More research is encouraged to make such specific miRNA connections more valuable, as they present a promising target group for novel therapies.Less prevalent amongst cases is the presence and discussion of the similar RBP, fused in sarcoma/translocated in liposarcoma (FUS/TLS). Following the discovery of TDP-43 and its mutants in ALS, FUS was identified to be associated in both familial and sporadic forms of ALS, which held considerable significance as both proteins share intense functional similarities as RNA binding proteins and display mis-localization and aggregation as main features ,68,69,70Although TDP-43 inclusions are absent in ALS patients with FUS mutations ,77,78 anFurthermore, FUS has been shown to promote optimal miRNA-mediated gene silencing via direct binding to certain miRNA and mRNA targets including mature miR-200c, with mutant FUS forms impairing AGO2 protein function in the miRNA-induced silencing complex (miRISC) . As a coHowever, beyond biogenesis, loss-of-function effects related to reduced miRNAs including miR-375 and its target genes, have also been elicited in vitro in human MNs upon induction of mutant FUS . ReducedWT) is not commonly associated with aspects of neurodegeneration including in ALS, although upon post-translational modification such as iper-oxidation, even if noninheritable, studies suggest the possibility of its additional toxic role in sALS [WT in Parkinson’s disease (PD) has sparked interest in its toxic ‘gain-in-function’, as aggregates of SOD1WT were discovered in postmortem idiopathic PD neural tissue [WT can then become dysfunctional, misfolding, and aggregating [WT in other NDs and controls are therefore required to confirm this hypothesis, and to identify whether toxicity from SODWT build-up is merely a common result of neurodegenerative-related stress.Unlike TDP-43 and FUS, superoxide dismutase (SOD1) is not classified as an RBP, despite sharing key roles ; however in sALS ,88, whic in sALS ,89,90,91 in sALS  into thel tissue ,94. It il tissue ,96, espel tissue ,98; fromregating . Notablyregating . To enliLocated in exon sequences, SOD1 mutations were initially thought to be purely due to a loss of physiological function, which would result in an increase in oxidative stress and eventual excitotoxicity. However, recent investigations have instead illuminated a gain of new toxic properties through its role in protein aggregation, as a result from its mutant-induced co-aggregation with other proteins  such as Moreover, in the literature, it is generally accepted that SOD1 and TDP-43 inclusions are exclusive of one another, particularly when examining mutant SOD1 patients, as is more common with fALS . HoweverInterestingly, as miRNAs do regulate various genes involved in oxidative stress response, and as the converse also proves true, it is important to consider the strength of interrelationship between miRNA dysregulation and ALS pathogenesis, especially as oxidative stress is so strongly related to both SOD1 and other parts of pathogenesis, potentially leading to other processes of degeneration, despite often being examined in separation to RNA dysregulation . The sigIn sALS individuals, SOD1 is not as commonly discussed as it is in fALS, where it mediates the disease in around 20% of affected individuals .In 2009, a paper by Williams et al. highlighted how miRNA-206 delays ALS progression in G93A-SOD1 mice, and was significant in confirming the overall importance of miRNA involvement in ALS pathogenesis . MediateG93A mice, compared to the total miRNA levels at any different stage of disease progression [G93A mice may be possibly reflected in pathological increase in miRNA biogenesis machinery.In a similar vein, Russell et al. (2018) investigated the regulation of select members of miRNA biogenesis pathways in pre-symptomatic, symptomatic, and end-stage SOD1gression . They usG93A) mice, a result similar to those previously discussed in the 2015 Butovsky study [G93A mice show the potential to be delayed [Furthermore, the recent work from Weiner’s laboratory implicated the role of miR-155, a glial-enriched miRNA, in its upregulation in the spinal cords of end-stage ALS model  has been particularly shown to propagate intercellularly via exosome-dependent and independent mechanisms , as is sConsidering this, one should always remain wary of the likelihood of ALS being attributed to several etiologies, and thus a value exists in understanding this final “common ground” before the more downstream pathogenic effects that are known to characterize the disease, particularly as this appears to be the tight interrelationship between miRNAs and RNA-modifying proteins, especially RBPs TDP-43 and FUS. Overall, these common properties in TDP-43, FUS, and other RBPs may also warrant future investigations on the existence of any direct relationship with miRNA dysregulation, as this will also clarify the extent of the miRNA-RBP two-way relationship, while also providing newer, plausible targets for novel therapies.As is the case with ALS, despite these heavy self-regulatory effects, RBPs are not immune to pathological changes. Both FUS and TDP-43 have been a focus for the past decade, with the latter strongly aligning with the pathology  in >95% In recent years, these prion-like domains in RBPs have been a source of speculation as they prove to be essential for “functional aggregation” and building SNPs, regulators of gene expression via nuclear retention of RNA ,150, lacMoreover, the relationship that RBPs have with SNPs must then also be appreciated, as both losses and gains in RBP function may prove to be protective and potentially essential in their association with de novo SNP development. A recent study  into endClinically indistinguishable ALS can also be caused by genetic mutations of SOD1, TDP43, or FUS, and can occur in the absence of known mutation as sporadic disease . In theiThis connection between these RBPs and SOD1 is highly plausible, especially as various TDP-43 and FUS forms are known to associate with mitochondrial impairment ,158, whiThese implications argue for the equal propensity for these pathological proteins to seed, intercellularly transmitting mutant or misfolded wild-type SOD1 through the release of naked aggregates by the dying cells, which, in turn, are taken up by macro-pinocyotosis and trigger seeded aggregation . AlternaHowever, another investigation showed the converse of this situation, in which administration of mutant SOD1 induced TDP-43 aggregation in the target cell population . SimilarThus far, a complex perspective has emerged between the RBPs and SOD1 in ALS. In defining the intricacies of the functional dependencies and influences between these RNA-modifying proteins themselves including their prion-like capabilities, we can finally attempt to clarify the intrinsic two-way relationship between these proteins and miRNA. From our previous discussions on miRNA biogenesis and TDP-43, FUS, and SOD1 see , it can In a recent study by Brennan et al. , clusterAs direct miRNA-to-protein interactions remain uncertain, it is also noteworthy that alterations in protein levels are instead attributed to a mix between pro-aggregation signaling and cellular mis-localization. Although most analyzed TDP-43 ALS-linked mutations accelerate aggregation in vitro , most FURegardless, since protein dyshomeostasis unifies several neurodegenerative diseases, and given the functional resemblance between RBPs, it is plausible to hypothesize that targeting ribonucleoprotein particle (RNP) assembly in human neurodegenerative diseases could be an effective strategy in the treatment of NDs. A better understanding of this process could shed much needed light on the mechanisms of regulation of this dynamic molecular machinery that governs specific cellular and physiological functions to maintain a non-disease state, and thereby elicit plausible future therapies, especially the potential for a common therapeutic strategy.Thus far, we have synthesized the importance of the three key misfolded proteins linked to ALS —TDP-43, SOD1, and FUS—whilst defining their relationships, interdependencies , and curExtensive downregulation of miRNAs has been discussed to be a common molecular determinant in different forms of ALS in humans, with pathogenic RBP mutations notably interfering with DICER and therefore, miRNA biogenesis, which then associates with abnormalities within the stress response system, as observed in ALS and other NDs. Whether miRNA dysregulation is upstream or downstream in pathogenesis is yet to be confirmed, however, the common ground of miRNA and RNA regulation, and RBP dysfunction, is ultimately undeniable across both sALS and fALS patients. In this context, Hornstein’s group  recentlyAs a diagnostic tool, miRNAs were first investigated in 2012 by de Felice et al., where the team highlighted the potential for peripheral leukocyte profiling after successful comparison of miR-338-3p to healthy controls . The samNovel treatment regimens may thus exploit the intricate two-way interaction between miRNA biogenesis and RBPs, especially as we can infer that miRNA dysregulation is likely to be the most critical upstream link, proving essential to the regulation of both (1) the RNA-binding proteins themselves (indirectly affecting their autoregulation), and (2) other gene expressions. Such genes include both STMN2  and UBQLelegans animal model. SOD1, however, presents a more complex situation, being recently implicated in a protective role upon nuclear re-localization [Encouraging are the recent developments on the therapeutic front at Prosetta Biosciences, San Francisco, USA, where they have established cellular models recreating the mis-localization of TDP-43 from nucleus to cytoplasm and the stress-induced aggregation of the cytoplasmic mis-localized TDP-43. The team identified several Hitfinder compounds that can prevent aggregate formation in stress granules, while also discovering others that instead confer dramatic re-localization of TDP-43 back to the nucleus. Moreover, these results with cellular models were complemented by the ability of both classes of compounds to relieve the motor paralysis displayed by a TDP-43-based transgenic C. lization . As a polization ,179.Further developments have also arisen, with a 2019 mouse study introducing viral-mediated antibody delivery to target the RRM1 degradation domain of TDP-43 inclusions . ShowingG37R transgenic mice, which resulted in reduced accumulation of misfolded SOD1 in the spinal cord, coupled with the increased survival by an average of 40 days. Thus, there appears to be a viable immune-therapy approach against misfolded SOD1 in fALS and sALS, which can be further expanded to other misfolded proteins.Finally, regarding our discussions in understanding the close interrelationship between SOD1 and RBPs TDP-43 and FUS, this re-examined perspective of the non-RBP may help researchers better understand the seemingly causative heterogeneity exhibited in the common mutant SOD1 fALS patients and those non-mutant SOD1 ALS patients. This may therefore act as a consolation in devising treatment approaches for such a heterogeneous disease, particularly as treatment response may therefore effectively affect beyond that single target , even if such a target proves to be downstream to central pathology, since ALS appears to be deeply integrated with multiple points of cyclical failure. In this respect, Liu et al.  have shoFinally, it is also worthy to consider the relationship miRNA holds between the potentially self-propagating pathological RBPs (as discussed in Here we have reviewed common proteomic themes that are not only mechanistically important in ALS, but may also shed light on proteinopathies and their molecular basis that are involved across several neurodegenerative diseases. To date, no single entity or event results in slowly progressive neurodegenerative diseases, and it is believed that several processes encompassing environmental, epigenetic, and genetic events may define a disease phenotype. Given this, the next generation of treatments should focus on combinatorial therapies that are selective for several of these decisive events that define a disease phenotype. As discussed, investigating the role of microRNAs and RNA-binding proteins provides only a snapshot of the causative mechanisms in ALS pathogenesis. However, their significance in disease progression is greatly recognized, and its unified discussion was necessitated. Since in several NDs, specific nuclear or cytoplasmic protein accumulation forms the causative neuropathological picture, it will be important to identify and ideally classify microRNAs regulating the translation of these targets, while studying the quantitative effects on the proteome of these therapeutic miRNAs. Although still hampered by the heterogeneity of ALS, this insight into these crucial players will hopefully guide future research attempts into more effective diagnostic advancements and potential avenues for therapy.


Two-dimensional (2D) materials and their van der Waals heterojunctions offer the opportunity to combine layers with different properties as the building blocks to engineer new functional materials for high-performance devices, sensors, and water-splitting photocatalysts. A tremendous amount of work has been done thus far to isolate or synthesize new 2D materials as well as to form new heterostructures and investigate their chemical and physical properties. This article collection covers state-of-the-art experimental, numerical, and theoretical research on 2D materials and on their van der Waals heterojunctions for applications in electronics, optoelectronics, and energy generation. The advent of graphene ,2,3, andDifferent types of 2D materials can form heterojunctions with each other or with bulk materials, without the need for close lattice matching . In thesTremendous amount of work has been done thus far on the physical and chemical properties as well as on the synthesis and the characterization of 2D materials such as graphene ,14, tranNanomaterials (MDPI), covers state-of-the-art experimental, simulation, and theoretical research on 2D materials and on their van der Waals heterojunctions for applications in electronics, optoelectronics, energy generation, and photocatalysis.This article collection, a reprint of the Special Issue “2D Materials and Van der Waals Heterostructures: Physics and Applications” published by From a material standpoint, the articles of this collection can be organized in three main categories: Graphene and graphene oxide, MXenes and transition metal (di)chalcogenides, and graphene-like materials.2 heterostructures [First principle calculations are applied to study the electronic and magnetic properties of Stone–Wales defected graphene  and the ructures , while eructures  and to rructures . Stone–Wales, formed by the rotation of a C-C bond in a hexagon ring, are the most common topological defects in graphene. They have been widely studied because they can lead to the opening of a band gap that is highly desirable for the application of graphene in electronic devices . Stone-W2) are changed after they are combined in an heterostructure. MoS2 [2 system are improved compared to those of the two separate single-layers. The band gap and the dielectric constants become larger for the graphene/MoS2 heterostructure, with redshift for the absorption coefficient, the refractive index, and the reflectance, and blueshift for the energy loss spectrum. First principle calculations are also applied by Qiu et al.  to demonre. MoS2 ,33 is thThe heterojunction formed by graphene with traditional 3D materials, which has been a promising research topic ,35,36,372V2O7 nanoparticles deposited on TiO2 nanorods followed by the addition of r-GO flakes. They show that electrophoretic deposition of p-type r-GO flakes on β-Cu2V2O7/TiO2 nanorods remarkably improves the durability, charge transfer resistance, and photocurrent density. Graphene oxide is the material produced by oxidation of graphite that includes oxygen functional groups. It has interesting properties that are different than those of graphene. The reduction of the oxygen content through chemical, thermal, and other methods leads to the so-called reduced graphene oxide (r-GO), a cheaper and lower quality form of graphene, yet with important applications ,40. r-GO2C, Ti4N3, Ti3CN, Mo2N, Mo2TiC2, Mo2Ti2C3, Cr2TiC2, etc. MXenes such as Nb2CTx, Ti2CTx, or Ti3C2Tx, with the surface terminated by Tx functional groups , combine a high metallic conductivity with the hydrophilic nature of their hydroxyl or oxygen terminated surfaces, behaving as a sort of “conductive clays”. MXenes have been applied to energy storage, water purification, chemical catalysts, electrochemical sensors, field effect transistor sensors, gas sensors, etc. [MXenes are a new, large family of layered materials consisting of transition metal carbides, nitrides, and carbonitrides. Examples of mono and double transition metal MXenes are Tirs, etc. . Transition metal (mono)chalcogenides (TMC)  are MS, 2, where M represents a transition metal and X denotes the chalcogen. Molybdenum disulfide (MoS2) and diselenide (MoSe2) [2) and diselenide (WSe2) [2) [Transition metal dichalcogenides (TMDs) are the most studied 2D materials after graphene ,43. They (MoSe2) ,46,47,48e (WSe2) ,50 are tSe2) [2) ,51,52 isSe2) [2) , flexiblSe2) [2) , 3d imagSe2) [2) , and tacSe2) [2) , as wellSe2) [2)  or photoSe2) [2) , have be3C2Tx MXene in combination with transition metal dichalcogenides to design new optical sensors based on surface plasmon resonance (SPR) to use for biosensing and chemical sensing. Highly sensitive SPR sensors have been previously demonstrated with coating of dielectric materials, graphene, or TMDs on metal films [3C2Tx-Au-TMDs in a modified Kretschmann configuration. The theoretical works of the authors show that it possesses enhanced sensitivity as compared to the bare Au film-based SPR sensor.Xu et al.  propose al films ,60. The 2 flakes is the subject of the work of Shi and coworkers [2 has a structure similar to the best-known MoS2, but exhibits stronger photoluminescence quantum yield at room temperature and larger spin-orbit coupling and is a promising 2D material for applications in optoelectronics and spintronics. The difficulty of controlling the interrelated growth parameters makes the synthesis of large-area monolayer WS2 still challenging. Therefore, the reported one-step chemical vapor deposition (CVD) process, by direct sulfurization of powdered tungsten trioxide (WO3) drop-casted on SiO2/Si substrates at atmospheric pressure that yields large-area monolayer WS2, is of great interest. Triangular monolayer WS2 flakes with edge lengths up few hundred microns and homogeneous crystallinity are obtained.The synthesis of large area and good quality TMDs is of paramount importance for their industrial exploitation. The fabrication of monolayer WSoworkers . WS2 has2, which is a TMD structurally similar to MoS2, but with a slightly lower bandgap (1.6 eV), is used in back-gated field effect transistors (FETs) by Urban et al. [2 exhibits strong optical absorption in the visible range, a good light-to-electricity conversion coefficient, and forms FETs with ambipolar behavior with most of the metals commonly used in electronics. Urban and coworkers fabricate WSe2 backgate FETs with Ni Schottky contacts and measure their electrical characteristics under different environmental conditions. They demonstrate that lowering the pressure in air-exposed WSe2 dramatically affects the electrical characteristics turning the FET conduction from the p- to n-type. Furthermore, from the electrical characterization at different temperatures, a gate modulation of the Schottky barrier (SB) at the contacts was proven. In addition, the work reports the temperature dependence of the carrier mobility and the subthreshold swing, as well as the photo response at several laser wavelengths. Some of the results are likely qualitatively valid for other TMD-based devices.CVD monolayer WSen et al. . Two-dim2Se3 [First principle calculations are again performed to investigate the electronic and optical properties of the β-polytypes of indium selenide, β-InSe , and car2Se3 . Recentl2Se3 . β-InSe is the most stable phase of InSe, due to the ABAB crystal stacking mode. The individual layer has a hexagonal structure and shows different electronic and optical properties compared to the bulk . MonolayBased on numerical work, Zhang at al. propose carbon selenide, β-CSe, as a novel ultra-thin stable material with wide indirect bandgap. The β-CSe exhibits slightly anisotropic mechanical characteristics and its bandgap and band-edge curvature are sensitive to in-plane strain, causing the carrier effective mass to be strain-dependent. Zhang and coworkers also propose a heterojunction obtained by stacking α-CSe on a β-CSe sheet. The α-CSe/β-CSe interface constitutes a type-II van der Waals p-n heterojunction with strong built-in electric field across the interface, due to the charges transferring from β-CSe to α-CSe. The built-in potential causes substantial energy band bending, which can be exploited to spatially separate photo-generated carriers in photovoltaic devices. Furthermore, as a metal-free photocatalyst, the α-CSe/β-CSe heterojunction is endowed with an enhanced solar-driven redox ability for photocatalytic water splitting via reduced electron-hole-pair recombination. This study will likely motivate experimental research on the synthesis and the properties of this new material as well as on the design of new devices.2 [2Se3 by interlayer fusion of PdSe2 [2Se3 by first principles calculations. They demonstrate that Pd2Se3 monolayers have a great potential as absorber material in ultrathin photovoltaic devices owing to their quasi-direct band gap of 1.39 eV, high electron mobility (> 100 cm2V−1s−1), and strong optical absorption (~105 cm−1) in the visible solar spectrum. Furthermore, the Pd2Se3 bandgap can be modulated and changed from indirect to direct by biaxial strain. More importantly, monolayer Pd2S3, obtained by replacing Se with S, is stable and can be used in a vertical stack with Pd2Se3 monolayer to form a type-II heterostructure. The simulation indicates that such a structure, used as a solar cell, could achieve 20% power conversion efficiency, higher than that of MoS2/MoSe2 photovoltaic devices. This numerical study presents several challenges for new experiments on 2D Pd2Se3 and Pd2S3 as well as on the application of their heterostructures for efficient solar energy conversion.Layered materials based on noble transition metals, such as Pd and Pt, have gained popularity after the successful exfoliation of PdSe2 ,67,68 anof PdSe2 ,70, Li aof PdSe2  study th3N4, and zinc oxide, g-ZnO, are used to form 2D heterojunctions with transition metal (di)chalcogenides. The investigation of CdS/g-C3N4 [2 [3N4 [3N4 as a function of biaxial strain and pH of the electrolyte, with the objective of optimizing the photocatalytic performances. The numerical simulations show that monolayer CdS weakly contacts with g-C3N4, forming a type II van der Waals (vdW) heterostructure. The predicted bandgaps and optical absorptions indicate that such a heterostructure can absorb visible light and the induced built-in electric field at the interface promotes the effective separation of the photogenerated carriers. Furthermore, the interface adhesion energy, bandgap, and band edge positions can be adjusted by applying a biaxial strain.The quest for efficient water-splitting photocatalysts motivates the first principle studies by Wang and coworkers ,72, in wS/g-C3N4  and g-Zn-C3N4 [2  and grap [2 [3N4  have sui2 or WSe2 are studied as a function of the rotation angles and the biaxial strain [2 heterostructures with appropriate rotation angles possess a suitable bandgap for visible absorption, proper band edge alignment, and effective separation of carriers, being promising visible water-splitting photocatalysts. Conversely, the water oxygen process of the ZnO/WSe2 heterostructures is limited by their band edge positions.The water-splitting photocatalytic properties of the heterostructures formed by g-ZnO with two-dimensional WSl strain  as well.l strain  and densl strain . Wang an3N4 or g-ZnO/WS2-based water-splitting solutions to prepare hydrogen fuel.These theoretical findings offer a sound basis to develop CdS/g-CAlthough graphene has proven to be an unmatched material due to its abundance of properties and applications, other 2D materials have been isolated or synthesized to better serve specific needs. Owing to their bandgaps, an example of a feature that graphene does not possess, transition metal (di)chalcogenides have emerged for instance as materials well-suited for electronics, optoelectronic, and photocatalytic applications.The layer control in two-dimensional materials provides an effective strategy to modulate their optical and electrical properties. The formation of van der Waals heterostructures, with enhanced features, offers a unique opportunity to fabricate new materials.This book offers a collection of research papers that cover the state-of-the-art of fabrication, properties, and applications of graphene and graphene-like materials, along with their heterostructures.2Se3/Pd2S3 or CdS/g-C3N4, and g-ZnO/WS2 are proposed based on first principle calculations.The electronic and optical properties of several popular 2D materials and their heterojunctions, as well as the opportunities for their exploitation in sensors, electronic and optoelectronic devices, and water-splitting photocatalysts, are extensively discussed. New 2D materials and new heterostructures like α-CSe/β-CSe, PdThese studies consolidate and extend the general knowledge of the physics and technology of 2D materials and offer many theoretical results that will likely be the challenging subject of forthcoming experimental investigations.


Dear Editor,IDO1 mRNA expression on prognosis in 33 diverse cancer types, identified 43 key genes involved in the effect, and defined the weighted average of all the 43 key gene expressions as 43‐gene score to reflect the integrated role of 43 key gene expressions in the relationship between IDO1 expression and cancer prognosis. We mined the potential regulator of 43 key genes and explored its impacts on regulating the expressions of 43 key genes and enhancing the therapeutic efficacy of IDO1 inhibitor  inhibition has been developed as a potential new tool in cancer immunotherapy and some IDO1 inhibitors have been in clinical trials.IDO1 expressionsIDO1 expression on prognosis in 33 diverse cancer types from The Cancer Genome Atlas (TCGA)  and X‐C motif chemokine ligand 1 (XCL1), still performed well in the validation set 2  regression model to compare the overall survival (OS) and progression‐free interval (PFI) of patients with high and low ) Figure . These tt Figure . We alsot Figure . For thet Figure . Within t Figure . Even so2 Figure . All of IDO1 had a beneficial effect on prognosis in patients with tumor immune subtype C1  or C2 (IFN‐gamma Dominant), a disadvantageous effect in patients with C3 (Inflammatory) or C5   Figure . We iden) Figure . The cors Figure . These sIDO1 high expression correlates to good prognosis in patients with high 43‐gene scores, a hierarchical logistic regression model was employed to fit the efficacy measures of 251 drugs across 983 human cell lines, and further to identify drugs more sensitive to that cell lines with higher 43‐gene scores. As a result, EGFR inhibitor gefitinib was mined  and the National Natural Science Foundation of China (NO. 11971117).The datasets used or analyzed in this study are available from the corresponding author on reasonable request.All the authors consent for publication.The authors declare no conflict of interest.SuppMat1Click here for additional data file.SuppMat2Click here for additional data file.SuppMat3Click here for additional data file.


Terahertz reflection behaviors of metallic-grating-dielectric-metal (MGDM) microcavity with a monolayer graphene embedded into the dielectric layer are theoretically investigated. A tunable wideband reflection dip at about the Fabry–Pérot resonant frequency of the structure is found. The reflectance at the dip frequency can be electrically tuned in the range of 96.5% and 8.8%. Because of the subwavelength distance between the metallic grating and the monolayer graphene, both of the evanescent grating slit waveguide modes and the evanescent Rayleigh modes play key roles in the strong absorption by the graphene layer. The dependence of reflection behaviors on the carrier scattering rate of graphene is analyzed. A prototype MGDM-graphene structure is fabricated to verify the theoretical analysis. Our investigations are helpful for the developments of electrically controlled terahertz modulators, switches, and reconfigurable antennas based on the MGDM-graphene structures. The three theoretical methods are combined to explore the reflection behaviors of the MGDM-graphene structure and their dependences on the parameters of mobility and carrier concentration of graphene.n manner . In thisn manner ,(3)C was deposited on a Si substrate by using a magnetron sputtering growth system (Denton Discovery 24) with a base pressure of 10−6 Torr. Ti (99.99% purity) and Au (99.99% purity) sputter targets were used. During the deposition, the anode bias is 160 V and the cathode current is 5 A. Second, a 9-μm thick BCB dielectric layer was deposited on the bottom mirror. A commercial BCB precursor  was spin-coated on the metallic mirror using 500 rpm for 10 s followed by 2000 rpm for 30 s, and the standard temperature–time diagram provided by the product manufacturer was used to carry out the thermal curing in a closed chamber full of nitrogen gas (99.9% purity). A step profiler  was used to test the thickness of the BCB layer. Third, a standard PMMA-assisted transfer procedure of CVD-growth graphene to the 9-μm thick BCB layer was processed. The wafers of CVD-grown single-layer graphene on copper foil were purchased from MukeNano . The nominal mobility is 2500 cm2/s/V. Raman scattering measurements  were performed to characterize the crystal quality of the transferred graphene sheet. Fourth, on the graphene sheet, a 1-μm thick BCB layer was deposited. Another commercial BCB precursor  was spin-coated on the metallic mirror using 500 rpm for 10 s followed by 5000 rpm for 30 s. The corresponding temperature-time diagram  was used to thermally cure the BCB layer. Finally, the 15 nm/500 nm thick Ti/Au metallic grating was made on the top BCB layer by using the standard photolithography and lift-off processes.The MGDM-graphene structure is composed of (from the Si substrate) an Au bottom mirror layer, a 9-μm thick BCB dielectric layer, a monolayer graphene sheet, a 1-μm thick BCB layer, and an Au grating layer. The periodicity of the grating is 30 μm. The metal strips are 15 μm wide and 0.5 μm thick. The dimension of the structure is 1 × 1 cm2 dielectric layer, the uncontrollable bulk free-carrier loss is negligible for the BCB dielectric layer, which will reduce the insertion loss effectively. Finally, the graphene layer is encapsulated in the chemically stable dielectrics, which prevents the graphene sheet from the extra residual impurities introduced during the fabrication of metal periodic structures and the deleterious effects of the environment.The basic principle of the MGDM-graphene is similar with the reported absorbers and modulators ,44 worki−1 related to the crystal defects in graphene, which indicates the good quality of the transferred graphene. The ratio of peak magnitudes of 2D (2670 cm−1) and G (1580 cm−1) is about 2.65. Such a high 2 D/G ratio is the signature of monolayer graphene sheet [μ = 1500 cm2/s/V and n = 7.0 × 1012/cm2) with incident angles of 0° and 11° are presented in zk is the wavevector in z direction, L is the thickness of the MGDM cavity, π and Gratingφ are the additional reflection phases at the bottom metallic mirror and the grating interface, respectively, and k is an integer. The wavevector zk can be expressed askx0 is the x-component of wavevector and M = 0, ±1, … is the grating diffractive mode number. The first dip at 3.35 THz corresponds to the resonant mode k = 1 and M = 0. The wavelength of the first dip at 3.35 THz is, minλ = c/(nBCB × minf) = 55 μm with c the speed of light in vacuum, BCBn the refractive index of BCB, and minf = 3.35 THz, which is longer than 4L = 40 μm. Such a discrepancy originates from the reflection additional phase at the grating layer Gratingφ at the resonant frequency. Because of the field constructive interference near the grating interface, the intensity of the local electric field increases, which enhances the graphene-induced absorption loss and leads to the reflection dip at 3.35 THz.The reflection spectrum of the MGDM-graphene device is measured using a Fourier transform infrared spectrometer . In order to eliminate the influence of water vapor absorption, the sample chamber of the spectrometer is evacuated. A reflection module (Bruker A510/Q) with a fixed incident angle of 11° is utilized to measure the reflection spectrum. A linear polarizer is inserted into the optical path between the radiation source and the sample to obtain the p-polarized wave . A numerical fitting procedure is carried out by using the commercial COMSOL software with carrier mobility and carrier concentration of graphene as the fitting parameters. The experimental reflection spectrum and the numerical reflection spectra .At frequency range larger than 5.0 THz, there exists big discrepancies between simulation and experiment. For the grating with 30 μm periodicity, the frequency of the first-order diffractive mode in the BCB layer is 6.2 THz. Thus the reflection features located above 6.2 THz are related to the first-order diffractive modes μ = 1500 cm2/s/V. The numerical reflectance using different methods  at the first dip as a function of carrier concentration is presented in M = 1, 2, …, 5) and the number of the Rayleigh modes in the dielectric layer is 35 . The MM results are in good agreement with the rigorous FEM results, which verifies the validity of the method and the correctness of our homemade code. The numerical results shown in R(n) = R0 + Aexp(−n / n0) with fitting parameters R0 = 0.085, A = 0.88, and n0 = 2.1 × 1012/cm2, from which the numerical MD can be derived as MD = A / (A + R0) = 91.2% and the insertion loss is 1 − A − R0 = 3.5%. 12/cm2, respectively. The FEM and MM results are in good accordance with each other. With increasing carrier concentration, the shape of the dip remains unchanged, but the peak frequency is blue shifted.For the MGDM-graphene structure, the reflection behaviors can be well understood with the concept of impedance matching or critical absorption. Thus the ECM is a valuable tool to analyze the reflection spectra of the structure and gain deeper understanding on the physical mechanisms behind such behaviors. In our calculations, as shown in 12/cm2 are shown in μ < 1500 cm2/s/V. However, such a relation of reflectance with carrier mobility is inverse when μ > 1500 cm2/s/V. As shown in 12/cm2), the values of the resistor and the inductor are determined by carrier mobility. Therefore, an optimal value of carrier mobility exists that satisfies the critical impedance matching condition. In our calculations, when μ > 3500 cm2/s/V, another shallower reflection dip emerges at 1.4 THz. z component) distributions for μ = 1500 cm2/s/V at the dip frequency of 3.35 THz and μ = 7500 cm2/s/V at the dip frequencies of 1.4 THz and 3.35 THz. The field distributions clearly show that the graphene surface plasmon (SP) modes are excited by the evanescent modes localized near the strip edges. The wavevector of the SP modes can be expressed as [v = c/ε1/2 is the speed of light in the dielectric and γ = 1/τ is the scattering rate. Equation (8) indicates that the loss of SP modes proportional to the imaginary part of SPk that is more dominant at lower frequencies. Therefore, because of the large loss, the reflection dip at 1.4 THz cannot be resolved for lower carrier mobilities. Carrier mobility is a key parameter to determine the electromagnetic properties of graphene. The FEM-based numerical reflection spectra with different carrier mobilities and a fixed carrier concentration of 7 × 10essed as .(8)kSP=Generally, in a metal-graphene hybrid structure, the space between the graphene sheet and the metallic array must be kept in deep subwavelength scale to maintain a stronger light–graphene interaction. In this case, the near-field interaction, in other words, the effects of evanescent-mode-excited SP modes propagation along the graphene sheet cannot be appropriately treated by the ECM, even in the frequency range that the wavelength is much longer than the periodicity of the metallic array. In recent years, several multi-mode ECMs  are deven = 7 × 1012/cm2 and μ = 7500 cm2/s/V calculated by the MM with different numbers of waveguide modes and Rayleigh modes. At the dip frequencies of 1.4 THz and 3.35 THz, only the fundamental waveguide mode and Rayleigh mode are the propagating modes. However, due to the deep subwavelength space between the metallic grating and the graphene sheet, the evanescent modes play key roles in the shape and reflectance of the reflection dips. As shown in N = 15 (31 Rayleigh modes being used to expand the electromagnetic fields in the upper and lower regions of the grating), there is a large difference between the numerical reflection spectra with M = 1, 3, and 5. Because of the small difference between the cases of M = 3 and M = 5, it is expected that the calculations are convergent when M > 5. N = 0, 2, 10, and 15 and a fixed waveguide mode number of M = 5. For the cases of N= 10 and N = 15, the two reflection spectra are completely overlapped. The above results indicate that the MM calculations are convergent when M > 5 and N > 10.n = 7 × 1012/cm2 and μ = 1500 cm2/s/V. This work is helpful for the developments of electrically controlled terahertz modulators, switches, and reconfigurable antennas based on MGDM-graphene structures.In conclusion, reflection spectra of a MGDM-graphene structure in terahertz regime are systematically investigated. The rigorous finite element method , the modal method, and the equivalent circuit model are utilized to study the reflection behaviors of the MGDM-graphene structure. A reflection dip near the Fabry-Pérot resonant frequency of the MGDM-graphene structure is found. The reflectance of the dip is very sensitive to the carrier concentration in the graphene sheet, which indicates that the structure can be used as modulators. The calculated modulation depth can reach 91.2% with a small insertion loss of 3.5%. There exists an optimal value of carrier mobility for obtaining the maximum modulation depth. The reflection behaviors and their dependences on the graphene parameters, carrier mobility and carrier concentration, can be qualitatively understood with the concept of impedance matching. Indeed, the results based on ECM can qualitatively describe the behaviors of the reflection dip. However, because the distance between the metallic grating and the graphene sheet is in deep subwavelength scale, near-field interactions play key roles in the reflection of the MGDM-graphene structure. The calculations based on MM quantitatively show the effects of high-order evanescent waveguide modes and Rayleigh modes, especially for the case of high carrier mobility. These near-field effects cannot be correctively treated by the ECM-based calculations. A prototype MGDM-graphene structure is fabricated. The experimental reflection dip near the Fabry-Pérot resonant frequency can be well reproduced with the fitting parameters of


Tissue engineering is an interdisciplinary field that combines principles of engineering and life sciences to obtain biomaterials capable of maintaining, improving, or substituting the function of various tissues or even an entire organ. In virtue of its high availability, biocompatibility and versatility, cellulose was considered a promising platform for such applications. The combination of cellulose with graphene or graphene derivatives leads to the obtainment of superior composites in terms of cellular attachment, growth and proliferation, integration into host tissue, and stem cell differentiation toward specific lineages. The current review provides an up-to-date summary of the status of the field of cellulose composites with graphene for tissue engineering applications. The preparation methods and the biological performance of cellulose paper, bacterial cellulose, and cellulose derivatives-based composites with graphene, graphene oxide and reduced graphene oxide were mainly discussed. The importance of the cellulose-based matrix and the contribution of graphene and graphene derivatives fillers as well as several key applications of these hybrid materials, particularly for the development of multifunctional scaffolds for cell culture, bone and neural tissue regeneration were also highlighted. In recent decades, the rapidly aging population, environmental stressors, frequent cases of traumatic injuries and chronic diseases lead to a growing interest in the revolutionary domain of tissue engineering (TE) ,2,3. TisPorous three-dimensional (3D) scaffolds are an important component of tissue engineering. These constructs are used to provide an appropriate environment for tissue and organs regeneration. Biological scaffolds  are an accessible option because they already contain a broad spectrum of signaling molecules with an important role in the processes of cellular morphogenesis and function development ,12. HoweCellulose remarks itself among the biomaterials used for scaffold production due to its high availability and renewability. Cellulose is mainly extracted from plant cell walls. The nano-scaled forms of plant cellulose—cellulose nanofibers (CNFs) and cellulose nanocrystals (CNCs), are obtained following specific mechanical and chemical treatments  ,19. In vCellulose can also be produced by certain microorganisms, in this case being called bacterial cellulose (BC). BC is considered to be the most biocompatible form of cellulose because it lacks biogenic impurities such as lignin and hemicellulose and only mild chemical treatments are required to ensure its purity . The nanPure cellulose lacks solubility in common organic solvents. This represents an issue when it comes to processing techniques where a stable polymeric solution is required to prepare the final material . Cellulose was dissolved so far only in mixtures of highly toxic solvents  ; howeverGraphene (GE) is an allotrope of carbon produced by top down  or bottom up techniques  . GE has 2SO4 in a microwave device. The material was kept at 180 °C and a pressure of 40 bar, for 2 h, under nitrogen flow. Following this treatment, black solid carbon spheres were obtained. The spheres were further dispersed in concentrated nitric acid (HNO3), ultrasonicated 30 min at 45 °C and heated at 90 °C for 30 min, under magnetic stirring to obtain nGO. The ultrasonication time is a decisive factor in obtaining materials with uniform and reproducible properties . . 112]. TIn another study conducted by Kumar et al., GO nanosheets and CNCs were employed as multifunctional crosslinking agents for polyacrylamide-sodium carboxymethyl cellulose (PAA-NaCMC) hydrogels, prepared by in situ free radical polymerization. Due to GO and CNCs hydrophilic nature and ability to provide sites for hydrogen and covalent bonding, both PAA and NaCMC had favorable molecular interactions with GO and formed strong interfacial bonds with CNCs. The synergistic effect of GO and CNC lead to an improvement of the viscoelastic mechanical properties, shape recovery behavior and self-healing ability of the interpenetrating PAA/NaCMC network. Still, further studied must be conducted in order to determinate if these hybrid hydrogels represent appropriate 3D microenvironments for tissue engineering applications .Polylactic acid is a biobased plastic obtained by bacterial fermentation processes. Its biodegradability and biocompatibility recommend it for replacing conventional petroleum-based plastics used in the biomedical field. Still, its mechanical properties need further improvement. CNCs and rGO were used as reinforcing fillers for PLA ,62. The This study suggests that rGO is not only a reinforcing agent for biopolymer matrices but can also induce an antimicrobial character, very useful for preventing infections in tissue engineering applications.Undeniably, cellulose and graphene are highly versatile materials and they can be employed in multiple ways to obtain hybrid composites with superior physico-chemical and biological features compared to cellulose or graphene alone. A summary of the cellulose/graphene composites for tissue engineering applications presented in the previous chapters is found in This review highlighted some of the recent discoveries regarding cellulose-based composites with graphene and graphene derivatives. As most of the described studies concluded, the combination of cellulose and graphene renders sustainable and cost effective composites with improved physico-chemical features and bioactivity. Cellulose and graphene can be labeled as complementary materials because the incorporation of graphene in cellulose-based matrices minimizes GE’s potential cytotoxic character and, in its turn, GE improves the biocompatibility of cellulose by providing cell binding sites and positively interfering in cellular differentiation processes and also its mechanical properties. The versatility of both cellulose and graphene is another important reason cellulose/graphene composites are needed in tissue engineering. Cellulose paper was used to develop electrodes for cellular electrical stimulation or in vivo tissue models for a better understanding of a specific tissue biology and experimental drug testing. Bacterial cellulose and cellulose derivatives were employed in the form of electrospun mats, membranes, and hydrogels as ECM-mimicking scaffolds for enhanced cell adhesion, growth and proliferation whereas cellulose nanocrystals and cellulose nanofibers were incorporated in various biopolymer matrices for a reinforcing effect. Some particularly interesting features for tissue engineering are related to GE and its derivatives ability to guide stem cells differentiation toward specific lineages  and also to the electrical conductivity and fluorescent properties that they provide to cellulose matrices, thus extending the areas of application of cellulose/graphene composites Also, a synergistic reinforcing effect was observed when both cellulose and graphene-based fillers were incorporated in various biopolymer matrices.The constant research activity in the field of cellulose/graphene composites lead so far to important discoveries in the area of tissue engineering. Even if these materials could represent promising alternatives to currently used medical techniques, the progress toward obtaining clinical products is slow. Future trends consist of the collaboration of clinicians, biomaterial scientists and engineers, with expertise in their own fields, to elaborate marketable and accessible products for therapeutic purposes.


Sarcoidosis is a systemic granulomatous disease caused by CD4+ cell-dominant inflammation. Meanwhile, diffuse panbronchiolitis is a chronic inflammatory respiratory disease predominantly caused by CD8+ lymphocytes and neutrophils. Herein, we report a rare case of sarcoidosis in which the clinical presentation had become evident as diffuse panbronchiolitis after splenectomy for sarcoidosis.Hemophilus influenzae. The titer of cold agglutinin was elevated, thereby confirming the diagnosis of diffuse panbronchiolitis. On the basis of the clinical and radiological findings, the condition of the patient improved with low-dose macrolide therapy for 3 months.A 23-year-old Japanese woman was referred to our hospital due to splenomegaly of unknown etiology. Upon admission, chest computed tomography scan revealed centrilobular and randomly distributed small nodules in both lungs. Bronchoalveolar lavage revealed a high proportion of lymphocytes and a decreased CD4/CD8 ratio. However, the biopsy specimens obtained from both the liver and lungs revealed noncaseating epithelioid granulomas, which confirmed the diagnosis of sarcoidosis. The patient underwent splenectomy due to progressive cytopenia and high risk of splenic rupture. After the surgery, the condition of the patient was consistently good for 3 months. Then, she gradually developed productive cough and dyspnea. Both sinus and chest computed tomography scan revealed chronic paranasal sinusitis and deterioration of centrilobular nodules in both lung fields, respectively. The second bronchoalveolar lavage revealed a high proportion of neutrophils, and the bronchoalveolar lavage fluid tested positive for The coexistence of sarcoidosis and diffuse panbronchiolitis has not been previously reported, and the hidden profiles of diffuse panbronchiolitis may have been revealed by splenectomy. Sarcoidosis is a systemic granulomatous disease of unknown etiology. The lungs and intrathoracic lymph nodes are the commonly affected regions, and the liver and spleen are the most commonly affected extrapulmonary organs , 2. A hiHemophilus influenzae or Pseudomonas aeruginosa.Meanwhile, diffuse panbronchiolitis (DPB) is a chronic inflammatory respiratory disease predominantly affecting East Asians . The typThe mechanisms of these two respiratory diseases are different, and the coexistence of sarcoidosis and DPB has not been observed in previous studies. Herein, we report a case of sarcoidosis in which the clinical presentation had become evident as DPB after splenectomy for sarcoidosis.A 23-year-old Japanese woman was referred to our hospital due to splenomegaly of unknown etiology and cytopenia. Before referral, she underwent intensive examinations, including bone marrow aspiration and spleen biopsy, at other medical care centers for the detection of hematologic, endocrine, and hereditary diseases in a differential diagnosis. However, a definitive diagnosis was not made. Upon admission, the patient presented with dyspnea upon exertion and abdominal distention. Chest CT scan revealed the presence of both centrilobular and randomly distributed small nodules in both lungs Fig. a. In addHemophilus influenzae. In addition, the cold agglutinin test had positive results, and paranasal sinus CT scan revealed inflammation of the maxillary sinus (Fig. The patient complained of gradually exacerbating dyspnea and increase in purulent sputum 3 months after splenectomy. Chest CT scan revealed the presence of centrilobular nodules with bronchial wall thickening in both lung fields Fig. . The bacnus Fig. e. Becausnus Fig. .Fig. 3aHerein, we report the coexistence of sarcoidosis and DPB, which became evident after splenectomy. The diagnosis of sarcoidosis was confirmed on the basis of the presence of noncaseating granulomas in the biopsy specimens obtained from several organs, including the liver, spleen, and lungs. Increased lymphocyte count in the BALF is commonly observed in patients with sarcoidosis; the CD4+ lymphocytes infiltrate into the alveoli, causing the high CD4/CD8 ratio in the BALF , 2. HoweHemophilus influenzae. Since splenectomy is a risk factor for infectious diseases caused by Hemophilus influenza, it may explain the exacerbation in DPB.Splenectomy might have triggered the exacerbation of DPB. The levels of serum ACE and lysozyme, which reflect the disease activity of sarcoidosis, decreased after splenectomy. By contrast, the presence of centrilobular nodules, which is one of the radiological features of DPB, was found on chest CT scan in the current case. Furthermore, the second BAL revealed both increased proportion of neutrophils and a positive bacterial culture for In the present case, the histological features of DPB were also confirmed; biopsy specimens obtained during the first bronchoscopy showed accumulation of foamy cells around the respiratory bronchioles where the distinctive feature is observed in patients with DPB . The detIn conclusion, the present case highlighted the complex presentation of the coexistence of sarcoidosis and DPB. If a patient with sarcoidosis presents with an atypical disease presentation, the coexistence of other diseases should be considered.


Exploring the relationships between free-living (FL) and particle-attached (PA) bacterial communities can provide insight into their connectivity and the partitioning of biogeochemical processes, which is crucial to understanding the elemental cycles and metabolic pathways in aquatic ecosystems. However, there is still intense debate about that whether FL and PA fractions have the same assemblage. To address this issue, we investigated the extent of similarity between FL and PA bacterial communities along the environmental gradients in Lake Wuli, China. Our results revealed that the west Lake Wuli was slightly eutrophic and the east lake was moderately and highly eutrophic. The alpha-diversity of the FL bacterial communities was significantly lower than that of the PA fraction in the west lake, whereas the alpha-diversity of the two fractions was comparable in the east lake. The beta-diversity of both communities significantly differed in the west lake, whereas it resembled that in the east lake. Moreover, functional prediction analysis highlighted the significantly larger differences of metabolic functions between the FL and PA fractions in the west lake than in the east lake. Suspended particles and carbon resource promote the similarity between the FL and PA fractions. Collectively, our result reveals a convergent succession of aquatic communities along the eutrophic gradient, highlighting that the connectivity between FL and PA bacterial communities is nutrient related. Particles are crucial components in aquatic ecosystems , servingExploring the relationships between the FL and PA bacterial communities has been of long-standing interests to microbiologists. For decades, the FL and PA bacterial communities have been considered to be significantly different. The PA lifestyle has considerable advantages over the FL lifestyle, including access to resources and protection from predators and deleterious environmental pressures . FurtherHowever, many updated and novel findings show only slightly different FL and PA bacteria communities . Modern Thus, any attempt to understand the aquatic communities must be placed in the context of the relationship between the FL and PA bacterial communities. Recent progress has found that the aquatic communities prefer an FL lifestyle when nutrient level is high, whereas they prefer a PA lifestyle when nutrient level is low . Thus, w2  in the north of Lake Taihu, China. Lake Wuli has an area of 8.6 km2  and is d2 . Since t2 . Since 22 , most arproducts . Being lproducts .Microcystis on the surface of Lake Wuli. In this case, 5 μm pore size is adequate to collect the PA bacteria . Eight additional characteristics were measured by standard methods (a (Chl-a).Secchi depth (SD) was determined by using a Secchi disk. Water temperature (Temp) and dissolved oxygen (DO) were assessed  methods : total n® cycle-Pure kit (Omega Bio-Tek). The V4 regions of the 16S rRNA genes were amplified using the primers 515F (GTGYCAGCMGCCGCGGTAA) and 806R (GGACTACNVGGGTWTCTAAT) (2 (25 mmol/L), 0.5 μl of each primer (10 μmol/L each), 30 ng of quantified template DNA measuring by Pico green, and 0.4 μl of Taq polymerase . To increase specificity and sensitivity during gene amplification, the touchdown PCR was conducted in a thermocycler : denaturation at 94°C for 5 min, 11 cycles of denaturation at 94°C for 1 min, annealing at 65°C for 1 min (temperature was decreased by 1°C every cycle until 55°C was reached), and extension at 72°C for 1 min  . Polymeror 1 min . NineteeThe pair-end sequencing was performed on an Illumina MiSeq platform. Unique barcodes were added to each sample, and the individual paired reads were initially merged by using FLASH (Fast Length Adjustment of Short reads) software . We remoCRA002048, which is publicly accessible at https://bigd.big.ac.cn/gsa.The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive  in BIG Data Center (Nucleic Acids Res 2019), Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number 1.All statistical analyses and visualization were carried out using ape, factoextra, gglot2, Hmics, and vegan packages in the R environment (version 3.2.2)kmeans function and were visualized by the fviz_cluster function.As an indicator for assessing the trophic level according to the national standard, the trophic level index (TLI) is presented . The TLIalpha_div and beta_div workflow according to usearch. We calculated four indices: Chao1, Richness, Simpson, and Shannon. To compare the statistical differences, we performed non-parametric Kruskal–Wallis rank tests. We also used non-metric multidimensional scaling (NMDS) analysis on the basis of four distance matrices: Bray–Curtis distance, Jaccard dissimilarity, and unweighted and weighted UniFrac distance. To determine significant difference of beta-diversity, ADONIS was used. To predict the functional profiles of bacterial communities, on the basis of gene bacterial community, we applied the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt)  . To perfOur results showed that the west lake and the east lake were distinct aquatic environments with statistically significant differences. Cluster analysis revealed that samples within the west lake and the east lake were separated from each other . We used-a was significantly lower in the west lake than in the east lake . The SD significantly decreased from 0.78 ± 0.06 m in the west lake to 0.29 ± 0.12 m in the east lake, whereas the TSS significantly increased from 14.83 ± 3.70 to 27.38 ± 4.64 mg/L (both P = 0.002). Water in the west lake contained more oxygen than that in the east lake . Of particular note was that the concentration of six nutrients significantly increased from the west lake to the east lake, namely, TN, TP, TDN, TDP, COD, and DOC .The concentration of Chla. In contrast, the number of OTUs exclusive to the PA bacteria decreased from the west lake to the east lake, with significantly negative correlations with TSS, DOC, COD, and Chl-a , however, in the east lake, the FL and PA fractions were as diverse as each other  (P < 0.01). In contrast, in the east lake, the difference between FL and PA fractions was insignificant . Together, the FL and PA bacterial communities exhibited a convergent succession from the west to east lake. To detect the potential factors influencing the similarity between these two communities, we used the linear fitting approach. High and significantly negative associations are found between their similarities and DOC, COD, TSS, and Chl-a (P < 0.05).After the sequencing depth to the least number of reads among each site  was normalized, four indices were chosen to represent the community alpha-diversity, namely, Chao1, Richness, Simpson, and Shannon. In the west lake, the FL fraction was significantly less diverse than the PA fraction  . The bet > 0.05) . The resP = 0.006), whereas seven others were lower in the FL fraction than in the PA fraction  (P = 0.04), with Actinobacteria being higher in the FL communities and Chloroflexi being higher in the PA communities  . Howevermunities .P < 0.05), whereas in the east lake, only two classes differed between the fractions (both P < 0.05) (P < 0.05). Furthermore, in the west lake, some anaerobic bacteria, such as Clostridium and Romboutsia, were significantly enriched in the PA bacterial community relative to FL counterpart. However, in the east lake, the anaerobic bacteria of the FL and PA communities were comparable with each other.At the finer taxonomic level, 30 class-level taxonomic groups were detected for the two bacterial communities ; both ba < 0.05) . At the  < 0.05) , most ofP < 0.05). In total, the KOs were clustered into 41 gene families, most of which belonged to membrane transport (14.24 and 12.62%), amino acid metabolism (12.63 and 12.19%), carbohydrate metabolism (12.14 and 12.40%), and signal transduction (7.19 and 8.16%) for FL and PA fractions, respectively. In the west lake, 68 KOs were significantly higher in the FL fraction than in the PA fraction, whereas 137 KOs were significantly higher in the PA fraction relative to the FL fraction. In the east lake, 11 KOs were significantly higher in the FL fraction than in the PA fraction, whereas 14 KOs were significantly higher in the PA fraction relative to the FL fraction.Based on the predicted bacterial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, 276 KEGG orthology groups (KOs) were obtained in the FL and PA bacterial communities, among which 205 and 25 KOs significantly differed in the west lake and the east lake, respectively  , amino acid metabolism , metabolism of other amino acids (mainly glutathione metabolism and phosphonate and phosphinate metabolism). In contrast, 16 gene families were significantly higher in the PA fraction than in the FL fraction  (starch and sucrose metabolism and amino sugar and nucleotide sugar metabolism), glycan biosynthesis and metabolism (mainly lipopolysaccharide biosynthesis and other glycan degradation), energy metabolism (mainly methane metabolism and sulfur metabolism), and signal transduction (mainly two-component systems). In the east lake, 14 gene families showed significantly higher relative abundance in the FL fraction than in PA fraction  (P < 0.05)  , includi < 0.05) , includi < 0.05) . In cont < 0.05) .Because FL bacteria and PA bacteria occupy different ecological niches, exploring their relationships sheds light on the nutrient cycles and major metabolic pathways in aquatic ecosystems. Some previous studies have demonstrated that FL and PA bacteria are significantly different from each other , whereasOur results showed that Lake Wuli could be divided into two significantly distinct aquatic regions: the east lake with slight eutrophication and the west lake with moderate eutrophication and hyper-eutrophication. The FL bacterial communities were less diverse than the PA fraction in the west lake, whereas they were as diverse as each other in the east lake. Furthermore, both compositional structures and metabolic functionalities of the FL and PA communities were significantly different in the west lake but become similar in the east lake. Thus, the FL and PA bacterial communities showed a convergent succession along the eutrophic gradient from the west lake to the east lake. Recently, an increasing body of evidence has shown that nutrient enrichment leads to biotic homogenization in aquatic habitats, including insects , macroinFor decades, aquatic bacteria have been artificially categorized into two distinct lifestyles: FL and PA . Howevertwo-component system in PA bacterial communities from the west lake to the east lake. This signal transduction pathway controls bacterial cell attachment to the substrate surface, which facilitates biofilm formation .The sequencing data generated by this study can be found in the BIG Nation Genomics Data Center (YH and GG conceived and designed the experiments. GX and XJ performed sample collection. KS and XT analyzed the data. YH wrote the manuscript. All authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


L1 is based on the guanidiniocarbonyl pyrrole cation and serves as a highly specific anion binder in order to target the interaction between Survivin and Histone H3. NMR titration confirmed binding of L1 to Survivin's Histone H3 binding site. The inhibition of the Survivin–Histone H3 interaction and consequently a reduction of cancer cell proliferation were demonstrated by microscopic and cellular assays.The protein Survivin is highly upregulated in most cancers and considered to be a key player in carcinogenesis. We explored a supramolecular approach to address Survivin as a drug target by inhibiting the protein–protein interaction of Survivin and its functionally relevant binding partner Histone H3. Ligand  Effective interruption: The supramolecular guanidiniocarbonyl pyrrole ligand L1 targets the Histone H3 binding site of the protein Survivin, which is highly upregulated in cancer. Inhibiting the interaction between the two proteins successfully reduced cancer cell proliferation. Survivin is overexpressed in almost all malignant tumors and is considered an early diagnostic and prognostic biomarker.The most successful approaches so far have used compounds that display specific, well‐characterized recognition properties for amino acids and peptides in order to functionally modulate PPIs.L1) as the ligand with the best docking score  65 and 68, aspartic acids (D) 70, 71, and 72, and glutamic acids (E) 75 and 76  68, aspartic acid (D) 70, 71, and 72, and glutamic acid (E) 75 . The PLA allows the visualization of protein–protein interactions within cells on an endogenous level. At first, two primary antibodies bind to the target proteins Survivin and Histone H3. Secondary antibodies that are conjugated to a matched pair of short single‐stranded oligonucleotides then recognize these antibodies. If the two targets are in close proximity (<40 nm), the oligonucleotides hybridize and ligate with two additional connector oligonucleotides to form a continuous circular DNA structure. DNA polymerase then amplifies these circular structures through rolling‐circle amplification with fluorescent nucleotides that can be detected as PLA signals with fluorescence microscopy. The PLA indeed revealed a significant decrease of the Survivin–Histone H3 interaction inside the cell upon n Figure  A,B.L1 could be shown to inhibit the interaction between Survivin and Histone H3 inside the cell, we wanted to investigate whether the inhibitor would consequently also interfere with Survivin's role in cell proliferation. Therefore, HeLa cells were treated with 50 μm of L1 and synchronized before they were fixed during mitosis. The cells were then immunostained to allow the microscopic identification of mitotic defects. Cells that displayed mitotic defects were assigned to one of the five following categories: Multipolar Pro‐/Metaphase, Multipolar Ana‐/Telophase, Lagging Chromosomes, Acentric Fragments, and Chromatin Bridges .L1‐treated cells showed a larger variety of mitotic defects in comparison to the control. In addition to acentric fragments and lagging chromosomes, also chromatin bridges and multipolar spindles could be observed  used for this assay is added to the cells and bioreduced into a colored formazan product. The quantity of formazan product measured at 490 nm absorbance is directly proportional to the number of living cells in culture. The assay revealed that L1 was able to successfully inhibit cell proliferation in all cancer cell lines tested ‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2d Figure  C. In thL1 on cancer cell proliferation are Survivin‐specific, we performed a rescue experiment in which we transiently transfected HCT 116 cells with Survivin–HA (Rescue) or with GFP (Control). After treating the cells with L1 for 72 h we measured cell proliferation via an MTS assay. We were able to observe that an overexpression of Survivin–HA nearly completely rescued the antiproliferative effect of L1 in all tested concentrations. While cell proliferation was reduced to 72 % (50 μm), 67 % (100 μm), and 55 % (200 μm) in control cells, cell viability could be restored to 97 % (50 μm), 89 % (100 μm), and 91 % (200 μm) in cells overexpressing Survivin–HA  should be addressed to the authors.SupplementaryClick here for additional data file.