The samples were characterized using X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). Compared with other methods, our strategy avoids using surfactants and high-temperature treatments. The electrodes exhibited excellent electrochemical performance, high capabilities, and a long cycle life. Various electrochemical properties were systematically studied using cyclic voltammetry and electrochemical impedance spectroscopy. The results showed that the specific capacitance of the MnO2/graphene/Ni composite prepared at 1 mA cm−2 of electrodeposition could achieve a scan rate of 10 mV s−1 at 292.8 F g−1, which confirmed that the graphene layer could remarkably improve electron transfer at the electrolyte–electrode interface. The capacitance retention was about 90% after 5000 cycles. Additionally, a MnO2/graphene//graphene asymmetric supercapacitor was assembled and it exhibited a high-energy density of 91 Wh kg−1 as well as had an excellent power density of 400 W kg−1 at 1 A g−1. It is speculated that the strong adhesion between the graphene and MnO2 can provide a compact structure to enhance the mechanical stability, which can be applied as a new method for energy storage devices.A novel MnO Supercapacitors ,5.2 as a supercapacitor material is its poor conductivity, which severely limits its applications. The above-mentioned deficiency can be improved by introducing active materials, such as carbon materials [2/graphene composites can be used as a supercapacitor. Li et al. [2/reduced graphene oxide composite, in which the composite displayed a high specific capacitance and excellent capacitance retention after 1000 cycles. Yu et al. [2-based nano-structured electrodes. Moreover, the composite exhibited excellent cycling performance in capacitance retention (>95%) over 3000 cycles. Sun et al. [2 nanoflake composites through a hydrothermal reaction. The 3D graphite network offers a pathway with a fast electron transport, while the MnO2 nanoflakes emanate from the surface backbone to minimize the interfacial contact resistance. Generally, electrochemical electrodes have also suffered from inadequate contact due to their low surface areas [The key to achieving a high-energy density and long cycle life is to fabricate novel electrode materials containing a design morphology, structure, and appropriate electrolytes. However, a major drawback for MnOaterials ,7, conduaterials ,9, or traterials . In receaterials ,12. Theri et al.  fabricatu et al.  developen et al.  construcce areas . Numerouce areas ,18,19,202 result in poor conductivity and weak mechanical properties, which inhibits the electrochemical properties and stability of the capacitors. Several methods have been reported for the fabrication of MnO2/graphene/Ni foams, such as the hydrothermal method [2 synthesized using the hydrothermal method experiences severe agglomeration, which decreases the conductivity and surface area of the electrode. Among these methods, collapses and cracks are serious problems during the preparation process; therefore, it is detrimental to the electrochemical performance and cycle life of capacitors. Firstly, graphene was completely adsorbed into the Ni foams using ultrasonic impregnation, with a large and close contact with the Ni foam substrate with a high mechanical strength. In using this method, the required thickness of film can be coated on the substrate, which is a simple process. Then, MnO2 is coated on the surface of the graphene/Ni foams using an electrochemical deposition method, with improvements to the speed of the electron transfers. Furthermore, the working electrode made using this technology has a high surface area and higher diffusion rate of the electrolytes.In addition, from the perspective of the fabrication process, the fragile structure and weak contact between graphene and MnOl method  and cheml method . The rGO42− exhibited a significant exfoliation efficiency. Compared with other anions, regarding the exfoliation efficiency of SO42−, it is inferred that the reduction potential of SO42− is lower (+0.20 V), that is, it is easier to generate SO2 gas and sulfate ions can effectively exfoliate graphite [In recent years, the electrochemical exfoliation method has been used to prepare graphene. Using the chemical effect of electric currents, the graphite electrode of the anode is exfoliated, forming graphene fragments in the electrolyte. Then, filtration and centrifugal purification are used to transfer the as-prepared graphene to the desired solution. The electrochemical stripping method has the advantages of simple operation, low cost, fast reaction time, and environmental friendliness. Khaled et al.  studied graphite .2 anchored onto Ni foam substrates. Graphene obtained using SO42− to exfoliate graphite is very environmentally friendly. The graphene was coated onto the Ni foams using the impregnation method and then the nanostructured porous MnO2 nanoparticles were precipitated onto the skeleton of the graphene/Ni composite foam via electrochemical deposition at a constant current. Compared with other methods, our strategy avoids using surfactants or high-temperature treatments. This structural design will enhance the transport rate of electrons and electrolyte ions during the electrode reaction. The MnO2/graphene/Ni composite greatly improves capacitor performance, with a specific capacity of 292.8 F g−1, which is about four times higher than that of graphene/Ni, and about five times higher than that of MnO2/Ni. It is expected that the MnO2/graphene/Ni electrode can obtain a higher specific capacitance and outstanding capacitance stability. This work offers new insights to consider in the construction of composite electrodes for high-performance supercapacitors. In the present work, we report a novel route to produce graphene and MnOAll chemicals used in this work were of analytical grade and were used without further purification. Nickel foam , manganese acetate tetrahydrate (99.9%), dimethylsulfoxide (99.9%), sodium sulfate (98%), ethanol (99%), acetone (99%), and ammonium acetate (99.9%) were from Sigma Aldrich. Sodium sulfate  was used as the electrolyte.42− was intercalated between the graphite layers, and the stripped graphene sheets floated in the electrolyte. Finally, the graphene was uniformly dispersed in the electrolyte using ultrasonic waves. The reaction time was 2 h. The electrolysis cell voltage was fixed at 15 V. After electrolysis, the electrolyte was filtered by vacuum suction and then the-obtained graphene was dried in a freeze-dryer. Finally, the obtained graphene powder was dispersed in 95% alcohol and shaken for 1 h. The concentration of the prepared graphene dispersion was approximately 1.0 mg mL−1.The anodic stripping method was used to synthesize graphene. A total of 0.1 M of ammonium sulfate was employed as the electrolyte, in which the SOBefore the graphene immersion process, the Ni foam was polished mechanically and cleaned in acetone, nitric acid, and deionized (DI) water using ultrasonication for 10 min. Then, the blank nickel mesh was immersed in the graphene solution for 10 min. The electrode sheet was placed in an oven at 100 °C for 1 h to adhere the graphene onto the nickel foam.3COO)2, 0.02 M CH3COONH4, and 5% DMSO. The MnO2 was deposited onto the graphene/Ni substrate using the electrochemical deposition method to fabricate MnO2/graphene/Ni electrodes. The input electric current per unit area of working electrode for the electrochemical deposition was the “current density”, expressed in mA·cm−2. The current densities of the electrochemical deposition were 1, 5, 10, and 15 mA·cm−2. The reaction time was 180 s. The samples were dried in a vacuum oven for 8 h at 60 °C. Finally, these composite electrodes were heated in a tube furnace at 250 °C with nitrogen gas for 2 h.An electrochemical deposition technique was used for the three-electrode chemical reaction . The electrolyte contained 0.1 M Mn mg, 0.12 (±0.02) mg, 0.18 (±0.02) mg, and 0.25 (±0.03) mg. It is reproducible for the mass weighing of the very light deposited material. The mass load for each sample was calculated and is listed in The deposited materials on the Ni foam were measured using an ultra-precise balance . The balance could be scaled to a mass of five decimal digits in grams. The balance was settled on an optical shockproof table. The operation required great care and patience. The mass of Ni (1 cm × 1 cm) was 52.96 (±1.22) mg and the as-coated graphene was approximately 0.12 (±0.02) mg for a 10 min immersion. Graphene/Ni was utilized as the substrate and electrodeposition technology was applied to deposit the MnO2/graphene/Ni electrodes. The structures of the prepared samples were examined using X-ray diffraction  with Cu Kα radiation (λ = 1.5406 Å). X-ray photoelectron spectroscopy  patterns were obtained using a monochromatic Al-anode X-ray gun. A binding energy of 284.6 eV for C was used to calibrate the charge-shifted energy scale. The spectra were deconvoluted for chemical identification using 100% Gaussian peaks. The Raman spectrum was determined using a Jobin-Yvon Lab Ram HR800 Raman spectroscope equipped with a 514.5 nm laser source.A field-emission scanning electron microscope  with an acceleration voltage of 80 kV was utilized to examine the microstructures of the as-prepared MnO2SO4 electrolyte. The electrochemical experiment was measured in a conventional three-electrode system using the MnO2/graphene/Ni foam composite (1.0 cm × 1.0 cm) as the working electrode, a Pt wire (1.0 cm × 1.0 cm) as the counter electrode, and a saturated Ag/AgCl electrode as the reference electrode.All electrochemical measurements were carried out in 0.5 M NaCyclic voltammetry (CV) and galvanostatic charging–discharging (GCD) were measured using a CHI 760D electrochemical workstation.Cs) could be obtained using the CV measurement with Formula (1) [sC is the specific capacitance (F g−1), i is the current (A), ν is the scan rate (V s−1), m is the mass of the electrode active material (MnO2) (g), and ΔV is the voltage range (V). In Formula (1), the Cs obtained is divided by 2 because the area of the CV curve is calculated by a cycle of oxidation–reduction, which is also the cycle of charge–discharge. Moreover, the CV curve area of the graphene is significantly small, indicating that the specific capacitance of graphene is much less than that of MnO2. Therefore, we only considered the mass of MnO2 as the electrode active material mass (The specific capacitance (mula (1) :(1)Cs=∫Vial mass . mC) was obtained according to the discharge curve of the GCD test using Formula (2):i (A) is the discharge current, Δt (s) is the discharge time, ΔV (V) is the discharging potential difference, and m (g) is the mass of the active material (MnO2). Moreover, the specific capacitance  were determined at an open-circuit voltage, with a bias of 10 mV for frequencies ranging from 100 kHz to 0.01 Hz, to test the electron transport properties.2-graphene/Ni, obtained from 5 mA cm−2 of the electrodeposition current density for 180 s, as the positive electrode and graphene/Ni as the negative electrode was constructed, and electrochemical characterizations were carried out in electrolytes containing Na2SO4. The as-fabricated asymmetric supercapacitor cell was denoted as MnO2/graphene/graphene. Moreover, the equilibrium mass ratio of the positive electrode (MnO2) to the negative electrode (graphene) could be expressed according to Formula (3):+ is the mass (g) of the active material (MnO2) in the positive electrode, m− is the mass (g) of graphene in the negative electrode C is the specific capacitance (F g−1), and ΔE is the potential window of the charge and discharge process (V). Based on Formula (3), the mass ratio of the two electrodes, m+/m−, is approximately 1.6/1.Finally, an asymmetric supercapacitor with MnO−1), and the power density, P (W kg−1), could be estimated from the discharge curve using Formulas (4) and (5):Furthermore, the energy density, E , which were attributed to graphene, MnO2, Au, and Ni. However, Au derived from the Au-coating of the sample for SEM image measurement, as shown in 2 has good dispersibility in the MnO2/graphene/Ni electrode. TEM was also utilized to identify the images of MnO2 and MnO2/graphene. It could be clearly observed that the prepared MnO2 structure was loosely arranged. The wrinkle-like morphology for graphene could be observed. Considering the MnO2/graphene was prepared by the deposition process, the graphene could restack, resulting in excessive surface agglomeration (meration .2 (JCPDS Card NO.44-0141) [2/graphene/Ni composite, as shown in 3 defects or disorder in carbon, and the G band provides useful information on in-plane vibration of sp2-bonded carbon atoms in a 2-D hexagonal lattice. The D band (~1345 cm−1) and G band (~1578 cm−1) were assigned to the characteristic bands of graphene. The G band represents the in-plane vibration of the sp2 carbon atoms. The D band is related to the breathing mode of κ-point phonons of the A1g symmetry [D/IG, represents the structural regularity of graphene. The R-value was proposed to be an indication of disorder in graphene. The smaller the R value, the greater the regularity is. As seen from −1) peak could be attributed to the symmetric stretching vibrations of Mn–O.The crystal structures of the prepared samples were characterized by XRD, as shown in 44-0141) . The ressymmetry . The rel2/graphene/Ni composites are shown in 2 was successfully deposited on the graphene/Ni foam. The peak at 654.1 eV was attributed to Mn 2p. The peaks at 285.7 eV (C-O), 284.8 eV (C-C sp3), and 284.2 eV (C=C sp2) were similar to those in the literature [3) and C=C (sp2) were due to the appearance of larger graphite fragments during the process of graphite stripping. The high-resolution Mn(2p) of the MnO2/graphene/Ni foam composite was amplified for fitting analysis at different current densities. The peaks at 654.1 eV and 653.3 eV were attributed to Mn 2p1/2, while the peaks at 642.7 eV and 641.7 eV were related to Mn 2p3/2, as seen in 1/2 and 2p2/3) at 654.1 eV and 642.7 eV, respectively, indicating that Mn was represented in the chemical state of Mn4+. The peak values were 653.3 eV and 641.7 eV . It was clearly observed that the specific capacitance of the MnOsC was higher. By increasing ν, the current became larger and the ions in the electrolyte did not have enough time to diffuse into the electrode materials. The capacitance performance of MnO2/Ni and MnO2/graphene/Ni electrodes were investigated using circle voltammetry at a scan rate of 100 mV s−1 for different current densities using the electrodeposition method, as seen in 2/graphene/Ni foam electrodes was much larger than that of the MnO2/Ni foam electrode. Moreover, the electrodeposition current density was high, causing the deposited mass of MnO2 to be large. However, the CV characteristic showed that MnO2/graphene/Ni did not change much, demonstrating that they were almost quasi-rectangular shapes. It was obvious that graphene could improve the conductivity of MnO2. In addition, due to the increase of MnO2 mass deposition on MnO2/Ni by increasing with the current density of the electrodeposition, the CV characteristic deviated from the rectangular shape , ν was lower and ar shape g,h. As s2SO4 solution was approximately a neutral electrolyte, which is friendly to the environment and was utilized as the electrolyte in this study. The MnO2/graphene/Ni electrodes showed a quasi-rectangular shape in the CV curves, indicating the capacitance characteristics of the MnO2 deposited onto the Ni foam electrode [2/graphene/Ni electrode in the Na2SO4 electrolyte was unlike that expected from an EDLC; the CV characteristic curve for an EDLC shows a nearly ideal rectangle [The choice of aqueous electrolyte was based on the size of the hydrated cations and anions, and on the mobility of ions . In addilectrode . The CV ectangle .2 of the composite electrode. It was calculated and the specific capacitance (sC) is listed based on 2+graphene, M) as active materials was calculated by sC′) and areal capacitance CsA′ based on sC′, which were also calculated for the comparison  represents the equivalent series resistance (ESR), including the ionic resistance of the electrolyte, the inherent resistance of the substrate, and the contact resistance of the active material/current collector interface [ct) at the electrode/electrolyte interface [In the high frequency region, the intercept at the real axis (Znterface . The spanterface . The slonterface . If the E) for the curve and real axis for the MnO2/graphene/Ni electrode (prepared at 5 mA cm−2 current density of the electrodeposition), the MnO2/graphene/Ni electrode (prepared at 15 mA cm−2 current density of the electrodeposition), the MnO2/Ni electrode (prepared at 5 mA cm−2 current density of the electrodeposition), and the MnO2/Ni electrode (prepared at 15 mA cm−2 current density of the electrodeposition) were determined to be 2.8 Ω, 3.1 Ω, 3.0 Ω, and 3.1 Ω, respectively. In particular, the MnO2/graphene/Ni electrode obtained from the electrodeposition at a current density of 5 mA cm−2 showed the smallest equivalent resistance, demonstrating that the electrode had better conductivity. Moreover, the as-obtained MnO2/graphene/Ni electrode (5 mA cm−2) showed the smallest semicircular arc-shaped impedance (0.15 Ω) in the high–medium frequency region, indicating that the charge transfer resistance (Rct) for the electrode was extremely low and that the ion diffusion path was very short. At high frequencies, the intercepts  electrode exhibited an equivalent series resistance (RE) that was lower than that of the other electrodes. This result further showed that the MnO2/graphene/Ni (5 mA cm−2) electrode had faster kinetics compared to the other three electrodes, which is beneficial in improving the capacitance performance of the composite material, especially at high charge/discharge rates for the supercapacitor [In this study, the MnOapacitor .2/graphene sample had a clear hysteresis loop, showing highly interconnected holes, and the material had an open-wide structure. The BET specific surface areas for the MnO2 and MnO2/graphene materials were 158.5 m2·g−1 and 179.2 m2·g−1, respectively, and the pore sizes were 3.7 nm and 7.8 nm, respectively. MnO2/graphene showed the largest BET specific surface area, which is attributed to the loosely arranged structure ) of the CV measurement at scan rates for the composite material consisted of two parts. One part concerned the current associated with the EDLC at the electrolyte interface or the initial fast Faraday reaction on the exposed electrode surface (capi). The other part concerned the current associated with the slow diffusion control process (difi). The capacitance contribution and diffusion control contribution can be calculated according to Formula (6) [ν is the scan rate, i(v) is the total current of the CV measurement, and a and b are variable parameters. The b value can be estimated from the slope of the log(i(v)) and log(ν). 2 /Ni and MnO2/graphene/Ni electrodes obtained from different electrodeposition conditions. The total current (mula (6) .(6)i(v)2/graphene/Ni electrodes indicated that 0.8 < b < 1 electrode was considered to be a pseudocapacitive material with a main capacitance storage, while the MnO2/Ni electrodes showed “0.5 < b < 0.8” as exhibiting the main Faraday (battery type) behavior [It can be observed that the MnObehavior ,41. b = 2/graphene/Ni was used as the positive electrode, graphene deposited on nickel foams was used as the negative electrode, and 0.5 M Na2SO4 aqueous solution was used as the electrolyte. Asymmetric supercapacitors were fabricated as devices for studying capacitive performance for practical applications. MnODuring the charge–discharge of a supercapacitor, a water-based electrolyte must avoid the generation of hydrogen and oxygen or other redox side reactions due to the electrolysis of water affecting the performance of the device. These phenomena can be revealed by their CV characteristics and a suitable operating potential window would be obtained.2/graphene//graphene asymmetric supercapacitor. The CV curves of the as-prepared asymmetric supercapacitor at a scan rate of 50 mV s−1 for different potential windows are shown in −1  of the cell using Formula (2). At current densities of 1 A g−1, 2 A g−1, 4 A g−1, 6 A g−1, 8 A g−1, and 10 A g−1, the specific capacitance (mC) of the MnO2/graphene/graphene device exhibited 1025 F g−1, 740 F g−1, 640 F g−1, 587 F g−1, 556 F g−1, and 531 F g−1, respectively.The GCD test of the assembled MnO2/graphene//graphene asymmetric supercapacitor with those recently published in the literature is summarized in the figure. In the MnO2/graphene//graphene asymmetric supercapacitor, at a power density of 400 W kg−1, the energy density was as high as 91 Wh kg−1 at 1 A g−1, and at a power density of 800 W kg−1, it remained at 66 Wh kg−1 at 2 A g−1, which is higher than that of the studied asymmetric supercapacitors in the literature [The energy density and power density of the asymmetric supercapacitor were calculated based on Formulas (4) and (5) according to the data obtained from the GCD characterization, as the Ragone plots in terature ,46,47,482/graphene/Ni electrode. The electrode prepared at a current density of 1 mA cm−2 using the electrodeposition method with a structure of a 3D framework and a 2D graphene layer exhibited a higher power output, where the highest capacitance (292.8 F·g−1) was obtained in a 0.5 M Na2SO4 solution. The Ni foams with a 3D framework provided a larger surface area, increasing the deposition sites for introducing MnO2. Graphene was considered as a buffer layer between the MnO2 and Ni foams to improve the electrical conductivity and interface contact. The coulombic efficiency remained at about 96% after 5000 cycles during the charge and discharge process. Therefore, the technology not only increased specific capacitance but also improved mechanical stability. A MnO2/graphene/graphene asymmetric supercapacitor was assembled and exhibited both a high-energy density of 91 Wh kg−1 and an excellent power density of 400 W kg−1 at 1 A g−1. We expect that this simple method may provide a convenient route for the large-scale production of MnO2/graphene/Ni electrodes with a high capacitance for high-energy storage in future.In summary, we employed a promising strategy for fabricating a high-performance MnO


Our simulations reveal that the photovoltage in these graphene systems presents important oscillations similar to the ones of irradiated magnetoresistance in semiconductor platforms but in the terahertz range. We also obtain that these oscillations are clearly affected by the voltages applied to the sandwiched graphene: a vertical gate voltage between the two hBN layers and an external positive voltage applied to one of the sample sides. The former steers the carrier effective mass and the latter the photovoltage intensity and the oscillations amplitude. The frequency dependence of the photo-oscillations is also investigated.We theoretically analyze the rise of photovoltage oscillations in hexagonal boron-nitride (h-BN) encapsulated monolayer graphene (h-BN/graphene/h-BN) when irradiated with terahertz radiation. We use an extension of the radiation-driven electron orbit model, successfully applied to study the oscillations obtained in irradiated magnetotransport of GaAs/AlGaAs heterostructures. The extension takes mainly into account that now the carriers are  In our simulations we first obtain that hBN-encapsulated graphene is mostly sensitive to terahertz (THz) radiation instead of microwaves (MW). We study the dependence of the photovoltage oscillations with respect to a vertical gate voltage which is able to tune the electron mass and in turn the oscillations position with respect to the magnetic field. Next, and keeping constant the gate voltage, we study the influence of an extra external voltage on the oscillations position and intensity. We obtain that we can increase the oscillations amplitude just by raising the external voltage without changing the radiation power. We have investigated also the photovoltage dependence with radiation frequency in the terahertz (TH) range. The results presented in this letter would be of special interest from the application perspective, for instance in nanophotonics; they could lead to the design of novel ultrasensitive terahertz detectors or to the proposal of a new generation of solar cells given the strong translation of radiation energy into electrical current.In this letter, we present theoretical results on the presence of MIRO-like magnetooscillations in the photovoltage of the trilayer system of h-BN encapsulated monolayer graphene. In this system the carriers are 50. In the same way, a vertical gate voltage can produce this asymmetry which, in this case, can be externally tuned. As a result a band gap opens at the Dirac point  giving rise to gapped monolayer graphene. Thus, monolayer graphene turns from semimetal into a semiconductor and the Dirac fermions become massive. The eigenenergies and eigenfunctions of the gapped graphene Hamiltonian in the presence of an external and perpendicular magnetic field, can be readily calculated52, for instance for the K valley:When monolayer graphene is placed on top of a substrate or encapsulated, the interaction between the layers gives rise to a potentials asymmetry between the graphene sublattices A and B52. On the other hand, close to the valence band top, the amplitude of the wave function is predominant at the B sublattice (B-sublattice polarised). Thus, around the conduction band bottom we can approximately express the eigenstates at the K valley as,An important point in this scenario is that close to the conduction band bottom in the gapped monolayer graphene, the Dirac fermions are A-sublattice-polarised51, for instance, near the conduction band bottom we can obtain an effective expression53K and ‘+’ to If we expand the gapped graphene HamiltonianB, we follow the previously developed radiation-driven electron orbits model36 starting from the Hamiltonian in Eq. :To study magnetotransport in encapsulated graphene under radiation and n in Eq. . Accordiw the frequency. Thus, the radiation-driven Landau states, perform a swinging motion where the massive Dirac fermions interact with the lattice ions resulting in a damping process of the oscillating classical motion. The corresponding oscillation damping is phenomenologically introduced through the 53.The time-dependent guiding center shift 53 vs B are a direct consequence of an interplay between the driven-swinging motion of the Landau orbits and the electron scattering with charged impurities. This harmonic motion performed by the Landau orbits can be revealed by measuring photovoltage on encapsulated graphene instead of the usual magnetoresistance53. Then, the corresponding oscillations are expected to be obtained. In our theoretical approach we first consider that one of the squared sample edges is connected to an external positive DC voltage, 36. A subsequent electric field and voltage drop, e is the electron charge, D(E). We focus on the states around the Fermi energy; electrons occupying these states will mainly take part in the scattering. Thus, 54:According to our previous theoretical model, the MIRO-like oscillations obtained when measuring irradiated magnetoresistancementclass2pt{minimmentclass2pt{minimThus, 55Following our model, when irradiated the Landau orbits begin to harmonically swing giving rise to shorter and longer scattering jumps depending on the magnetic field see Fig. . Then, tB for a gated hBN-encapsulated monolayer graphene. The radiation frequency is 700 GHz and B. The hBN/graphene/hBN sandwich yields a bandgap in the monolayer graphene beeing tuned by a gate voltage between the two outer hBN layers56. This allows us to select the Dirac fermions effective mass just by tuning the gate voltage. With the latter we can tune as well the charge density (Fermi level) in the monolayer graphene. Thus both, effective mass and charge density, can be simultaneously altered by a varying vertical electric field (gate voltage). Therefore, for a definite gate voltage the system has a definite band gap and charge density. Based on a previous work56, the electric field we have used in the simulations ranges from 0.10 to 1 V/B. In previous simulations it was found that irradiated magnetoresistance (instead of photovoltage) of sandwiched hBN graphene presented MIRO-like oscillations at THz frequencies too53. In order to contrast with experiment41 we can obtain approximate values of 56 adapted to the sample thickness of experiment41. Our calculations, based on basic electrostatics, yields a charge density 41. Then, each curve exhibited in Fig. A keeping its magnitude approximately constant irrespective of B as In Fig. entclass1pt{minimaentclass1pt{minimaB for an opposite scenario to Fig. B instead. This result has been experimentally obtained in GaAs/AlAs platforms under MW and THz57. In contrast to the previous figure, where a varying gate voltage made change the MIRO-like oscillations positions, here the varying external voltage does not affected them at all. They keep the same positions irrespective of In Fig. B. Four different frequencies in the THz range are presented: 0.7, 1, 1.5 and 2.0 THz. We observe that as the frequency rises the number of oscillations increases too but the oscillations amplitude lowers. The former turns out obvious and the latter is expected according to our theory as the frequency shows up in the denominator of the amplitude. These results agree with experimental results41 and with the frequency dependence with standard MIRO obtained in semiconductor platforms and MW. More simulations have been run at higher frequencies confirming the trends in terms of number of oscillations and decreasing amplitude.In Fig. Summing up, we have presented a theoretical approach on the appearance of photovoltage oscillations in h-BN encapsulated monolayer graphene irradiated with terahertz radiation. In our model we have extended the radiation-driven electron orbit model to the case of massive Dirac fermions. Our simulations have revealed that the photovoltage in these graphene systems presents important oscillations in the terahertz range. In the same way, these oscillations are clearly affected by the different voltages applied to the sandwiched graphene; mainly, a vertical gate voltage between the two hBN layers that steers the effective mass and an external positive voltage that affects the photovoltage intensity and the oscillations amplitude. We have also studied the frequency dependence on photovoltage obtaining similar results as in previous MIRO, i.e., when the frequency increases the number of oscillations increases and the amplitude lessens. The results above would be of interest from the application point of view in any field where the radiation-matter interaction is key being based on graphene. For instance, novel ultrasensitive terahertz detectors or sensors, a new generation of solar cells given the strong translation of radiation energy into electrical current, etc.


Methods. 90 patients diagnosed with SCLC from January 2019 to November 2020 were selected as the test group, including 72 males and 18 women, 58.7 ± 6.6 years; 30 healthy subjects were selected from the physical examination center, including 18 males, 12 females, and 60.3 ± 7.0 years. There were no statistical difference in sex and age factors between the trial and control groups (p > 0.05). Selected SCLC used chemotherapy regimen: cisplatin + etoposide (EP), carboplatin + etoposide (CE), and SCLC group were divided into three subgroups of disease progression group, partial remission group, and disease stability group according to the treatment effect. Comparison of the differences in sPD-L1 expression content between the experimental and control populations. Plasma sPD-L1 levels were dynamically monitored pre- and posttreatment in 90 patients with small-cell lung cancer and were associated with efficacy among subgroups. Meanwhile, the risk factors for patient sPD-L1 expression content were analyzed by logistic regression. Results. Plasma sPD-L1 levels were higher in the SCLC group than in the healthy people group . In the disease progression group of the SCLC group, sPD-L1 levels were decreased in the SCLC group, sPD-L1 in some remission group was increased after treatment, and sPD-L1 levels in the disease-stable group (p > 0.05). Multivariate logistic regression analysis showed that factors promoting increased sPD-L1 expression in SCLC patients included increased smoking, brain metastasis, and ProGRP expression . Conclusion. (1) Higher peripheral sPD-L1 expression in SCLC patients than in healthy patients, and the expression levels were closely related to efficacy. (2) Dynamic changes in s PD-L1 were correlated with clinical efficacy. (3) The progression of sPD-L1 and ProGRP in SCLC patients showed the same extent during remission and stabilization, suggesting the effect of s PD-L1 in the evaluation of SCLC tumors and the reflection of the tumor marker ProGRP.Background soluble programmed death-ligand 1 (sPD-L1) expression in lung squamous cell carcinoma and lung adenocarcinoma is associated with disease progression, and sPD-L1 expression in small cell lung cancer (SCLC) may have similar manifestations and become a potential marker for treatment. The purpose of this study was to observe the changes of plasma sPD-L1 expression in SCLC patients.  The annual incidence and mortality rate of lung cancer are the first in the world, and lung cancer is also the primary cause of death of cancer in China , 2. LungPromed death 1 receptor (PD-1) is a receptor protein present on the surface of immune cell T cells acting with programmed death-ligand 1 (PD-L1), and PD-L1 is a protein expressed on the surface of tumor cells . It has PD-L1 is divided into two types: membrane-type (mPD-L1) and soluble (sPD-L1). Domestic studies have found that peripheral blood changes in sPD-L1 were associated with disease progression in patients with lung cancer before and after chemotherapy, but this study only included patients with lung squamous carcinoma and lung adenocarcinoma, and the changes in SCLC patients have not been fully studied . This stDiagnostic criteria for SCLC refer to the <Individualized Treatment of Lung Cancer> : the diaInclusion criteria for this study: (1) meet the patients diagnosed with SCLC; (2) first diagnosed in the hospital, not treated; (3) informed of their own condition; and (4) agree to accept the experiment and sign the study consent form. Exclusion criteria for this study: (1) psychiatric patients or other patients who cannot cooperate; (2) incomplete medical records or replaced other treatment methods or hospital patients; (3) severe internal cerebral organic or vascular lesions, liver, and kidney metabolic dysfunction; and (4) patients without interrupted treatment or withdrawal for various reasons.p > 0.05). General data of the two groups are shown in Small cell lung cancer group: after screening with the above criteria, 90 naive patients diagnosed with SCLC by pathological examination from January 2019 to November 2020 were included in the trial group, including 72 men and 18 women, aged 58.7 ± 6.6 years. The selected patients had complete medical records, including gender, age, smoking status, and tumor stage  and carboplatin + etoposide (CE) systemic chemotherapy for 4 cycles, to evaluate the treatment effect. The efficacy of SCLC patients was evaluated according to the evaluation criteria of the 2016 edition of the <Individualized Treatment of Lung Cancer>  and was x ± s), group comparison using independent sample t-test; count data by [n (%)], group comparison by 2 test, p < 0.05 is statistically significant. Univariate logistic regression analysis was used to screen for independent variables that were potentially dangerous for sPD-L1, where factors for p 0.10 and clinically important indicators were included in the multivariate logistic regression equation to analyze independent risk factors for sPD-L1.Data analysis was performed using SPSS21.0 statistical software. Measurement data are indicated as (p < 0.01) is shown in Peripheral sPD-L1 levels in lung cancer were (1.74 ± 0.82) ng/ml and (0.59 ± 0.33) ng/ml, and sPD-L1 in lung cancer than benign and controls , see The results of the univariate Logistic regression analysis showed that the tumor stage, stage, smoking, brain metastasis, and the increased ProGRP expression content were the influencing factors of the increased sPD-L1 expression. After adjusting for other factors, the results of the multivariate logistic regression analysis showed that the factors promoting increased sPD-L1 expression in SCLL patients included increased smoking, brain metastasis and ProGRP expression content (both In this study, sPD-L1 levels were significantly higher in the SCLC group compared with the control group, suggesting high sPD-L1 expression in SCLL patients. The sPD-L1 levels were decreased in the disease progression group, sPD-L1 in the partial remission group, and relatively small fluctuations of sPD-L1 in the disease-stable group. The reason for the different changes in sPD-L1 content on chemotherapy may be that the level of sPD-L1 expression in vivo is proportional to the inhibitory effect on T cells, and the inactivated T cells after inhibition cannot remove tumor cells, making them escape immune surveillance and thus easier tissue infiltration and distant metastasis . RelatedSmall cell lung cancer has the characteristics of high malignancy, strong invasion, and easy metastasis and mainly relies on chemiotherapy and chemotherapy. PD-1/PD-L1 pathway block inhibitors have become a new breakthrough point in the treatment of SCLC in nearly 20 years. Previous studies have found that plasma sPD-L1 has high specificity and sensitivity in reflecting SCLC tumors and may become a novel SCLC tumor marker . In thisSimilarly, the present findings found that the factors that promoted increased sPD-L1 expression in SCLC patients also included smoking and brain metastases. Previous studies have shown that smoking is one of the important risk factors for the progression of SCLC , 16. BraOne of the limitations of this study lies in the collection of cases and the statistics of the data, where the influence of various influencing factors on sPD-L1 expression should be further analyzed from multiple angles. Although a certain number of data statistics were conducted in this trial, the statistical samples are still small, and a large number of randomized controlled studies are still necessary in the future. Therefore, in the future experimental research, the collection of the study sample size should be increased, and the interaction between the influencing factors should be compared and analyzed, and extend the follow-up time as long as possible to draw a more comprehensive conclusion and better guide the treatment of SCLC patients.Peripheral blood sPD-L1 expression was higher in SCLC patients than in healthy individuals, and the expression levels were closely related with efficacyDynamic changes in sPD-L1 were correlated with clinical efficacyThe progression of sPD-L1 and ProGRP in SCLC patients showed the same extent during remission and stabilization, suggesting the effect of sPD-L1 in the evaluation of SCLC tumors and the reflection of the tumor marker ProGRP


Such a design could yield a scalable and cost-effective THz source.With incredibly high carrier mobility and saturation velocity, graphene would be an ideal candidate for a miniaturized solid-state cyclotron radiation source. A planar semicircular graphene arc geometry was investigated for emission in the 0.5–1.5 THz range. Analytical studies, confirmed by finite element simulations, show that the emitted THz frequencies are inversely proportional to the arc radius given a fixed charge-carrier velocity. The simulations show that the desired frequency spectrum can be obtained with design radii ranging from 50 to 150 nm. Interestingly, the radiated spectrum is independent of the frequency of the stimulation of the graphene nano-arcs. The simulations also indicate that the total output power correlates well with the Larmor formulation. The device is expected to emit 1 nW/cm Promising applications range from a new construction material4 to a room temperature superconductor5. While most of the electronics applications for graphene involve its use as a field effect transistor to eventually replace silicon for computing applications, few have explored its use in radio frequency (RF) emissions6. Much of graphene’s RF applications have involved design and construction of conventional RF components such as transmission lines, waveguides7, and antennas9. More recently, graphene’s high carrier mobility10 and saturation velocity11 has been explored for its application as a solid state implementation of a free electron laser (FEL) and associated devices such as the wiggler13.Sixteen years since its discovery8. The monolayer thickness of graphene makes it highly desirable for compact form factor applications. In another such application, a graphene substrate is used to enhance the response and tunability of plasmonic antennas9. By applying a back-gate field to the graphene substrate and altering the graphene’s bandgap the antenna can respond to a much wider span of incident wavelengths compared to the same photoconductive structure without graphene.The use of graphene in RF emitter applications is primarily due to its high carrier mobility, high saturation velocity, and its tunable band gap. Highly conventional approaches and applications recreate existing RF structures in grapheme—namely the patch antenna12. With this approach, emissions at THz frequencies are possible that are not dependent on the existence of THz switching technologies. Experimental implementations of corrugated graphene have shown that THz emission is possible13. Such an approach involves etching the periodic trenches onto a Ge substrate and transferring the graphene onto the patterned substrate. The graphene contours the substrate resulting in the desired corrugation. Expected power output for this device ranges from 1 pW/cm2 to 10 nW/cm2.Less conventional RF emitter applications envision graphene as a substrate which can mimic the behavior of vacuum-based particle accelerator devices such as the cyclotron, FEL, or wiggler. Models of corrugated graphene show that under a constant DC bias, electromagnetic radiation can be emitted with a frequency equal to the carrier drift velocity divided by the corrugation period16. Such methods subject graphene to a magnetic field such that quantized cyclotron orbits via the quantum Hall effect occur. Optical stimulus, by means of a laser, pumps electrons from the valence band to the conduction band of the graphene at energies set by graphene’s dispersion relation and by the Landau levels. Photon emission via transition between Landau levels occurs at far-infrared (FIR) and terahertz frequencies.Other cyclotron based radiation methods involve radiative transitions between Landau levels in grapheneIn this paper, the application of graphene as a miniaturized solid-state cyclotron radiation source in the form of semicircular arcs is explored. A design geometry should satisfy the desired frequency output range from 0.5 to 1.5 THz while being scalable with existing semiconductor processing methods. Modeling begins with a simple rotating dipole model as an idealized scenario for the device to obtain estimates for the power spectrum and radiation pattern. A finite element model that better represents the actual structure and allows for finite width and electronic contacts is also developed. To facilitate future device scalability, design requirements for higher density device arrays are considered.17. To model such a device and obtain performance estimates, we begin with a first principles equivalent analytical model in which the graphene device is approximated as a rotating electrical dipole18. In the dipole model, all the available charge carriers in the semicircular arc are concentrated in a singular point charge at the arc’s inner radius   3) are men below  where \dAn expression for dimensionless Fourier transformed Poynting vector From the dimensionless Poynting vector, critical values for this expression are sought to understand how the power output S is related to normalized frequency .36 Fig. . For \doThe simulations for the dipole model agree with the analytical model in that the target frequency is achieved. However, the peak power emission is at a frequency greater than the target. For the 0.5 THz system, the peak power occurs at 0.67 THz 27 applicable in phased array technology28 can be integrated with the graphene device to achieve the desired operating conditions. This may be the more desirable solution in terms of cost compared to the laser-based solution due to the soon to be readily commercially available 5G integrated circuits and the associated compact form factor. Such technological developments may allow for a graphene THz emitter system-on-a-chip.For any meaningful power to be obtained, large arrays of the device are necessary. To achieve the desired coherence, integration of the device with a photoconductive antenna with external laser stimulus would be an ideal solution due to the superior bandwidth of optical domain over the electrical or RF domain2. With a highly scalable planar semicircular geometry along with existing semiconductor processing methods, this predicted power range can be realized and potentially leading to low-cost THz emitter sources.A solid-state implementation of a THz cyclotron radiation source in graphene has been investigated through analytical dipole models and finite element simulation and results indicate that such a device is feasible. Designs in the 0.5–1.5 THz are supported by a semicircular arc geometry and can emit power in the range of 1 nW/cmFinite element simulations of the simple dipole model in both classical continuous rotating formulation and modified semicircuslar conditions followed by a semicircular arc of graphene in steady state RF and non-equilibrium transport conditions were also performed. In COMSOL Multiphysics, a point dipole located in the center of the coordinates was created with charge equivalent to the sum of all free carriers of the graphene arcs that correspond to each target frequency (0.5 THz and 1 THz).−2 is used as such a value can be realistically obtained at room temperature while having mean free paths on the order of 1 This value is obtained by multiplying the arc area by the charge density. In this study, a charge density of In addition, a modified dipole model was developed to capture the frequency spectrum and radiation pattern. Much like the classical model, all the arc’s charge is concentrated to a point and orbits the origin in a counterclockwise fashion at a fixed radius. Unlike the classical model, the modified dipole model is only valid for ½ of an orbital period. The system is expected to emit a range of frequencies in which the target frequency is emitted uniformly in the plane of rotation. According to the analytical results Fig.  a peak e17. First, using COMSOL’s AC/DC module, a direct current (DC) simulation was performed. The straight edges of the arc were set as ports with fixed potential where one was ground and the other 1 V. This simulation allows for verification of the field gradient and current flow along the arc. Next, a steady state RF simulation of the arcs stimulated at their respective target frequencies is performed to calculate the power output. Lastly, a non-equilibrium transport simulation is performed on the arcs for a time of 1/2 of a full orbital period with a Gaussian pulse stimulus centered at 40 GHz, 10 GHz, and 4 GHz. This stimulus frequencies were chosen as they can be readily obtained with existing technology.More realistic models were developed to help prove the concept, where a finite arc width (100 nm) is considered. The graphene layer was modeled as a boundary with sheet resistivity specified by the manufacturer 430


Our experiments reveal that the hybridization between moiré bands in WS2/WSe2 exhibits an unusually large momentum dependence, with the splitting between moiré bands at the Γ point more than an order of magnitude larger than that at K point. In addition, we discover that the same WS2/WSe2 superlattice can imprint an unexpectedly large moiré potential on a third, separate layer of graphene (g/WS2/WSe2), suggesting new avenues for engineering two-dimensional moiré superlattices.Moiré superlattices constructed from transition metal dichalcogenides have demonstrated a series of emergent phenomena, including moiré excitons, flat bands, and correlated insulating states. All of these phenomena depend crucially on the presence of strong moiré potentials, yet the properties of these moiré potentials, and the mechanisms by which they can be generated, remain largely open questions. Here, we use angle-resolved photoemission spectroscopy with submicron spatial resolution to investigate an aligned WS Transition metal dichalcogenide heterostructures show strong interactions and can imprint a moiré potential to a separate layer. K point for graphene and monolayer TMDs. To achieve a deeper fundamental understanding of moiré superlattices, it is therefore critical to reveal their electronic structure across a broad range of energies and momentum space and to understand the mechanisms by which moiré superpotentials can be generated and imposed.Moiré superlattices composed of stacked two-dimensional materials present a versatile platform for engineering and investigating new quantum states of matter  (2/WSe2 (g/WS2/WSe2), the aligned WS2/WSe2 heterostructure can imprint an unexpectedly large moiré potential on the graphene layer  with submicron spatial resolution to address these questions by investigating two types of moiré superlattices. In an aligned WS emerges , we obsene layer , present2/WSe2 moiré superlattice sample investigated in this study. In this heterostructure, the WS2 and WSe2 are aligned and are both 10°-twisted with respect to the graphene layer , the center region of g/WS2/WSe2 moiré superlattice can be identified and investigated. KG (graphene K point), together with overlaid density functional theory (DFT) calculations of the band structures for individual monolayer graphene, WS2, and WSe2. The hybridization between the graphene and TMD layers can be observed by the formation of distinct gaps where their bands intersect, as shown by the white arrow in In 2 and WSe2 are qualitatively similar, with their valence band maxima both located at their respective K points (KTMD), which are hundreds of millielectron volts above the valence band at Γ [e.g., 500 meV for WSe2  electronic states belong only to WS2/WSe2. In a purely nonhybridized scenario, WSe2 and WS2 would individually contribute only a single band at Γ, whereas in 2 and WSe2 layers. By comparing the binding energies of these three bands with those of single-layer WSe2  . Such a large lattice mismatch leads to elastic energy of more than two orders of magnitude higher to form commensurate domains compared to that in MoSe2/WSe2 superlattices, making it unlikely that the WS2 and WSe2 could be commensurate. In addition, data from 2 or WS2 monolayers, potentially due to zone folding from the small moiré Brillouin zone. For instance, the effective mass for the middle band at Γ in g/WS2/WSe2 is approximately m* = 4.1 m0, as opposed to only m* = 1.4 m0 in the absence of TMD moiré superlattice . Given the large energy splittings observed here , it may be possible to construct moiré superlattices with emergent electronic states surviving to room temperature, for instance, in indirect-gap heterostructures such as moiré superlattices between two individual TMD bilayers, where the valence band maximum is at Γ instead of K.We believe that the unusually large momentum dependence of the splitting of the moiré minibands arises from the momentum dependence of the orbital character of the transition metal 2 and WSe2 layers, making any hybridization effects with the graphene layer largely irrelevant. However, when the graphene bands approach EF, the effects of any interactions between the graphene bands and the underlying moiré superpotential should become pronounced. As shown in KG give rise to multiple replica Dirac points, which are separated by the WS2/WSe2 moiré wavevector (Gmoiré = 0.07 Å−1), where the intensity of the first-and second-order replicas is >30% of the original band and even third-order replicas are evident. An idealized triangular moiré superlattice should result in a perfectly hexagonal pattern of replica Dirac points, but instead, we observe a sizeable distortion of this hexagonal pattern  in the data of k = 1.4%, determined by comparing the separation and angles between different graphene Dirac points  to its known lattice constant (1.703 Å−1). This large distortion , as would also be expected if final state effects played a critical role. Second, the presence of energy gaps between the graphene and WSe2 and WS2 bands (noted by the white arrow in T = 300 K) and experimental energy resolution (ΔE = 125 meV), which would likely obscure any small gaps caused by the moiré superpotential.While it is possible that these replicas could also potentially arise from final state photoelectron diffraction effects  were determined by angle-resolved optical second-harmonic generation (SHG). A pulsed laser with a duration of 100 fs at 800 nm was used as the excitation source, and the cross-polarized SHG signal was collected at 400 nm. A sixfold symmetry of the SHG signal was resolved by rotating the excitation polarization with respect to the sample orientation. The heterostructure was assembled using a layer-by-layer dry transfer technique described in  substrate by heating the stamp to 180°C. The heterostructure was then rinsed in chloroform and isopropyl alcohol to remove the melted polycarbonate film and cleaned using an atomic force microscope tip in the contact mode.Atomically thin flakes were exfoliated from bulk crystals onto silicon substrates with 285-nm oxides. Monolayer WSe−5 torr before transportation and loading into the Microscopic and Electronic Structure Observatory ultra-high vacuum facility at beamline 7.0.2 of the Advanced Light Source in Berkeley. The samples were annealed at 300°C for 10 hours before ARPES measurements. ARPES data were collected using a hemispherical Scienta R4000 electron analyzer with the energy and momentum resolutions set to 125 meV and 0.015 Å−1, respectively. The photon energy was set to 70 eV with the incident beam focused using an x-ray capillary to a nominal spot size of ~1 μm. Samples were maintained at room temperature throughout measurements.After assembly and cleaning, the samples were sealed in a vacuum chamber inside an inert gas glovebox and then pumped to 102, and WS2 were performed using the Perdew-Burke-Ernzerhof generalized gradient functional  (500 Ry) was used for the wave function (charge density), and a Γ-centered 16 × 16 × 3 Monkhorst-Pack (MP) mesh  was used for the wave function (charge density) along with a Γ-centered 21 × 21 × 5 MP mesh. The calculated graphene Dirac cones are renormalized to match the experimentally observed Fermi velocity of vF = 1.13 × 106 m s−1. The DFT calculations for WSe2/WS2 (graphene) were then downfolded onto a manifold of 22 (k-point mesh as the ARPES data and for construction of the constant energy contours.DFT calculations of freestanding graphene, WSe


Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Regions targeted are shown on the 3D structure of RNA-bound TDP-43. Tar DNA binding protein (TDP)-43 is a nucleic acid binding protein consisting of three domains, a folded N-terminal domain, two RNA Recognition Motifs RRM1 and 2) and a mostly unstructured C-terminal domain where most of the known disease-associated mutations occur  localized in a defined amyloidogenic core19,20 and (iii) implicated in dimerization of RRM2 which is thought to lead to TDP-43 aggregation,21 similar to the dimer interface residues of SOD1 observed in familial ALS.22 Shodai and colleagues used a subconstruct of TDP-43 consisting of amino acids 241–260, to generate hybridomas which were later selected for their ability to bind TDP-43 RRM2 but not E246G/D247G RRM2. The resulting antibody was called 3B12A and recognized only highly dense TDP-43 structures in the nucleus, cytoplasmic TDP-43 with an impaired NLS as well as nearly 80% of TDP-43 inclusions in anterior horn cells of ALS patients. This led to the conclusion that exposed E246/D247 residues on TDP-43 may be a marker of TDP-43 inclusions in ALS/FTLD.In 2012, Shodai and collaborators developed an antibody against misfolded TDP-43 based on the assumption that RRM2 aberrant conformation is linked to pathological TDP-43.and D247 . Intriguvia a RIDPEDGETK sequence found in the 3B12A heavy chain.23 That sequence exhibits a high PEST score, which typically defines sequences rich in proline, glutamic acid, serine, and threonine that act as degradation signals.24,25 Further addition of a CMA (chaperone-mediated autophagy) sequence to the 3B12A antibody, resulted in efficient cell clearance of misfolded TDP-43 and reversed TDP-43 induced toxicity in HEK293A cells overexpressing cytoplasmic misfolded TDP-43  as well as in cerebral cortex of newborn mice transduced with TDP-43mNLS,C173S/C175S.23 Even though further testing of this strategy needs to be considered, especially in adult models and/or patient derived induced stem cells, this was the first example of direct targeting of TDP-43 by an antibody leading to cellular clearance of pathological aggregates with therapeutic promise.The same group later discovered the ability of the 3B12A antibody to induce proteasome degradation et al.,26 and is described as targeting the TDP-43 RRM1 domain. The rationale for this approach was based on TDP-43 RRM1 being implicated in aggregation via its misfolding,27 similar to RRM2, and/or by its oxidation.28 Another reason to target TDP-43-RRM1 was to disrupt its interaction with p65 NF-κB, which binds TDP-43 NTD and RRM1 and leads to inflammation in glial cells and sensitizes neurons to toxic insults.29 Although it should be noted that the binding between TDP-43 and p65 was shown through immunoprecipitation and not direct biophysical interactions. To generate hybridomas, they used TDP-43 encompassing part of the N-terminal region, the nuclear localization signal (NLS), and the entire RRM1 domain, which presumably spans amino acids (aa) 31 to 176 as this is the interface with p65 they describe.29 Then, they selected antibodies based on their ability to detect the input TDP-43 protein and to disrupt the p65 interaction, which led to the E6 antibody. Transfection of E6-derived vectors encoding single-chain fragment variable (scFv) antibodies induced proteasome and autophagy-driven degradation of TDP-43 in HEK293 cells. Viral-mediated expression of a scFv antibody (named VH7Vk9), further reduced LPS-induced inflammation markers in mouse cortex. Finally, treatment with VH7Vk9 improved cognitive function in TDP-43G348C mice, a well-known model of familial ALS/FTD30 as well as motor performance in another model of familial ALS/FTD, namely TDP-43A315T mice.30Another antibody was developed by Pozzi Even though the exact binding site of the antibody remains obscure and could very well implicate TDP-43-NTD, VH7Vk9's ability to induce TDP-43 degradation by promoting polyubiquitination of TDP-43 without addition of a degradation signal is striking. Analysis of the VH7Vk9 sequence might reveal a PEST sequence, similar to 31 These antibodies were raised against residues 198–216 of RRM2 , that contributes to the formation of hydrogels38 and the very beginning of the hydrophobic region (residues 318–340) that can adopt both helical and thioflavin-T-positive filaments reminiscent of β-amyloid.39–42 The third part is a cell-penetrating peptide: Tat (RRRQRRKKRG) or Poly-d-Arginine (d-Arg)8. The C-terminal derived peptides were unsurprisingly not further pursued because of low solubility. The peptide D4, which contains E246/D247 residues, showed the strongest ability to reduce TDP-43 levels in an N2a cell line overexpressing TDP-43, while peptides lacking the hydrophobic adamantine moiety had no effect. The results were recapitulated in Drosophila overexpressing TDP-43. While enhanced degradation of TDP-43 by the D4 peptide is implied because of the adamantane moiety, the authors did not assess the effect of the D4 peptide on TDP-43 ability to autoregulate its own RNA or on cytoplasmic inclusions. Nevertheless, this study highlights again the seemingly central role of E246/D247 in TDP-43 misfolding and aggregation, making it an attractive therapeutic target in neurodegeneration.In another recent effort to promote clearance of TDP-43 aggregates, Gao  parts33 . The fir43 The emerging aminoquinoline compounds augmented caspase-7 degradation of TDP-43 in human neuroglioma H4 although the exact binding site and mechanism of action of those compounds were never elucidated.There are very few studies that focus on directly targeting TDP-43, probably due to the lack of pockets traditionally considered as druggable. The very first study targeting TDP-43, in 2013, used a high-throughput alpha-screen to find inhibitors of DNA binding.44 examined the effect of acridine derivatives potential to mitigate TDP-43 aggregation, since acridine-based compounds were previously shown to inhibit amyloid formation of PrPSc, among others45 (N-carboxy methyl imidazolium)methyl}acridine] dibromide, able to significantly reduce in vitro TDP-43 amyloid-like aggregation as well as TDP-43 inclusions in a yeast model cell. More recently, Babinchak et al. showed the ability of 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid (bis-ANS), and other similar compounds such as Congo Red, to modulate the liquid–liquid phase separation (LLPS) of TDP-43.46 While those studies demonstrate the potential of planar molecules in binding and mitigating TDP-43 aggregation/liquid phase separation, those compounds will require extensive validation in terms of toxicity and off-targeting properties since most of them are related to intercalant molecules or are known to be extremely toxic.In 2016, Prasad and collaboratorsothers45 . The autin silico approach targeting the RRMs,47 more specifically the nucleic acid binding interface of RRM1, since mutations inhibiting nucleic acid binding completely reversed ALS phenotypes in TDP-43 overexpressed Drosophila models.48 We validated one compound, rTRD01, through NMR spectroscopy and Microscale Thermophoresis (MST), obtaining a binding constant in the micromolar range (kD = 89.4 ± 0.8 μM), a relatively weak affinity that will be improved using structure activity relationship (SAR) studies. Interestingly, this compound was able to displace (GGGGCC)4 RNA, but not the native binding of (UG)6 repeats, probably due to lower affinity of TDP-43 for (GGGGCC)4 (nanomolar) compared to the canonical sequence (sub-nanomolar). Lastly, investigation of this compound in an ALS Drosophila model resulted in reduced locomotor defects.In recent years, our laboratory has focused on rational, structure-based targeting of TDP-43. Our first discovery used an These experiments characterized the first small-molecule directly targeting TDP-43 to identify therapeutics for ALS, even though RNA-recognition pockets are more shallow than conventional kinase ATP-binding pockets. It is important to note that although rTRD01 was obtained from a screen against RRM1, it could potentially also bind to RRM2 . HSQC-NM49 The NTD is implicated in oligomer formation and support of nucleotide binding,50–52 among other functions. Interestingly, nTRD22 was shown to bind specifically to the NTD, with an affinity of 145 ± 3 μM, but was also observed to (i) shift residues in the RRM domains, as demonstrated by HSQC-NMR and (ii) displace canonical UG6 binding, unlike rTRD01 that directly targeted the RNA binding domains. We hypothesized that nTRD22 could affect the RRM domain through allostery, although current studies are ongoing to define how the NTD portion of TDP-43 influences the RRM domains. nTRD22 was further able to reduce TDP-43 protein levels in rodent primary motor neurons, recapitulating TDP-43 RNA binding-deficient mutants and supporting impaired TDP-43 binding to nucleic acids. Finally, nTRD22 mitigated motor impairment in a Drosophila model of ALS. This study not only shows the possibility of TDP-43 NTD to be targeted by small molecules, but also a possible therapeutic interest for such a strategy.Another molecule we recently discovered is nTRD22 , found u6 RNA binding which might help achieve higher specificity with fewer off-target effects than rTRD01.Through these works, potential allosteric interactions between TDP-43 domains were brought to light, even though further investigation is needed to understand the precise mechanism. This insight proposes new intrinsic regulatory roles of TDP-43, as well as a new landscape of therapeutics. As stated before, targeting the NTD resulted in a better inhibition of canonical UG53 Three different NMR techniques were used, saturation transfer difference (STD), water ligand observed via gradient spectroscopy (WaterLOGSY) and Carr–Purcell–Meiboom–Gill (CPMG), to screen 89 cocktails, each containing 10 small molecules. A secondary screen on individual compounds, using the same NMR techniques, revealed four hits that were further examined using Chemical Shift Perturbations (CSPs) of the 15N-labeled tandem RRMs of TDP-43. Three of these hits, 1, 2 and 3, were able to induce significant CSPs on RRM2 residues G245, E246, H256, I257 and S258 (4bs254) using the data driven approach HADDOCK and was predicted to form a hydrogen bond with the side chain of S258.Other than our studies, an effort to find molecules targeting TDP-43 using a fragment-based NMR study identified hits that bound to the RRM domain.and S258 . This gr21,55 which questions the efficiency of this approach. An alternative strategy to inhibit nucleic acid binding could be to target D247, which makes a salt bridge with R151, stabilizing the RRM1-RRM2 orientation when RNA is bound56  to these small molecules is a potential new avenue. PROTAC relies on two covalently combined molecules, one recognizing the protein target and the other able to recruit an E3 ubiquitin ligase for ubiquitination and subsequent degradation of the protein target.57 Even though TDP-43 is already ubiquitinated in pathological aggregates, antibodies targeting TDP-43 were able to direct TDP-43 towards degradation with and without direct ubiquitination.23,26 PROTAC targeting of TDP-43 is thus a potential new strategy, with the caveat that the approach does not target well-folded physiological TDP-43 over inclusions. From this review, it is clear that targeting residues E246 and especially D247 is of high interest, since they seem to be exposed in TDP-43 inclusions.23 The coupling of targeting this pathological surface with a degradation strategy led to efficient clearing of aggregates.Despite its lack of traditional targetable pockets, we and others have shown the ability of small molecules to bind TDP-43, albeit with a rather low affinity.32,33 it is highly unstructured in the soluble form and forms polymorphic fibrils,58 making rational design of molecules difficult. Further, there is disease and tissue heterogeneity of TDP-43 C-terminal fragments in terms of composition and structure. Nevertheless, recent efforts, led by the Eisenberg laboratory among others, in structurally characterizing TDP-43 CTD peptides,42,58–61 with and without mutations, will help tremendously in targeting this region. Based on similar efforts to structurally characterize tau segments driving aggregation by MicroED, inhibitors of tau aggregation were developed by targeting VQIINK steric zipper interfaces with peptides derived from the same sequence (VQIINK).62 Based on these studies, they suggest tau amyloid polymorphism with distinct structures of tau fibrils. Similar efforts on structurally defining patient derived TDP-43 inclusions, which are possibly polymorphic, are very likely to provide in the future the mean to design small molecules or biologics that might specifically target these structures.In defining therapeutics that can target the predominantly unstructured C-terminus of TDP-43, there are two plausible modes of action: the peptides could either modulate or disrupt protein–protein (PPI) interactions that occur through the C-terminus. There are also other mechanisms we do not consider, such as modulation of condensate, either directly or through condensate formation, or binding to other non-proteinaceous entities. On the other hand, targeting the TDP-43 CTD seems highly challenging. Peptides targeting the CTD failed;Although none of the strategies described here have led to compounds that have reached clinical trials, several promising targeting options have been developed. Given the challenges consistently faced in neurodegenerative disease drug development, there needs to be extreme care in choosing appropriate: (i) animal models, potentially in combination with patient derived stem cells, to translate specific disease hallmarks being targeted, (ii) formulation, delivery route and ability to eventually cross the blood–brain–barrier by the drug candidates and (iii) better clinical trial design, for optimal and successful development of therapeutic candidates.Further experiments are needed to define efficiency and/or utilize combinations of therapies to achieve clearance of toxic aggregates as well as inhibition of TDP-43 pathology.There are no conflicts to declare.