Densityfunctional theory (DFT) corroborates the experimental results andreveals the intercalation mechanism, whereby P2O5 dissociates into small fragments catalyzed by defects in the graphenethat then permeates through lattice defects and reacts at the heterointerfaceto form P2O5. This process can also be usedto form new confined metal phosphates .While the focus of this study is on P2O5 intercalation,the possibility of intercalation from predissociated molecules catalyzedby defects in graphene may exist for other types of molecules as well.This in-depth study advances our understanding of intercalation routesof large molecules via the basal plane of graphene as well as heterointerfacechemical reactions leading to the formation of distinctive confinedcomplex oxide compounds.Intercalation is the process of inserting chemical speciesintothe heterointerfaces of two-dimensional (2D) layered materials. Whilemuch research has focused on the intercalation of metals and smallgas molecules into graphene, the intercalation of larger moleculesthrough the basal plane of graphene remains challenging. In this work,we present a new mechanism for intercalating large molecules throughmonolayer graphene to form confined oxide materials at the graphene-substrateheterointerface. We investigate the intercalation of phosphorus pentoxide(P To date,much of the research surrounding the intercalation of monolayer graphenehas focused on the intercalation of metals  and smallgas molecules . However, the intercalation of moleculesthrough the basal plane of monolayer graphene that are significantlylarger than the lattice parameters of graphene remain challenging.This is because the size and energy barrier for intercalation inhibitsthe permeation of such large molecules.26 The abilityto intercalate large molecules could further expand the toolsets forsubsurface and heterointerface engineering of 2D layered materialsand therefore enrich the material choices available for the fabricationof heterostructures and intercalation compounds used in energy storage,optoelectronics, thermoelectric, catalysis, etc.29Intercalation is a topotactic insertionprocess of organic or inorganicchemical species  between theinterfaces and heterointerfaces of two-dimensional (2D) layered materials.This process is known to form a variety of intercalation compounds,notably in graphite, encompassing a diverse range of intercalantswithin the host of the 2D layered bulk crystal.x1–Gex,30 Fex1–Cox,31 etc.) and compounds  have been formed at graphene-substrate heterointerfacesvia chemical reactions. In all of these cases, however, chemical speciesare individually introduced in a sequential manner when intercalatinggraphene. This is done to prevent prereactions in the vapor phasebetween the individual elements prior to intercalation. Such prereactionsusually lead to the formation of clusters at defect sites on the graphenesurface rather than intercalating through the lattice itself and forminga compound at the heterointerface.Chemicalreactions enabled by confinement to the heterointerfacesof 2D layered materials provide a pathway to circumvent the limitationon intercalating large molecules directly through the basal plane.That is, individual chemical species or multiple small fragments ofthe initial state of the molecule would first intercalate throughtypically available pathways in the graphene lattice, and then recombineat the heterointerface via chemical reactions. So far, a variety ofalloys (Sn2O5) molecules directly from the vapor phase to form P2O5 at a graphene-substrate heterointerface. The formation ofconfined P2O5 was confirmed using a varietyof chemical analysis and spectroscopic techniques as well as microscopicsurface and cross-sectional imaging. Density functional theory (DFT)was used to corroborate experimental results and to deduce the mechanismfor the intercalation of P2O5 molecules throughthe basal plane of monolayer graphene. First, P2O5 dissociates into small fragments  when interacting withthe graphene surface. These small fragments consistently showed lowerenergy barriers for intercalation through defects commonly observedin the graphene lattice. Once the small fragments intercalate, theyreact at the heterointerface to form P2O5. Weshow that the intercalation of P2O5 at the graphene-substrateheterointerface can tune the electronic structure of the grapheneoverlayer through strain and charge transfer. In addition, we showthat this process can also be used in the formation of new confinedmetal phosphates by intercalating P2O5 intoa graphene-substrate heterointerface initially containing a confined2D indium metal to form InPO4. Although this study focuseson the intercalation of P2O5, the concept ofintercalation from predissociated molecules catalyzed by defects ingraphene could be possible in other classes of molecules. Ultimately,this study provides an important steppingstone for advancing the understandingof intercalation pathways of large molecules though the basal planeof graphene as well as heterointerface chemical reactions to formunique confined complex oxide compounds.In this work, we report amechanism of vapor phase intercalationof large molecules through the heterointerface of monolayer grapheneto form confined oxide materials underneath graphene with a chemicalcomposition that resembles the initial state of the large intercalantmolecule itself. Unlike prior work, where chemical species and/orelements were sequentially introduced into the heterointerface, singlemolecules were introduced directly into the vapor phase for intercalationthrough the basal plane. This mechanism was revealed by investigatingthe intercalation of phosphorus pentoxide (P2O5) can be deduced from our DFTcalculated ground state structure whenit is adsorbed onto the surface of pristine monolayer graphene . The formation of such large poresin graphene is, however, energetically unfavorable.40 In fact, other theoretical studies have predicted largeenergy barriers for permeation of many atoms and molecules throughpristine graphene.26 In our case, we experimentallyshow that it is possible to intercalate P2O5 through monolayer graphene transferred onto germanium substrateswithout the need for large pores to serve as intercalation pathways.In our studies, germanium was used as a substrate due to the limitedsolubility41 and low diffusivity42 of phosphorus into germanium, allowing to fullycapture and study the formation of P2O5 at graphene-germaniumheterointerfaces. To intercalate P2O5, we preparedmonolayer graphene on germanium substrates which were then annealeddownstream of SiP2O7 at 950°C . From scanning tunneling microscopy(STM) imaging of the bubble surface (46 Upon further inspection of the surface using energy-dispersive spectroscopy(EDS), strong phosphorus and oxygen signals confined to the graphenebubbles were observed . During the ion sputteringprocess, the graphene surface was first etched. This resulted in arapid decrease in the C 1s core-level peak intensity . The peak intensities for the Ge,O, and P core levels increased upon sputtering of graphene , which serves as additionalevidence on the confinement of phosphorus oxide at the graphene–germaniumsubstrate heterointerface after samples were exposed to a flux ofP2O5.As shown in  surface 1c, insetobserved 1d. This observed 1f,g also–1, is highlighted in 2) heat map, which is related to the localabsorption spectra of the material, and therefore, useful for determiningthe chemical environment of the intercalant.482O5 using high-resolutionsynchrotron-based nano-FTIR measurements (see –1), the P–O bridgingmode (1060–1125 cm–1), and the P=Oterminal oxygen stretching modes (1135–1235 cm–1).49 The intensity of the P=O bondin the heat map . A near-field white light IR image of a regionof the sample containing graphene bubbles, spectrally averaged over∼610–1400 cments see . Evidentheat map 2b reache2O5, while the XPS corelevels in 2O5  intercalates through the basal plane of graphene,we first examined the adsorptive properties of these molecules onfive different graphene systems, consisting of pristine graphene andfour graphene lattice defect configurations (Supporting Information). This survey was performed to factor in differentinteraction parameters of distinct chemical environments on the intercalationprocess. The configurational space of the adsorptive states (chemisorptionvs physisorption) was thoroughly explored by including a multitudeof initial interacting geometries for both P2O5 and P4O10 on each of the different graphenelattice defect configurations  forces. In comparison, interactionsbetween the more stable P4O10 molecule and allgraphene systems were vdW in nature. In the case of covalent bondingbetween P2O5 adsorbents and graphene, P atomsconsistently demonstrated a higher affinity toward graphene. Thisis shown by the greater adsorption energy of P2O5 to graphene through the P atom (denoted by P2O5(P) in 2O5 approachinggraphene with its O atom (designated by P2O5(O)) either relaxed to drastically different interaction geometriesto allow bond formation between carbon and phosphorus or had a muchlower total adsorption energy when compared to P2O5(P). The only exception was P2O5(O)chemisorbed to S defects, in which both the atoms of the O and P bondedcovalently to the graphene defect site. Such trends can be rationalizedby the fulfillment of covalency and increased charge transfer stabilizationof carbon atoms at defects when bonding to less electronegative Patoms in P2O5.To gain a deeper understanding into the mechanism by which phosphoruspentoxide Purations 3b. As su46 and the presence of defects is thus theprecondition for P2O5 intercalation. A quantitativedescription of intercalation through defects is complicated by thecompetition between diffusion and bonding with carbon atoms at defectsites. This gives rise to three different energy profiles correspondingto distinct pathways.51 To address thesecomplexities, we employed a case-by-case strategy by calculating thepenetration barriers for fragments of P2O5 ofvaried size and chemistry based on calculated and experimental evidencefrom the literature.45 Based on experimentalevidence of P2O5 confinement at the graphene-germaniumheterointerface, the intercalation of molecular P2O5 in its entirety was first investigated. Point defects ofvarious sizes were examined, with the largest created by removing9 adjacent carbon atoms in an isolated graphene sheet . In all scenarios, P2O5 decomposed into fragments solvated by carbon atoms at thedefect sites. Notably, the energetic profile of P2O5 permeating through large defects showed a negative reactioncoordinate energy curve with small intermediate energy barriers asa result of the bonding of the fragmented P2O5 molecule to the defect site. Despite this negative reaction coordinateenergy curve, a barrier of at least 7.7 eV was still present for fragmentsto desorb from the defect and diffuse into opposite sides of the monolayergraphene . From this, we ascertain that intercalationis only possible from significantly smaller molecular fragments ofP2O5. Developed from these findings, we proposea mechanism involving three consecutive steps of realistic energybarriers to intercalate P2O5 through the basalplane of monolayer graphene. First, chemisorbed P2O5 decomposes into atoms or small molecular fragments. The resultingspecies then intercalate separately through point defects and thenreact underneath the graphene monolayer to form P2O5 at the confined heterointerface.Pristine graphene has been predicted to be impermeableto mostgaseous species under nonextreme conditions,2O5 intoPO2 and PO3 by cleaving the single bond betweenP and bridging O. Energy barriers for both reactions are shown in 2O5. These findings were consistent with the results ofadsorption state calculations, as covalent interactions and chargetransfer between the defects and adsorbed molecules weaken the intramolecularbonds. Having substantiated the possibility of the catalytic dissociationof adsorbed P2O5 at defect sites, we then calculatedthe energetics of smaller fragments intercalating through point defects.Phosphorus monoxide (PO), the simplest oxide of phosphorus, was chosenas the subject of this study. Given the positive correlation betweenan intercalant size and the energy barrier required for its permeationthrough graphene point defects, we postulate that the intercalationof PO provides a baseline for the minimum energy barrier applicableto the diffusion of any potential phosphorus oxide molecules throughmonolayer graphene. In the focused reaction coordinate diagram  defects without the introduction of defects of larger sizes.When penetrating through S- and D-defects, the molecule decomposedinto individual atoms with the rate limiting step having an energybarrier as high as 8 eV. On the other hand, PO wassurprisingly permeable at Q-defects. It diffused through the Q-defectwithout further fragmentation, with a barrier of approximately 2 eV, comparable to the energy required to break down chemisorbedP2O5. Finally, to compare atomic phosphorusand oxygen diffusing through the four different types of defects ingraphene , further corroboratesthe formation of the P2O5 nonplanar cage-likestructure at the graphene-substrate heterointerface after intercalationof phosphorus oxide fragments as suggested from our DFT calculations.Furthermore, it is possible to deconvolute the effects of charge transferand strain on the doping level of graphene by performing a correlationanalysis of the G and 2D peak positions between the nonintercalatedand intercalated samples  dI/dV measurements of the intercalated graphene surface  of the sampleat the tunneling site. Two local minima were observed in all dI/dV curves, that is, one at V = 0 which was the phonon scattering gap (green dashed line), andthe another at the Dirac point where the LDOS of graphene reachesits minimum (yellow dashed line).63 From V = 0) after intercalation, which indicatedthat P2O5 led to p-type doping of graphene.Graphene inherits highly delocalized π-electrons. Any modificationto the spatial extent of the charge density of these π-electronsor tilt of the π-orbitals leads to significant changes to thephysical properties of graphene.O–Pbond S3, furthO–Pbond S3, furthO–Pbond S3, furth66 the impact of possible deformation on the electronicstructure of monolayer graphene was studied. Our density of states(DOS) calculations based on (4 × 8) supercells of graphene suggestedthat the electronic structure near the Fermi level did not undergosignificant change, despite an increase in the overall system energywith respect to the increased strain. While compressive and tensilestress led to horizontal stretches and compression of the total DOS,respectively, the overall electronic structure near the Fermi leveldid not vary . We observed thatboth pristine and deformed graphenes behaved as semimetals. As a result,strain alone did not significantly contribute to the experimentallyobserved p-type conductive properties in the Raman and STS measurements.While nonuniform strain and formation of bubbles on the graphene monolayercould cause variations in the distance between graphene and underlyinggermanium substrate, the impact of the germanium surface on the electronicstructure of graphene becomes negligible when the separation reaches∼2 nm . Notably, evenin regions where the graphene monolayer was only a few angstroms fromthe top layer of the germanium surface atoms, the presence of germaniumstill does not induce semiconducting behavior in graphene. Similarly,while the exposure to P2O5 caused changes inDOS of graphene far above and below the Fermi level, the overall electronicproperties of pristine graphene with adsorbed molecules remained semimetallic,with characteristic converging overlap between the bottom of the conductionband and the peak of valence band  chemisorbed to S-defect being themost notable case  to bond with germanium 69 with excellent dielectric properties that initially gaininterest as a gate material for InP formed via surface oxidation.73 However, the formation of dimensionally confined indium phosphatesremains largely unexplored, thus impending a more comprehensive understandingof their physical properties and potential applications. In our case,we demonstrated the successful formation of confined indium phosphatesby intercalating P2O5 into a graphene-SiC heterointerfaceinitially containing confined mono- to bilayer indium also formedby intercalation.74 We identified the compositionof the confined indium phosphate at the heterointerface by investigatingthe In and P core-levels using high-resolution XPS .In addition to the typical peaks for indium metal (black dashed line),the XPS spectra exhibited new peaks around 445.8 and 453.3 eV in theintercalated sample (blue dashed line). These two new peaks were up-shiftedby 1.1 eV from the peak position of the In2O3 reference (red dashed line).75 Furthermore,a strong phosphorus signal was detected in samples intercalated withP2O5 3 and other metastable oxide phases could alsoform at such confined spaces68 and therefore are important to investigate in future studies.Although phosphorus has limited solubilityermanium 2i. To futudy see . Indium ithP2O5 6b. There2O5, can permeate the basalplane of graphene andintercalate into the heterointerface. This was evident from the strongP and O signals that were detected underneath the graphene surfacefrom spectroscopic measurements and microscopic cross-sectional imaging and analysis in TEM. Althoughthe physical size of the molecule was larger than that of the graphenelattice, fragments of the molecule could intercalate through typicalpathways in the graphene lattice. This was revealed by calculatingthe penetration barriers for fragments of P2O5 of varied size and chemistry through pristine and defected grapheneof different configurations. The complexity of the interaction processof large molecules through the basal plane of graphene cannot be generalizedinto a single step process. However, a two-step mechanism, based onrealistic permeation energy barriers, was proposed for the intercalationof P2O5: (i) P2O5 firstdissociated into small fragments  catalyzed by pointdefects in the graphene lattice; (ii) these fragments once intercalatedcan chemically react at the confined graphene–substrate heterointerfaceforming a condensed phase that chemically resembles the initial stateof the molecule. It has been shown that the intercalation of P2O5 at the graphene-substrate heterointerface couldeffectively tune the doping level of graphene via charge transfer.Moreover, the intercalated P2O5 (and/or itsfragments) can also act as reactants and further contribute to otherinterfacial reactions, for example, the conversion of 2D indium into2D indium phosphate at the heterointerface between graphene and SiC.Although our findings only focus on indium phosphates, our resultsdemonstrate the potential of this approach for the conversion of othermetals  and alloys. Furthermore, spatial controlover the distribution of defects, such as localized irradiation usingplasma processing,76 can promote the selectivearea intercalation of metals and/or alloys under specific regionsof graphene. While the focus of this study is on P2O5 intercalation, the possibility of intercalation from predissociatedmolecules catalyzed by defects in graphene may exist for other typesof molecules as well. This in-depth study advances the comprehensionof intercalation routes of large molecules via the basal plane ofgraphene as well as heterointerface chemical reactions leading tothe formation of distinctive confined complex oxide compounds.In summary, we demonstrated that largemolecules, such as P17 SiP2O7 (Saint-GobainInc.) was utilized to produce an upstream flux of P2O5 to the samples. First, the center of the furnace was setto 950 °C at a ramping rate of 55 °C/min (stage I) and thendwelled at 950 °C for 45 min (stage II). In stage II, the measuredtemperature for the sample and SiP2O7 was 600and 950 °C, respectively. Samples were then naturally cooledto room temperature under argon flow.The intercalation process was performedat 1 atm in a single-zone furnace under argon flow. Two kinds of sampleswere used in this study: transferred CVD graphene (Graphenea) ontocleaned Ge(110) substrates (MTI Corp.) and 2D indium samples intercalatedat graphene-SiC(0001) heterointerface, as reported by Rajabpour etal.hν = 1486.6 eV). Ramanmeasurements were performed on a Renishaw inVia system with a 488nm laser (maximum power at 100 mW). STM was performed in a closed-cycleRHK Pan Scan Freedom SPM system in UHV (∼1 × 10–10 mbar) at a base temperature of 10 K. dI/dV measurements were taken using a built-in digital lock-inamplifier operating at 1.3156 kHz with a 10 mV excitation amplitude.Moreover, nano-FTIR of the graphene bubbles was performed on a commercialscattering-type scanning near-field optical microscope (s-SNOM) setup(Neaspec Inc.), and the collected spectra were normalized to thatobtained on a silicon sample using the same acquisition parameters.Nano-FTIR of the P2O5 reference sample was performedon a synchrotron infrared light-based nano-spectroscopy (SINS) setup .SEM and EDS were performedon a Thermo Fisher Scios 2 dual-beam microscope. The cross-sectionalsamples of graphene bubbles for TEM analysis were prepared using afocused ion beam (FIB) Zeiss NVision 40 FIB-SEM. The target locationwas extracted from the specimen and attached to a copper FIB gridusing a conventional FIB milling and lift-out procedure. The HAADFimage and STEM-EDS mappings on the cross-section of graphene bubbleswere collected with a Thermo Fisher Scientific Talos 200× operatedat 200 kV. HAADF was performed with a spot size less than 1 nm witha convergence semiangle of 10.5 mrad. Furthermore, XPS spectra anddepth profiles were carried out in a Thermo-Fisher K-Alpha Plus XPSsystem and in a Kratos Axis Ultra DLD system using a monochromaticAl Kα source  calculations, a grid of 5 × 4 ×1 was used. To obtain density of states (DOS), a grid of 9 ×9 × 1 was adopted for best precision. For more information onsimulating the reaction mechanism, see the Supporting Information.DFT calculations wereperformed using the generalized gradient approximation (GGA) withthe Vienna ab initio simulation package. The projector-augmented-wave(PAW) method was used, and Grimme’s DFT+D2 was applied to betteraccount for the van der Waal’s interaction between graphenemonolayer and absorbed species.


Through qualitative analysis of the response mechanism of graphene PTE devices, we find that the electrode-induced doping of graphene channel near the metal-graphene contacts play a key role in the terahertz PTE response. This work provides an effective way to realize high sensitivity terahertz detectors at room temperature. A highly sensitive room-temperature graphene photothermoelectric terahertz detector, with an efficient optical coupling structure of asymmetric logarithmic antenna, was fabricated by planar micro-nano processing technology and two-dimensional material transfer techniques. The designed logarithmic antenna acts as an optical coupling structure to effectively localize the incident terahertz waves at the source end, thus forming a temperature gradient in the device channel and inducing the thermoelectric terahertz response. At zero bias, the device has a high photoresponsivity of 1.54 A/W, a noise equivalent power of 19.8 pW/Hz The terahertz (THz) radiation 0.1–10 THz) is located in the transition area between electronics and optics and includes a wide electromagnetic frequency spectrum between microwaves and infrared, and its optoelectronic hybrid characteristics have a wide range of potential applications, including wireless communication, spectroscopy, material science, sensing and imaging, etc. –10 THz i,3. SincePTE) of PTE detector is the integral of the product of Seebeck coefficient and temperature gradient along the conduction channel of the device. The formula isBT << EF, according to Mott equation, S can also be written asB is Boltzmann constant, e is the electron charge, σ is the electrical conductivity of the material, EF is Electron energy. From Equation (2), S is proportional to the conductivity and the derivative of energy, so the Seebeck coefficient can be regulated by adjusting the Fermi energy level, which is generally divided into gate control and chemical doping. For PTE detectors, if we assume that the Seebeck coefficient varies in a small range along the channel, the asymmetric distribution of temperature is necessary. Photothermoelectric (PTE) detectors are a kind of optical-thermal detector based on the PTE effect. Unlike photoconductive and photovoltaic detectors whose spectral response range is limited by the active semiconductor bandgap used in the detector, PTE detectors are known for their ultra-wideband response operation at room temperature and zero driven bias ,10,11,12Since the discovery of graphene in 2004, researchers have begun to study various 2D materials in depth, and the potential use of these materials as photodetectors in a wide range of electromagnetic spectrum is an important research direction ,17,18,19In this work, a simple antenna coupled asymmetric structure has been used to achieve the excellent device performance of graphene PTE detectors, which can be compared with the state-of-the-art two-dimensional materials terahertz detectors. Furthermore, we propose a qualitative model to analyze the highly sensitive PTE response caused by asymmetric coupling. In particular, we found that the metal-graphene contacts play a key role in the terahertz PTE response. Our results have important guiding value for further optimization of PTE terahertz detectors for two-dimensional materials in the future.2 was used for the construction of graphene PTE detectors. The detectors were fabricated by standard planar micro-nano device processes and two-dimensional material transfer techniques. Firstly, the coupling structure of the metal antenna (5 nm Ti/40 nm Au) was prefabricated by lithography, electron beam evaporation, and lift-off processes. Then, the highly oriented pyrolytic graphite was mechanically dissociated into micron-sized few-layer graphene (~30 nm) using blue film tape, and the graphene flake was accurately transferred to the channel area of the device by using 3D mechanical transfer platform and PDMS-assisted transfer technology. The graphene device is encapsulated with metal leads onto a custom PCB board for subsequent electrical and optical measurement.We used FDTD electromagnetic simulation to simulate and optimize the antenna coupling structure of the detector, which has excellent local field enhancement for far-field terahertz waves. Because high-resistivity silicon has high terahertz transmittance and can effectively reduce the reflection of terahertz waves, a substrate of high-resistivity silicon  covered with 300 nm SiO2. The output port of the multiplier is waveguide-coupled via a standard gain horn antenna, which emits linearly polarized high-frequency radiation into free space. The fundamental frequency microwaves are electrically modulated, and then electrically modulated terahertz radiation is output from the VDI multiplier and irradiated onto the device. In detail, a terahertz beam electrically modulated with a frequency of 1 kHz is irradiated onto the detector, and the generated photocurrent signals are amplified by a low-noise current amplifier (SR570) and then recorded by an oscilloscope (Tektronix MSO2024B). The noise spectrum of the detector is obtained by the spectrum analyzer (Keysight N9322C). The test process of the device was all carried out in room temperature and air environment. The output characteristic curve of the device was firstly measured using a high-precision digital source meter (Keithley 2400). The SMB100A microwave source (110 kHz–20 GHz) was used to drive a VDI solid-state 6-fold frequency multiplier to produce high-frequency radiation (75 GHz–110 GHz) with a power density of 5 mW/cmIn order to enhance the PTE response of graphene to improve the performance of terahertz detection, it is necessary to design an efficient asymmetric optical coupling structure. We designed a logarithmic antenna coupling structure which can make the local enhancement region of terahertz field at the source terminal of the device. A) is an important parameter to evaluate the performance of the detector. Its calculation formula isph is the photocurrent signal of the detector, Pin is the power density of the terahertz beam, and A is the area of the detector. In this measurement, the power density of the terahertz beam is 5 mW/cm2, and the area of the detector is 600 µm × 300 µm (including the antenna). As shown in n is the noise value at the modulation frequency, and RA is the responsivity of the detector. The noise spectrum of detectors usually contains several different main noise sources, including 1/f noise, shot noise and thermal noise (Johnson-Nyquist noise) [1/2 at 105 GHz, showing good detection sensitivity. The performance comparison of the 2D material-based terahertz detectors is shown in In the following, we discuss on the speed of the PTE detector, which is usually defined as the time measured from 10% up to 90% on rising edge of signal as well as the recovery time . As shown in t noise) ,29,30. T1 is the Seebeck coefficient in the metal-doped area, S0 is the Seebeck coefficient of graphene away from the metal electrode, T0 is the metal temperature, T1 and T2 are the temperature at the end of the doped graphene, and Th is the highest temperature point of channeled graphene. According to Equation (5), the electrode-induced doping of graphene channel near the metal-graphene contacts play a key role in the terahertz PTE response. The thermoelectric response of graphene is determined by the electrode-induced doping on graphene and the temperature difference along graphene channel. Due to the good doping of metals to graphene, this ensures the difference of Seebeck coefficients between the doped and undoped regions of graphene. Considering the contribution of Seebeck coefficient difference, the PTE response will be further improved if the signs of the Seebeck coefficient are opposite. Furthermore, the location of the optical coupling antenna in the graphene channel determines the temperature difference required to achieve the graphene PTE response. It can also be seen that when the coupling antenna is located in the middle of the device channel, due to the symmetrical configuration, the temperature difference will be zero, and the PTE response is completely suppressed. As the coupled antenna moves away from the center of the graphene channel, the temperature at the end of the graphene doping region near the coupled antenna will be closer to the maximum temperature point, and the effective temperature difference to drive the PTE response of the graphene will be expanded, thus improving the graphene PTE response. In order to optimize the device performance in the future, we proposed a qualitative theoretical model to analyze the high terahertz sensitivity caused by the asymmetric antenna coupling structure. As shown in 1/2, and a response time of 900 ns. Furthermore, through qualitative analysis of the response mechanism of graphene PTE devices, we find that the electrode-induced doping of graphene channel near the metal-graphene contacts play a key role in the terahertz PTE response. These results show that the optical coupled structure we designed effectively improves the thermalelectric terahertz detection sensitivity, providing an effective way to further improve the performance of two-dimensional materials terahertz detectors in the future.In summary, we achieved sensitive graphene-based PTE terahertz detectors by using an efficient asymmetric antenna coupling structure, which exhibits excellent zero bias detection performance in the frequency range of 75 GHz to 110 GHz. The measurement results show that the graphene device has a zero bias photoresponsivity of 1.54 A/W, a noise equivalent power of 19.8 pW/Hz


This paper builds on the context and recent progress on the control, reproducibility, and limitations of using graphene and graphene-related materials (GRMs) in biomedical applications. The review describes the human hazard assessment of GRMs in in vitro and in vivo studies, highlights the composition–structure–activity relationships that cause toxicity for these substances, and identifies the key parameters that determine the activation of their biological effects. GRMs are designed to offer the advantage of facilitating unique biomedical applications that impact different techniques in medicine, especially in neuroscience. Due to the increasing utilization of GRMs, there is a need to comprehensively assess the potential impact of these materials on human health. Various outcomes associated with GRMs, including biocompatibility, biodegradability, beneficial effects on cell proliferation, differentiation rates, apoptosis, necrosis, autophagy, oxidative stress, physical destruction, DNA damage, and inflammatory responses, have led to an increasing interest in these regenerative nanostructured materials. Considering the existence of graphene-related nanomaterials with different physicochemical properties, the materials are expected to exhibit unique modes of interactions with biomolecules, cells, and tissues depending on their size, chemical composition, and hydrophil-to-hydrophobe ratio. Understanding such interactions is crucial from two perspectives, namely, from the perspectives of their toxicity and biological uses. The main aim of this study is to assess and tune the diverse properties that must be considered when planning biomedical applications. These properties include flexibility, transparency, surface chemistry (hydrophil–hydrophobe ratio), thermoelectrical conductibility, loading and release capacity, and biocompatibility. The interdisciplinary field of tissue engineering (TE) comprises the use of biomaterials, biological active agents, including cells, and engineering to restore or develop biological substitutes for various tissues in the body . AssemblCells may be grown in two-dimensional (2D) or three-dimensional (3D) cultures. Generally, 2D cultures comprise the growth of cells on a flat surface, such as a flask or petri dish. This method is commonly used in research given its cost-effectiveness, feasibility, and ease of observation when analyzing cells; however, it lacks the capacity to accurately resemble in vivo cellular environments. On the other hand, 3D cultures, which may be performed using the hanging-drop method, microfluidic platforms, or scaffolds, allow for interactions between cells and the extracellular matrix (ECM) to take place . As suchScaffolds are structures that are used in both in vitro and in vivo TE applications and serve as support to ensure the growth of the ECM, cell adhesion, and subsequent tissue growth . ScaffolThe development of scaffolds that can encourage neural tissue regeneration has generated much interest for GRMs. Recent studies have demonstrated that GRMs encourage the adhesion, proliferation, and differentiation of various cells, including embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs), and induce pluripotent stem cells. Many researchers have found that scaffolds based on conductive materials can boost NSC proliferation and differentiation into neuronal or glial cell lineages . GRMs arIn 2015, Jakus et al. demonstrated that human mesenchymal stem cell (hMSC) adhesion, viability, proliferation, and neurogenic differentiation may be supported by 3D printable graphene (3DG) . These pMolecularly changing the surfaces of neural probes with anti-inflammatory agents, adhesion of proteins, and bioactive chemicals comprises one method of regulating the inflammatory process and improving neural electrode incorporation into brain tissue . HyaluroA significant challenge in using neural electrodes for recording brain activity both in vitro and in vivo is developing novel materials that produce seamless neural interfaces with high sensitivity. Another issue that has driven the creation of innovative materials is ensuring long-term stability. By considerably boosting the signal-to-noise ratio, electroactive nanomaterials such as silicon nanowires , carbon The ECM is a critical component of all types of tissues and serves as a natural scaffold for cells to adhere to and differentiate. The ECM, therefore, contributes greatly to the homeostasis and morphogenesis of tissues. In 3D TE, scaffolds may be developed using various polymeric or non-polymeric materials to mimic the ECM of target tissues. When selecting biomaterials for scaffolds, it is important to choose a material with properties that are suitable for the target tissue and cell types being used as the properties of the material should mimic those of the ECM of the target tissue. This will ensure that the material will contribute to obtaining the desired results.The properties of various scaffolds can differ in terms of structure, rigidity, strength, pore size, and the concentrations of the polymers used . The comBiomaterial-related scaffolds provide porous networks, mechanical and structural support, shape, and hierarchical structures with hydrophilic properties to allow for cell attachment, cell–cell communication, proliferation, and differentiation for tissue regeneration in TE. To date, most synthetic biomaterials for TE applications may be generated from lactic acid, caprolactone, or glycolide monomers, which can form poly(L-lactide), polycaprolactone, and poly(L-glycolic acid) materials or copolymers .Chitosan, alginate, starch, collagen, HA, cellulose, fibrin, silk, and their derivatives may also be utilized to build scaffolds . To manaRecent studies have assessed the potential of silkworm silk as a unique biomaterial that may address many of the shortcomings of the current materials used in TE scaffolds. The natural protein, silk fibroin (SF), which is obtained from silkworm silk, has been studied as a potential biopolymer for TE due to its biocompatibility, tunable biodegradation, minimal immunogenicity, adaptability to different forms , excellent mechanical strength, and ease of accessibility ,25. SF cHA, a polymer that is composed of linear glycosaminoglycan and is abundant in the ECM, has been shown to impact cell signaling pathways, which is critical in TE. Clinical trials have further shown that HA is useful in treating osteoarthritis, and the US Food and Drug Administration has approved HA as a biomaterial for human use .Stem cells are usually grown in vitro in a monolayer on a flat plastic substrate. This method, however, cannot fully replicate the characteristics of cells in their native microenvironments. Thus, it is important to offer an adequate microenvironment for developing functional tissues by creating biomimetic scaffolds that are analogous to stem cell niches . ConductTo date, various biological materials made of natural or synthetic materials have been used for peripheral nerve regeneration, including HA, SF, polypropylene alcohol, sodium alginate, gelatin, chitosan, and polyacrylamide (PAM) ,37,38,39Due to their excellent biocompatibility, ability to retain water, and drug-delivery capabilities, hydrogels have recently become widely used in TE including nerve regeneration . For exaDue to their excellent biocompatibility, PAM hydrogels are frequently used in the field of peripheral nerve regeneration . Pure PAOne reason why graphene has drawn the interest of scientists worldwide is its advantage to be involved in a significant number of applications due to its unique characteristics . It has 2 hybridization, which makes it electroconductive  expression . GraphenTE has allowed for improved diagnostic and therapeutic techniques. Tissue and organ transplantation methods may also be improved through TE with various biomaterials. Biomaterials have been proven to be useful in developing biomimetic tissue constructs; however, different host tissues have different physical, chemical, and electrical properties, which individual biomaterials may not be able to replicate independently. Developing composite or hybrid materials is therefore necessary to ensure each property of a tissue is mimicked effectively . Graphenl-lysine, can control the electrical resistance of the materials and subsequently facilitate the adhesion of neural cells and outgrowth of neurites [Lu et al. demonstrated that GO can interact with DNA oligonucleotides via multiple interactions and thus could be used to protect them from enzymatic cleavage while delivering the oligonucleotides into target cells . Tang etneurites .Various methods may be used to characterize 3D graphene-related scaffolds. For example, the morphology of a graphene-related scaffold may be determined using transmission electron microscopy or atomic force microscopy imaging ,110. RamGraphene has the capacity to simulate the complex signaling systems in the nervous system—neurons connect electrical messages using chemical signals, such as acetylcholine —given it2+ oscillations in the neurons doubled in comparison with that in the control group. These findings suggest that GRMs may encourage the growth of neural networks and improved brain circuits. Liu et al. developed an implanted graphene-related brain electrode to track electrophysiological and neurochemical signaling in vivo [2O3 nanocomposite was developed. This rGO-modified electrode provided increased electron transport between tissue and electrode surfaces, lower detection limits, and greater sensitivity to hydrogen peroxide than standard gold electrodes did. Feng et al. also exhibited the use of soft nanofibers based on graphene for the monitoring of brain activity [3 plasma treatment prior to the reduction in graphene oxide nanofibers (GO-NFs) to produce the G-NFs. The ultrathin graphene shells of the G-NFs, which completely enveloped the nanofiber surfaces, resulted in high electrical conductivity and excellent flexibility. Thus, neurons on the G-NFs generated more neurite branches and expanded faster than neurons on the graphene films and tissue culture plates did. Neurons on the G-NFs also exhibited elevated levels of class III beta tubulin (TUJ1) and microtubule-associated protein 2 (MAP2) due to the geometric cues of the G-NFs, which closely mirrored nanofibers and mature neuronal markers. By applying electrical stimulation on neurons through G-NFs (referred to as G-NFs/ES), a growth rate that was noticeably boosted and approximately twice as fast as that of neurons on the G-NFs was identified. The activation of the calmodulin-kinase pathways by Ca2+ influx, which is driven by the depolarizing effect of the voltage-gated Ca2+ channels induced by G-NFs and increases intracellular Ca2+ concentrations, may have been the reason for this stimulation. Furthermore, the 3D G-NF nanofibers had a considerable impact on the development and growth of motor neurons. The G-NFs provided an anisotropic electron transfer at the points where the neurons made contact, which could have led to localized electrical stimulation.GRMs have been utilized in brain interfaces and electrical recordings due to their electrical properties ,120. A u in vivo . To measactivity . NegativNumerous studies have highlighted the use of graphene-related scaffolds in facilitating the adhesion and differentiation of neural cells ,126. NerThe “gold standard” for healing damaged nerves or gaps in clinical settings is autologous nerve grafting with sutures. Long defects or gaps are challenging to fix due to the slow rate of axon regeneration (approximately 2–5 mm/day). A sufficient supporting bridge, also known as a conduit, is therefore needed to reconnect damaged nerves .In a study by Hong et al. , a 2D gr2/g) and 3D porous structures. Additionally, their interconnected gaps improved cellular communication and allowed for efficient nutritional mass transfer for cells. Furthermore, the 3D-GFs displayed microscale topographic features, such as curvatures or anisotropic microstructures, which was in contrast with the features of 2D GRMs. These findings indicate that GFs may facilitate enhanced neuronal differentiation.Li et al.  further Despite the fact that GRMs have been extensively used to create films  or 3D scJakus et al. used graphene and poly(lactide-co-glycolide) (PLGA) to generate a bioink, which they then utilized to 3D print a nerve conduit with a specific size . They deIn a study by Feng et al. on the influence of GO and rGO membranes on the differentiation of adipose stem cells (ADSCs) into nerve cells, it was discovered that GO had a stronger effect on the ability of ADSCs to differentiate into neurons after 7 days of culture . One of Another possible treatment option for neurodegenerative illnesses involves the growth of NSCs, according to Huang et al., who embedded NSCs in hydrogels that were made by combining graphene or GO with polyurethane (PU) using 3D bioprinting . The visIn a study by Niu et al. , rat indIn another study by Magaz et al. , electroIn order to create a GO/antheraea pernyi silk fibroin (ApF)/poly(L-lactic acid-co-caprolactone) (PLCL) scaffold, Wang et al. coated GO onto an electrospun ApF/PLCL composite scaffold . FollowiSince graphene is a multifunctional carbon nanostructure, it is not infrequent for it to be utilized in cancer treatments and therapies. QDs, other carbon nanomaterials, GO, and graphene itself are usually involved in processes such as tumor screening, chemotherapies, and photothermal and photodynamic therapies . GraphenThe surface of graphene has been found to exhibit covalent and noncovalent activities, which are of utmost importance for its interactions with cancer cells, tissues, and anticancer drugs . VariousAcidic pH and hydrogen peroxide are two of the features that play a vital role in the activities of tumor microenvironments. Lin et al.  showed tGRMs are attractive for drug delivery and gene delivery especially because their surface can be tuned easily from highly hydrophobic to highly hydrophilic . A proper functionalization can lead to a proper hydrophyl-hydrophobe ratio and thus the delivery rate can be adapted according to the needs. Moreover, GRMs are able to absorb visible and infrared light and thus photothermia can be generated with the main aim to act as a triggering factor in delivery. These findings highlight graphene as an ideal platform for gene and drug-delivery technologies . Gene therapy is a medical approach that either treats or prevents disease by targeting genetically and adversely altered genes through various nanocarriers, such as graphene . Lo et aGO has also been used as a nanocarrier for methotrexate, a drug against cancer cells, to test if the toxicity of the drug can be enhanced in tumors. Abdelhamid and Hussein  tested tIt is also critical to consider the antimicrobial and antibacterial activities of graphene to achieve an in-depth understanding of its mechanisms and functions for biomedical applications. Biofilm formation is one of the most common ways to study a microorganism colony . HoweverE. coli. The results revealed the activity of E. coli was restrained and high levels of antimicrobial efficacy were achieved on the graphene and GO aluminum plates. Additionally, graphene nanowalls have been used as coatings for stainless steel-related materials and exhibited high activity against Gram-positive and -negative bacteria. The bacterial membranes appeared to be damaged following their exposure to the sharp edges of the graphene nanowalls [Various microbes have been identified for use in medical devices such as ventilators, urinary catheters, and dentistry devices. Developing devices with antimicrobial coatings is therefore necessary to diminish contamination levels. GRMs can be utilized to create suitable nanomaterial layers or device coatings to eliminate microorganisms . Graphenanowalls . Along with the intrinsic antimicrobial activity of the GRMs, more complex formulations based on GRMs and metal and metal-oxide nanoparticles, polyelectrolytes or antimicrobial agents were proposed. Certainly, the GRMs/Ag(/Polymer) or GRMs/ZnO(/Polymer) binary(/ternary) systems are some of the mostly studied GRM-based antimicrobial supports . A speciSome of the most important applications of the GRMs are presented in It has further been found that the high surface area of graphene in conjunction with its high chemical stability  enhancesNeuroMem, a neurodevice that exploits graphene to mirror the activity of synapses in the brain, is an extraordinary and promising development for future practices in the field. It is a low-cost memristor device that not only portrays behavioral and neurological data but also provides access to memories through enhanced neuroimaging . GraphenGraphene has been given the title “material of the future” and is increasingly being introduced in all the fields within science. However, it is necessary to consider the potential toxic effects of graphene in animal and human health. Over the years, environmental and biological safety concerns have been raised about the use and risks of graphene. Although graphene appears advantageous due to its abovementioned properties, studies have shown that it is associated with cellular apoptosis, necrosis, autophagy, cytoskeletal disorders, organelle and protein dysfunction, oxidative stress, physical destruction, DNA lesions, and inflammatory responses ,177. Graphene can also appear noxious if it is conglomerated in inordinate amounts in tissues and organs , such asThe type and quality of graphene are significant factors that must be considered in biomedical applications since they can affect mammalian cells and lead to cell membrane lesions and, consequently, apoptosis. These issues comprise some of the major challenges in the commercialization of graphene. There is therefore a need to develop GRMs with exceptional quality and in large amounts with little cost . Despite the abovementioned challenges, the focal point in developing GRMs is controlling the size of graphene products, which will allow for toxicity to be diminished in animals and humans . In a stThe toxicity of graphene can also be reduced by forming polymer nanocomposite molecules with GRMs. The materials can be constrained through the polymer matrix nanocomposites, which further restricts their permeability. Enriched oxygen graphene molecules can further diminish the hydrophobicity of polymeric matrices to assist in cell adhesion and expansion . By elucidating the mechanisms of graphene and considering the current comprehension of its functionalities, it can be assumed that not all GRMs can necessarily be characterized as hazardous. Likewise, not all of the materials can be characterized as harmless . NumerouDespite there being many studies that demonstrate the promising characteristics of graphene in scaffolds for nerve TE, implants, and therapeutic drug-delivery vehicles, several studies have shown that graphene can exert toxicity in the host or to cells ,182,183.Another limitation of using graphene nanoparticles in biomedical applications involves their shapes, which typically comprise sharp edges. These edges have been found to be damaging to cell membranes as they can penetrate the membranes edge-first, especially when the graphene particles are of a small size . SignifiOther studies have shown that graphene itself can be non-biodegradable, which can lead to toxicity and hinder effective tissue regeneration . BiodegrGiven the potential of using graphene in biomedical applications, many studies have aimed to determine methods to reduce its toxicity and improve its biocompatibility. Although graphene does not degrade on its own, its carboxylate derivatives can degrade under suitable conditions . StudiesGraphene has also been demonstrated to be hazardous in vivo in animal experiments. For example, one study found that after injecting GO into the lungs and liver, GO aggregated in a dose-dependent manner . These nFollowing functionalization with PEGylation, graphene has been found to act differently in vivo and be far more biocompatible. PEGylated graphene with a diameter between 10 and 50 nm has been found to exhibit low levels of cytotoxicity over the course of 1 month. PEGylated graphene has also been found to accumulate and then be gradually removed over time . The decAnother study examining the impact of GO on medical devices examined the biocompatibility of GO after the implantation of subcutaneous and peritoneal tissue at two oxygenation levels. The findings revealed an inflammatory response that resembled a usual reaction to a foreign body. GO (20 mg/kg) was injected into several tissues with varied C-to-O ratios. Flow cytometry was used to measure the number of inflammatory cells. The macrophage levels were lower in the GO-treated groups than in the control group during the course of a 2-week monitoring period. Notably, larger monocyte numbers and a stronger pro-inflammatory milieu were linked to higher GO oxidation levels. The variables that determine graphene-related toxicity are therefore the dose of graphene used, its size, the treatment period, and the number of layers of graphene. It has also been proposed that the surface characteristics of graphene and its derivatives, such as the functional groups and their chemical structures, are directly connected to the toxicity of the materials. Cytotoxicity may, however, be reduced by crosslinking the derivatives with biocompatible materials or controlling the sizes of the compounds through synthetic methods . Graphene-related products can further damage cells and induce oxidative stress. Consequently, while functionalizing graphene and its derivatives, it is crucial to consider their purity. Overall, given that GRMs come in various sizes and shapes and can be produced through various methods, determining and minimizing the toxicity of the materials for clinical usage is essential.Overall, studies in the field have produced conflicting results. Many studies have demonstrated the cytotoxicity of graphene nanomaterials in TE applications, whereas others have indicated that they are biocompatible. These inconsistencies may be due to several causes, including the cell types being assessed and their genetic background, experimental techniques and parameters, culture conditions for in vitro experiments, the derivatives and forms of graphene being used, and their physicochemical properties. Further studies are therefore necessary to understand the correlation between these factors and graphene-related cytotoxicity. A larger number of methods to functionalize graphene for use in specific TE applications, such as in neurodevices, targeted drug delivery, implants, DNA sensing, and scaffolds for tissue regeneration, are also needed given the numerous factors that can influence the cytotoxicity and efficacy of graphene-based and -coated materials and devices. Moreover, many studies have assessed the toxicity of graphene and its derivatives in lung or liver cells, but few have studied the cytotoxic effects of graphene on neural cells. Elucidating these issues and further studying the impact of graphene on neural cells will allow for in vivo applications to be more successful, which may eventually lead to human clinical trials taking place and, finally, the commercial and biomedical use of GRMs and devices in nerve TE.


TDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.We have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.TDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors , Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.TTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease. N-methyl-D-aspartate (memantine) (Alzheimer’s disease (AD) is the most common form of dementia accounting for more than 35 million people affected worldwide. It is considered a chronic illness and also a highly concerning world health problem. As the main risk factor is age and different studies predict an increase of the life expectancy of the population, an important escalation of the number of AD patients is expected in the following years . In thismantine) .In the last years, a new protein has attracted the focus in the field of neurodegenerative diseases: transactive response DNA-binding protein of 43 kDa (TDP-43). Hyperphosphorylated TDP-43 was identified as the main component of ubiquitinated protein aggregates found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients . Since tParticularly in AD, several studies have determined the impact of the deposition of TDP-43 in patients’ brain, stablishing that it aggravates the memory loss and the hippocampal atrophy. Furthermore, TDP-43 pathology has been found in half of the patients that were considered to havepure Alzheimer’s disease . MeanwhiTDP-43 is an important protein involved in the transcription, splicing and transport of numerous RNAs and it is found mainly in the nucleus where it exerts its main functions. However, at physiological conditions, it presents a localisation equilibrium with the cytoplasm, where it can be found in a 5–20% of the total amount of the protein . In pathin cellulo and in vivo models , cell division cycle kinase 7 (CDC7), glycogen synthase kinase 3 (GSK3) and tau tubulin kinase 1 (TTBK1) the better characterized . Brain po models .in vivo pharmacokinetic profiles with a 2 to 3:1 ratio regarding brain to plasma penetration and show motor neuron protection and decrease of TDP-43 phosphorylation in the spinal cord of TDP-43-transgenic mice after chronic treatment , penicillin/streptomycin , Fetal Bovine Serum (FBS) , polyvinylidene difluoride (PVDF) membranes for Western blots , Chemiluminescence (ECL) system , Pierce BCA Protein Assay kit , protease inhibitor complete mini mixture .50 values regarding kinase inhibition together with effective permeability values that predict their ability to cross the blood–brain barrier (BBB), are provided in Kinase inhibitors IGS2.7 and VNG1.47 were synthetized in our laboratory following previous described procedures . Their cAntibodies used in this study are listed in Blood samples from two healthy controls and two patients suffering from severe AD were obtained after written informed consent. Patients were diagnosed in the Hospital 12 de Octubre  as severe Alzheimer’s disease patients based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) . ClassifPeripheral blood mononuclear cells (PBMCs) were isolated on Lymphoprep™ density-gradient centrifugation following the manufacturer’s instructions . Lymphoblastoid cell lines (LCLs) were established by infecting peripheral blood lymphocytes with the Epstein Barr virus (EBV) as previously described .6 cells/mL) that contained 1% penicillin/streptomycin and 10% (v/v) fetal bovine serum (FBS). U2OS cells were obtained from the American Type Culture Collection and grown in DMEM media, supplemented with 10% (v/v) fetal bovine serum and 1% penicillin/streptomycin. All cell lines were grown at 37°C in a humidified 5% CO2 atmosphere.Lymphoblastoid cell lines were grown in suspension in T flasks in an upright position, in RPMI 1640 medium  or IGS2.7 (5 μM). Conditioned medium was collected after 72–96 h and added to healthy cells in a ratio 3:1 with fresh medium. After 72 h cells were harvested and processed for Western blotting or immunofluorescence analysis.2, 0.5% (vol/vol) sodium deoxycholate, 0.5% (vol/vol) NP-40 and 0.1% (vol/vol) SDS), containing 1 mM phenylmethylsulfonylfluride (PMSF), 1 mM sodium orthovanadate, 1 mM sodium pyrophosphate and protease inhibitor mixture). Pierce BCA Protein Assay kit was used to determine the protein content of the extracts.Cells were collected by centrifugation, washed with PBS, and then lysed in ice-cold RIPA buffer (50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 5 mM EDTA, 15 mM MgClEqual amounts of proteins (50 μg) were resolved by SDS–polyacrylamide gel electrophoresis, transferred to polyvinylidene fluoride (PVDF) membrane and blocked with 5% BSA in TTBS 1X. The antibodies used are listed in Immunofluorescence analysis was performed on cells grown on coverslips. For the attachment of lymphoblastoid cells, the coverslips were previously coated with a solution of 0.025% Gelatin  for 30 min at room temperature followed by a solution of 1 mg/mL poly-L-lysine  diluted 1:50 in Borax buffer  overnight at 37°C. Cells were then fixed for 25 min with 4% paraformaldehyde and permeabilized with 0.1% Triton X-100 for 10 min. Then samples were blocked with PBS-1% BSA for 60 min at 37°C.Cells were incubated with the primary and secondary antibodies described in N-termini with Cy5 to provide a fluorescent kinesin binding peptide. Their synthesis and labelling has been previously described  and VNG1.47 (10 μM). After the CM treatments, the probe Cy5-KBP was added to the cells at 2.5 μM for 15 min at 37°C. Peptides were washed using DMEM without phenol red and imaged using a confocal laser scanning microscope Leica TCS SP8 with a 63x oil immersion objective that included a humidified incubation chamber, a CO–1. Track mean displacement and track mean velocity were calculated and normalized to control cells in each experiment. Data were analyzed by one-way ANOVA using GraphPad Prism 8 software. For multiple comparisons, Bonferroni’s correction was applied.Single-particle trajectories were analyzed with the TrackMate plugin from the ImageJ software. Specifically, the LoG detector and the linear motion LAP tracker were used to detect and link particles with an estimated blob diameter of 1 μm and at a maximum distance of 2 μM. More filters were included to discard trajectories with less than 5 spots and with a maximum speed of 1 μm sp-value <0.05” was considered statistically significant.Statistical analyses were performed using Graph Pad Prism software version 6 . All the statistical data are presented as mean ± standard error of the mean (SEM). Statistical significance was estimated using two-tailed Student’s t-test for statistical comparisons between groups, or one-way ANOVA followed by the Bonferroni test for multiple comparators. A “VNG1.47 and IGS2.7 have shown to be effective in the experimental treatment of lymphoblasts from ALS patients which are characterized by presenting TDP-43 hyperphosphorylated cytosolic aggregates, the main pathological hallmark of ALS . We haveWe next investigated whether the reduction of this post-translational modification restores the nucleus-cytoplasmic functional balance of TDP-43 and reduces the aberrant F-actin cytoskeleton protrusions, reminiscent of tunnelling nanotubes or TNT-like structures that characterized these AD lymphoblasts . With thThe prion-like properties of TDP-43 have been described in several TDP-43-linked diseases. We have recently documented the prionic behaviour of this protein in AD lymphoblasts throughout conditioned medium (CM) experiments which contains a 25 kDa TDP-43’s prionic fragment . To furtFirst, we cultured AD lymphoblasts treated with and without the kinase inhibitors for 72 h. These pre-treated (ptCM) and non-treated (CM) mediums from AD lymphoblasts were collected and added to healthy control lymphoblasts for 72 h. Immunofluorescence staining with an anti-TDP-43, revealed the presence of TDP-43 pathological changes such as cytosolic localisation and generation of TDP-43 aggregates in healthy cells exposed to CM from AD lymphoblasts compared to control cells  . HoweverFinally, we analysed the phosphorylation status of TDP-43 in these CM studies. TDP-43 phosphorylation was shown to be higher in healthy cells exposed to CM from AD lymphoblast than in those exposed to CM from healthy cells in both, the full-length protein and in the 35 kDa fragment . HoweverIn previous studies, we have shown that human osteosarcoma U2OS cells treated with the conditioned medium from lymphoblasts from severe AD patients also showed increased phosphorylation and mislocalization of TDP-43 . BecauseU2OS cells were treated with conditioned medium from healthy lymphoblasts and lymphoblasts from two different severe AD patients for 72 h. A significant reduction on the average displacement of Cy5-KBP particles was found compared to U2OS treated with conditioned medium from healthy controls, showing a deficit in the intracellular transport in AD samples . FurtherIncreasing amount of evidence indicates that TDP-43 pathology may play an important role in AD. TDP-43 inclusions have been found in approximately 50% of necropsies, most often in severe cases of AD, suggesting that TDP-43 can influence AD pathology and neurodegeneration. The presence of TDP-43 pathology in AD brain has been associated with greater memory loss and brain atrophy.To date no effective treatment for AD exists, pre-clinical pharmacological approaches aimed at blocking disease progression had been focused at the clearance of extracellular deposits of β-amyloid, formation of intracellular neurofibrillary tangles, or preventing inflammation and oxidative stress among other processes . On the in vivo and in vitro  and the Spanish National Research Council Institutional Review Board (15 March 2007).ÁM-R, AM, and CG: conceptualization. LM-G, EC, and CT-B: methodology. LM-G, EC, CT-B, VP, and VN: investigation. ÁM-R and AM: resources. AM, LM-G, and VN: writing—original draft preparation. EC, CT-B, LM-G, CG, VP, ÁM-R, and AM: writing—review and editing. AM and VP: funding acquisition. All authors have read and agreed to the published version of the manuscript.


Streptococcal species.Rapid diagnostic testing (RDT) allows antimicrobial stewardship programs (ASP) to intervene early in the setting of sepsis and septic shock leading to lower rates of death. Combining RDT with ASP results in faster antibiotic de-escalation compared to RDT alone; however, the utility of this approach for Streptococcal bacteremia is unproven. The objective of this study was to evaluate the impact of RDT with real-time ASP intervention on blood cultures growing Streptococcus spp. bacteremia over two 6-month periods. During the pre-RDT period, patients were prospectively followed by ASP who provided recommendations based on gram-stain and organism identification results. During the post-RDT period, blood cultures were tested by GenMark ePlex BCID-GP that identifies S. agalactiae, S. anginosis group, S. pneumoniae, S. pyogenes and Streptococcus spp. within 90 minutes which were reported directly to ASP for recommendations on antibiotic discontinuation, de-escalation, and additional diagnostic testing.Retrospective, observational study comparing patients with Table 1). The median ages were 58 and 56, 62% and 68% were men, and a total of 12% and 16% were immunocompromised. The mean qSOFA scores were 1.9 and 2. The most common Streptococcus spp. was S. mitis (figure 1). Prior to RDT, the median time to antibiotic de-escalation was 88 hours. Following implementation of RDT, median time to de-escalation was 42 hours (P=0.002). De-escalation to targeted therapy improved from 50% to 86% in post-RDT (P< 0.01). Transition to oral antibiotics increased from 14% to 30% (P=0.08). There were no differences in hospital re-admission or acute kidney injury. A trend toward decreased 30-day mortality was identified in the post-RDT period (P=0.06).94 patients were included in the analysis, 50 pre- and 44 post-RDT. Across cohorts, patient demographics, clinical characteristics, and severity of illness were comparable (Streptococcal bacteremia. We noted significant reductions in broad-spectrum antibiotic use and a trend towards lower mortality. Larger studies are needed to demonstrate the full potential of this approach.Our study highlights the impact of RDT with ASP intervention on clinical outcomes for patients with Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support


Graphene is a two-dimensional (2D) material with a single atomic crystal structure of carbon that has the potential to create next-generation devices for photonic, optoelectronic, thermoelectric, sensing, wearable electronics, etc., owing to its excellent electron mobility, large surface-to-volume ratio, adjustable optics, and high mechanical strength. In contrast, owing to their light-induced conformations, fast response, photochemical stability, and surface-relief structures, azobenzene (AZO) polymers have been used as temperature sensors and photo-switchable molecules and are recognized as excellent candidates for a new generation of light-controllable molecular electronics. They can withstand trans-cis isomerization by conducting light irradiation or heating but have poor photon lifetime and energy density and are prone to agglomeration even at mild doping levels, reducing their optical sensitivity. Graphene derivatives, including graphene oxide (GO) and reduced graphene oxide (RGO), are an excellent platform that, combined with AZO-based polymers, could generate a new type of hybrid structure with interesting properties of ordered molecules. AZO derivatives may modify the energy density, optical responsiveness, and photon storage capacity, potentially preventing aggregation and strengthening the AZO complexes. They are potential candidates for sensors, photocatalysts, photodetectors, photocurrent switching, and other optical applications. This review aimed to provide an overview of the recent progress in graphene-related 2D materials (Gr2MS) and AZO polymer AZO-GO/RGO hybrid structures and their synthesis and applications. The review concludes with remarks based on the findings of this study. Graphenarticles . It has perature ,11,12. GThe GO and RGO are used as supporting platforms for biological binding processes due to their ease of functionalization, non-covalent binding, and variable hydrophobicity ,14,15. B1, sp2, and sp3 [2 carbons  with relatively large surface areas exhibits novel properties and is used in different industrial sectors [Among different materials, carbon-based materials play an important role in civilization . Carbon, and sp3 . The dif and sp3 . Carbon  and sp3 . Carbon  sectors ,45,46,47 sectors ,50,51,52 sectors . Recent  sectors  on the f sectors ,56. Grap sectors . CNTs we sectors . In 1991 sectors  was the  sectors . CNTs, wOrganic dyes are one of the biggest families in the synthetic organic domain. For example, in the textile domain, the most common dyes can be classified in two ways: (i) based on their application characteristics or (ii) based on their main chemical structure ,61,62. TThe azobenzene family is the photochromic molecule capable of changing shape and polarity upon light irradiation. Azobenzene is a molecule able to change conformation from trans to cis upon light  and reveThis section discusses existing graphene-based materials that can serve as the basis for functionalization and GO syntheses available in the literature. Various functionalization methods for graphene and the azobenzenic functionalization of GO are also discussed.−1 (relativistic speed) [Graphene oxide, which has better oxidative characteristics than graphene, or nanoporous graphene (NPG) could be employed instead of graphene alone ,67. Becac speed) . Graphenc speed) . Graphenc speed) . Becausec speed) . Graphenc speed) . A schemc speed) .The functionalization of graphene and graphene derivatives has increased the number of potential applications of graphene-based materials. Covalent functionalization, non-covalent functionalization, substitutional doping of graphene, and hybridization with nanoparticles, nanowires, and other materials have been classified as functionalization modes based on the methods and materials used . These v4 and HNO3 to oxidize graphite. Hummer’s approach combines graphite, potassium permanganate, and H2SO4 in a solution. The conjugation of stacked graphene sheets is broken down into nanoscale sp2 graphitic domains surrounded by extremely disordered oxidized domains (sp3 C/C) and carbon vacancy defects when graphite is oxidized [There are two approaches:top–down and bottom–up, to synthesize GO. In thetop–down approach, physical methods such as mechanical/ball milling, sputtering, laser ablation, etc., are used. In chemical methods, there are two approaches such as chemical and green routes. It is necessary to define graphene composites before proceeding with the analysis. Graphene composites are any graphene-based materials that have been changed . The GO is the most well-known graphene composite material, produced via the chemical exfoliation of graphite. Graphene has been severely oxidized and contains a range of oxygen functions. Many theories ,78 have oxidized . The pheoxidized .4 with fuming HNO3) [2SO4, HNO3, and KClO4 [2SO4 and KMnO4. There are two ways to prepare RGO: chemical reduction and annealing at a high temperature. The most effective thermal annealing method [2 hybridized carbon atoms. Graphene can easily be converted to GO and RGO. G is hydrophobic, whereas GO is hydrophilic. As a result, GO is easily dispersible in water. GO contains aliphatic (sp3) and aromatic (sp2) domains, increasing surface interactions. A range of approaches for surface modification of graphene has been developed in response to the increased interest in employing graphene as a reinforcing filler in polymer matrices to construct multifunctional materials. The filler-matrix bonding interaction considerably impacts the final composite properties. Most dispersion processes result in non-covalent composites in which the polymer matrix and filler connect via relatively weak dispersion forces. To enhance stronger interfacial interaction, researchers are increasingly focusing on creating covalent connections between graphene-based filler and the supporting polymer. Graphene becomes best functionalized via sp2 stacking complexation or by inserting particular moieties on edge or basal planes (2-conjugated carbons [Hummers and Offeman  developeng HNO3) . The fornd KClO4 . Later, nd KClO4  developeg method  is thermg method ,90. Howel planes  due to t carbons .AZO chromophore has received extensive research as a molecular solar thermal storage material because of its ability to absorb light in the ultraviolet-visible range and release heat based on reversible isomerization . AZO preElectrostatic interactions between GOscis, a negatively charged material (carboxylate groups) on basal planes and edges , and theLi et al.  describeMost AZO-functionalized GO is mainly described for energy storage; very few investigations used the capability of AZO-GO for pollutant sensing and removal. The pesticide residues and metabolites in food, water, and soil are major issues. Fenitrothion (FT)  phosphorothioate) and modifying graphite pencil electrodes with AZO-GO displays excellent performance for the detection of these pollutants . The lowThe removal of bacteria from water is also of great interest, as the WHO declared in 2017 that ESKAPEE bacteria pose a serious public health problem . In thisA variety of photo energy conversion or storage devices may be made using photo-induced variations in microstructures, electrical characteristics, steric effects, and optical response of AZO moieties. AZO moieties functionalized with GO/RGO may reflect, prolong, and boost the optically controlled conductance, absorption, catalytic behaviour, and electrostatic response of the composite’s constituents. AZO-GO composites have many advantages: high quantum yields, charge transfer in nanoseconds at the interface, energy storage in chemical bonds, electrochemical catalytic activity, the regulated electrostatic environment surrounding carbon-conjugated structures, and ultrafast isomerization in a few picoseconds (10–12 s) . Table 1Photoswitches are molecules that alter structurally when exposed to light irradiation. Depending on the light irradiated wavelength, AZO can stay in two different isomeric forms, such as trans and cis. Its typical isomerization characteristics, including a moderate change in dipole moment, a low photobleaching rate, and a substantial conformational change, make it an excellent choice for the coupling counterpart in light-driven molecular switches. For instance, Kizhisseri et al.  found thH) and cis-to-trans thermal barrier (aE). RGO-cis-ortho-AZO remains thermally stabilized for a prolonged half-life (5400 h) through intramolecular hydrogen bonds, substantially longer than RGO-para-AZO (116 h). The RGO-para-AZO has a thermal storage capacity of 269.8 kJ kg−1 with a single intermolecular hydrogen bond, while RGO-ortho-AZO has a thermal storage capacity of 149.6 kJ kg−1 (44.55% less) with several inter- and intra-molecular hydrogen-bonds of AZO. The AZO-GO hybrid has the potential to use as energy storage material with the good thermal stability of cis-hybrid and substantial energy density of around 240 Wh kg−1 because of the lightweight structure and significant grafting density of AZO moieties, as stated by Pang et al. [−1 and 2230 Wkg−1, respectively. Optimizing molecular interactions with high-density, adjustable RGO-bis-AZO storage allows for the creation of solar-heat conversion materials. Luo et al. [−1 due to steric hindrance, intermolecular H-bonds, extended storage lifespan (52 days), and an outstanding cycling performance for 50 visible light-irradiated cycles at 520 nm, making substituted AZO-based graphene a stable, high-energy, and recyclable molecular solar thermal storage material. One of the key difficulties is developing multifunctional materials to harness solar energy as a sustainable resource. Solar thermal fuels have the potential to store solar energy in chemical bonds or structures and then release that energy as heat. AZO derivatives have a high potential for solar energy storage owing to their reversible isomerization, high light absorption, and thermal reversion regulated by steric structure and functional group. Feng et al.  developeg et al. . They deg et al. . Due to o et al.  reported2 g−1), AZO-GO materials have the potential to be used in electrochemical capacitors [Due to their inherent conductivity and extraordinarily high specific area  with AZO molecules can meet ever-growing and -challenging multifunctional system demands. Oxygen-containing groups on GO/RGO enable covalent and non-covalent composite synthesis, producing well-defined and customizable physical and chemical characteristics. These characteristics include increased quantum effects, effective charge transfer at the interface, electrostatic changes surrounding π-conjugated structures, optically controlled conductance, heat storage in chemical bonds, and steric conformation. These materials can be used in various devices such as photoswitches, photodetectors, phototherapy, molecular junctions, sensors, flexible photonics and electronics, solar thermal storage, smart devices, and biological-based recognition. In addition, these solar-powered materials might lead to eco-friendly, innovative, and sustainable goods. However, there are still some challenges, such as ensuring effective linkages between GO/RGO and AZO moieties, a comprehensive understanding of complex interactions between GO/RGO and AZO, low quantum and thermal storage yields of photoswitching isomers, modulating photochromic and electronic properties to enhance light sensitivity and shorten response time need to address for applying such multifunctional responsive materials with great success. A detailed analysis of the working process of GD-AZO composite materials, focusing on the molecular interaction between these structures, is also required to increase our understanding for future advancement.