ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA‐catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A‐induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low‐molecular sulfides in the cytoprotection and aging.Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species ( O2−·), hydrogen peroxide (H2O2), and hydroxyl radical, is important cellular toxicants that generated as products or by‐products in cells. A series of antioxidant mechanisms maintain intracellular redox homeostasis. When they deficit, overproduction of ROS causes DNA mutations and protein dysfunction, which eventually leads to cell injury and aging. The thiomethyl group that exists on the surface exposed methionine (Met) residues has been recognized as a key endogenous antioxidant defense , including superoxide . In previous studies, it has been shown that in the first step of MsrA‐catalytic oxidation, a sulfenic acid residue on Cys72 of MsrA forms by ROS attacking (MsrA‐CYO). Thus, we analyzed the orientation of different MsrA substrates in the active site of MsrA‐CYO . We found DMS adopts a preferred orientation with the distance of O‐S 3.8 Å (Table S1). In the presence of DMS binding, the distances of donor and acceptor atoms (D‐H···A) between the O atom from CYO72, the H atom from Tyr103‐OH, and Glu115‐COOH were 3.6 and 1.6 Å, respectively. Another question is whether the preferred orientation of DMS in the active site formed easily. Thus, energy barrier was used to evaluate the difficulty of orientation. Steering molecular dynamics (SMD) can operate single molecules to move closer or apart just like the working mode of atomic force microscopy. For oxidative reaction catalyzed by MsrA, substrates including DMS were pulled 16 Å away from MsrA and then pulled to the active site of MsrA. Curves of works showed how much energy was required to pull substrates to the active site as close as possible . It was obvious that much less energy was required for pulling DMS than Met substrates, indicating that the formation of sulfonium intermediate on DMS occurs more easily. As shown in Fig. S2C, DMS fitted properly in the catalytic pocket of MsrA, which also indicated DMS was a dominant substrate of MsrA.m) was incubated with different concentrations of DMS, and its binding was measured by fluorescence anisotropy. As shown in Fig. m), indicating a direct binding of DMS to MsrA.The DMS conformation from docking experiment indicated that DMS could easily bind to the catalytic pocket of MsrA Fig. A, which et al., 2O2‐induced luminescence was not inhibited by 0.1 mm DMS . Neither MsrA nor nonactive MsrA alone (1 μm) had a perceptible effect on the luminescence intensity . Meanwhile, cotreated with 0.1 mm DMS and MsrA (1 μm), but not nonactive MsrA, remarkably reduced the luminescence signal intensity to 52 ± 5% . In electron paramagnetic resonance (EPR) assay, hydroxyl radical was induced by Fenton reaction and trapped by DMPO to form a stable spin adduct DMPO‐OH. The signal intensity of DMPO‐OH adducts was not changed by MsrA or nonactive MsrA alone . However, cotreatment with 0.1 mm DMS and MsrA (1 μm) decreased the DMPO‐OH signals to 73 ± 1% when compared to the group cotreated with 0.1 mm DMS and nonactive MsrA .Previous studies indicate that DMS exhibits antioxidant function in marine algae (Sunda P < 0.01), respectively, indicating that Cys72 is the most critical one among these three residues. Furthermore, it was found that the predicted key residues  were conservative in various organisms , indicating that this catalytic mechanism may exist extensively.As predicated, Tyr103 and Glu115 facilitated the transfer of oxygen atom to DMS via the formation of hydrogen bond . The Phe73 and Trp74 increased the binding of DMS to the pocket via the hydrophobic force. To validate this model, three single site mutants  were built. The peroxidase activity was measured by the ability to scavenge hydroxyl radicals in EPR tests  was used to evaluate total ROS. Application of AA (100 μg mL−1) for 0.5 h induced an increase of the total ROS level to 256 ± 15% of control . Pretreatment of PC12 cells with DMS (1 and 5 μm) significantly decreased the ROS level to 125 ± 14% and 100 ± 18% of control, respectively  and high concentrations (10 and 100 μm), DMS significantly attenuated H2O2‐induced lipid peroxidation from 159 ± 7% to 131 ± 4%, 123 ± 6% and 120 ± 8% in the brain, respectively , and this was reduced to 90 ± 15% of basal level by 5 μm DMS (P < 0.01).To further investigate the biological function of DMS, we observed the effect of DMS on cell lines. ROS production in PC12 cells was stimulated by antimycin A (AA), a mitochondrial respiratory complex III inhibitor. AA increased the levels of Drosophila, the lipid oxidation product MDA decreased significantly with the treatment of DMS (10 μm) in aged Drosophila from 15.2 ± 0.5 nmol mg−1 protein to 11.3 ± 0.6 nmol mg−1 protein . We further tested whether DMS exerted lifespan‐extending properties in Drosophila. The mean survival time of control group was 48.25 ± 0.91 day. Meanwhile, the mean survival time was extended to 54.80 ± 1.06 day (10 μm), 59.95 ± 1.11 day (100 μm), and 55.99 ± 0.58 day (1000 μm) with DMS exposure . However, DMS did not prolong the lifespan of Drosophila at low concentrations .MsrA has longevity benefits in different organisms. As a substrate of the peroxidase activity of MsrA, DMS may exert longevity benefits. In C. elegans. MitoSOX red was used to detect the superoxide contents in aged C. elegans . Treatment with 10 μm DMS remarkably decreased superoxide content to 228 ± 26% (P < 0.01). Worms were fed with DMS medium at three different concentrations: 1, 5 and 10 μm. The mean survival time of DMS‐treated worms was extended from 21.00 ± 0.52 day to 22.77 ± 0.59 day (1 μm), 25.23 ± 0.72 day (5 μm), and 26.11 ± 0.71 day (10 μm), respectively . The MDA content decreased significantly with DMS (5 μm) treatment in aged worms from 161 ± 10% to 125 ± 13% of control . These results support the hypothesis that DMS mediates longevity via alleviating the accumulated oxidative damage in aged animals.A similar effect of DMS was observed in ans Fig. C,D. The 2O2 (150 μm) was used to induce oxidative stress on SH‐SY5Y cells. After treatment for 12 h, the cell viability of SH‐SY5Y cells decreased to 59 ± 7% of control group. DMS increased the cell viability of SH‐SY5Y cells under oxidative stress to 81 ± 2% at 6.25 μm, 90 ± 3% at 12.5 μm, 88 ± 3% at 25 μm, 82 ± 4% at 50 μm, and 76 ± 4% at 100 μm , the cell viability in DMS‐treated groups increased to 76 ± 2% (6.2 μm), 79 ± 3% (12.5 μm), 82 ± 3% (25 μm), 84 ± 3% (50 μm), and 84 ± 5% , 62 ± 5% (500 μm), and 70 ± 6% (1000 μm) of control . As shown in Fig. P < 0.01). However, in MsrA shRNA group, the effect of DMS (10 μm) on AA‐induced superoxide production was abolished  on cell viability against H2O2 was also abolished. With control shRNA, the DMS increased the cell viability of PC12 cells from 68 ± 2% in H2O2 group to 93 ± 3% in DMS group . With MsrA shRNA, DMS showed little effects on the cell viability under oxidative stress (70 ± 4% in H2O2 model group vs. 78 ± 4% in DMS group). The protective effect of DMS on lipid peroxidation was also abolished, which resembled the findings in the H2O2‐induced cell death. As shown in Fig. 2O2 model group (160 ± 7%).We then analyzed how DMS at low micromolar range scavenged ROS in PC12 cells. Considering the intrinsic catalytic function of MsrA in the oxidation of thiomethyl groups, we tested whether the antioxidation effect of DMS is dependent on MsrA. After treatment with lentiviral‐expressed specific short hairpin RNAs (shRNA) against MsrA , the expression level of MsrA decreased to 22 ± 6% (msra‐1 expression to 10 ± 5% of control group (L4440 plasmid) in C. elegans . In msra‐1 RNAi group, lifespan was significantly shortened from 22.5 ± 0.8 day to 17.8 ± 0.6 day, which suggested that MsrA plays a critical role. DMS (10 μm) could not extend lifespan in msra‐1 RNAi group . As shown in Fig. 2O2 was used to introduce oxidative stress to test the resistance of worms. The survival rates of worms in each group were evaluated after 3 h in S‐basal buffer containing H2O2 (10 mm). The survival rate of DMS‐treated raised from 44 ± 2% (control RNAi) to 62 ± 4% . However, DMS failed to elevate the survival rate of worms treated with RNAi plasmid. The survival rate of msra‐1 RNAi group (28 ± 2%) showed no significant difference with that of msra‐1 RNAi with DMS group (33 ± 6%).In Fig. 6 cell count. As shown in Fig. 2O2‐treated groups raised significantly to 184 ± 16% and 281 ± 20% of control, respectively . The endogenous cellular DMSO was at 5.73 nmol per 5 × 10et al., et al., −1 wet tissue (at about 1 μm) in rat brain, 2.42 ± 0.09 nmol g−1 wet tissue (at about 2 μm) in rat heart, and 1.09 ± 0.11 nmol g−1 wet tissue (at about 1 μm) in mice brain  and from 2.53 ± 0.12 to 1.44 ± 0.07 nmol g−1 (heart), respectively . MitoSox red was purchased from Invitrogen . DMEM/F12, RPMI1640 and fetal bovine serum were purchased from HyClone . NaBH4 was obtained from Sinopharm chemical reagent . SPME holder and 75‐μm carboxen‐PDMS SPME fiber was purchased from Supelco . Ni‐Trap nickel‐chelating column was obtained from Qiagen . Thrombin kit was purchased from New England Biolabs . Fast Mutagenesis System was obtained from Transgene . MDA and cell survival rate kits were obtained from Jiancheng Biotech .AA, dithiothreitol (DTT), H2DCF, HC. elegans N2 worms were grown on E. coli OP50 using standard techniques on 20 °C . The Drosophila strain w1118 was used in all control crosses and as the background for generation of transgenic lines. All Drosophila stocks were maintained, and all experiments were conducted at 25 °C on a 12‐h: 12‐h light: dark cycle at constant humidity using standard sugar/yeast/agar (SYA) media. Adult male Sprague Dawley rats and C57BL/6J mice were obtained from the Experimental Animals of Tongji Medical College, Huazhong University of Science and Technology. The rats/mice were housed on a controlled 12‐h: 12‐h light cycle at a constant temperature (24 ± 1 °C) with free access to water and food and allowed to acclimate a week. The use of animals for experimental procedures was conducted in accordance with the Guide for Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health. The experimental procedures were approved by the Animal Welfare Committee of Huazhong University of Science & Technology.The wild‐type Brenner, . The RNAet al., 4 and analyzed by SPME‐GC‐MS. Headspace sampling of DMS was carried out with a SPME holder equipped with a 75‐μm carboxen‐PDMS SPME fiber. Samples were incubated for 5 min at 35 °C and then extracted for 10 min at the same temperature. Then, the GC/MS analysis was performed with GC‐MS analysis using Agilent 6890N‐5975B GC‐MS system . The injector temperature was 200 °C, and injections/SPME desorptions were made in splitless mode. Helium was used as a carrier gas with linear velocity 40 cm s−1. The MS analyses were carried out in a SIM scan mode, with a scan of m/z 47 and 62. Electron ionization was used at energy of 70 eV. The temperature of the ion source and the transfer line was 190 and 150 °C, respectively. The acquisition of chromatographic data was performed by means of the Chemstation Software (Agilent).Different tissue samples were collected and prepared as described by published report , and MsrA/nonactive MsrA (1 μm) were added before the Fe (II) and H2O2. Samples (20 μL) were loaded into a quartz tube, and the EPR spectra were recorded at room temperature. The EPR microwave power was set to 4.88 mW. The modulation frequency was 9.76 GHz. The time constant was 81.92 ms, and conversion time was 81.92 ms. A sweep time of 41.94 s was used. Each sample was scanned once. A sweep width of 100 G was used for experiments with DMPO. The receiver gain was set to 3.17 × 103. Simulation and fitting of the EPR spectra were performed using the Bruker WinEPR program.Dimethyl pyridine N oxide (DMPO) was used as a free radical trapper. EPR signals were detected with a Bruker e‐scan EPR spectrometer  as previous report . The PC12 cells were cultured in RPMI1640 supplemented with 15% horse serum, 2.5% fetal bovine serum, and 100 U mLA third generation of self‐inactivating lentivirus vector  containing a CMV‐driven GFP reporter and a U6 promoter upstream of the cloning sites (Age I and EcoR I) was used for cloning shRNAs. The target sequence for rat MsrA was 5′‐AGCACGTCAGCTTTGAGGA‐3′ and for control scrambled shRNA was 5′‐TTCTCCGAACGTGTCACGT‐3′. PC12 cells were infected with lentivirus at a multiplicity of infection (MOI) of 20 for 8 h. Then, the medium was replaced with fresh complete medium. After 72 h, cells were observed under fluorescence microscopy to confirm that more than 80% of cells were GFP‐positive.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.See details in the Supplementary Methods section.t‐test or LSD test post hoc ANOVA. The Kaplan–Meier method was used to compare the differences in survival rates between groups. A P‐value < 0.05 was considered statistically significant.Data are expressed as mean ± SEM Significance of differences between groups was determined by Student's This work was supported by grants from the National Basic Research Program of China  and the National Natural Scientific Foundation of China . It was also supported by PCSIRT (No. IRT13016), the National Key Scientific Instrument and Equipment Development Project of China (No. 2013YQ03092306) and Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province (2015CFA020) to J.G.C.No competing financial interests exist.Appendix S1 Methods.Fig. S1 DMS serves as a dominant substrate of MsrA.Fig. S2 The catalytic pocket model of DMS‐MsrA interaction.Fig. S3 DMS decreases the luminal chemiluminescence in vitro, while MsrA enhances the OH˙ scavenge property.Fig. S4 Neither MsrA nor non‐active MsrA alone has a perceptible effect on ESR signals.Fig. S5 DMS does not prolong the lifespan of Drosophila in low concentrations.Fig. S6 MsrA shRNA significantly inhibits the expression of MsrA in PC12 cells.Fig. S7 The effects of MsrA RNAi are evaluated by RT‐PCR and RT‐qPCR.Fig. S8 The detection method of DMS is built using GC‐MS.Table S1 Distances (Å) between atoms CYO‐S/CYO‐O and S atom; S from DMS, 1 EMS, MPS, L‐Met, AMN, Tripep, Hexpep.Click here for additional data file.


Aortic graft infection is a potentially lethal complication of open and endovascular repair of aortic aneurysms. Graphene is the only existing two-dimensional material, and its unique structure gives graphene and its derivatives a plethora of original characteristics. Among other characteristics, graphene demonstrates bacteriostatic and bactericidal effects that could potentially resolve the problem of graft infection in the future. Data already exist in literature supporting this antibacterial effect of graphene oxide and reduced graphene oxide. Combining these materials with other substances enhances the antibacterial effect. Additionally, it looks feasible to expect antibiotic-delivering graphene-based graft materials in the future. Based on already published data, we could conclude that regarding graphene and its derivatives, the blessing of bactericidal effect comes with the curse of human cells toxicity. Therefore, it is important to find a fine balance between the desired antibacterial and the adverse cytotoxic effect before graphene is used in graft materials for humans. Prosthetic graft infection is a grave and frequently lethal complication of both open and endovascular repair of aortic aneurysms (AA). Despite its relatively low overall incidence, the absolute numbers of graft infection are rising, as the use of synthetic grafts  has become an everyday occurrence in both elective and emergency AA repair, with a reported graft infection incidence of 0.2 to as high as 6% in EVAR cases –4. Overain situ reconstruction of the aorta using either cryopreserved allografts or autologous veins is a similarly disabling method of aortic reconstruction after infected graft excision , and epitaxial growth . FurtherS. aureus and E. coli bacteria (In existing literature, pristine graphene sheets have already been reported to have bacteriostatic and bactericidal properties. These two properties are of great interest for bioengineers committed to improve the graft materials of today to become less prone to bacterial infection. In a recent detailed review of graphene’s future in the grafts materials engineering, it seems that despite existing data supporting these beneficial properties of graphene, not all publications agree to the extent and efficacy of these . In thisbacteria –20. The bacteria . At presbacteria –24.N-carbazole, lactoferrin, diazonium salt, poly-l-lysine, and polyhexamethylene guanidine hydrochloride are a few of the substances used to increase the bactericidal and bacteriostatic effects of graphene sheets (S. aureus and S. epidermidis, although secondary hematogenic contamination with Gram-negative bacteria is also possible. rGO shows the strongest antibacterial effect toward both Gram-positive and Gram-negative bacteria, but in order to achieve the best possible antibacterial effect against the usual bacteria involved, further studies have to examine various combinations of graphene and other substances, although some evidence already exist (In addition to the nature of the material surface, binding other molecules to graphene can also affect its bactericidal or bacteriostatic effect. Silver particles, platinum particles, chitosan, polyvinyl-e sheets , 25–27. dy exist .Graphene has been used as a delivery agent for medication since 2008 . Since tInfection-resistant graphene-based graft materials could be constructed today with the already existing knowledge and technology. In the near future, these same graft materials could go a step further and evolve into infection fighting antibiotic-delivery agents. Unfortunately, before we see these steps ahead of current bioengineering, the question of biocompatibility and biotoxicity should be resolved . Graphenin vivo studies by a multidisciplinary team of bioengineers and vascular surgeons are necessary in order to research the potential role of graphene and its derivatives in building infection-resistant aortic grafts and provide the necessary data on patency, biotoxicity, and biocompatibility. These future materials would further reduce the incidence of graft infection that remains a lethal complication of open and endovascular aortic repair.Graphene and its derivatives could potentially lead the way to new and truly infection-resistant or bactericidal graft materials that can be primarily used in aortic or other arterial repair in order to avoid the occurrence of graft infection, not fighting an already-occurring infection. A proper animal model and NP—conception, data collection, literature review, manuscript writing, and critical appraisal. DS—data collection and critical appraisal. TL—conception and critical appraisal. CK—conception, manuscript writing, and critical appraisal. All the authors have accepted the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Graphene aerogels with high surface areas, ultra-low densities and thermal conductivities have been prepared to exploit their wide applications from pollution adsorption to energy storage, supercapacitor, and thermal insulation. However, the low mechanical properties, poor thermal stability and electric conductivity restrict these aerogels’ applications. In this paper, we prepared mechanically strong graphene aerogels with large BET surface areas, low thermal conductivities, high thermal stability and electric conductivities via hydrothermal reduction and supercritical ethanol drying. Annealing at 1500 °C resulted in slightly increased thermal conductivity and further improvement in mechanical properties, oxidation temperature and electric conductivity of the graphene aerogel. The large BET surface areas, together with strong mechanical properties, low thermal conductivities, high thermal stability and electrical conductivities made these graphene aerogels feasible candidates for use in a number of fields covering from batteries to sensors, electrodes, lightweight conductor and insulation materials. Compared with those aerogels, graphene aerogels possess larger Brunauer-Emmett-Teller (BET) surface areas (SBET > 500 m2∙g−1)8 and ultra-low densities10 because of the very high SBET of a single graphene sheet 11. Tang et al. synthesized ultra-light graphene aerogels with densities from 1.8 mg∙cm−3 to 27.2 mg∙cm−3 using different starting graphene oxide (GO) concentrations. Despite the good thermal conductivity of single-layer graphene (4.84 × 103–5.30 × 103 W·m−1·K−1)12, the nanoporous structure, low density, and perfect opacity of graphene aerogel depress the gaseous thermal conductivity13, solid thermal conductivity14, and radiant thermal conductivity10, respectively. Moreover, Yue et al.10 demonstrated the defects in graphene, and the relatively small sizes of the graphene sheets further suppressed thermal conductivity. Due to the larger thermal contact resistance at the interfaces between adjacent GO sheets15, Xie et al. prepared graphene aerogels with ultra-low thermal conductivities (as low as 4.7 × 10−3–5.9 × 10−3 W·m−1·K−1) at room temperature approximately 80% lower than that of air (0.0257 W·m−1·K−1 at 20 °C).Inorganic17, highly compressibility (strain>50%)17, recoverability18 and thermal insulation10. The poor mechanical, thermal, and electric properties restrict their applications in energy storage, catalyst supports, supercapacitor, and thermal insulation. Ultralight and ultra-flyweight graphene aerogels have highly compressibility and recoverability at maximum strain ≥50%, however, the compression strengths were in the order of KPa19. Several studies have promoted the mechanical properties of graphene aerogels. Zhang et al.7 created mechanically strong graphene aerogels which were dried by supercritical CO2 and with L-ascorbic acid as the reducing agent. The yield strengths and Young’s moduli of these aerogels ranged from 0.04 MPa to 0.66 MPa and from 1.2 MPa to 6.2 MPa, respectively, with densities in the range of 12–96 mg∙cm−3. Huang et al.20 have prepared PEI-crosslinked graphene aerogel with yield strength and Young’s modulus of 1 MPa and 20 MPa. The thermal stability of graphene aerogels was depended on reduction level. High-temperature annealing of graphene aerogels results in enhanced thermal stability22 and an increase in Young’s moduli by one order of magnitude22. Graphene aerogel annealed at 400 °C exhibits significantly improved thermally stability compared with GO and as-prepared graphene aerogel21. With annealing temperature increases from 1050 °C to 2500 °C, the graphene aerogels become more resistant to oxidation in air and exhibit an approximately 200 °C improvement in oxidation temperature22. The bulk electrical conductivity of macroscopic 3D graphene networks was less than 1 S/m24. The electrical conductivity of graphene aerogels increased to >550 S/m after annealing at 2500 °C22. Chen et al.21 have studied the effect of various reducing agents on the electrical conductivities of the graphene aerogels and found that the electrical conductivity of the hydrogel prepared using HI and NaHSO3 have higher values.Taking advantage of larger surface areas or lower thermal conductivities, current researches on graphene aerogels mainly focused on the ultra-light weightIn this paper, we prepared mechanically strong graphene aerogels with large BET surface areas, low thermal conductivities, high thermal stability and electric conductivities via hydrothermal reduction and supercritical ethanol drying. Annealing at 1500 °C resulted in slightly increased thermal conductivity and further improvement in mechanical properties, oxidation temperature and electric conductivity of the graphene aerogel. The large BET surface areas, together with strong mechanical properties, low thermal conductivities, high thermal stability and electrical conductivities made these graphene aerogels feasible candidates for use in a number of fields covering from batteries to sensors, electrodes, lightweight conductor and insulation materials.25. Graphene hydrogels were prepared by hydrothermal reduction of GO dispersions with the assistance of a mild reducing agent NaHSO3. The obtained gels were dried using supercritical ethanol to obtain the graphene aerogels, the resulting samples were referred to as GA-S. The obtained GA-S samples were then heat treated at 1500 °C, the resulting samples were labeled as GA-S-1500C. The GA-S and GA-S-1500C prepared with various concentrations of GO (CGO) were denoted as GA-Sx and GA-Sx-1500C, where x is the concentration of GO dispersion in milligram per milliliter. In addition, we investigated the effect of the drying process by freeze-drying graphene aerogels with GO aqueous dispersion of 5 mg∙mL−1 using the same method as that for GA-S, but deionized water, instead of ethanol, was used to purify the hydrogels. The resulting sample were denoted as GA-F.The synthesis of the mechanically strong graphene aerogels with cylindrical morphology is illustrated in Fig. The removal of a large amount of water from the highly porous network interconnected by partial overlapping or coalescing flexible graphene sheets resulted in the formation of the 3D framework. The graphene aerogels exhibited an interconnecting porous structure of randomly oriented graphene sheets with wrinkled texture. The obtained hydrogels had smaller pore sizes, because of remarkable shrinkage in the volume of GO dispersion during hydrothermal reduction process. The poor microscopic structure of GA-F Fig.  was main26. They both circumvent the destructive differential capillary stresses of conventional evaporative drying either by transferring the solvent into its supercritical state or by replacing the solvent mainly with supercritical CO2, thus suppressing any liquid-vapor interface inside the sol-gel product27. The usually used ethanol was chosen as supercritical drying solvent in our experiments. When ethanol in autoclave was forced to a temperature and pressure above its critical point 28, it transformed into a supercritical fluid. Above the critical point, the various properties of supercritical ethanol are between those of gas and liquid. Although the density of supercritical fluid is similar to that of liquid, the viscosity is similar to that of gas, and its diffusivity is between the two states29. Because the supercritical fluid has lower viscosity and higher diffusion velocity than liquid, it can easily diffuse through the pores of the gel, resulting in higher drying efficiency. Shrinkage of a gel during drying is driven by the capillary pressure, which can be reduced by reducing surface tension of the pore liquid, and supercritical drying eliminates surface tension and keeps the structure of original fine framework of the graphene gels from destroying to obtain aerogels30. Drying process impacted the microstructure of aerogels, and further affected the physical properties of aerogels, such as bulk density, mechanical property, thermal and electrical conductivity. The microscopic morphology of GA-S and GA-S-1500C graphene aerogels prepared with 1, 2, 5, and 10 mg∙mL−1 GO are shown in Fig. GO from 1 mg∙mL−1 to 10 mg∙mL−1 or after high-temperature annealing, the pore structure of graphene aerogels appeared to be much finer and ordered, so, the network architecture, especially those of GA-S10 and GA-S10-1500C, became much “stronger” to support greater external load. The scanning images of graphene aerogels prepared by supercritical drying and freezing drying demonstrated supercritical dried graphene aerogels had more fine, uniform and ordered microscopic morphology. Digital photographs of the GA-S and GA-S-1500C samples are shown in Figs Supercritical drying methods include high temperature supercritical drying from solvents such as methanol, ethanol and acetone, and low temperature supercritical drying from carbon dioxide3-type hysteresis loop at high relative pressure, which was typical characteristic for aggregates of plate-like particles and open large pores31. The total adsorption volumes and the size of the hysteresis loops of the GA-S samples decreased as CGO increased. Moreover, the pore size distribution of GA-S and GA-S-1500C calculated by the BJH method indicated a large proportion of mesopores in a narrow distribution from 3 nm to 5 nm with peak pore diameter of approximately 3.8 nm , pore volumes, and average pore diameters of GA-S and GA-S-1500C were shown in Table BET of the graphene aerogels were much lower than 2600 m2∙g−1 of the theoretical value for a single graphene sheet11 because of the layering or overlapping of graphene sheets8. This values apparently improved by reducing CGO or enhancing the exfoliation of graphene sheets during the self-assembling process6. The SBET and pore volume of GA-S1 at approximately 600 m2∙g−1 and 4.487 cm3∙g−1, respectively, decreased to corresponding values of 435.6 m2∙g−1 and 2.153 m3∙g−1 for GA-S10 as CGO increased. The dramatic decline in the surface area of the graphene aerogels at high CGO was attributed to the improved sites of partial overlapping or cross-linking of the flexible graphene sheets generated during the self-assembling process to form a 3D network with higher density. The healing or repairing of defects in the graphene sheet reduced the textural mesopores, accounting for the lower SBET of GA-S-1500C than GA-S. However, the SBET of GA-S-1500C increased from 336.5 m2∙g−1 with 1 mg∙mL−1 CGO to 440.8 m2∙g−1 with 10 mg∙mL−1 CGO, this trend was also broadly applicable to the desorption surface area cumulated by BJH method  was attributed to the presence of isolated double bonds that resonate at frequencies higher than that of the G-band of graphite32. The presence of G-bands for GA-F and GA-S at 1586 and 1590 cm−1, respectively, were ascribed to the recovery of the hexagonal network of carbon atoms with defects33. After hydrothermal reduction, the significant increase of ID/IG for GA-F and GA-S indicate a decrease in the average size but an increase in the number of sp2 domains upon reduction of the exfoliated GO32. The reduction effect obviously cannot be considered as the healing or repairing of defects in GO34. Annealing at 1500 °C resulted in the evident decrease in ID/IG, strongly suggesting the removal of a considerable number of defects in the graphene sheets. The intensity of the two-dimensional (2D) peak (2695 cm−1) for GA-S-1500C increased dramatically, revealing better graphitization of graphene sheets after annealing at 1500 °C35.The XRD patterns of GA-F, GA-S, and GA-S-1500C compared with those of GO and graphite are depicted in Fig. 36, C=O , and O–C=O 37 , C–O )37 Fig. . However)37 Fig.  only exh eV Fig.  correspo−3 obtained from purified hydrogel dried by supercritical ethanol. A 75.0 mg graphene aerogel cylinder could support a 2 kg counterpoise, at least 26000 times their own weight  were 5.13 and 0.25 MPa, respectively, whereas those of GA-F (ρ = 48.0 mg∙cm−3) with the same CGO were only 1.05 and 0.06 MPa, respectively 22 for GA-S increased from approximately 625 °C to nearly 705 °C after annealing. This improvement in thermal stability was ascribed to the decrease in the amount of oxygenated functional groups which improved the ability of graphene aerogels to tolerate higher temperature in the air. The GA-S and GA-S-1500C samples exhibited the same tendency in thermal conductivities at room temperature, which both improved with the increase of bulk density  were much higher than those of the graphene aerogels prepared by Tang et al.9 (1.8–27.2 mg∙cm−3), the thermal conductivities  for GA-S shown in Fig. −1∙K−1). This result could be ascribed to the finer pore structure of our graphene aerogels. The thermal conductivity of graphene aerogels can be as low as <0.01 W∙m−1·K−1, but bulk density and mechanical property was very low15. To indicate the thermal stability of graphene aerogels more visually, the GA-S-1500C graphene aerogel was tested in a hot flame of an alcohol burner  also enhanced the electrical conductivity of GA-S-1500C samples. Although, the GA-S10-1500C has higher electrical conductivity than recent reported graphene aerogels43, but lower than the highly crystalline graphene aerogels , hydrogen peroxide , and sodium hydrogen sulfite (NaHSO3) were purchased from Tianjin Bodi Chemical Co., LTD. . Potassium permanganate (KMnO4), concentrated sulfuric acid , and hydrochloric acid  were obtained from local suppliers .Graphite flakes  were used to prepare GO through a modified Hummers’ method. Sodium nitrate  hydrogels. The obtained hydrogels were first purified in a large amount of ethanol for at least 1 week and then dried using supercritical ethanol at 270 °C with a pressure of 8 MPa to obtain the graphene aerogels. The resulting samples were referred to as GA-S. The obtained GA-S samples were then heat treated at 1500 °C for 1 h under N2 atmosphere. The resulting samples were labeled as GA-S-1500C. The GA-S and GA-S-1500C prepared with various concentrations of GO (CGO) were denoted as GA-Sx and GA-Sx-1500C, where x is the concentration of GO dispersion in milligram per milliliter. In addition, we investigated the effect of the drying process by freeze-drying graphene aerogels with GO aqueous dispersion of 5 mg∙mL−1 using the same method as that for GA-S, but deionized water, instead of ethanol, was used to purify the hydrogels. The resulting sample were denoted as GA-F.GO was prepared from natural graphite using the improved Hummers methoders Fig. . The lar−1 under air atmosphere. The bulk electrical conductivities of cylindrical graphene aerogels were measured by four-probe method with metal electrodes attached to the ends of samples.Atomic force microscopy  in tapping mode at a scan rate of 0.999 Hz was performed to obtain AFM images of the GO sheets. The bulk densities of the resulting aerogels have been calculated by the mass of the graphene aerogel divided by its volume. The microscopic morphology of the graphene aerogel was investigated via a scanning electron microscope . Nitrogen adsorption–desorption measurements were performed using a Micromeritics 2020 ASAP instrument at 77 K. Surface areas were calculated using the BET (Brunauer-Emmett-Teller) method, and the pore size distribution was calculated by the Barrete-Joynere-Halenda (BJH) method. XPS (X-ray photoelectron spectroscopy) analysis of GO, GA-F, GA-S, and GA-S-1500C was performed on an ESCALAB 250Xi photoelectron spectrometer . X-ray diffraction (XRD) patterns of GO, graphene aerogels, and natural graphite were analyzed by a D/max-RB XRD . Raman spectra were measured by irradiation with laser light at 532 nm in a Renishaw spectrometer. Compression tests were conducted using an electronic universal material testing machine  with loading capacity of 1000 N at a constant loading speed of 2 mm/min. Thermal conductivity was measured by hot wire technique using a thermal conductivity measuring instrument . Thermal stability of the graphene aerogels was investigated by thermogravimetric analysis  with a heating rate of 15 °C∙minSupplementary Information


Sarcoidosis is a multisystemic granulomatous disease of unknown origin. Chronic cutaneous lupus erythematosus (CCLE) is an autoimmune disease that is associated with autoantibody production and T-cell dysfunction. Cutaneous manifestations of sarcoidosis may mimic CCLE and vice versa making it difficult to reach a diagnosis clinically.We present a case of a 57-year-old woman with long-standing sarcoidosis who presented to clinic with diffuse painful plaques that were very distinct and suggestive of CCLE. She had a family history of both sarcoidosis and CCLE. The patient was immediately started on topical corticosteroids and oral hydroxychloroquine. Skin biopsy and the absence of direct immunofluorescence confirmed a skin manifestation of her previously diagnosed sarcoidosis, despite the clinical morphology favoring classic CCLE.Sarcoidosis may have diverse manifestations and may mimic other disease processes. A detailed history along with a low threshold for biopsy is important for determining a diagnosis. Sarcoidosis is a multisystemic granulomatous disease of unknown origin. Cutaneous manifestations are present in 30 % of patients with sarcoidosis and may be the first presenting sign . On physA 57-year-old African-American female presented with hyperpigmented plaques on the face, scalp, arms, hands, buttocks, legs, and feet. She has had similar lesions over the past fifteen years and described them as burning, itchy, and painful.There were dermal papules on the perinasal and periocular areas. The ears displayed plaques with adherent scale and follicular plugging in both conchal bowls and preauricular regions Fig. . The antShe had been diagnosed with systemic sarcoidosis twelve years prior as well as hypertension and congestive heart failure eight years earlier. Her medications included aspirin, metoprolol, and ibuprofen as needed for pain. The patient reported a history of lupus (unknown subtype) in her maternal aunt and sarcoidosis in her maternal sister and two uncles.Laboratory studies included complete blood count with differential, complete metabolic panel, brain natriuretic peptide, erythrocyte sedimentation rate (ESR), and angiotensin-converting-factor (ACE). The only abnormal values were an ESR of 41 mm/h (reference range 0-30 mm/h) and ACE of 73 nmol/mL/min (reference range 9–67 nmol/mL/min).Given the patient’s history of long-standing lesions; photodistribution; and the presentation of plaques with dyschromia, atrophy, follicular plugging, and raised borders, a diagnosis of CCLE was favored. While the patient had a past medical history of sarcoidosis, her current lesions appeared classic for CCLE and both conditions were present in her family history. Given the information and clinical presentation, a biopsy proved necessary as a purely clinical diagnosis was not adequate.Two punch biopsies were taken from a plaque on the left arm and sent for histopathology and direct immunofluorescence. Pathology exhibited non-caseating granulomas Figs.  and 5 wiOur patient represents a case of sarcoidosis with skin manifestations that closely imitate those of CCLE. The lesions seen in sarcoidosis are divided into specific and nonspecific subgroups based on histologic findings. Specific lesions occur in 9-15 % of patients and exhibit noncaseating granulomas . The mosIn sarcoidosis, noncaseating granulomas can be found in tissues and organs such as the skin, lungs, and lymph nodes. These granulomas consist of aggregates of epithelioid histiocytes, giant cells, and mature macrophages . They arCutaneous manifestations of CCLE include erythematous to violaceous scaly plaques with prominent follicular plugging that often results in scarring and atrophy. They are found most commonly on the face, scalp, ears, and less commonly on the mucosal surfaces, conjunctivae, and genital mucosa. Plaques usually appear in a photodistributed pattern, although not always necessary. Skin morphology includes dyspigmentation in longstanding lesions with hypopigmentation in the central region and hyperpigmentation at the periphery . HypertrHistologically, CCLE plaques are found to have inflammatory infiltrates in the superficial and deep dermis as well as the surrounding adnexal structures. Keratinocyte damage and hyperkeratosis are present in the epidermis with possible prominence of amorphous and eosinophilic colloid bodies in the epidermis and/or upper dermis. Melanin deposits within macrophages are located in the dermis. Lymphohistiocytic cellular infiltrates that are often pronounced are located in the dermis at perivascular and periadnexal locations. If histopathology is equivocal for CCLE, direct immunofluorescence may be helpful. In cutaneous lupus, antibody deposition is seen at the dermal-epidermal junction and around hair follicles . While mWithout a biopsy, one might be quick to diagnose this individual with known sarcoidosis with superimposed CCLE based on the clinical morphology. Her plaques had all the characteristic cutaneous findings including dyschromia, atrophy, adherent scales, central hypopigmentation, and hyperpigmentation at the periphery. However, histology did not show follicular plugging or lymphohistiocytic cellular infiltrates. Immunofluorescence studies were also negative. Histology was pathognomonic for sarcoidosis exhibiting non-caseating granulomas, giant cells, and a lymphocytic infiltrate. In the end, strong clinical inclination was not enough and a biopsy was the necessary factor in determining a definitive diagnosis.


Gate modulation of the carrier density is still visible at 150 K, which is lower than the glass transition temperature of most liquid gating electrolytes.We have developed a technique to tune the carrier density in graphene using a lithium-ion-based solid electrolyte. We demonstrate that the solid electrolyte can be used as both a substrate to support graphene and a back gate. It can induce a change in the carrier density as large as 1 × 10 The liquid gating technique has been successfully applied in the study of novel field-effect transistors457891012131415162 thin film can be used to make a proton gate18202114 cm−2, which is much larger than that induced by oxide dielectrics and comparable with that induced by liquid electrolytes. Additionally, the LICGC solid electrolyte can tune the carrier density in graphene samples at temperatures as low as 150 K, which is much lower than the glass transition temperature of most ionic liquid/polymer electrolytes.The electronic properties of many materials strongly depend on their carrier density. In recent years, a technique called “liquid gating” has been widely used in materials research and development of flexible electronics123 solution in deionized water. The floating graphene/PMMA layer was then transferred onto the LICGC substrate, and the PMMA layer was removed with acetone. The samples were then annealed in a hydrogen–argon atmosphere for 7 h. The electrical contacts to graphene were made from indium pellets. The few-layer graphene samples were mechanically exfoliated from highly oriented pyrolytic graphite onto the LICGC substrate using the well-known tape method. The exfoliated few-layer graphene were typically tens of micrometers in size. The standard e-beam lithography technique was used to pattern Ti/Au (5 nm/55 nm) microelectrodes. Single-layer graphene samples were initially grown on copper substrates by the chemical vapour deposition (CVD) technique. The growth details can be found in our previous paper2 substrate. The geometrical capacitance of the EDL is given by Cg = εseε0/d, where εse, ε0, and d are the relative permittivity of the solid electrolyte, the vacuum permittivity, and the spacing of the EDL. Because Cg is inversely proportional to the spacing between the double layer, a large surface roughness may increase the local spacing of the EDL and thus reduce its geometrical capacitance. As we will show below, although not atomically flat, the LICGC substrate can create a considerable gating effect. Solid electrolytes with smaller surface roughness are always preferred. A solid electrolyte with an atomically flat surface is ideal to form a homogenous EDL, and also crucial for direct thin-film growth on solid electrolyte substrates using advanced thin-film growth technique such as molecular beam epitaxy (MBE), because it can give a clean and lattice-matched  interface between the solid electrolyte substrate and the thin-film material.We used an atomic force microscope (AFM) to investigate the surface roughness of the LICGC substrate. Gr, and RSE are the resistance of the graphene sample and the LICGC substrate. Ri is the interfacial resistance between the LICGC substrate and the silver paint, estimated to be greater than hundreds of megohms. By contrast, the resistance between the gold electrode and the liquid electrolyte, estimated from our own experiences, is in the megohm range. The ionic conductivity of LICGC is approximately 0.1 mS cm−1 at room temperature, which is also one order of magnitude lower than that of DEME-BF4 (a widely used ionic liquid)−1). As shown in We first demonstrate the gating effect of the solid electrolyte on single-layer graphene. R) versus gate voltage (Vg) curves. Similar resistance discontinuity has been observed in liquid gating experiments13 cm−2 in the wet transferred single-layer graphene sample, and approximately 1.0 × 1014 cm−2 in the exfoliated few-layer graphene sample. The observed gate tuning capability of LICGC on graphene is similar to the reported value for EMIM-BF4 (1.0 × 1014 cm−2), and slightly smaller than that reported for DEME-TFSI (2.5 × 1014 cm−2); which are both commonly used ionic liquid gating electrolytesTo quantize the gate tuning capability of the solid electrolyte, we measured the carrier density change for a series of single- and few-layer graphene samples. The single-layer graphene covered a large portion of the LICGC substrate. The measurement for these samples gave an average gating effect of the solid electrolyte. The few-layer graphene samples had sizes on the micrometer scale. The gating effect on these small samples was more affected by the local surface roughness of the LICGC substrates. In both situations, we found that the LICGC substrate can realize considerable carrier density tuning. R versus Vg curves for five macroscopic single-layer graphene samples. These samples were cut from neighbouring areas on a large graphene sheet grown on the copper substrate. In these samples, the initial positions of the Dirac point should be similar. Gate modulation of the resistance is visible in all of the samples except for the one measured at 100 K. This suggests that the Li ions are still displaceable at a temperature as low as 150 K, which is lower than the glass transition temperature of most known ionic liquids. We also found that the resistance peak shifted towards higher gate voltage as the temperature decreased, and the width of the resistance peaks became wider. This behaviour can be attributed to two possible reasons. First, because the gate tuning of the carrier density in graphene can be viewed as a charging/discharging process of the EDL capacitor, the RC time constant determines how fast the carrier density change occurs. The ionic conductivity of solid electrolytes follows Arrhenius law and decayed exponentially with temperature, which leads to increased resistance of the solid electrolyte. The interfacial resistance between LICGC substrate and the silver paint can also become greater at low temperature. The longer RC time constant leads to slower carrier density modulation. Second, at low temperatures, a high gate voltage is required to overcome the energy barrier for Li ions to approach the LICGC–graphene interface. Assuming that only the RC time constant affects the gate tuning behaviour, we expect that all of the resistance peaks should appear below a common voltage threshold after a sufficiently long time. However, we found the opposite case in the experiments: at low temperature, the resistance peak did not appear even after a long time unless we moved to a higher gate voltage. We thus believe that the combination of both effects results in the shift and widening of the graphene resistance peak. Detailed experimental evidence is given in the We investigated how the performance of the LICGC solid electrolyte varies with temperature. All liquid electrolytes have a specific glass-transition temperature, below which ion movement in the electrolytes is frozen and the electrostatic gate tuning ability is lost. To make a comparison with the liquid gating technique, we carried out back gate voltage sweeping experiments at various temperatures. The results described above prove the concept of using solid electrolytes to tune the carrier density in thin-film samples. Because solid electrolytes are widely used in the research of Li-ion batteries and fuel cells, there is a long list of available materials that can be used to perform electrostatic gating. In the following paragraph, we will discuss the criteria for selecting a solid electrolyte for electrostatic gating.σ can be expressed as σ = nZeμ, where n is the number of ions per unit volume, Ze is the charge of the ions, and μ is the ion mobility. As previously mentioned, the mobility follows the Arrhenius law and it exponentially decreases with decreasing temperature. Most solid electrolytes used in Li-ion battery research are good candidates for room temperature electrostatic gating, while the solid oxide electrolytes used in fuel cells usually only work at high temperatures. The LICGC substrate used in this study has an ionic conductivity of the order of 10−4 S cm−1 at room temperature. Other electrolytes containing Li ions can reach of the order of 10−3 S cm−1. By contrast, the ionic conductivity of organic liquid electrolytes is generally in the order of 10−2 S cm−1. Materials with higher ionic conductivity are always favorable. Recently, new lithium solid electrolytes with high ionic conductivities have been reported, such as Li10GeP2S12, which exhibits ionic conductivity higher than 10−2 S cm−1 at room temperature. These materials are worthy of further investigation.It is essential to reduce the serial resistance in the RC circuit model to get a smaller RC time constant so that the carrier density change in the sample can keep up with the applied gate voltage. The interfacial resistance between the solid electrolyte and the gate electrode should be reduced, and the solid electrolytes with higher ionic conductivity are highly desired. The interfacial resistance is an active research field in Li-ion battery, which depends strongly on the material choices of solid electrolytes and cathode/anode electrodesThe second factor that needs to be taken into account is the surface roughness. As solid electrolytes are used as the substrate to support thin-film samples, a flat substrate surface is required. LICGC is one of the few commercially available solid electrolytes with a polished surface. To further improve this technique, a solid electrolyte with an atomically flat surface is highly desired. Such solid electrolytes may form a homogeneous EDL with large geometrical capacitance, which can enhance the electrostatic gating effect. Furthermore, a solid electrolyte with an atomically flat surface is an ideal substrate for advanced thin-film growth techniques such as MBE. It can create a much cleaner interface between the solid electrolyte and the thin-film sample compared with the interface made by transferring thin-film samples to the surface of a solid electrolyte. Although most of the solid electrolytes developed for energy storage research are in ceramic or polycrystalline forms, there are some single-crystal solid electrolytes, such as potassium-doped β-alumina. This will be important to advance the solid electrolyte gating technique.2Te3 gated with an ionic liquidSome other factors should be considered. The chemical stability under ambient conditions is important for practical applications. LICGC is a good material in this sense because it is not sensitive to humidity, unlike many ionic liquids. Solid electrolytes with high electrochemical decomposition potentials are also preferable so that large gate voltages can be applied. Using LICGC as the back gate, the gate voltage is limited between −2 and 3.5 V. We also attempted to apply higher gate voltages. As shown in the In summary, we have discussed the advantages of the LICGC solid electrolyte gating technique over the existing liquid gating technique. The LICGC solid electrolyte can serve as both the substrate to support the sample and the back gate. It can achieve a similar carrier density tuning ability to liquid electrolytes, while maintaining an uncovered sample surface. Therefore, it provides the possibility of combining the electrostatic carrier density tuning technique with other surface-probe techniques. The combination of these techniques will be very useful, for example, to monitor evolution of the Fermi level by continuously tuning the carrier density in superconducting materials. LICGC substrates provide a strong and full solid-state gate tuning capability, making them more suitable for practical applications than liquid electrolytes. A sample fabricated on top of a LICGC substrate will also not suffer from problems that may be encountered in liquid gating, such as damage caused by the stress created during the freezing of the liquid electrolyte. All of these advantages make solid electrolyte gating a promising technique for future applications.How to cite this article: Zhao, J. et al. Lithium-ion-based solid electrolyte tuning of the carrier density in graphene. Sci. Rep.6, 34816; doi: 10.1038/srep34816 (2016).


Quenching thermoelectric effects in graphene leads to an extraordinary increase of the linear dynamic range in photodetectors. 3-intercalated graphene using laser irradiation. Photocurrent measured at these planar junctions shows an extraordinary linear response with an LDR value at least 4500 times larger than that of other graphene devices (44 dB) while maintaining high stability against environmental contamination without the need for encapsulation. The observed photoresponse is purely photovoltaic, demonstrating complete quenching of hot-carrier effects. These results pave the way toward the design of ultrathin photodetectors with unprecedented LDR for high-definition imaging and sensing.Graphene-based photodetectors have demonstrated mechanical flexibility, large operating bandwidth, and broadband spectral response. However, their linear dynamic range (LDR) is limited by graphene’s intrinsic hot-carrier dynamics, which causes deviation from a linear photoresponse at low incident powers. At the same time, multiplication of hot carriers causes the photoactive region to be smeared over distances of a few micrometers, limiting the use of graphene in high-resolution applications. We present a novel method for engineering photoactive junctions in FeCl Intense research activity on graphene-based photodetectors (3 has been found to result in record-high levels of hole-doping (≈ 1 × 1015 cm−2) with a room temperature electrical conductivity up to 1000 times larger than that of pristine graphene while maintaining equivalent absorption over the visible wavelength range  response and an LDR as large as 44 dB, which is at least 4500 times larger than that of any previously reported graphene photodetector  defines a new paradigm in ultrathin, high-LDR photodetectors.The light-assisted design of integrated and atomically thin optoelectronic circuits is a step forward to a new frontier in high-definition sensing applications, whereas FeCl3 introduced only between the top three carbon layers. Intercalation of FeCl3 molecules into mechanically exfoliated FLG on a Si/SiO2 substrate was conducted using a previously reported method (0 peak at 1580 cm−1 due to the E2g phonon mode of pristine graphene as well as the blue-shifted G1 = 1615 cm−1 and G2 = 1625 cm−1 peaks of the same mode caused by the charge doping of FeCl3 molecules adjacent to only one side of a graphene layer (stage 2) or sandwiching the carbon atoms (stage 1) .The starting material to achieve our goal is an intercalated four-layer graphene flake with FeCle 1) see . Upon itpeak see . All the3 intercalation in graphene, we exposed a 5.5-μm-wide section of the intercalated flake to a raster laser scan (15.3 MW/cm2 for 3 s in 0.5-μm steps). Raman spectra were collected at incrementally spaced locations across the laser-exposed region both before and after illumination, as shown in 1 and G2 peaks along a 21-μm line scan. Uniform removal of the G2 peak from the entire rastered region demonstrates that FeCl3 molecules may be displaced from arbitrarily mapped areas. The degree of intercalation remains unchanged away from the irradiated area, with the resolution of FeCl3 displacement defined by the laser spot profile. The marked effectiveness of laser-induced deintercalation over a significant fraction of the FeCl3-FLG flake area presents an elegant method, akin to optical lithography, which can be used to locally customize the chemical functionalization of graphene layers.To ascertain the effectiveness of laser irradiation as a method for locally tailoring FeClet al. , across a graphene junction formed by regions with a differing density of states. If the junction is illuminated, a local increase of temperature (ΔT) results in the diffusion of carriers and an opposing photovoltage (VPTE = ΔS ΔT) is generated. Hot-carrier dynamics are generally recognized to dominate photocurrent generation in supported graphene devices because of inefficient cooling of electrons with the lattice (nph) of carriers, which, in the presence of an in-built electric field, are separated and induce current at the electrodes  generated in one of several measured monolayer graphene devices (section S2.4), where α = 2/3 was obtained with 10 mV applied between the source and drain. On the other hand, the photoresponse of FeCl3-FLG is strikingly different from that of pristine graphene, exhibiting a linear dependence extending beyond three logarithmic decades of incident laser power. The observed difference originates from the charge carrier dynamics. More specifically, in pristine graphene, the chemical potential (μ) lies close to the charge neutrality point, and the small Fermi surface imposes tight constraints on the maximum energy lost through momentum-conserving acoustic phonon emission  (Th >> Tl) and are instead cooled via short-range “supercollision” processes at sites of disorder  to justify the observed linear power dependence (Th can be explained by the ultrahigh levels of charge density (up to 3 × 1014 cm−2 per layer) achieved through FeCl3 intercalation  illuminated by a laser (spot diameter l0) isR is the resistance of the graphene layer and η is the carrier mobility. For a doped graphene layer with a charge carrier density above n ≈ 3 × 1013 cm−2, the Bloch-Grüneisen temperature (TBG = ΔEac/kB) exceeds 300 K  from several micrometers (L/2. Using the low-energy density of states for monolayer graphene and a minimum conductivity of σmin ≈ 4e2/h (min(1 + μ2/Λ2), where Λ ≈ 140 meV. The Mott relation for thermopower (IPTE/IPVE ≈ − 0.06 using 3-FLG p-p′ junctions and acts in the opposite direction to dominant photovoltaic processes. Opposing photocurrents at p-p′ junctions have previously been predicted in monolayer graphene transistors with split electrostatic gates (S ∝ −σ−1 (dσ/dμ)), the density of states of graphene dictates that these gradients will always point in opposite directions so long as the chemical potentials on each side of a photoactive junction are both situated in the valence band (p-p′ junctions) or in the conduction band (n-n′ junctions) away from the charge neutrality point. As a result of these findings, we take the direction of photocurrent signals shown in 3-FLG detectors.To identify the origin of photocurrent at p-p′ junctions of FeCl3-FLG–based photodetectors would not require thermal isolation and could be packed to a far higher density than undoped graphene monolayers, making them well-suited for imaging applications over a broad spectral range.Through chemical functionalization, the selective quenching of thermoelectric processes in graphene could prove to be a highly useful tool for extending the use of graphene-based light sensors beyond microbolometers and modulators suitable for infrared wavelengths. Pixels of FeCl3-FLG detectors is characterized by an extraordinary LDR. The noise-equivalent power (NEP) of our device was measured to be 4 kW/cm2 (see section S2.2), thus resulting in an LDR of 44 dB. This is 4500 times larger than that of previously reported graphene photodetectors (LDR ≈ 7.5 dB)  to red (685 nm). Fits of the power exponent at each wavelength give the following: α375 = 0.99 ± 0.01, α473 = 1.05 ± 0.06, α514 = 0.97 ± 0.03, α561 = 0.99 ± 0.01, and α685 = 0.95 ± 0.05. For the multitude of FeCl3-FLG devices measured, we observed no deviation from a strictly linear power dependence in the whole measured power range. This indicates that the ultrahigh degree of charge carrier doping introduced by FeCl3 intercalation acts as a unique stable method for quenching thermoelectric effects and fixing the photoresponse to an extended linear dynamic regime, avoiding the sensitivity to processing methods and environmental conditions, which pristine graphene photodetectors (Iph/Popt(λ), of a p-p′ junction is displayed with and without correcting for reflections from the Si/SiO2 substrate (section S6). The photoresponse remains markedly consistent across the entire visible range, where ℜ(λ) varies by only one order of magnitude, with values >0.1 mA/W, which are typical for high-end all-graphene photodetectors , where NA is the numerical aperture of the objective]. To explore the density to which graphene-based imaging pixels may be packed in the absence of hot-carrier effects, we use scattering-type near-field optical microscopy  to define photoactive junctions below the Abbe limit. This technique has been used extensively to study the plasmonic –grown graphene has already been demonstrated . Raman spectra were acquired with a Renishaw spectrometer equipped with a 532-nm laser focused to a 1.0-μm spot through a 50× objective lens. An incident power of 1 mW was used for all measurements, and spectra were recorded with a 2400 g/mm grating. A charge-coupled device acquisition time of 5 s was used.Raman spectroscopy measurements used to characterize the degree of intercalation in FeClT = 300 K, P = 1 atm) in air. The laser power was varied from 1.5 μW to 1 mW by analog modulation of the laser diodes and the use of neutral density filters along the beam path. All the devices studied have been measured in air over a time scale longer than 1 year, during which no change in the photoresponse was observed.A continuous-wave laser beam from a multiwavelength  solid-state laser diode array was focused onto the sample through a 50× lens, producing a spot size of 1.0 μm. A high-resolution microscope stage (minimum step size of 0.05 μm) was used to produce spatial maps of the photocurrent. Electrical measurements were performed in short-circuit (zero bias) configuration using a DL Instruments Model 1211 current amplifier connected to a Signal Recovery model 7124 digital signal processing lock-in amplifier. The lasers were modulated at a frequency of 73.3 Hz with a transistor-transistor logic signal from a direct digital synthesizer function generator, which was used as a reference signal for the lock-in. All measurements were performed under ambient conditions  tip, which creates a strong, exponentially decaying field at its apex. The tip is then scanned across the sample, operating in tapping mode, allowing parameters, including topography and scattered light emission, to be measured with subwavelength resolution (


Lung adenocarcinoma (AD) is a common variant of non-small cell lung cancer (NSCLC). Programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) are promising immunotherapy targets and its expression may be an important biomarker of predicting clinical response. In this study, we evaluated PD-L1 expression in conjunction with clinicopathological characteristics and outcomes in resected lung adenocarcinoma.P = 0.219, highly correlated). PD-L1 was highly expressed in male patients and smokers with lung adenocarcinoma , while no associations were identified between PD-L1 expression and age, tumor size, clinical stage, positive pleural invasion, lymph node metastasis, or therapy methods. Overexpression of PD-L1 was a significant indicator of shorter recurrence free survival time and overall survival . Multivariate analysis revealed that PD-L1 expression was an independent risk factor for poor recurrence free survival and overall survival .This study included 133 cases of lung adenocarcinoma. PD-L1 expression rate in lung adenocarcinoma was 16.5% at the mRNA level and 13.5% at the protein level, and the kappa coefficient of the two examination methods was 0.824  rabbit monoclonal antibody. mRNA levels of PD-L1 were evaluated using PD-L1 overexpression is more frequently observed in male patients and smokers in lung adenocarcinoma. PD-L1 expression is an indicator of worse prognosis in surgically resected lung adenocarcinoma patients. Lung adenocarcinoma is a common variant of non-small cell lung cancer (NSCLC). In recent years, there have been dramatic advances in the treatment of lung adenocarcinoma because of the development of therapies targeting driver oncogene alterations, for example, drugs targeting the epidermal growth factor receptor (EGFR) mutation or the anaplastic lymphoma kinase (ALK) fusion , 2. HoweImmune checkpoints are inhibitory pathways that can maintain self-tolerance and protect peripheral tissues by modulating immune response . Overexpin situ hybridization at the mRNA level. Furthermore, we compared the expression of PD-L1 with clinicopathological characteristics and outcomes in lung adenocarcinoma.In this study, we evaluated PD-L1 expression using immunohistochemistry at the protein level and by The clinicopathological characteristics of the lung adenocarcinoma patients are summarized in Table The growth pattern of lung adenocarcinoma was classified into lepidic (16 tumors), acinar (65), mucinous (8), solid (18), papillary (19), and micropapillary (7) patterns. Pleural involvement was identified in 92 cases. Positive node metastasis was present in 53 cases.P = 0.219).Of the 133 cases of lung adenocarcinoma examined in this study, the PD-L1 expression rate in lung adenocarcinoma detected by IHC and ISH was 13.5% (18/133) and 16.5% 22/133), respectively. The two techniques were consistent in identifying 110 cases as PD-L1 negative, and 17 cases as PD-L1 positive. Representative cases of IHC and ISH results are shown in Figure 2/133, reP = 0.019); in smokers than non-smokers (P = 0.002); and in solid, papillary, or micropapillary growth pattern tumors compared to acinar and lepidic growth pattern tumors (P = 0.000). No significant association was detected between expression of PD-L1 and patient age , tumor size , clinical stage , pleural involvement (P = 0.553), or lymph node metastasis (P = 0.439).Expression of PD-L1 was significantly higher in male patients than in female patients (P = 0.000) and OS (P = 0.000)  and overall survival (OS) times were 32.00 and 34.70 months, respectively. Forty-eight patients experienced recurrence at a median follow-up time of 14.00 months. Twenty-one patients died at a median follow up time of 22.60 months. Kaplan–Meier analysis revealed that PD-L1 expression was significantly associated with a shorter RFS . A recent study compared and validated 6 commercially available PD-L1 monoclonal antibodies . Their results showed that all 6 antibodies had high levels of concordance (R2 = 0.76–0.99). They further suggested that previously described differences in PD-L1 expression in tissue are independent of the antibody used and likely attributable to tumor heterogeneity, assay- or platform-specific variables, or other factors [Evaluating human epidermal growth factor receptor-2 in breast cancer by IHC, which is economic and time-saving, has been successful. Efforts are being made to establish a method to evaluate PD-L1 expression by IHC. A multitude of detection PD-L1 IHC antibodies have been utilized, including the Ventana SP263 and SP142 clones, and the Dako 28–8 and 22C3 clones –13. VariThe PD-L1 expression rate in lung adenocarcinoma samples in our study was about 13%. Previously reported expression rates of PD-L1 using different IHC antibodies range from 8% to 55% in lung adenocarcinoma or NSCLC patients –18. ThisIn our study, we observed significant correlation of PD-L1 expression with clinicopathological characteristics. PD-L1 expression is associated with smoking habits. Smoking exposure may induce inflammatory as well as suppressive effects on the immune system . Others Expression of PD-L1 was reported to be correlated with poor clinical outcomes in a number of human cancers, including lung, melanoma, breast, bladder, ovarian, pancreatic, esophageal adenocarcinoma, and kidney tumors . In our In conclusion, we have demonstrated that expression of PD-L1 was present in 13.5% of lung adenocarcinoma patients and was associated with a poorer prognosis. Further studies are warranted to confirm PD-L1 expression, and the therapeutic effect of PD-1/PD-L1 blockade, in clinical trials.One hundred and thirty-three patients were enrolled in this study, and underwent a surgical operation with a final diagnosis of lung adenocarcinoma at Peking Union Medical College Hospital  between January 2012 and December 2015. For poorly differentiated cases, additional immunostaining for Napsin A and thyroid transcription factor 1 (TTF-1) was performed to confirm the final results.th, 2016.Clinical information for the patients was retrieved from the PUMCH digital database, including age, gender, smoking habit, clinical stage, treatment methods, RFS, and OS. Clinical stage was determined at the time of surgery, according to the American Joint Commission on Cancer (AJCC), 7th edition, tumor-node-metastasis staging system. RFS was defined as the time from operation to relapse or until the endpoint of the study. OS was calculated as the time from surgery to death or until the endpoint of the research, which was April 30For each tumor sample, hematoxylin-eosin staining (HE) slides were all re-reviewed by two experienced pathologists to confirm the final diagnosis. The growth pattern of lung adenocarcinoma was defined according to the guidelines of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system that includes lepidic, acinar, papillary, micropapillary, and solid predominant patterns. Both pathologists had no knowledge of the clinical information or PD-L1 expression status of these cases during the review. Additionally, the following pathological characteristics were evaluated: tumor size, pleural invasion, and node metastasis status.This study was approved by the Institutional Review Board of Peking Union Medical College Hospital. Informed consent was obtained from all patients before they underwent the operation.The selected area of representative morphology was labeled on the HE slides. The corresponding formalin-fixed paraffin-embedded (FFPE) primary tumor specimens were obtained from the Department of Pathology. A tissue microarray (TMA) construction machine  was used. Three core-tissue biopsies, 1.0 mm in diameter, were collected for each case.The IHC study was performed on formalin-fixed, paraffin-embedded TMA sections, with a thickness of 4 μm, using standard autostaining protocols on a Ventana Benchmark ULTRA autostainer . The PD-L1 antibody used in our study was SP263 . Tumors with positive membrane staining in more than 25% of the whole tumor were deemed positive, as suggested in a study by Ratcliffe et al. .in situ hybridization (ISH). An RNAscope FFPE 2.0 HD detection kit  was used according to the manufacturer’s instructions. Briefly, 5 μm-sections were deparaffinized, boiled with pre-amplification reagent for 15 minutes and submitted to protease digestion followed by hybridization for 2 h with a mixture containing target probes against human PD-L1, ubiquitin C (UBC) as a positive control, and the bacterial gene DapB as a negative control. Hybridization signals were detected with 3,3′-diaminobenzidine. Positive staining was indicated by brown punctate dots in the cytoplasm or nucleus. PD-L1 mRNA expression levels were categorized into 5 grades according to the manufacture’s scoring guideline: score 0, no staining or < 1 dot per cell; score 1, 1–3 dots per cell (visible at 20–40X); score 2, 4–10 dots per cell (visible at 20–40X); score 3, > 10 dots per cell and < 10% positive cells have dot clusters (visible at 20–40X); score 4, > 10 dots per cell and > 10% positive cells have dot clusters (visible at 20–40X). We grouped score 0, 1, 2 as negative, 3 and 4 as positive.For detection of PD-L1 expression, at the mRNA level, we used The relationship between PD-L1 expression and clinicopathological characteristics was analyzed using the chi-squared test. Survival analysis was calculated by the Kaplan-Meier method, the log rank test was used to compare the difference of two groups, and multivariate analysis using the Cox regression model was conducted to analyze the related clinicopathological features. All tests were 2-sided. P < 0.05 was considered statistically significant. The statistical analyses were performed using SPSS software .κ-value was considered as follows: value ≤ 0.40, poor to fair concordance; 0.41–0.60, moderate concordance; 0.61–0.80, substantial concordance; 0.81–1.00, almost perfect concordance.For analysis of concordance between the results of IHC and RNA ISH, the kappa value was calculated. The significance of the


Q) factor to ~18.5 from ~3.23 at room temperature and normal pressure, the limited effects of air damping on resonance behaviors at 10−2 and 105 Pa were demonstrated by characterizing graphene F-P resonators with open and micro-air-gap cavities. Then in terms of optomechanical behaviors of the resonator with an air micro-cavity configuration using a polished ferrule substrate, measured resonance frequencies were increased to the range of 509–542 kHz from several kHz with a maximum Q factor of 16.6 despite the lower Knudsen number ranging from 0.0002 to 0.0006 in damping air over a relative pressure range of 0–199 kPa. However, there was the little dependence of Q on resonance frequency. Note that compared with the inferior F-P cavity length response to applied pressures due to interfacial air leakage, the developed F-P resonator exhibited a consistent fitted pressure sensitivity of 1.18 × 105 kHz3/kPa with a good linearity error of 5.16% in the tested range. These measurements shed light on the pre-stress-dominated pressure-sensitive mechanisms behind air damping in in situ F-P resonant sensors using graphene or other 2D nanomaterials.We demonstrated a miniature and in situ ~13-layer graphene nanomechanical resonator by utilizing a simple optical fiber Fabry-Perot (F-P) interferometric excitation and detection scheme. The graphene film was transferred onto the endface of a ferrule with a 125-μm inner diameter. In contrast to the pre-tension induced in membrane that increased quality ( Due to zero pressure difference at both sides of the suspended membrane, the resonators with venting gas channels typically operate at lower pressures than a normal pressure, which also correspond to a comparatively low vibration damping condition. For instance, viscous damping is not the dominant dissipation process for the resonator reported in [Kn = λMFP/ldevice [λMFP is the mean free path of air molecules and ldevice is the graphene device characteristic length, ranges from 0.01 to 10. However, in reality, air damping is a significant viscous dissipation mechanism when nanomechanical resonators are operated in a moderate vacuum or near ambient conditions. Moreover, resonance characteristics in air micro-cavity also completely differ from those in a vacuum chamber [2 have found that the tension resulting from the fabrication process could increase the resonant frequency [These aforementioned experimental studies have significantly boosted the understanding of graphene resonance characteristics. However, in these experiments, graphene flakes are generally mechanically exfoliated by means of well-controlled forces ,11,14, a0−4 mbar . It shou0−4 mbar , whereinorted in  because /ldevice , where λ chamber ,25. Althrequency , especia2 ferrule endface with a diameter of 125 μm that is by far larger than several microns in previously reported resonators [2 mating sleeve was herein fabricated to make the comparative analysis of pre-stress-dependent resonance behaviors. Then, the resonance performance with varying pressure differences ranging from 0 to 199 kPa was tested by the presented simple optical fiber F-P interferometric resonance readout, which exhibited a pressure sensitivity of 1.18 × 105 kHz3/kPa that was by far superior to that represented by the cavity length changes for the same F-P sensor. The results validated the developed F-P resonator and the measured resonance frequencies in contrast to Q factors revealed the more strongly dependence upon the stress tensor in nanomembranes [Hence, in this paper, from the viewpoint of in situ applications of graphene-based F-P resonant sensors, we developed a simple and miniature micro-air-gap-based optical fiber F-P resonator covered with a chemical vapor-deposited (CVD) ~13-layer graphene circular diaphragm instead of beam-shaped diaphragm in  in ordersonators ,17,19,22embranes , in compembranes . 2 mating sleeve onto whose endface the graphene film, working as a light reflector, is adhered by van der Waals forces. The initial cavity lengths between the fiber end and ferrule endface for the two types of samples are confirmed by an optical spectrum analyzer (OSA)  via a 1-μm resolution translation stage. Then, the magnification scanning electron microscope  image of as-transferred multilayer film on the ceramic ferrule with a 125-μm diameter hole, as shown in ®). Note that the procedure of preparing the film from a commercial CVD 10–15-layer graphene sample  and transferring it onto the endface of a ferrule is same as that in [ that in . The thi that in . Ir in the F-P cavity in R1 and R2 are the reflectivities of the graphene membrane and fiber endface, respectively; Ii is the incident intensity; θ is the phase difference between two adjacent beams, and ξ is the coupling coefficient of cavity length loss [R2 is confirmed as 2.5% by measuring the interference of F-P cavity formed by two SMFs. As the lattice expands or contracts because of laser power-induced temperature change, the equilibrium positions of atoms and consequently the interatomic forces change, which induces the shift in the phonon energies and then membrane motion [t represents time; A, f, and ϕ are the vibration amplitude, frequency, and phase angle, respectively. According to the resonance motion of diaphragm, Ir in Equation (1) can be rewritten as:λ is the wavelength of incident light. In , Bunch egth loss . R2 is ce motion . Assuminδmem) of the suspended structure will modulate the reflectivity of the F-P interferometer created by both the graphene membrane and SMF. Since δmem creates a time-dependent variation of tension within the membrane, the δmem-related incident light intensity needs to be confined to an appropriate range rather than an undesirable higher light intensity, which otherwise will cause nonlinear mode coupling and internal resonances related with complex energy transfer between various vibrational modes [Q factor of the mechanical resonators are closely related with the dimension and physical properties of the resonator material, such as pre-tension, mass density and Young’s modulus, in addition to damping conditions. In this case, the resonance behaviors of pressurized graphene in air can be determined by extracting optically-actuated thermally-induced membrane displacements perpendicular to the graphene diaphragm.From Equation (2), the resulting motion  and 10−2 Pa (vacuum pressure), where viscous damping was remarkably different since the Knudsen number Kn was confirmed as around 0.0006 and 6350, respectively. For the former, viscous damping becomes significant. On the contrary, the latter is not in the viscous damping regime. Then regarding the limited impact of air damping on resonance behaviors, the conventional F-P sensor probe was also utilized to further investigate the pressure-sensitive resonance behaviors at pressures ranging from 101 to 300 kPa, i.e., a relative pressure range of 0–199 kPa, with a corresponding lower Kn value ranging from 0.0002 to 0.0006.f and Q of the two clamped circular graphene diaphragms at two typical pressures (105 and 10−2 Pa) representing viscous and free molecule flow damping regimes because of Kn = 0.0006 and 6350, respectively. Note that the two diaphragms are correspondingly adhered to the ferrule endfaces in the two types of sealed and open F-P probes as mentioned in The photothermal displacement spectrum from the graphene resonator contributes to analyzing the dependence on the primary effect suffering from the membrane thickness-dependent bending rigidity or initial pre-tension. Q factor of graphene-based nanomechanical resonators spans from 2 to 2 × 105, as it is strongly dependent on the sample fabrication and measurement conditions [Q (around 3.2–3.4) when the air pressure is reduced to 10−2 Pa from an atmospheric pressure, thereby implying a lower pre-stress value which is closely concerned with the interfacial energy between graphene and supporting substrates. In accordance with the membrane-to-plate behavior of 2D mechanical resonators with certain thickness [fair, fmem and fplate are the resonance frequency in air damping, XXX, and XXX, respectively; ρ is the mass density of graphene with certain adsorbates; ρair is the density of air; r, S, E, t, and υ are the radius, tension, Young’s modulus (1 TPa), thickness and Poisson’s ratio (~0.17) of graphene, respectively; Γ is a non-dimensionalized added virtual mass incremental factor as a function of mode shapes and boundary conditions. Note that Γ = 0.746 in the fundamental resonant mode f0,1. Hence, the resonance frequencies at various pressures enable the estimation of ρ and S simultaneously by fitting measured frequencies, along with the established continuum model. In this way, we estimated the pre-tension S0 to be 1.32 × 10−5 N/m for the resonator mentioned in ρ = 10ρg, where ρg is the mass density of pure graphene. The resulting equivalent mass density is similar to graphene resonators in [For the F-P resonator with open cavity configuration, no pressure gradient exists within the membrane, which indicates that the mechanical response in nditions . Herein,hickness , the reshickness :(3)fairators in ,12,13, wQ factor of ~18.5 with a higher pre-tension S0 of 0.022 N/m at normal pressure on basis of the aforementioned model. Furthermore, the Q factor increases to ~75.37 by lowering the atmospheric pressure to 10−2 Pa, although the value is much less than those reported in previous literature [−5 Torr [f under tensile tension, which conforms to the trend obtained in Equation (3). The small frequency shift of about 15 kHz also partly results from the limited pre-tension. As a result, the benefit of reduced air damping with decreasing pressure will gradually become remarkable, particularly for the resonator with greater pre-tension. Note that the tension is primarily caused by the fabrication process, where the friction between the graphene and the oxide surface stretches the graphene sheets across the trench or hole [2 ferrule-supporting suspended graphene was polished with diamond sheets in different grit sizes of 3 and 1 µm . The residuals on polished surface were cleaned by ultrasound equipment. ®, MS60, Guangzhou, China) of a ferrule endface before and after polishing. Small burrs and impurities at the edge of circular hole can be clearly found in In contrast, the F-P resonator with sealed cavity configuration in terature . A likel[−5 Torr ,13,17,19[−5 Torr ,16,38. IR-square of about 92.7%. Additionally, in terms of small fluctuations relative to the fitted output, a decent linearity of 5.15% was obtained due to fast dynamic response of the suspended membrane. After that, a conventional F-P interferometric readout scheme was also performed for the fabricated sensor to evaluate the presented F-P resonant detection. Referring to R-square of 53.5% in the negative going direction. Unfortunately, the sensor demonstrated a more inferior response in the positive going direction. It can be clearly observed that the measured three time results deviated from each other, particularly at the second cycle where an almost zero response occurred. For the remaining two cycles of positive measurements, an extremely low sensitivity of around 1.57 nm/kPa was recorded. It should be pointed out that during the F-P interferometric experiment, a broadband laser source  was used to illustrate the sensor, and the reflection spectrum was then monitored by an OSA (AQ6370C) with a wavelength resolution of 0.02 nm. With regard to the clamped circular graphene film made of a linear isotropic elastic material, based on the spherical shell equation, the relationship between the diaphragm deflection ω and the pressure change P is defined by [σ0 is the pre-stress of graphene that was confirmed as ~0.24 GPa on basis of the measured resonance frequency. Then a theoretical pressure sensitivity of 1121 nm/kPa was solved according to Equation (4), which exceeded, by far, the aforementioned measured 1.91 or 1.57 nm/kPa. The resulting load-deflection behavior primarily resulted from a lower pressure difference that was concerned with the slow air leakage of F-P cavity covered with large-sized CVD multilayer graphene film. Moreover, the phenomenon became more serious in pressure rise measurement than in pressure drop measurement because of longer air balance process in the air chamber. Although recent advances in graphene synthesis and processing have enabled demonstration of atomically-thin 2D membranes showing mechanical sturdiness and hermetic sealing [2 in cross-sectional area is generally chosen to reduce the possible risk of leakage from random defects in large-area nanomembranes [Referring to fined by :(4)P=4σ sealing ,41, a liembranes  or poorlf and Q) over the tested pressure range. Owing to the rising pre-stress tuned by the polished substrate, the measured f was increased to more than 500 kHz well above the frequency of 60–80 kHz in ρ = 10ρg mentioned above, an improved pre-tension S0 for the F-P resonator using the polished surface of a ferrule as film substrate was calculated to be 1.05 N/m. However, a slight frequency deviation up to about 33 kHz existed between them, which is to a great extent due to the presence of non-uniformly distributed adsorbates or polymethylmethacrylate (PMMA) residuals and the stress distributions in the graphene-substrate interface during membrane transfer and sensor fabrication as mentioned above. In the light of the aforementioned Equation (3) relating to fmem, fplate and f in the membrane, plate, and cross-over regime, respectively, it can be inferred from 5 kHz3/kPa with a good linearity error of 5.16% was achieved in the tested range, which is far below the theoretical predicted sensitivity of 1.32 × 107 kHz3/kPa in terms of the Equation (5) as follows:E and ρ are assumed as 1 TPa [ρg as mentioned above, respectively. The great deviation between the measured and predicted resonant frequencies possibly results from the equivalent density-dependent impurity and defect effects in transferred suspended graphene with a large membrane dimension, the pre-tensioned-membrane size effect and boundary instability of clamped circular graphene diaphragm in air damping. It should be added that the discrepancy between the measured values and predicted ones is also dependent on the presence of higher eigenmodes featuring the nonlinear oscillation mode coupling with rolling frequency multiplication components, which results from the alternating tension in graphene because of higher vibration amplitude comparable to the thin membrane thickness [hickness ,44. Accohickness , therebyQ factor can be determined by the full width half-maximum of the Lorentzian resonance peak; however, there is no exact dependence of Q on resonance frequency. However, as illustrated in the inset in Q factor decreases as a function of external pressure that is represented by pext, approximately proportional to 1/pext, which is well in agreement with the variation in [Q factor from ~13.3 to ~16.6 fluctuates around 14.9, which is weakly associated with fundamental frequencies. The average Q factor is ~14.9 for the resonator surrounding the air at normal temperature, which is obviously better than that with extremely low pre-tension (1.32 × 10−5 N/m) in Q factors are also superior to the results at atmospheric pressure in [Q factors from 17 to 600 and resonant frequencies from 7 MHz to 206 MHz at room temperature [Q factor for the resonator presented in this paper is relatively significant in the limited test frequency range. Note that it is known that the increase in membrane size enables to reduce f and Q in viscous damping, but to enhance Q in free molecule flow damping. Consequently, engineering structural size-dependent tensile stress in membrane-type resonators can further elevate Q by raising instinct energy stored in graphene membranes [Then, according to the inset in ation in . Furtherssure in ,22. Thenperature , the chaembranes .Q factor values are by far less than most of the results reported in previous literatures. The resulting primary reason is that those resonators in [Kn > 104. However, according to the remarkably reduced Q factors in reported experimental results, the resonators in [Kn decreases to the range of 10–50. Then when Kn < 0.01, air damping becomes a significant viscous dissipation mechanism, which causes the Q factor to drop sharply. Thus, the presented resonator in this paper exhibited a same order of Q factor as those working at normal pressure in [Q factor. This suggests that the adhesion conditions at the graphene-substrate interface should be controlled reasonably. Unfortunately, since the adsorbates would generate additional masses and tensions that will result in the dispersion of resonant responses among different samples, the damping mechanism-dependent Kn should be designed optimally by engineering membranes suspended on F-P resonators. In consideration of the film integration in resonators, the facile-fabricated and in situ F-P resonator is vital for dynamical performance evaluation in actual applications, along with its corresponding simple F-P photothermal actuation and detection scheme. Compared with previous graphene nanomechanical resonators reported in It is worth pointing out that the experimental results elucidate that a simple and miniature open or sealed optical fiber F-P pressure-sensitive resonator with large-scale graphene or other 2D diaphragms could be successfully developed without need of complicated free-space optical actuation experimental setups. In order to further elaborate the uniqueness of the developed F-P resonator, some typical experimental works on graphene nanomechancial resonators were summarized and listed in ators in ,11,12,15ators in ,22,31 shssure in ,22,31 anssure in . The thi−2 Pa due to the free molecule flow damping. Then according to the interaction with the air, the pressure-induced modal frequencies from 509 to 542 kHz were further identified with little dependence on Q ranging 13.3–16.6. Despite lower measured Q factors in comparison to the value up to 2 × 105 reported in previous studies where vacuum pressure of <10−6 Torr or low temperature of <50 mK were generally set, the experimental results herein demonstrated a pressure sensitivity of 1.18 × 105 kHz3/kPa with a linearity error of 5.16%. Although its sensitivity was far below the predicted one possibly because of impurity and defect effects in graphene, pre-tensioned-membrane size effect and boundary instability of clamped diaphragm in air damping, the fabricated graphene-based F-P resonator demonstrated a preferable response to applied static pressures, compared with a conventional F-P interferometer with same micro air-cavity configuration. Therefore, this study could shed light on the resonance behavior in situ observed in 2D nanomechanical resonators in air damping, along with strain-tunable substrate microstructure and thin film vacuum encapsulation.Two types of simple, miniature, and in situ mechanical F-P resonators with open and sealed cavities were fabricated to characterize the resonance behaviors of a nanothick graphene diaphragm suspended onto a large-area 125-μm inner diameter ferrule endface by using simple optical interference excitation and detection. The effects of gas pressure-induced damping and pre-tension in membranes on resonance characteristics were experimentally investigated in the absolute pressure range of 101 to 300 kPa at room temperature. Due to a smaller pre-tension in membrane, the micro air-cavity-based graphene device exhibited the lower resonance frequency of 59 kHz but remarkable Q factor of ~75.37 at 10


Programmed death-ligand 1 (PD-L1) is thought to play a critical role in immune escape by cancer, but whether PD-L1 expression can influence prognosis of patients with solid tumors is controversial. Therefore, we meta-analyzed available data on whether PD-L1 expression correlates with overall survival (OS) in such patients. PubMed, EMBASE and other databases were systematically searched for cohort or case-control studies examining the possible correlation between PD-L1 expression and OS of patients with solid tumors. OS was compared between patients positive or negative for PD-L1 expression using scatter plots, and subgroup analyses were performed based on tumor type and patient characteristics. Data from 59 studies involving 20,004 patients with solid tumors were meta-analyzed. The median percentage of tumors positive for PD-L1 was 30.1%. OS was significantly lower in PD-L1-positive patients than in PD-L1-negative patients at 1 year (P = 0.039), 3 years (P < 0.001) and 5 years (P < 0.001). The risk ratios of OS  were 2.02 (1.56-2.60) at 1 year, 1.57 (1.34-1.83) at 3 years and 1.43 (1.24-1.64) at 5 years. Similar results were obtained in subgroup analyses based on patient ethnicity or tumor type. The available evidence suggests that PD-L1 expression negatively affects the prognosis of patients with solid tumors. PD-L1 might serve as an efficient prognostic indicator in solid tumor and may represent the important new therapeutic target. Immune co-stimulatory and co-inhibitory receptors determined the functional outcome of T cell receptor (TCR) signaling and immune surveillance . Tumors PD-L1 also plays a key role in binding to PD-1 receptors expressed on activated T cells in T cell co-suppression and depletion –11. PD-LIn addition to serving as a therapeutic target, PD-L1 may also be useful as a prognostic biomarker . HoweverA total of 1,258 records were retrieved from PUBMED, EMBASE, Web of Science and EBSCO , 3 years (P < 0.001) and 5 years  were PD-L1-positive and 3,206 (64.4%) were PD-L1-negative. PD-L1 expression was associated with significantly worse OS at 1 year (P = 0.004), 3 years (P = 0.005), and 5 years  were PD-L1-positive and 1,404 (59.3%) were PD-L1-negative. PD-L1 expression was associated with significantly worse OS at 1 year (P = 0.017), 3 years (P = 0.010) and 5 years , 3 years P = 0.005) and 5 years , 3 years (P = 0.040) and 5 years  primary solid tumors in human patients; (2) The main content of the articles is to analyze the relationship between the expression of PD-L1 and the prognosis of solid tumors in patients; (3) a hospital-based or population-based case-control or cohort design, regardless of sample size; (4) immunohistochemical assay of PD-L1 expression as high and low PD-L1 expression; (5) all patients underwent surgery; and (6) adequate reporting of overall survival (OS) data. When eligible studies involved overlapping patient populations, only the most recent or complete report was included. Studies were excluded if they were letter, summary of meeting and review; if they were published in a language other than English; or if they failed to report adequate data; or they investigated metastatic tumors. Gray literature  was not included into this study. Reference lists within identified articles were also searched manually to identify additional articles.The primary outcome in the meta-analysis was OS. This outcome was compared between patients showing high or positive PD-L1 expression and patients showing low or no expression, as defined within the individual studies.Two researchers  independently screened studies for inclusion. Disagreements were resolved by discussion and, when necessary, consultation with a third author (S.Z). The first author's name, year of publication, country, number of patients, and tumor type were extracted from each study, and OS results for 1, 3 and 5 years were extracted from tables or Kaplan-Meier curves.2statistics. Survival results were analyzed using scatter plots generated in Prism 5 . The results for different patient groups were compared using the log-rank test. The threshold of statistical significance was defined as P < 0.05.Forest plots of OS were generated using RevMan 5.3 . Weighted risk ratio (RR) estimates were generated from pooled data using Mantel-Haenszel random-effects meta-analysis, unless no statistically heterogeneity, in which case fixed-effects meta-analysis was performed. Statistical heterogeneity in meta-analyses was assessed using Cochrane's Q and I