This paper investigates the electrical performance of graphene-based on-chip spiral inductors by virtue of a physics-based equivalent circuit model. The skin and proximity effects, as well as the substrate loss effect, are considered and treated appropriately. The graphene resistance and inductance are combined into the circuit model. It is demonstrated that the electrical characteristics of the on-chip square spiral inductor can be improved by replacing copper with graphene. Moreover, graphene exhibits more effectiveness in improving the inductance in tapered inductors than uniform ones. With the improvement of CMOS technologies, radio-frequency integrated circuits (RF ICs) have become possible and have drawn increasing attention in the past decades. To make RF ICs lightweight, multi-functional, and low-cost, on-chip spiral inductors with high inductance density and low power consumption have been widely utilized in the design of low-noise amplifiers, voltage-controlled oscillators, and filters . In order to improve the inductor performance, it is intuitive to pursue high inductance density and quality factors. There are various factors affecting inductor characteristics, such as substrate resistivity and metal thickness. Increasing metal thickness can improve the quality factor by minimizing Ohmic losses but is counter-productive at high frequencies due to accentuated proximity effect loss . The magTo facilitate the miniaturization of RF ICs, the scaling down of on-chip spiral inductors is inevitable . HoweverCarbon nanomaterials, including carbon nanotube (CNT) and graphene, have been proposed as promising alternative candidates for interconnected applications. They have been demonstrated to have unique physical properties such as a long mean free path (MFP), extremely high ampacity, and large thermal conductivity, and they exhibit superior performance and reliability to traditional metal wires ,7,8,9. MThis paper aims to provide a simple circuit model for investigating graphene-based inductors. Firstly, the equivalent circuit model of an on-chip tapered spiral inductor is developed, with the proximity effect and substrate loss taken into account. The quantum contact resistance, scattering resistance, and kinetic inductance of graphene ribbon (GR) are combined into the model to explore the electrical characteristics. By virtue of the circuit model, the electrical performance of graphene-based inductors is investigated, with some guidance provided for future development. The rest of this paper is organized as follows. On-chip spiral inductors can be divided into rectangular, square, circular, hexagon, and octagonal types according to their geometries. Due to their simple configuration, square spiral inductors are widely used in the design of RF ICs, as shown in ance RSi . To obtaThe dc resistance of a spiral inductor is calculated byrefer to . Furtherrefer to (4)d=Ldcy effect . The oxide and silicon capacitance are calculated byY-parameters and plotted in To evaluate the circuit model, a set of square spiral inductors are simulated using a full-wave electromagnetic simulator, i.e., ANSYS HFSS . In the simulation; the silicon conductivity is 10 S/m, and the geometrical parameters are as follows: It is evident that the results obtained by the circuit model agree well with the simulated results. The uniform spiral inductor possesses smaller dc resistance than the tapered one but has larger high-frequency resistance due to skin and proximity effects. The effective inductance of the spiral inductor can be increased by introducing tapering, and therefore, the quality factor can be improved. According to Faraday’s law of electromagnetic induction, the current change in the metal turns of a spiral inductor produces time-varying magnetic flux. As the magnetic flux is proportional to the inductor area, the decreased size degrades the inductance density, thereby limiting the scaling of RF ICs. Kinetic inductance, which originates in the kinetic energy required by mobile charge carriers in alternative electromotive force, is usually ignored in conventional metals due to their small relaxation time and large conducting channel number . Howevernsidered . The cornsidered (10)Nch=fficient . The kinetic inductance of a single-layer GR is given by (11)LK≈8It is worth noting that graphene tends to graphite as the layer number increases . HoweverAs shown in mated as (12)RS≈1formance . As showformance . It is wAlthough an anomalous skin effect exists in GR due to the large ratio of in-plane to out-plane MFP, it mainly appears as the operating frequency exceeds several tens of gigahertz . TherefoThe effective width in depth . The effNote that the width in both the numerator and denominator cancel out, and the effective conductivity would be irrelevant to the width. Therefore, the conductivity can be treated as a constant for a specific GR line in the modeling of graphene-based inductors. By utilizing the above equations and circuit model shown in For graphene-based on-chip spiral inductors, the inductance mainly comes from the magnetic inductance and the kinetic inductance, which originates in the kinetic energy required by mobile electrons, and its value depends on the number of conduction channels. In order to characterize the influence of kinetic inductance, the inductances of copper and graphene-based on-chip spiral inductors made of copper and graphene are plotted in 5, Br2, FeCl3, and KI are continually being investigated [2-doped graphene becomes lower than that of bulk copper, and the Fermi level reaches 0.5 eV [2-doped graphene are considered, i.e., the conductivities are set as 5 × 107 S/m and 108 S/m, respectively. In general, graphene doping can increase the Fermi level and thereby decrease the resistive loss. Moreover, the coupling effect between adjacent graphene layers can be alleviated and finally cancelled by intercalation doping. Therefore, alternate dopants such as AsFstigated ,22. Amons 0.5 eV . Here, t2-doped graphene are plotted in 7 S/m, the quality factor of a graphene-based spiral inductor is slightly lower than that of its copper counterpart. However, as the graphene conductivity exceeds 108 S/m, the quality factor can be significantly improved due to the reduction of metal resistive loss. By virtue of the circuit model in Further, the parametric study of graphene-based on-chip spiral tapered inductors was conducted. The influence of thickness on the inductor characteristics is shown in In summary, the graphene-based on-chip square spiral inductors are investigated by virtue of the circuit model. Although graphene possesses large kinetic inductance, its advantage over copper becomes significant only when the inductor dimensions are smaller than a certain value. This is, the area of the nanoscale inductor can be reduced by replacing copper with GR. On the other hand, the conductivity can be increased by employing doping techniques, thereby improving the inductor quality factor. However, the simulation is realistic, and much effort should be devoted to the fabrication of high-quality GRs. In this paper, the ultimate electrical performance of graphene-based spiral inductors was investigated theoretically. The equivalent circuit model of a traditional on-chip spiral inductor was developed and verified. The graphene kinetic inductance was combined into the model, and the electrical characteristics of on-chip spiral inductors made of copper and graphene were captured and compared. In the modeling procedure, it was found that the quantum contact resistance has little influence on the inductor performance. Graphene could be superior to its copper counterpart for building inductors when the geometry is very small, indicating that graphene is more suitable for future nanoscale RFICs. Moreover, a tapered spiral inductor could better play the advantage of graphene than a uniform one, as the inner ring has larger kinetic inductance. Although graphene possesses high kinetic inductance, the quality factor of the graphene-based inductor may be limited by its resistive loss, and therefore, the intercalation doping technique should be pursued. By virtue of the circuit model, the influences of geometrical parameters on the performance of graphene-based on-chip spiral inductors were finally explored, with several design guidelines provided.


In recent years, terahertz waves have attracted significant attention for their promising applications. Due to a broadband optical response, an ultra-fast relaxation time, a high nonlinear coefficient of graphene, and the flexible and controllable physical characteristics of its meta-structure, graphene metamaterial has been widely explored in interdisciplinary frontier research, especially in the technologically important terahertz (THz) frequency range. Here, graphene’s linear and nonlinear properties and typical applications of graphene metamaterial are reviewed. Specifically, the discussion focuses on applications in optically and electrically actuated terahertz amplitude, phase, and harmonic generation. The review concludes with a brief examination of potential prospects and trends in graphene metamaterial. Terahertz radiation (0.1 THz–10 THz) is situated between microwave and infrared light, possessing the properties of photonics and electronics ,3,4,5,6.A wide variety of active materials have been used for terahertz applications, including traditional bulk semiconductor materials, two-dimensional materials, phase-change materials, and liquid crystal materials, which are easily modulated when the carrier concentration is under externally applied electrical or optical stimulus. Graphene stands out due to its easy integration and its unique properties over a broad spectrum, especially in the terahertz band. ,8,9,10. Metamaterials is a rapidly developing direction that has been extensively boosted to metasurfaces and meta-atom structures ,30,31,32This review aims to discuss the development of terahertz metamaterial devices utilizing graphene. 2/ℏc . T. T65]. TA two-dimensional material heterostructure can also compensate for the defects of traditional materials, exhibiting a strong light–matter interaction. Weis et al. designed an optically controlled modulator based on a graphene–silicon heterostructure . CompariThe graphene and the metamaterial combination present an effective solution to achieving tunable phase shift. Balci et al. applied graphene capacitors integrated with metallic SRRs, demonstrating a novel electrically tunable phase modulator . The graCompared with the phase shift induced by resonance, the Pancharatnam–Berry (PB) phase comes from the rotation angle of the structure. Ding et al. designed a metasurface based on the PB phase to modulate the phase of the cross-polarized transmitted wave . The phaOther patterned graphene structures, such as graphene nanoribbons and graphene split rings, have also been investigated to achieve phase modulation. Lu et al. proposed the monolayer graphene as nanoribbons, exploring a significant phase modulation of graphene . The surIn contrast to the transmissive modulator, a metallic mirror is added below the dielectric substrate in the reflector phase modulator. Therefore, the incident wave propagates in a multi-path between the top and the bottom layers, resulting in resonance on the top metasurface and the bottom reflector for a large phase modulation range. Kakenov et al. placed the monolayer graphene on the metal plate, which operates as a back reflector and gate electrode . The gatSun et al. proposed another graphene coupling structure composed of multiple resonance modes to attain a more extensive depth, including dipole resonance, LC resonance, and SRR resonance , as showZhang et al. also realized a broadband phase modulator based on the graphene–metal hybrid structure . The metIndependent of resonant structure, Chen et al. designed a graphene metasurface based on the tunable Brewster angle with a high modulation depth and a large bandwidth , as showOwing to its high-quality mechanical flexibility, good thermal conductivity, and ultra-high carrier mobility, graphene has excellent potential for wideband photodetection in the terahertz band. The core principle of the photodetector is to convert the incoming light signal into an electrical signal, which means that the conductivity of the material changes during the process. Several different mechanisms by which this can be accomplished in graphene have been reported, mainly including the photovoltaic effect (PVE) , the phoIt is worth noting that graphene shows high wave locality, and it supports the propagation and the dynamic tunability of surface waves. Therefore, graphene can be regarded as a very encouraging platform for integrated optoelectronics of terahertz antennas, such as resonant antennas ,95, hybrhene FET . Figure 2/glass-to-graphene heterostructure synthesized by a layer-by-layer transfer technique [2 and graphene significantly improved the charge transfer efficiency in the device. Meanwhile, the results showed that the band arrangement of layered heterostructures can be controlled by lattice engineering of 2D nanosheets to improve the photoelectric properties. Similarly, Guan et al. showed that heterojunction formation by doping graphene could improve the light-detection capability of detections in their device based on ferroelectric polarization of In addition to the coupling efficiency mentioned above, detectors made of single materials tend to have powerful dark currents, resulting in a large NEP and a low detection rate. Graphene combines with other 2D materials to form an interlayer van der Waals heterostructure. The high-energy potential barrier formed can effectively inhibit the disorderly motion of photoelectrons to reduce dark noise. Related work has made remarkable progress across a broader spectrum. Xu et al. proposed a photodetector with a few-layer MoSechnique . The ohmf LiNbO3 . The detf LiNbO3 ,110. Caof LiNbO3 .Other methods, such as defect engineering , improveIn addition to improving the performance parameters of the detector itself, an urgent challenge is how to apply it to the existing communication systems and achieve multi-platform compatibility without affecting the excellent performance of devices. Asgari et al. proposed an efficient optical detection method for monocrystalline and polycrystalline graphite, which was based on chemical vapor deposition (CVD) growth, with equivalent noise power < 1 perature . Tuning perature . Under caveguide , a high-Compared with the graphene THz devices mentioned above, graphene-based THz generation is still in a much earlier stage. Because the traditional THz radiation equipment is complicated and expensive, the generation of THz is significantly more challenging than generating more extended wavelength sources (microwaves). −1, 10−2, and 10−3, respectively, in the normalized spectral amplitude for 0–2.5 THz  , BP 158158, and


We present a simple dual band absorber design and investigate it in the terahertz (THz) region. The proposed absorber works in dual operating bands at 5.1 THz and 11.7 THz. By adjusting the graphene chemical potential, the proposed absorber has the controllability of the resonance frequency to have perfect absorption at various frequencies. The graphene surface plasmon resonance results in sharp and narrow resonance absorption peaks. For incident angles up to 8°, the structure possesses near-unity absorption. The proposed sensor absorber’s functionality is evaluated using sensing medium with various refractive indices. The proposed sensor is simulated for glucose detection and a maximum sensitivity of 4.72 THz/RIU is observed. It has a maximum figure of merit (FOM) and Quality factor (Q) value of 14 and 32.49, respectively. The proposed optimal absorber can be used to identify malaria virus and cancer cells in blood. Hence, the proposed plasmonic sensor is a serious contender for biomedical uses in the diagnosis of bacterial infections, cancer, malaria, and other diseases. The extraordinary qualities of graphene have inspired investigators to learn more about its many potential uses ,2,3. The2O3 layer between two patterned graphene layers, four narrow absorption peaks are achieved. However, the bands have a large full width half maximum (FWHM) range, and the patterned graphene is more difficult to fabricate than the graphene sheet. In [Numerous graphene based absorbers have been proposed with multilayer structures and wideband absorption. One of the strong interactions that has recently been included into the metasurface system is bound states in the continuum (BIC), which is capable of encapsulating electromagnetic wave energy in the metasurface without radiation leakage . To lessheet. In , using dheet. In . Howeverheet. In  that it heet. In . The proWith this motive, some THz sensors have been proposed using graphene  and usin2 substrate with a thickness of 3 In this study, a rather simplistic and compact absorber structure with a dual absorption peak for sensing applications is suggested. A single layer of graphene and an incredibly thin layer of SiO2 substrate with thickness In this section, the proposed absorber unit cell structure is depicted with a single sheet of graphene and four small sized gold bars.  εr=2.25 . Hence,  εr=2.25 ,37. The  εr=2.25 ,39. To l6×107S/m  is used.2 is due to the high conductivity of the graphene.2 layer. As shown in the z-axis. To excite the GSPs, the incident wave’s electric field is polarised in the x-direction at the graphene-substrate interface. Due to GSPs and incident wave interaction, perfect absorption is achieved by graphene. Furthermore, the high confinement of GSPs makes the Fabry-Perot cavity resonance strong and results in the perfect absorption by the proposed absorber. The Kubo’s formula can be used to estimate the conductivity of the graphene as follows:The Fabry-Perot cavity between gold layers and graphene traps the incident wave that passes through SiOion time . Graphenion time . Using [ion time , the graThe proposed gold metasurface based absorber for sensor application is simulated using CST Microwave Studio software based on three dimensional (3D) FDTD techniques. The unit cell’s z-direction is surrounded by an open boundary condition, whereas, in the factor Q ,42,43, tFurther, to evaluate the dependency of resonance frequency on structural parameter and to produce the optimized design, parametric analysis has been carried out. The proposed absorber will have a perfect absorption if the Fabry-Perot cavity resonance is coupled to GSP resonance. This can be achieved through the optimal selection of orted in  that, thAs mentioned, Hence, The impact of incidence angle on the absorption spectrum is seen in The frequency shift of the proposed sensor depends on the analyte thickness. It can be seen from FWHM is full width at half maximum. The refractive index of water is Sensing quality of THz sensors can be measured by two main parameters, sensitivity w=1.3594 . For theAround 250 million individuals worldwide contract malaria each year, making quick malaria screening essential . A healtThe proposed sensor can be fabricated using standard techniques. Additionally, because it has undergone extensive research, the recommended sensor has the capacity for ultra-high sensing for a variety of applications, including the detection of water contaminants or the detection of malaria.In 2 substrate. Other strategies and approaches for producing graphene with dimensions less than a nanometer have been researched and are presented in [Recent fabrication and reporting of several biosensors based on metamaterials demonstrates a strong agreement between the results of simulation and measurement ,51,52. Tented in .In this study, we suggest a THz absorber for sensor use. Due to the confinement of the graphene surface plasmon, the suggested absorber exhibits an extremely precise and condensed absorption peak. The simulation findings demonstrate the response’s tunability by adjusting the graphene chemical potential, which aids in having a perfect absorption at a specific frequency. Additionally, it is demonstrated that the response is insensitive to the angles of incidence up to 80°. With a high sensitivity of 4.72 THz/RIU, FOM of 13.88, and high Q value of 32.49, the proposed absorber can be a suitable candidate for bio-medical applications. This sensor is a suitable choice for THz sensing, such as glucose detection and malaria illness diagnosis, because of its simple design, ease of production, and good responsiveness.


MAPK3, P-ERK was measured. P-ERK is decreased in hyperproliferative but increased in hypoproliferative NPCs. While these P-ERK changes are not responsible for the phenotypes, P-ERK and bFGF response are inversely correlated with the defects. Finally, we analyzed iPSCs and discovered that 16pDel displays hyperproliferation, while idiopathic iPSCs were normal. These data suggest that NPC proliferation defects are common in ASD.Neural precursor cell (NPC) dysfunction has been consistently implicated in autism. Induced pluripotent stem cell (iPSC)-derived NPCs from two autism groups (three idiopathic [I-ASD] and two 16p11.2 deletion [16pDel]) were used to investigate if proliferation is commonly disrupted. All five individuals display defects, with all three macrocephalic individuals  exhibiting hyperproliferation and the other two I-ASD subjects displaying hypoproliferation. NPCs were challenged with bFGF, and all hyperproliferative NPCs displayed blunted responses, while responses were increased in hypoproliferative cells. mRNA expression studies suggest that different pathways can result in similar proliferation phenotypes. Since 16pDel deletes  •NPC proliferation defects are common in idiopathic and 16p11.2 CNV-deletion ASD•All macrocephalic I-ASD and 16pDel individuals have hyperproliferative NPCs•NPC proliferative responses to bFGF correlate inversely with P-ERK levels•Both NPCs and IPSCs derived from 16pDel individuals exhibit hyperproliferation In this article DiCicco-Bloom and colleagues show proliferation defects in neural precursor cells from idiopathic and 16p11.2-deletion forms of autism. Those exhibiting macrocephaly were hyperproliferative, while two idiopathic individuals displayed hypoproliferative phenotypes. Interestingly, 16pDel individuals also exhibited iPSC-hyperproliferative defects. These findings suggest that dysregulated proliferation may be a common phenotype in multiple forms of autism and span developmental stages. Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by difficulties with social interactions and communication and the presence of repetitive and restricted behaviors. Most ASD cases are idiopathic, having no known genetic cause, and only 15%–20% of ASD cases are caused by known mutations such as copy number variants (CNVs) or monogenic mutations . AlthougMAPK3, which encodes ERK1. Both the deletion and the duplication are correlated with increased autism risk  subgroups, while the other individuals exhibit hypoproliferation. Interestingly, the proliferation phenotype is inversely correlated with P-ERK levels and response to basic fibroblast growth factor (bFGF), a mitogen that stimulates the ERK pathway. In examining whether proliferation dysregulation is specific to the cells of the brain, we find that the I-ASD cohort shows no differences in their iPSCs. In contrast, iPSC proliferation in 16pDel ASD subjects parallels the increases seen in NPC proliferation. In aggregate, our findings suggest that idiopathic and 16pDel subgroups share a common phenotype of dysregulated NPC proliferation that for our datasets is inversely correlated with P-ERK levels and bFGF stimulation.To generate an I-ASD dataset, male autism probands and sex-matched, unaffected siblings from three families were chosen from the larger New Jersey Language and Autism Genetics Study (NJLAGS) A Bartle, 2014. NFor the 16pDel cohort, we selected from RUCDR Infinite Biologics the only two deletion males diagnosed with autism by the Simons VIP cohort for whom iPSCs were created see . Both maFor each subject, multiple iPSC clones were generated. To ensure pluripotency and quality control, iPSC lines were karyotyped and assessed for expression of molecular makers of pluripotency . A minim3H]thymidine labeling, S-phase labeling index, cell enumeration assays, and apoptotic marker cleaved caspase-3 immunocytochemisty (ICC). Using this strategy, we found that all I-ASD subjects display NPC proliferative differences compared with unaffected sibling controls. I-ASD individuals from two different families (families 1072 and 1012) exhibited reductions in NPC proliferation, whereas in the third macrocephalic ASD subject (family 1077), NPCs exhibited an increase in proliferation.To rigorously define proliferation in human NPCs, we employed a multi-tiered strategy consisting of simple and reproducible assays followed by more in-depth analyses to further characterize neurogenesis. We examined multiple measures of cell proliferation and cell death: total DNA synthesis by [3H labeling , comparing multiple separate derivations of NPCs derived from four sibling iPSC clones with those from five ASD iPSC clones. The ASD NPCs exhibited a significant 65% reduction in DNA synthesis at 48 h by labeling A. To seelabeling B. In exalabeling C, and AS at 24 h D. These Similar to family 1072, ASD-1012 NPCs also exhibited a decrease in DNA synthesis, by 20% at 48 h E, and a In marked contrast to these two hypoproliferative families, macrocephalic ASD-1077 NPCs displayed a 60% increase in DNA synthesis I that waIn sum, all I-ASD NPCs display a proliferation phenotype (two hypoproliferative and one hyperproliferative) compared with their respective sibling. Notably, all three I-ASD individuals are not related to one another and remain genetically undefined, yet they converge on proliferative defects.To inquire if NPC proliferation is also altered in the 16pDel cohort, we compared NPCs from the 16pDel individuals with two sex-matched genetically typical controls. Both 16pDel individuals are macrocephalic and exhibit a significant increase in DNA synthesis at 48 h A. Specif+ cells compared with NIH controls at 24 h , that is required for normal control of cortical progenitor proliferation . FollowiIn contrast, ASD NPCs that exhibited hypoproliferation (I-ASD-1072 and -1012) displayed an increase in DNA synthesis sensitivity and response to bFGF stimulation D and 4E.ID2 and METRN) compared with sibling controls . A multiplex, high-throughput Quantiplex panel was developed for 21 genes that are used as markers for human NPC proliferation. NPCs from the two I-ASD families with the greatest differences in proliferation (families 1072 and 1077) were examined. Family 1077 revealed no significant changes A, while controls B. In concontrols C and 5D. markers  and S3 aMAPK3, which encodes ERK1. Given that ERK signaling affects cell growth and proliferation, we measured levels of phosphorylated and total ERK1 protein. We first examined NPCs with a hyperproliferative phenotype. As expected, NPCs from both 16pDel individuals exhibited a 50% reduction in total ERK1 protein and P-ERK1 . Interestingly, the opposite signaling pattern was observed: a 50% increase in the levels of both total and normalized P-ERK1 . We titrFinally, we assayed for proliferation phenotypes in additional cell types such as iPSCs. Interestingly, none of the three I-ASD iPSCs displayed significant changes in DNA synthesis at 48 h A nor in In contrast, proliferation of the iPSCs from the two 16pDel individuals exhibited increased DNA synthesis at 48 h, with 16pDel-1 increasing by 360% and 16pDel-2 by 148% C. This iIn this study, we employed a rigorous approach to assess neurogenesis utilizing 53 NPC derivations from 24 distinct iPSC lines of 10 individuals, to compare the proliferation phenotypes between an idiopathic ASD subgroup and the genetically defined 16pDel model. Proliferation defects were observed in all five ASD NPC lines across both subgroups, which is interesting in light of their clinical and genetic heterogeneity. We also uncovered hyperproliferation defects in macrocephalic individuals from both subgroups, with this study being the first to report proliferative defects in 16pDel NPCs. These data suggest that dysregulation of proliferation is a common defect in ASD, manifesting as either “too little” or “too much.”Our proliferation results are supported by other studies. Proliferation defects have been reported previously using iPSC-derived NPCs for both idiopathic ASD and other CNVs, such as 7q11.23 . For exaWhile we observe consistent proliferation phenotypes, the cellular mechanisms are likely to be different between subgroups and ASD individuals. I-ASD NPCs from two families  with normal head circumference exhibited significantly decreased proliferation. Family 1072 NPCs demonstrated a much greater decrease in proliferation that was paralleled by a reduction in S-phase entry and an increase in cell death, while for family 1012, a smaller decrease in proliferation correlated with a significant increase in cell death, with no difference in cells engaged in S phase. Understanding the mechanisms responsible for the decrease is an issue for future study.Importantly, our results also add to the mounting evidence that autism NPCs from those with macrocephaly exhibit a hyperproliferation phenotype. While macrocephaly is well described in individuals who carry the 16pDel, this is the first evidence that their derived NPCs exhibit a proliferation phenotype. While both males have the same CNV deletion, they exhibit differing levels of increased proliferation, highlighting the heterogeneity of autism even within a genetically defined subgroup. Although the macrocephalic I-ASD family 1077 individual also displayed hyperproliferation, the mechanism is likely different. Indeed, compared with respective controls, family 1077 NPCs had no changes in the levels of P-ERK1 nor in NPC molecular markers, while 16pDel exhibited many mRNA differences and decreased P-ERK. Further, our findings of increased proliferation in 16pDel NPCs are in contrast to a previous study that did not find changes in proliferation or S-phase entry . While eThe idea that either too little or too much of a neurodevelopmental process may contribute to autism neuropathogenesis has broad support across multiple studies. For example, both deletion and duplication lead to neurodevelopmental phenotypes of Rett syndrome and MECP2 duplication syndrome ; the FXSNPCs from all idiopathic and 16pDel ASD cases displayed altered mitogenic responsiveness to bFGF, an important regulator of neurodevelopment . NotablyMAPK3 gene has been suggested to contribute to the head size changes in 16p11.2 individuals  and others have identified calcium and MAPK signaling as central nodes in ASD . Mutatioividuals .MAPK3/ERK1 deletion in the 16p11.2 CNV phenotype, we examined potential contributions to ASD NPC proliferation by measuring P-ERK1/2 protein levels. Our studies indicate that in four of the five ASD individuals, the absolute levels of P-ERK1 correlated inversely with the levels of NPC proliferation. In hypoproliferative I-ASD NPCs, we observed increased levels of P-ERK1 protein at baseline, a change that may underlie their increased sensitivity to bFGF stimulation. Conversely, in hyperproliferative NPCs from 16pDel individuals, we observed ∼50% reduction in P-ERK1 levels, as expected given the hemizygous genetic status of CNV deletion carriers. This reduction in absolute P-ERK1 protein levels may potentially contribute to the blunted responses to bFGF in the 16pDel cohort. It is notable that, unlike the 16pDel mouse model  as detailed in 3H labeling, cell counting, EdU, and activated caspase-3 ICC) were performed as detailed in Proliferation and apoptosis assays (6 cells/dish) from passages P3 to P8 were plated in 35 mm dishes and analyzed at 48 h  was designed and ordered through Invitrogen and used with standard protocols on triplicate samples see .Statistical Package GraphPad Prism version 7.0d  was employed. Statistical testing involved two-tailed Student’s t tests or two-way ANOVA with Sidak’s multiple comparison test where specified. Data are expressed as the mean ± SEM Outliers were determined with the ROUT test and removed from analysis. In each figure legend, the number of iPSC clones used, number of total NPC derivations, number of experiments, and number of wells are detailed for each individual. For all statistical tests, sample size was the number of individual data points including all technical and biological replicates .https://www.sfari.org/resource/simons-searchlight/) by applying at https://base.sfari.org.Approved researchers can obtain the Simons Searchlight population dataset described in this study (Conceptualization, J.H.M., E.D.-B., J.F., L.B., C.W.L., and Z.P.P.; methodology, J.H.M., P.M., P.L.Y., E.D.-B., and M.W.; formal analysis, M.W., R.C., S.P., P.M., P.L.Y., and M.M.; investigation, R.C., M.W., S.P., M.M., P.L.Y., C.W.L., A.M., C.P., X.Z., and C.R.M.; writing – original draft, M.W., R.C., M.M., J.H.M., and E.D.-B.; visualization, M.W., R.C., S.P., and M.M.; writing – review & editing, M.W., R.C., M.M., J.H.M., and E.D.-B.; funding acquisition, J.H.M. and E.D.-B.; resources, J.F., L.B., C.W.L., and P.L.Y. created and validated all I-ASD and sib iPSC lines used in this study, and NPC lines were generated by P.L.Y., P.M., M.M., S.P., M.W., and R.C.; supervision, J.H.M., E.D.-B., P.M., and C.W.L.The authors declare no competing interests.


A wide variety of transition metals, including copperand gold,have been successfully used as substrates for graphene growth. Onthe other hand, it has been challenging to grow graphene on silver,so realistic applications by combining graphene and silver for improvedelectrode stability and enhanced surface plasmon resonance in organiclight-emitting diodes and biosensing have not been realized to date.Here, we demonstrate the surface passivation of silver through thesingle-step rapid growth of nanocrystalline multilayer graphene onsilver via low-temperature plasma-enhanced chemical vapor deposition(PECVD). The effect of the growth time on the graphene quality andthe underlying silver characteristics is investigated by Raman spectroscopy,X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy(XPS), and cross-sectional annular dark-field scanning transmissionelectron microscopy (ADF-STEM). These results reveal nanocrystallinegraphene structures with turbostratic layer stacking. Based on theXPS and ADF-STEM results, a PECVD growth mechanism of graphene onsilver is proposed. The multilayer graphene also provides excellentlong-term protection of the underlying silver surface from oxidationafter 5 months of air exposure. This development thus paves the waytoward realizing technological applications based on graphene-protectedsilver surfaces and electrodes as well as hybrid graphene-silver plasmonics. For instance, it hasbeen challenging to produce highly oriented pyrolytic graphite toan areal dimension larger than ∼ (0.1 × 0.1) m2. In the case of graphene growth, chemical vapor deposition (CVD)is a common scalable approach to achieve large-scale high-qualitygraphene synthesis. Common transition-metal substrates such as Ni2 and Cu3 are used alongwith high processing temperatures to pyrolyze hydrocarbon moleculesto activate CVD graphene growth.4 Othertransition-metal substrates such as Ag,5 Au,7 Pt,8 Ru,9 and Co10 have beenreported for CVD graphene synthesis.The unique electronicand optical properties of graphene have stimulatedan extensive range of scientific research and technological applications.Additionally, multilayer graphene may be regarded as an alternativeto graphite in many graphite-related applications with the benefitsof much better scalability in the lateral dimensions11 In addition, substratesinvolving temperature-sensitive materials such as polymers would bedamaged under high-temperature processes, preventing their applicationsfor flexible materials.12 Moreover, thecurrent industrial trend of net zero carbon emission by 2050 makesthe high-temperature process unfavorable due to high energy consumption.Research progress has been made to reduce the growth temperature forCVD graphene. For instance, a growth temperature of 100 °C hasbeen reported through the use of a benzene precursor.13 Moreover, near-room-temperature growth has been demonstratedby utilizing liquid metal nucleation.14 Despite the fact that these novel approaches have greatly reducedthe growth temperature, they require sophisticated processing stepsthat are incompatible with industrial processes and large-area production.15One of the drawbacks ofCVD graphene growth is that it is a high-temperatureprocess, typically close to the melting points of the metal foils.Under such conditions, aged quartz furnaces and evaporated metal couldlead to contamination.16 have further loweredthe required temperatures for PECVD growth of graphene by forced convectionto increase the reaction probability of excited species or radicalson the substrate surface before their recombination. To date, thereported growth temperatures for various PECVD graphene synthesismethods are found to range from 160 to 700 °C on various substrates.22On the other hand, a scalable and industrially compatibleprocessfor low-temperature graphene growth is the plasma-enhanced CVD (PECVD)method. The key factor that allows PECVD to reduce growth temperaturelies in the plasma, which contains reactive species to promote growth.Recently, Kim et al.23 This problemmay be mitigated by the combination of graphene with silver, whichhas been reported to increase the stability of the silver nanowireelectrodes24 and theoretically predictedto enhance the SPR sensitivity while preventing oxidation.23 On the other hand, the inert nature of silverhas made it difficult to be used as a substrate for graphene growthwith the standard CVD techniques. Among the limited reports of graphenegrowth on silver, one approach involves evaporating atomic carbononto the surface of a single-crystalline Ag(111) substrate at elevatedtemperatures under ultrahigh vacuum conditions for in situ scanningtunneling microscopy studies.25 The otherapproach utilizes a high-temperature, atmospheric-pressure CVD processwith solid camphor as the carbon precursor and silver foil as thesubstrate in a gas mixture of Ar and H2.5 Despite these progresses, direct graphene growth on silverat low temperatures remains a challenging task.26Silver is commonly used as the electrode for organic light-emittingdiodes and in biosensing due to its strong surface plasmon resonance(SPR). However, silver is prone to oxidation, which would degradethe device performance.In this work, we show the viability of direct growthof nanocrystallinemultilayer graphene on a silver thin film via low-temperature PECVD,where the growth configuration involves flipping the substrate downwardso that the silver thin film faces away from the direct plasma. Thesuccessful growth of nanocrystalline multilayer graphene is confirmedby Raman spectroscopy. X-ray diffraction (XRD) studies of the silverthin films after the PECVD process further reveal the improvementof silver crystallinity. Studies by transmission electron microscopy(TEM) reveal that the resulting multilayer graphene is of turbostraticstacking. We further propose a growth mechanism of graphene on silverfrom studies of the X-ray photoelectron spectroscopy (XPS) and cross-sectionalannular dark-field scanning TEM (ADF-STEM) and demonstrate that XPSdata may be used as a nondestructive means to infer the average graphenethickness in agreement with the ADF-STEM results. Confirmed throughXPS, the surface of silver fully covered by the directly grown multilayergraphene exhibit no traces of oxidation after 5 months of ambientair exposure, which is in stark contrast to the XPS data of a controlledsilver surface without graphene coverage, implying perfect passivationof silver by the PECVD-grown multilayer graphene. The excellent protectionof silver from oxidation provided by PECVD-grown graphene and theimprovement of the underlying silver crystallinity after the PECVDprocess suggests that our approach paves ways toward realistic technologicalapplications of graphene-protected silver electrodes and surfacesas well as hybrid graphene-silver plasmonics.22.1The Ag substratein this work included a Si substrate covered with a 100 nm-thick Tiadhesion layer and a 500 nm-thick Ag thin film on top, both depositedvia an electron-beam (e-beam) evaporator.2.22SO4:H2O2 = 3:1 in volume) at room temperature. Afterward, O2 and H2 plasma were separately used to clean boththe quartz tube and the sample holders. The plasma system involveda microwave power source (Sairem) and an Evenson cavity. Prior toplasma ignition, CH4 of 1 sccm and H2 of 4 sccmwere added into the quartz tube with a total pressure of 100 mtorr.The Ag side of the Ag/Ti/Si substrate was flipped downward and placedon the sample holder before the PECVD process as shown in Before thePECVD process, the interior of the quartz tube was rinsed with nitricacid to remove potential silver residue, while sample holders werecleaned with piranha solution . Afterthe PECVD process, polymethyl methacrylate (PMMA) was spin-coatedon the silver samples covered with PECVD-grown graphene, which wasfollowed by silver etching with a gold etchant  inorder to transfer the graphene grown on silver to a SiO2.3α X-ray source and a hemispherical energy analyzer under a pass energyof 10 eV was used for the high-resolution scan, whereas a pass energyof 80 eV was used for X-ray induced Auger spectroscopy (XAES) of theC KLL Auger region. In addition, the XPS signal was used for estimatingthe graphene thickness, as elaborated in a later section. The instrumentwork function was calibrated with respect to the Ag 3d5/2 signal. Cross-sectional ADF-STEM and TEM plane view images wereacquired by aberration-corrected JEOL ARM-200F operated at 200 kV.Selected-area diffraction was performed using JEOL JEM2100F at 200kV. XRD (Rigaku Smartlab) was performed using Cu Kα radiation and a Ge (220) double-bounce monochromator for Kα2 elimination.Raman spectroscopiccharacterizations for graphene growth and quality confirmation weremade by using a Raman spectrometer  equipped witha 514 nm laser. Atomic force microscopy with PeakForce tapping mode was used for surface morphology characterization.XPS (Kratos Axis Ultra) with a monochromated Al K32 substrate with the transferred grapheneas shown in 2. Interestingly, despite very high I(D)/I(G) ratios for all samples, the distinct2D and 2D′ peaks indicated good graphene crystallinity of ourPECVD-grown graphene. The 2D and 2D′ peaks of graphene resultfrom intervalley and intravalley phonon scattering, respectively;neither has needs for defect activation.28 Therefore, one may expect that as the defect concentration increased,2D and 2D′ peaks would have become worse defined due to imperfectelectron dispersion, as demonstrated by Eckmann et al.29 In this context, had the high I(D)/I(G) ratios found in our graphene samples beenrelated to high defect concentrations, distinct 2D and 2D′peaks would not have existed.I(D)/I(G)]and the D-to-D′ Raman mode intensity ratio [I(D)/I(D′)], respectively.31 As shown in I(D)/I(G) ratio decreasedslightly with increasing growth time, which implied changes in thegrain size with growth time. The grain size of graphene L can be estimated by the I(D)/I(G) ratio through Elaser =2.41 eV. From I(D)/I(G) ratios suggest that the graphenegrown on silver thin films via our PECVD method was nanocrystalline.Meanwhile, as shown in I(D)/I(D′)ratio for different growth times was between 8 and 9, suggesting thatthe defect types were a mixture of sp3 bonds for I(D)/I(D′) = 13 and vacancy defectsfor I(D)/I(D′) = 7, althoughprimarily the vacancy type.30On the other hand, it is known that the grain sizeof grapheneand its defect types may be extracted by analyzing the D-to-G Ramanmode intensity ratio [I(2D)/I(G) may be used for determining the graphene thickness,with I(2D)/I(G) > 1 implyingmonolayergraphene. In addition, the full width at half-maximum (fwhm) of the2D peak may provide further information about the number of graphenelayers, with an fwhm of ∼24 cm–1 for single-layergraphene32 and of ∼50 cm–1 for bilayer graphene.34 However, turbostratic stackingof graphene could also give rise to Raman spectral characteristicssimilar to those of single-layer graphene. In this context, the I(2D)/I(G) ratio and the fwhm of the 2Dpeak for our PECVD-grown graphene on silver shown in A common perceptionin the Raman spectral analysis of grapheneis that the 2D to G peak intensity ratio 35 On the other hand, differentdoping levels of graphene could also lead to a spectral shift of thepeak position. As discussed by Lee et al.,36 the doping level and strain effect in graphene may be separatedby plotting the 2D peak position versus the G peak position. Followinga similar analysis, the 2D peak position versus the G peak positionof the PECVD-grown graphene on silver showed slightly hole-doped andslightly compressively strained, as demonstrated in Section S1.Besidesthe number of graphene layers and the grain size, Ramanspectroscopy could also shed light on the doping and strain of graphene.The spectral shift of either the 2D or G peak, along with the correspondingGrüneisen parameter, could be used to extract the strain effectof graphene.37To understand the effect of the flipped substrateconfigurationon the gas flow during the PECVD graphene growth, a computationalfluid dynamics (CFD) simulation was carried out. As shown in Figure S2 shows theAFM characterizationof the surface morphologies of a sample before and after the PECVDprocess. After PECVD graphene growth, the AFM image of the surfacemorphologies was still dominated by the underlying silver layer andrevealed a large coalesce of grains and facets, as shown in Figure S2a–c. In contrast, the silversurface before the PECVD process exhibited apparent granular structures,as shown in Figure S2d. The facet formationafter the PECVD process may be attributed to the stabilization ofgraphene on the metal surface.38 The increasedroughness after PECVD may be attributed to the coalescence of smallergrains, leading to a much larger grain boundary.Figure S3. The increased Ag (111) intensitycounts after PECVD for different growth times were all much greaterthan that before the PECVD graphene growth process. A similar peakintensity for all growth times was observed. Given that no activeheating source was involved in our PECVD and that the sample temperaturewas about 232–260 °C through plasma heating, which wasmuch lower than the melting point of silver (961.8 °C), the improvedcrystallinity of Ag (111) after the PECVD process when compared tothe reference sample may be attributed to the sufficient thermal energy12 provided by plasma activation. The improvedAg crystallinity could provide added benefits for silver plasmonicapplications.40Meanwhile,the changes in the crystallinity of silver after thePECVD process, as characterized through XRD measurements, are shownin 2 were also present. The Si 2pregion scans were carried out as shown in Figure S4, which confirmed the existence of SiO2 on thesurface. The origin of the SiO2 will be discussed in alater paragraph.The chemical changes inthe silver thin film quickly after thePECVD process were characterized via XPS as shown in Figure S5, which also confirmed the dominant contribution of sp2 carbon. Moreover, neither metal carbide formation41 nor bonding between the observed Si and graphene couldbe inferred from the absence of any apparent peak around the bindingenergy of 282–283 eV. The extent of hybridization of carbonmay be revealed by comparing the “D-parameter” in theC KLL Auger region, where the D-parameter is defined by the peak separationin the first derivative of the Auger spectrum;42 a larger D-parameter would indicate a higher sp2 hybridization percentage. Using the results from the XAES studies, we obtained the first derivativeof the spectra for different growth times shown in Figure S6e–g. In addition to the spectra of differentsamples before differentiation, the XAES of a graphitic referencehas been included in Figure S6d,h to validatethe data processing. As shown in Figure S6, the graphene sample with 15 min growth time exhibited the largest D value, suggesting a higher sp2 percentage thanthose samples with either 10 or 5 min growth time. This finding alsocorroborated the lower I(D)/I(D′)ratio shown in 3-like defects.The graphene formation on silver after PECVD wasfurther verifiedthrough XPS C 1s spectra as shown in I(D)/I(G) ratios in the Raman spectrum).ADF-STEM images as shown in 43 and by Cumpson et al. that suggested a “thickogram”graphical approach.44 Specifically, thegoverning equation for the thickogram is given byIo and Is are the integrated spectral area under thepeaks from the overlayer and the substrate, respectively; So and Ss are the corresponding relative sensitivity factors; Eo and Es are thekinetic energies of the overlayer element (carbon) and substrate element(silver), respectively; λo is the photoelectron inelasticmean free path, t is the overlayer thickness, and θ is the emissionangle. In this work, λo for graphene was 1.06 nm,42 and θ for the XPS system was 0°.Additionally, we note that the XPS spectra used for the thickogramanalysis must be recorded with the same number of scans and pass energy.Comparing the direct imaging of graphene layersby ADF-STEM withXPS characterizations, we investigate whether XPS studies may provideuseful information about the average number of graphene layers, similarto previous studies by Hill et al. that proposed to determine theoxide thin film thickness through XPSThe advancement of computational power since the graphical approachinitially proposed by Cumpson et al. has enabled the numerical computationof sample thicknesses based on the given XPS data. Using the XPS datataken on our PECVD-grown graphene on silver samples with differentgrowth times, we find that the extracted overlayer thicknesses for 15, 10, and 5 min growth times are 1.22, 0.55, and0.63 nm, respectively, which are in reasonable agreement with theADF-STEM imaging. Therefore, we have confirmed that XPS data may beused to infer the graphene thickness in addition to Raman spectroscopicanalysis and ADF-STEM imaging.46 the growth mechanism of graphene on silver is expectedto be similar to the surface adsorption mechanism on Au. In this contextand noting a previous work by Lu et al. on PECVD graphene growth onAu that demonstrated bilayer graphene growth for H2/CH4 ≥ 1 after 5 min,20 ourfinding of bilayer graphene growth on silver for the same growth time(5 min) with H2/CH4 = 4 appeared to be consistentwith the previous report.Based on the XPS and ADF-STEMdata, we hypothesize the PECVD graphenegrowth mechanism on silver, which is schematically shown in On the other hand, when the growth time was extendedto 10 and15 min, three or four graphene layers were observed. As shown in theADF-STEM images in 47 However, the penetration growth mechanism could not support graphenegrowth for more than bilayer due to the restricted penetration ofcarbon atoms,47 which contradicts our observation.It is worth noting that a penetration graphene growth mechanismhas been previously proposed by Wu et al.I(D)/I(G)ratios. However, higher plasma power would lead to more ejected Sispecies into the plasma and therefore the undesirable result of moreSi incorporation into the graphene layers during the growth. Thisconsideration therefore constrains the choice of plasma power duringthe PECVD growth of graphene on silver.Since the graphene growth temperature is dependent on the plasmapower, where higher power results in higher temperatures, it is conceivableto apply plasma power greater than 10 W to achieve larger graphenegrain sizes with smaller 45An important issue toaddress for the usefulness of our nanocrystallinemultilayer graphene is to evaluate its ability for surface passivationbecause the small grain sizes are accompanied by many grain boundaries,which may lead to compromised surface passivation because gas moleculescould pass through the grain boundaries and react with the underlyingsilver. Fortunately, we found that the multilayer nature and turbostraticstacking of our PECVD-grown graphene could compensate for the drawbackof many grain boundaries. 4In conclusion, we reporta low-temperature single-step method fordirect graphene growth on silver by PECVD for long-term surface passivation.Raman spectroscopic studies of the graphene-on-silver samples suggestedthat they consisted of nanocrystals with an overall good crystallinequality, underwent a slight compressive strain, and exhibited slighthole doping, with vacancies being the primary defects in the samples.Using CFD simulations, the benefit of using the flipped substrateconfiguration during the PECVD graphene growth was revealed. FromAFM and XRD characterizations, the silver surface morphology and crystallinityafter the PECVD process were found to differ from those before thePECVD process, with improved crystallinity after PECVD. The numberof graphene layers grown on silver was verified by cross-sectionalADF-STEM images, which varied from 2 to 4 layers depending on thegrowth time. The stacking order of the multilayer was confirmed throughTEM electron diffraction to be turbostratic. We further proposed amechanism for the PECVD growth of graphene on silver based on thefindings from the XPS and ADF-STEM studies and demonstrated that XPSdata may be used for the nondestructive thickness determination ofgraphene. Moreover, the multilayer graphene was found to protect theunderlying silver against oxidation for at least 5 months of ambientair exposure. The combined benefits of passivation and improved crystallinityof silver by PECVD-grown graphene imply that our approach paves theway toward scalable technological applications based on graphene-protectedsilver surfaces and electrodes as well as hybrid graphene-silver plasmonics.


Various prognostic biomarkers of disease progression  have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/cytostatic drugs/biologics.Many factors confirm the autoimmune nature of sarcoidosis and help in determining the strategy of patient management and treatment initiation. However, the causes and the mechanisms of disease progression that result in fibrosis and insufficiency of the affected organ remain unclear. This narrative review aims to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy. The following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with a genetic predisposition (SNP in genes GREM1, CARD15, TGF-β3, HLA-DQB1 According to the current concept, sarcoidosis occurs as a result of an exposure to various exogenous or endogenous antigens in subjects with a genetic predisposition to autoimmune disorders and is associated with the development of non-necrotizing granulomas in different organs .The search for etiologic factors of sarcoidosis has revealed various infectious agents  as well as non-organic factors  that could be associated with its development , 3. LongBased on the pathologic findings, sarcoidosis is currently believed to be a granulomatous disease that can be either acute, subacute or chronic and is most commonly (in >90% of cases) associated with the involvement of the lungs and mediastinal lymph nodes as well as other organs and tissues and the development of non-necrotizing granulomas , 5, 6. IThe aim of this review is to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy.The data for the narrative review were collected from the studies published in international databases MEDLINE, Current Contents, PubMed, Elsevier between 2001 and 2021 using the search words of “sarcoidosis, progression, pathogenesis, genetic markers, laboratory markers, treatment.” Inclusion criteria were original research with observation of patients with progressive sarcoidosis and comparison group (group without progression or the studied group before the progression), review articles and research articles on pathogenesis of sarcoidosis.The key feature of the pathogenesis of sarcoidosis is the formation of granulomas in the lungs, mediastinal lymph nodes, skin and other organs. In patients who are genetically predisposed to this disease, a contact of antigen-presenting cells  with an unknown foreign antigen results in the dysregulated immune response that is manifested as granulomatous inflammation . The maiMacrophages, dendritic cells and epithelial cells are the first cells to react with the antigens due to the presence of Toll-like receptors. Long-term exposure of Toll-like receptors to foreign antigens results in activation and epithelioid differentiation of macrophages, which then start producing pro-inflammatory cytokines . Having bound to the antigen, dendritic cells migrate to lymph nodes, where they present the antigen to T-lymphocytes. Further activation of immune cells involves various chemokines such as CCL5 (for Th1) and CCL2 (for Th2). Much attention has been recently paid to the role of Th17 lymphocytes in the pathogenesis of sarcoidosis. These cells are a CD4+ lymphocyte subset that express IL-17A and have pro-inflammatory or anti-inflammatory properties as a result of the local inflammatory environment. Granuloma macrophages in patients with sarcoidosis were shown to express CCR20 thus attracting Th17 cells, while IL-23 expression causes a significant increase in IL-17A concentrations , 14. Sinin vitro and in vivo models have also demonstrated the presence of M2 at the initial stages of granuloma formation. There is growing evidence of the role of mTOR signaling pathway in the granuloma formation demonstrated in studies of molecular mechanisms of macrophage dysfunction. The activation of mTORC1 in murine macrophages was shown to result in the disease progression and formation of granulomas just as in humans with progressive sarcoidosis  should be the main objectives of disease profiling determining future personalized therapeutic approaches .The development of a chronic disease is associated with individual characteristics of the immune system indicating the existence of some genetic predisposing factors. Several candidate genes have been described in literature:GREM1 encodes gremlin, a highly conserved glycoprotein, a member of the BMP antagonist family (Members of the TGF-β superfamily), including TGF-βs and bone morphogenetic proteins (BMPs). Heron et al.  15 gene (nucleotide oligomerisation domain (NOD)2) encodes an intracellular protein CARD15 of the NOD family. These proteins are involved in innate immunity through recognition of muramyl dipeptide, a component of bacterial cell wall peptidoglycan . It was p = 0.04; corrected p = 0.2; OR, 2.9)  .*06:02, HLA-DRB1*07/14/15 genotypes were associated with chronic sarcoidosis  pulmonary disease compared with the self-limiting group. Among these processes most significant changes were revealed in intracellular signaling (NF-kB and JAK-STAT cascades) and cell life  .In some cases when it is impossible to eliminate the pathogen or chronic autoimmune inflammation develops , 24–26, The causes of fibrosis are unknown. However, some characteristics have been described in patients with chronic sarcoidosis.Biopsy specimens obtained in patients with a progressive disorder demonstrated Treg with BTNL2 and ANXA11 mutations whose gene products have anti-inflammatory and immune regulatory properties. It is possible that Treg downregulate the effective inflammation and contribute to the development of chronic sarcoidosis , 29.The role of Th2 in the progression of sarcoidosis is being actively studied. It has been suggested that a transition from a Th1 to a Th2 cytokine signature may occur in chronic sarcoidosis, perhaps as a response to persistent inflammation . The patM2 macrophage polarization, as reflected by an increased CD163 expression, is associated with an enhanced antigen presentation within a select subset of regulatory T cells, leading to lower concentrations of IFN-γ and higher concentrations of IL-10 upon stimulation. Moreover, IL-13 has anti-inflammatory properties, including suppression of TNF-α release.IL-13 can stimulate macrophages to release TGF-β . In patiIL-13 and CCL2 secreted by Th2 were implicated in the pathogenesis of lung fibrosis models, including in idiopathic pulmonary fibrosis , 38 Tab. CCL2 prCCL18 has been directly implicated in fibrosis . CCL18 pM2 polarized macrophages preferentially express Arg1, which results is an increased arginase. Arginase metabolizes arginine to ornithine, a precursor for the collagen substrate proline . Th2 cytCytokines released during the granuloma formation and macrophage transformation directly activate JAK-STAT pathway, which supports chronic inflammation . High prThe current understanding of sarcoidosis progression is shown in M. Tuberculosis peptides, P. Acne, carbon nanoparticles). In various studies, mice have developed multiple areas of granulomatosis , which may indicate the features of the immune response in healthy mice, allowing for more effective elimination of pathogens. The granulomas observed in the experiment were shown to exist only if there was a continuous exposure to the adjuvant. We believe that sarcoidosis patients are chronically exposed by one or several triggers that contribute development and persistence of granulomas  knockout gene described the development of granulomas showing epithelioid-like macrophages, M2 macrophage polarization, and mTORC1 pathway activation . TSC2 doSome pathogenesis-related changes in the pulmonary tissue are accompanied by alterations in peripheral blood and bronchoalveolar lavage fluid in patients with progressive sarcoidosis. Accordingly, the observed correlation between some parameters and the development of granuloma inflammation in the tissues has revealed markers for sarcoidosis progression, namely increased levels of neopterin molecule synthesized from macrophages, sIL-2R marker of T-cell activation, chitotriosidase secreted by active macrophages, neutrophil-derived collagenase and elastase , and a lIncreased number of Th17 in peripheral blood  and highSome clinical characteristics such as extrapulmonary manifestations , composite physiologic index (CPI) - the index of lung function variables, which correlates with the degree of interstitial disease and CT measurements - the degree of fibrosis, enlargement of the pulmonary artery and the measures of diffuse lung carbon monoxide (DLCO) percentages were shown as markers of severity of pulmonary sarcoidosis , 55, 56.The use of Scadding radiographic stages can also predict the prognosis, the stage I disease was associated with the spontaneous resolution in 60 to 90% patients, while with an increase of stages the percentage of resolution possibility decreased (up to 0% in stage IV fibrotic disease) .The whole list of possible laboratory and clinical markers predicting the progression of sarcoidosis is presented in In some patients, sarcoidosis may be associated with a failure in the affected organ, which requires treatment. However, a substantial proportion of patients are likely to subsequently develop a chronic or progressive sarcoidosis, an estimated percentage of 10% to 20% of patients will have sequelae, and a fatal outcome is observed in 6–7% of cases . The aimRegulation of the immune response, as well as prevention of fibrosis due to suppression of the overactive macrophages, T-cells and cytokine  production can be the main approaches of the sarcoidosis treatment , 61.TNF-α, INF-γ) that contribute to the development of granulomas  . The mecanulomas , 64. Theanulomas .Recent studies have showed evidence for a role for humoral immunity in the sarcoidosis development indicating the possible use of anti-B-cell therapy. Therapy with anti-CD20 monoclonal antibody rituximab was associated with clinical improvement in sarcoidosis patients, which is most likely due to the role of “naive” and/or B- memory cells in the development of sarcoidosis –67. The The prescribing factor for these therapy could be the finding of autoantibodies on BAL or blood serum, such as autoantibodies to mutated citrullinated vimentin (anti-MCV) , 69, andvia IL4-independent pathways. Thus, the desirable anti-inflammatory effects of MTX are leveled by an increased risk of fibrosis . The main objective of the use of this group of drugs is to overcome the adverse effects of corticosteroids, taper their dose up to complete discontinuation (steroid-sparing effect). Methotrexate is the most commonly used second-line therapy agent. Methotrexate is a folic acid antagonist, which suppresses the production of TNF-α through adenosine A2A receptors, simultaneously inducing IL-4 and IL-13 that are up-regulators of M2 polarization. MTX can also polarize M0 to M2 fibrosis , 71.Leflunomide, a dihydroorotase inhibitor, can be used alone or in combination with methotrexate, including in patients with generalized, progressive disease or with incomplete effect from other therapy. Leflunomide affects the inflammatory process by inhibiting Th17 cells and activating Tregs . AzathioThe third line includes the use of biological targeted therapy . TargeteBased on the hyper-expression of JAK-STAT pathway in granuloma cells the JAK-inhibitors were used in the treatment of patients with different types of sarcoidosis. The cases of efficient use of tofacitinib and ruxolitinib were described in pateints with cutaneous , 83, mulThe described therapies can be beneficial for patients with weakened immune response, which can be diagnosed with the BAL or blood biomarkers, such as increased levels of neopterin, sIL-2R, chitotriosidase, neutrophil-derived collagenase and elastase , increasThe described algorithm of the pathogenesis-based therapy of sarcoidosis is presented on *06.02, HLA-DRB1*07/14/15) as a result of granulomatous inflammation following an antigen presentation in the lungs. It either causes immune system impairment or activates autoimmune disorders. Thus, the antigen elimination becomes impossible, and immune cells change their differentiation  during the chronic inflammation process and start producing cytokines  and enzymes (Arginase) resulting in fibroblast activation and the development of fibrosis.Based on the results of this analysis of published data, the following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with genetic predisposition  have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/ cytostatic drugs/biologics see .However, currently it is difficult to determine which prognostic markers can be considered indicators for the use of corticosteroids/cytostatic agents/biologics, therefore clinical studies are needed to evaluate the diagnostic significance of determining the described genetic and laboratory markers for selecting a management strategy.At the moment, one of the problems of studying sarcoidosis is the lack of a clear connection of pathogenesis, a specific biomarker and the choice of treatment option. The solution of this practical issue can be aimed at: determining a group of patients with a low probability of self-limitation; pathogenetic justification for choosing a group of the 2nd and 3rd line therapy, based on the specific laboratory markers; determining patients at risk of relapse after drug withdrawal. For progress in these areas, it is necessary to continue research in the field of animal models of sarcoidosis, the connection of laboratory markers with variants of the course of the disease and their changes against the various therapy options, conducting clinical trials. This may make it possible to form clearer criteria for prescribing therapy, which in turn will increase its effectiveness.AM and IK conducted analysis of the materials and wrote the manuscript. AS conducted analysis of the materials, wrote the manuscript, and was a coordinator of the project. DK, YZ, and AG wrote the manuscript. PY was a coordinator the project and wrote the manuscript. YS was a coordinator of the project. All authors have read and agreed to the published version of the manuscript.This work was supported by the grant of the Government of the Russian Federation for the state support of scientific research carried out under the supervision of leading scientists, agreement 14.W03.31.0009.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Maize Cao is first author on ‘ Maize CaoHow would you explain the main findings of your paper to non-scientific family and friends?TARDBP). TDP-43 binds to DNA and RNA, which are critical to gene expression. Every cell type has a special function that is determined by RNA transcripts. This is what makes cells unique from one another. When TDP-43 function is impeded, the interaction with RNA transcripts is lost, affecting the gene expression of the cell. This can lead to a change in biological function, which can be detrimental. By combining published studies of TDP-43 loss of function that have used RNA sequencing to analyse gene expression, we can determine what RNA transcripts (or parts of transcripts) have been changed in various cell types. Identifying these changes are essential for unravelling the functions of TDP-43 and shed light on the cause of disease.Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are debilitating neurodegenerative diseases. The causation of disease is difficult to untangle, but a common denominator is the dysfunction of a protein called TDP-43 (encoded by What are the potential implications of these results for your field of research?TARDBP mRNA targets drives pathogenesis and disease phenotype remains unclear. By assessing TARDBP/Tardbp mRNA targets in human and rodent models, in neuronal and non-neuronal cell types, we can then verify which of these targets are also regulated by TDP-43 in human ALS/FTD neurons. These mRNA targets act as markers that can reveal how TDP-43 loss of function is associated with neurodegeneration. Further, by identifying common markers, we can exploit them to probe for evidence of TDP-43 dysfunction in various cell models used in research. They may also serve as potential biomarkers of disease and/or targets for therapeutic drugs.The impairment of gene expression and splicing regulation are now widely accepted features of ALS with TDP-43 proteinopathy, but how the specific complement of What has surprised you the most while conducting your research?“The most significant challenge [in ALS research] is uncovering the mechanism of disease to determine effective targets for treatment.”This study is an amalgamation of published TDP-43 knockdown studies and was a pandemic ‘lockdown’ project that started when lab access became limited. As I didn't start my PhD versed in bioinformatics, it was a good opportunity to practice. What surprised me the most was how much I enjoyed it, despite the steep learning curve. When conducting the study, the component of comparing the differential exon usage from published studies was the most interesting to me. As my own research involves TDP-43 knockdown as well, it was always satisfying to see my findings validated in the literature. The findings of this paper have contributed to my research in more ways than I could have imagined, and I hope others in the field will find it useful too, particularly with the supplementary webpage that provides the results in one place.Describe what you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?The heterogeneity in ALS/FTD is one of the biggest hurdles in the field. The increasing number of genetic mutations associated with ALS alone highlights the multitude of cellular processes that could become impaired in disease. Consequently, the most significant challenge is uncovering the mechanism of disease to determine effective targets for treatment. Dysfunctional TDP-43, being the pathological hallmark of disease, certainly holds a lot of promise for uncovering mechanisms. However, as we found, TDP-43 is quite heterogeneous in function too! Over the next few years, ALS will likely move into stratified medicine, where treatment is tailored towards the genetics of the individual.What changes do you think could improve the professional lives of early-career scientists?From my experience, early-career scientists experience a lot of self-doubt, even when they are motivated and passionate about their research. I think this is brought upon by uncertainty and imposter syndrome when trying to find their ‘niche’ in the space. That is why I think mentorship, career guidance and peer-support is incredibly important.What's next for you?Currently my most imminent goal is completing my PhD. After that I would like to continue as a postdoctoral researcher. I also have a keen interest in RNA biology and would like to explore that further in my work. Collaborating and working with overseas groups would be another goal of mine, as I enjoy travelling and learning from people with different worldviews.


Graphene has exceptional electronic properties, such as zero band gap, massless carriers, and high mobility. These exotic carrier properties enable the design and development of unique graphene devices. However, traditional semiconductor solvers based on drift-diffusion equations are not capable of modeling and simulating the charge distribution and transport in graphene, accurately, to its full extent. The effects of charge inertia, viscosity, collective charge movement, contact doping, etc., cannot be accounted for by the conventional Poisson-drift-diffusion models, due to the underlying assumptions and simplifications. Therefore, this article proposes two mathematical models to analyze and simulate graphene-based devices. The first model is based on a modified nonlinear Poisson’s equation, which solves for the Fermi level and charge distribution electrostatically on graphene, by considering gating and contact doping. The second proposed solver focuses on the transport of the carriers by solving a hydrodynamic model. Furthermore, this model is applied to a Tesla-valve structure, where the viscosity and collective motion of the carriers play an important role, giving rise to rectification. These two models allow us to model unique electronic properties of graphene that could be paramount for the design of future graphene devices. Graphene has been the focus of various research topics for the last two decades and is pushing toward the market ,2, and eThis article is structured as follows. The transport properties of graphene depend on many internal and external parameters, such as its deposition technique, impurities, type of materials in contact with graphene, operating temperature, etc. These aspects need to be accurately considered for the design of next-generation graphene-based electronic devices in order to account for the effects, such as nonlinear contact doping, due to metals. To exploit the full potential of graphene’s exotic properties, one should be able to access and manipulate the Fermi level of graphene. Making use of graphene in electrical devices requires shifting the Fermi level, by gating and making contacts with metals, which inherently dopes the graphene locally and results in Fermi level shifts. Both of these effects, gating and contact doping, can already be analyzed under static conditions where there is no net current flowing through the graphene. The key relations that determine the electrostatic charge and Fermi level distribution are the Thomas–Fermi equation and Poisson’s equation. These equations can be written for the analysis of charge distribution of graphene under electrostatic conditions. Using the equilibrium Fermi–Dirac function th order . Electro), as in . Gate poIn this work, Equation (2) has been discretized using the Finite Element Method (FEM) with a triangular mesh and with scalar  shape functions and is solved iteratively together with Equation (1), by using successive under-relaxation method as in ,23. EquaIn addition to the analysis of gating on graphene, the contact doping and Fermi level pinning due to the contact of metals on graphene  can alsoThe accurate analysis of semiconductor devices requires advanced models for the charge carrier transport. The traditional drift-diffusion models (DDM) start losing their validity as the operation frequencies increase , and theBy assuming the geometry is 2-D, and separating the components of the vectorial quantities, this set of HDM equations can be written in a more compact way: M in 1-D  and 2-D M in 1-D . HoweverThe hydrodynamic properties of charge transport in graphene have been demonstrated multiple times, such as its viscosity effects ,10, PoisAnother very important parameter for hydrodynamic transport is the momentum-relaxation-time constant that reveals itself in the right-hand-side collision term of the momentum-conservation Equation (5). This parameter is primarily dependent on the scattering mechanisms taking place, and for high-temperature applications, phonon scattering would be the primary scattering mechanism. The momentum-relaxation-time constant for phonon scattering in graphene as a function of Fermi level, phonon velocities, mass density, and acoustic deformation potential can be obtained by following the formalism in ,34. For 2 is used as the gate-insulator material.Moreover, carrier-saturation velocity also plays a significant role for the transport and can be written as ,36:(12)vThe last missing parameter for the HDM of graphene is energy-relaxation time that appears in the collision term of the energy conservation Equation (6). For this work, it is taken as 1 ps for high-temperature operation ,38. HaviIn order to test and analyze the developed 2-D hydrodynamic solver for graphene, a 2-D device geometry, as in The developed HDM solver for graphene is applied for the device geometry given in The narrow width, in the order of 10 nm, of the graphene device in ghost elements”, just outside the device domain, and their presence is felt through the numerical-flux term in the DGTD-FEM formalism [There are two types of boundary conditions used in this structure, the first one is the ohmic contact condition on the boundaries ‘a’ and ‘b’, to make sure the potential is applied on electrons, so they can enter and leave the structure without resistance. The other boundary condition is applied on the edges of the Tesla valve structure. For that purpose, an isolation boundary is used to eliminate the possible flow outside of the computational domain. This isolation condition is implemented weakly, by assuming zero velocity just outside of the graphene device. In other words, usage of the DGTD method allowed us to assign zero velocity for the carriers on the “ormalism . For theormalism , and timElectron flow directions and velocities can be seen in For the same level of bias applied from the contacts in both the easy- and hard-flow cases, the diodicity yields to ghost’ elements). Therefore, the velocity profiles in the narrow channels, as in The classical Poiseuille flow is a well-known phenomenon, due to hydrodynamic effects and the collective motion that occurs when fluids flow in a long duct, such as a pipe. It has also been shown that under certain circumstances, the electrons in graphene also demonstrate the Poiseuille flow, while carrying a current ,9. In orTwo separate solvers to model and simulate the charge behavior in graphene have been developed. The first simulator combines the nonlinear Poisson’s equation with the Thomas–Fermi equation in graphene, for the computation of the Fermi level and carrier distribution under the gate potential and contact doping, due to the metal layers. An example scenario is given in The developed solvers can be adopted for the development of next-generation graphene devices, especially for THz applications, by modeling and making use of the carrier inertia effects, viscosity effects, and possible ballistic charge transport. Furthermore, graphene nanoribbons (GNR) can also be modeled with this approach, by using appropriate carrier velocity and phonon-scattering times, emerging due to edge effects. Moreover, a parallel solver for the HDM can be implemented in the next generation, thanks to the employed DGTD algorithm.