We propose a novel method to achieve tunable plasmon focusing in graphene/photonic-crystal hybrid structure exhibiting all-angle negative refraction at terahertz frequencies. A two-dimensional photonic crystal composed of a square lattice of dielectric rods is constructed on the substrate of a graphene sheet to provide the hyperbolic dispersion relations of the graphene plasmon, giving rise to the all-angle plasmonic negative refraction. Plasmon lensing induced from the negative refraction is observed. We show that the ultracompact graphene-based system can produce sub-diffraction-limited images with the resolution significant smaller than the wavelength of the incident terahertz wave. Moreover, by adjusting the Fermi energy of the graphene, the imaging performance of the proposed system can remain almost invariant for different frequencies. Our results may find applications in diverse fields such as subwavelength spatial light manipulation, biological imaging, and so forth. As the rapid development of information processing in the past few decades, miniaturization and integration have become the prevailing trend of electronic-photonic system used for digital communication. Suffered from the diffraction limit, traditional photonic devices are bulky and cannot be integrated with the electronic components on the same chip. Surface plasmon-based photonics offer a solution to this dilemma. Surface plasmons (SPs) are electromagnetic wave which propagates along the metal/dielectric interface and can be guided by metallic nanostructures beyond the diffraction limit1471012Graphene, a two-dimensional material where carbon atoms are arranged in a honeycomb lattice, has attracted significant attention due to its linear dispersion and zero electron density of states at the Dirac point141823In this paper, we show that all-angle negative refraction of plasmons can be achieved in graphene/photonic-crystal hybrid structure. We demonstrate that plasmon focusing based on the negative refraction can be used to attain subdiffraction-resolution imaging at THz frequencies. Our results show that the resolution of the image is significant smaller than the wavelength of the graphene plasmon. Furthermore, the focusing performance of the proposed structure can be maintained for different frequencies by changing the Fermi energy of the graphene.a and pillar radius r. The surface normal of the PC is along ΓM [(11) direction]. Ion-gel is sandwiched between TPX and ITO/SiO2 substrate. Gold patch on the graphene sheet is used as an electrode and ITO is used as the other electrode. In the following simulations, graphene sheet is treated as an ultrathin layer with thickness 0.5 nm, the radius of Si pillars is set as r = 0.3a, where a = 2 μm. Metal micro-particle, illuminated by an incident beam, can work as an optical antenna which can convert the incident light into a localized near-field. When such an antenna is placed on graphene, the high-momentum near-field components match the wave vector of the graphene plasmon, thus exciting graphene plasmonsT = 300 K), the graphene optical conductivity obeys a Drude dispersion model35Before the investigation of the properties of the propagating graphene plasmons, we need to evaluate the effective index of the graphene plasmons. The complex surface conductivity of graphene can be deduced from Kubo formula−13 s, which corresponds to the measurement under the DC mobility μ = 10000 cm2/(V·s)36εr1 and εr2, the dispersion relation of plasmon in graphene can be written as37In the following simulations, the relaxation time is set as τ = 6.4 × 10neff = kspp/k0.The effective index of the graphene plasmon can be obtained from Ef = 0.8 eV, we calculated the plasmonic band structures using the plane wave expansion methodω = 0.0468 × 2πc/a. M. In these cases, group velocity determined by ∇kω(k) points toward MΓM direction as illustrated in Next, we investigate the band structures of the graphene plasmon in the considered system. The eigenfunction of the graphene/PC hybrid structure was derived (see Methods). For the considered system at the Fermi energy ΓM direction, if the equifrequency contour is convex, the incident plasmon wave will couple to a Bloch mode that propagates into the graphene-PC region on the negative side of the boundary normal direction. As shown in k · ∇kkω ≥ 0, it means that the group velocity is not opposite to the phase velocity along the ΓM direction. Therefore, the negative refraction of the plasmon wave in the considered graphene-based system does not involve a negative effective index.When the propagating plasmon is incident from the graphene-TPX region to the graphene-PC region, the wave-vector component parallel to the interface is conserved so that the boundary condition is satisfiedc/a to 0.0468 × 2πc/a, i.e., from 6.96 to 7.02 THz. Compared to the previous design of AANR using PC structureSuch a negative refraction phenomenon can be used to realize plasmonic imaging with subwavelength resolution. To achieve better imaging performance, it requires that the graphene plasmon wave at any incident angle experiences negative refraction when entering the graphene-PC region. To achieve this phenomenon, the graphene-PC contour should be convex and larger than the graphene-TPX contour. In this case, the incident wave at any incident angle, from −90° to 90°, can be refracted with negative refraction angle in the graphene-PC region, which is named the all-angle negative refraction (AANR). From the calculation results, we find that AANR can occur in the first band. When the Fermi energy is set as 0.8 eV, the AANR frequency range is from 0.0464 × 2πa from the left-hand surface of the PC. Ez field in the considered system with Ef = 0.9 eV. Here the frequency is 0.0494 × c/a = 7.41 THz, which lies within the AANR frequency range. It is seen that the plasmon wave is focused on the right-hand side of the graphene-PC region. The central position of the image of the dipole is at a distance 1.20a from the right-hand surface of the PC. Similar plasmon imaging behavior can be achieved at different frequencies by choosing a suitable Fermi energy of graphene.To demonstrate how the AANR of the graphene plasmon can be used for THz imaging, we have performed finite-difference time-domain (FDTD) simulations with perfectly matched layer boundary conditions on the graphene-based hybrid system. The simulations were conducted via FDTD SOLUTIONS, a commercial 3D FDTD-method Maxwell solver. As shown in Ef = 0.6 eV and f = 6.03 THz, Ef = 0.7 eV and f = 6.51 THz, Ef = 0.8 eV and f = 6.975 THz, Ef = 0.9 eV and f = 7.41 THz, respectively. It can be seen from To evaluate the imaging quality, 0 to 0.187λ0 (λ0 is the wavelength of terahertz wave in vacuum) as the Fermi energy increases from 0.6 eV to 0.9 eV, which means that tunable imaging has been achieved at THz frequency range. Our simulations show that such a system can resolve two point sources, oscillating in phase, with a distance of For the comparison of the imaging resolution at different Fermi energy, we plot the FWHM of the point images versus the Fermi energy in In summary, we reported a novel design of graphene/PC hybrid structure to achieve tunable plasmon lensing. We showed that a 2D PC patterned on the substrate of a graphene sheet can realize all-angle negative refraction of the graphene plasmon in the first energy band, which results from the hyperbolic dispersion relations of the graphene/PC structure. We also showed that such a negative refraction of graphene plasmon can be electrically tuned by adjusting the Fermi energy of graphene, making adjustable wide-range negative refraction possible. In the presence of the tunable negative refraction effect, subdiffraction imaging was attained and the imaging performance can be maintained for different frequencies by changing the Fermi energy of the graphene. Our results suggest an effective mechanism for controlling the propagation of graphene plasmon and may find applications in ultra-compact subwavelength spatial light modulators.r and ε1 respectively, the Si cylinders are arranged in a square with a lattice constant of a, the dielectric constant of TPX is ε2. The graphene-Si region and the graphene-TPX region have different values of effective index for the in-plane plasmons.Consider a graphene sheet is deposited on a 2D PC, which is composed of a 2D array of Si cylinders surrounded by TPX background. Assume that the radius and the dielectric constant of Si cylinders is neff = kspp/k0 = ksppc/ω, where the wave vector of the graphene plasmon kspp can be described by In the THz frequency range, the optical conductivity of graphene obeys the Drude dispersion model  is the dielectric constant of Si or TPX. Since the energy of the plasmon is strongly confined at the graphene sheet, we only consider the Ez componentswhere kspp can be expressed by valid Helmholtz equationFor the propagating plasmon (TM mode), εspp(r) is the effective dielectric constant for the graphene-Si or graphene-TPX region. By expanding Ez(r) and εspp(r) in reciprocal space, the eigenfunction of our system can be derived aswhere ψ(G) and Ez(G) are the Fourier expansion coefficient of εspp(r) and Ez(r). ψ(G) can be expressed as,where the Combining To facilitate the calculation, we define three matrices A, B, and C:Combining β = ω2/c2. By changing the form of the where By using Scheme for fabricating our proposed device is shown in On the other hand, a monolayer graphene is fabricated on Cu substrate using chemical vapour deposition (CVD) methodHow to cite this article: Zhong, S. et al. Tunable plasmon lensing in graphene-based structure exhibiting negative refraction. Sci. Rep.7, 41788; doi: 10.1038/srep41788 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Moreover, we combine GHPM with metal-insulator-metal (MIM) structure to propose another symmetrical GHPM with a modulation depth of 0.6 dB·μm−1. Our modulators which utilize the light-matter interaction tuned by electro-doped graphene are of great potential for many applications in nanophotonics.Electro-optical modulators which work at the near-infrared range are significant for a variety of applications such as communication and sensing. However, currently available approaches result in rather bulky devices which suffer from low integration and can hardly operate at low power consumption levels. Graphene, an emerging advanced material, has been widely utilized due to its tunability by gating which allows one to realize active optical devices. Plasmonic waveguides, one of the most promising candidates for subwavelength optical confinement, provide a way to manipulate light on scales much smaller than the wavelength. In this paper, we combine the advantages of graphene and plasmonic waveguides and propose a tunable graphene-based hybrid plasmonic modulator (GHPM). Considering several parameters of the GHPM, the modulation depth can reach approximately 0.3 dB·μm High-integration density of optical devices and miniaturization of device size remain major challenges in micro and nanotechnology. Due to the existence of the diffraction limit, traditional optical devices are difficult to operate in micro-nano size. Plasmons, the collective oscillations of valence electrons in conducting materials, possess a number of appealing properties for photonic technologies, the most salient of which are (1) their small spatial extension compared with the light wavelength; (2) their strong interaction with light; (3) the huge optical enhancements produced by the strong interaction. Compared to other waveguides, plasmonic waveguides can break the diffraction limit and provide subwavelength optical confinement by storing optical energy in electron oscillations within dissipative metallic regions8. Therefore, plasmonic waveguides have been regarded as one of the most promising candidates for manipulating light on nanoscale.The need for fast, compact and low-energy consumption electro-optical modulators has motivated research into optical structures capable of guiding light with deep subwavelength confinement10. (2) High speed operation. With a carrier mobility as high as 200,000 cm2/(Vs) at room temperature  in our simulation), graphene-based electronics may have the potential to operate at ultrafast condition (over hundreds of GHz)11. The Fermi energy and hence the optical absorption can be rapidly modulated via band-filling effect13. (3) Strong light-graphene interaction. A monolayer graphene can possess a much higher optical absorption of ~2.3%, which is much higher than that of compound semiconductors at the same thickness14. What’s more, the strong plasmonic response of graphene also makes it a promising material to manufacture highly integrated devices. For graphene plamsonics, there are two classes: propagating (waveguide) and localized (nanostructure) graphene plasmons. And for coupling of graphene plasmons, there are also two classes: near-field (directly) and far-field (phase) coupling. Recently, some novel processes based on phase-coupling scheme of localized graphene plasmon resonances have been proposed to realize ultra-high contrast optical modulations16. (4) Compatibility with CMOS processing. During the past decade, graphene-based optoelectronics integrated with CMOS processing have been already demonstrated that makes it attractive in numerous applications such as graphene optical modulators17, detectors and sensings19. Based on these advantages, graphene-based modulators will be competitive with ultrafast modulation speed and low operation voltage across a broad optical bandwidth. Although there are many kinds of graphene-based modulators has been demonstrated20, it is still largely unexplored to combine the graphene with plasmonic waveguides.Graphene, a single layer of carbon atoms in a hexagonal lattice, holds an attractive potential to realize fast and compact optoelectronic devices. For applications in optical modulators, graphene has several unique characteristics. (1) Broad optical bandwidth. Graphene has a constant absorption from visible to infrared wavelengths which covers the optical fiber communication bandwidth−1 can be obtained at the wavelength of 1550 nm. What’s more, combining with the metal-insulator-metal (MIM) structure, the modulation depth can reach 0.6 dB·μm−1. These results open a viable route toward electro-optical modulation within technologically important frequency range.In this paper, we propose a tunable graphene-based hybrid plasmonic modulator (GHPM) combining the advantages of graphene and plasmonic waveguides. By realistic simulation, a significant modulation depth of ~0.3 dB·μm24 to simulate the plasmons dispersion.Before describing the structure of our device, it is essential to explore the optical response of monolayer graphene firstly. Whether our device is modulated by the exciting graphene plasmons or interband absorption, the result is demonstrated as follows. The graphene plasmons dispersion is shown in Fig. EF, the property of graphene performs as the interband absorption due to the strong quantum quenching via coupling to interband absorption. And in our research , ћω is always larger than 2EF so that the property of graphene shows as interband absorption instead of plasmon modes excitation. Incidentally, interband absorption modulates the propagating modes by affecting the graphene conductivity derived by Kubo formula (details see Methods) and further changing the refractive index as shown in Fig. Figure EF ≈ 0.4 eV. Due to the effect of optical Pauli blocking here, the optical absorption of graphene is close to zero. This effect is based on the change of graphene optical conductivity induced by the shift of the Fermi energy produced by electrical doping (details see Methods). To completely block optical absorption in graphene at the wavelength of 1550 nm, we need to shift the Fermi energy from pristine values of EF = 0 to EF = 0.4 eV.As shown in Fig. m and diameter d separated from a silicon slab of permittivity εd and thickness hd by a nanoscale dielectric gap of permittivity εs and thickness h. And a monolayer graphene is inserted between the silicon slab and the silica substrate. The dielectric material surrounding the silver nanowire is the same material used as the substrate. In our simulation, the electrodes are far enough on the guide mode so that those effects can be neglected. In order to clearly display the structure of our device, we neglect the cladding surrounded the metal nanowire in Fig. In this paper, we propose a plasmonic modulator tuned by a monolayer graphene. This device is compatible with the conventional integrated circuits process. Figure d = 12.25 and εs = 2.25 at 1550 nm29. The refractive index of Ag is 0.14526 + i11.35926. At first, the cylinder diameter, gap thickness and silicon slab thickness are set at 200, 4 and 50 nm, respectively. The conductivity of graphene is derived above. In the following study, we study the GHPM firstly, in which the modulation is realized by shifting the Fermi energy by electrical doping from 0 eV to 0.4 eV at the wavelength of 1550 nm. Then, we adjust the cylinder diameter d, the dielectric gap width h and the silicon slab width hd to control the modulation depth.In the simulations, we choose the working wavelength at 1550 nm. Figure −1 27), the modulation depth of our modulator can reach approximately as high as 0.3 dB·μm−1 at low gating voltages where the cylinder diameter, gap thickness and silicon slab thickness are set at 200, 4 and 50 nm, respectively. Meanwhile the insertion loss is approximately 0.02 dB·μm−1 which can be neglected. To further research the relationship between modulation depth and the structure parameters, we calculate the modulation depth by varying the cylinder diameter d, the dielectric gap thickness h and the silicon slab thickness hd. Relevant results are shown in Fig. Here we mainly analyze the modulation depth of this proposed modulator. Compared to the previous hybrid modulators  waveguides29. Although IMI waveguides suffer lower propagation loss, the MIM waveguides provide tighter modes confinement near the graphene layer due to the SPPs modes coupling. As the modes distribution shown in Fig. −1 which is higher than that of GHPM where the cylinder diameter, gap thickness and silicon slab thickness are set at 200, 4 and 50 nm, respectively. Meanwhile the insertion loss is 0.05 dB·μm−1 which is much smaller than the value of modulation depth.Actually, there are many proposed plasmonic waveguides utilizing the insulator-metal-insulator (IMI) structure to achieve long range propagation−1 is achieved for a broad band of wavelengths, from 1350 nm to 1600 nm. Another significant parameter shown in Fig. As shown in Fig. As shown in Fig. −1. What’s more, the modulation depth of the SGHPM is achieved a higher value (~0.6 dB·μm−1) than that of the GHPM. Our hybrid modulators have a great potential in graphene-based nanoscale optical devices.In this paper, we have proposed a tunable graphene-based hybrid plasmonic modulator (GHPM) combining the advantages of graphene and plasmonic waveguides. The modulated optical signals are obtained by electrically tuning of the graphene’s refractive index and the subwavelength confinement is achieved via plasmonic waveguides. The numerical simulations at the wavelength of 1550 nm have shown that the GHPM with relatively low loss and nanoscale light confinement can gain an attractive modulation depth of nearly 0.3 dB·μm30. At temperature T = 296 K, the conductivity σ of graphene is given bytotal is the conductivity of monolayer graphene which consists of intraband conductivity σintra and interband conductivity σinter and ћ is the reduced Plank’s constant. σ0 = 60.8 μS, λ = 1550 nm, relaxation time τ1 = 1.2 ps for interband conductivity and τ2 = 10 fs for intraband conductivity are constants, so that the conductivity of graphene is calculated as a function of Fermi level EF. The permittivity of monolayer graphene is derived byIn our research, as relative discussion proposed in the text, the optical response of graphene is described by the conductivity which is modeled utilizing Kubo formula31, as shown in Figs EF is the Fermi level at gate voltage Vg, vf is the Fermi velocity ~106 m/s, and α = ε0εd/(e × hd) is the capacitor constant. In the case of hd = 20 nm, when the gate voltage is swept from 0 to ~8 V, EF changes from 0 to ~0.4 eV to achieve modulation. Thus the proposed modulators can be electrical tuned through electric field effect.In our proposed modulators, the carrier concentration in monolayer graphene is dynamically controlled by employing a top-gate voltageThe mode properties are investigated by means of the finite-element method (FEM) with the scattering bound condition.Mp is given byER is the extinction ratio and L is the active region length. The ER is calculated byPmax and Pmin is the maximum and minimum electromagnetic power, respectively. The Pmax and Pmin are given bykmax and kmin is the maximum and minimum imaginary part of the effective mode refractive index, respectively.The modulation depth Aeff/A0), where A0 is the diffraction-limited mode area and defined as λ2/4, and the effective mode area Aeff is defined as the ratio of the total mode energy and the peak energy density which is given byWm and W(r) are the electromagnetic energy and energy density, respectively .The normalized effective mode area is defined by (f3dB) is calculated byR (~600 Ω) and C (~0.2 pF) are the total resistance and total capacitance of modulators, respectively. After considering the contact resistance and quantum capacitance of monolayer graphene33, the modulation speed of the proposed modulators is ~1.3 GHz. And the energy consumption of our modulators are calculated byVpp ≈ 8 V is the peak-to-peak voltage here. 1/4 comes from the fact that in an NRZ signaling scheme, and for a random bit sequence, one complete charge/discharge cycle occurs on average once every four bits32. Thus the energy consumption of our modulators is at the level of 1 pJ/bit.Here we briefly evaluate the modulation speed and the energy consumption of our proposed modulators. Since the two modulators have the same basic structure, their modulation speed and power consumption are approximately equal. The modulation speed which can be described by 3 dB bandwidth (


New synthesis routes to tailor graphene properties by controlling the concentration and chemical configuration of dopants show great promise. Herein we report the direct reproducible synthesis of 2-3% nitrogen-doped ‘few-layer’ graphene from a solid state nitrogen carbide a-C:N source synthesized by femtosecond pulsed laser ablation. Analytical investigations, including synchrotron facilities, made it possible to identify the configuration and chemistry of the nitrogen-doped graphene films. Auger mapping successfully quantified the 2D distribution of the number of graphene layers over the surface, and hence offers a new original way to probe the architecture of graphene sheets. The films mainly consist in a Bernal ABA stacking three-layer architecture, with a layer number distribution ranging from 2 to 6. Nitrogen doping affects the charge carrier distribution but has no significant effects on the number of lattice defects or disorders, compared to undoped graphene synthetized in similar conditions. Pyridinic, quaternary and pyrrolic nitrogen are the dominant chemical configurations, pyridinic N being preponderant at the scale of the film architecture. This work opens highly promising perspectives for the development of self-organized nitrogen-doped graphene materials, as synthetized from solid carbon nitride, with various functionalities, and for the characterization of 2D materials using a significant new methodology. In recent years, graphene has attracted an enormous amount of attention thanks to its extraordinary electronic, optical, mechanical and thermal properties, which make it a promising material for a wide range of applications, including energy conversion and storage, electrochemistry, electronics, sensors and solar cells8. Recently, Ferrari et al.9 published a roadmap for graphene, highlighting both fundamental and technological challenges in the field. The authors focus on different ways to synthesize tailored graphene properties. Among the properties that need to be fully controlled in many applications are electronic properties, and synthesizing remains challenging.Graphene, a two-dimensional carbon material, consists of a single layer of sp13. Introducing dopants in graphene can tune the electronic properties of the modified material and change it from an n-type into p-type semiconductor. Such a perspective is encouraged by the story of nitrogen doped carbon nanotubes (N-CNT), which greatly extended the applications of such a material16.Theoretical and experimental studies have revealed that the semi-conductor properties of graphene-based materials can be controlled by doping graphene materials with heteroatoms, including nitrogen20, segregation growth21, solvothermal process22, arc discharge23, or by post-synthesis treatment, including thermal treatments25, plasma treatments28, or hydrazine hydrate treatments29. The direct synthesis methods have the potential to create higher homogenous doping within the bulk graphene than post-synthesis treatments, which only lead to surface doping. Most of these methods enable the incorporation of nitrogen contents within the first at.%, with various bonding configurations including pyridinic N (two C-N bonds in a hexagon), pyrrolic N (two C-N bonds in a pentagon) and quaternary N (three sp2 C-N bonds) ones. The advantages of nitrogen-doped graphene have been highlighted in many recent papers, including better electrochemical activities than noble metal catalysts to reduce CO2 gas30, almost double reversible discharge capacity compared to pristine graphene due to the large number of surface defects induced due to doping by nitrogen31, a high activity rate, long-lasting stability and outstanding crossover resistance for electrocatalysis of oxygen reduction reaction in alkaline medium32. According to a review by Wang et al.12, the main challenges remain the need for large-scale N-doped graphene materials, as well as better control of the nitrogen concentration, bonding and depth distribution within the graphene material. Our paper focuses on such objectives by exploring the ability of pulsed laser deposition (PLD) to synthetize solid nitrogen-carbon sources as precursors for nitrogen-doped graphene films. PLD has been less well studied than other methods to obtain graphene films, but is a versatile deposition method, known to enable a wide range of film nanostructures and compositions, sometimes beyond the limit of solubility33. This approach may be particularly fruitful for the synthesis of solid carbon graphene precursors containing a wide range of heteroatom concentrations, and thereby making it possible to study their catalytic transformation into doped graphene films.In recent years, several approaches have been proposed to synthesize nitrogen doped graphene (NG) films either by direct synthesis, including chemical vapor deposition35 by depositing few-layer self-organized pure graphene (fl-graphene) by vacuum thermal annealing, in the presence of a metallic Ni catalyst, of a solid-state carbon source constituted of an amorphous carbon film (a-C). We previously showed that a femtosecond laser is particularly suited to deposit very thin layers of a-C, with extremely low internal stress36 and an architecture of predominantly Csp2 rings37. The carbonaceous films can be converted into graphene by in situ vacuum thermal annealing in the presence of a nickel thin film catalyst. Moreover, PLD, optionally combined with plasma assistance, has also been shown to be capable of incorporating up to 28 at.% of nitrogen in the a-C film to form an amorphous nitrogen-containing a-C:N film, by ablating the carbon source in the presence of nitrogen gas40. The fl-graphene films have previously been shown to be highly efficient as active substrates for molecular diagnosis by surface-enhanced Raman spectroscopy (SERS) and for electrografting, to develop new high-performance electrodes for electrochemical detection41.To prepare NG films, we exploited our recent successOur NG films were obtained in a three-step process, (i) synthesis of a-C:N films by femtosecond pulsed laser ablation, (ii) synthesis of a super-imposed metallic nickel film by thermal evaporation, and (iii) thermal annealing in vacuum, to generate the nitrogen-doped graphene films on the top surface of the Ni catalyst. Our nanoscale investigations of the architecture and chemistry of NG combined classical analyses with an original Auger mapping investigation, to the best of our knowledge never previously undertaken, which provided significant insights into the development and control of graphene-based thin layers.2 substrate. The amorphous carbon nitride (a-C:N) and Ni catalyst layers were synthesized successively by femtosecond pulsed laser deposition (fs-PLD) and thermal evaporation, respectively. A reference a-C film with no nitrogen incorporation was also synthesized. Fig. NG films were synthesized by vacuum annealing of a sandwich type of Ni/a-C:N architecture deposited on a SiO46. The thickness of a-C film usually ranges between 2 and 40 nm (and even 80 nm in the case of a-C:Si:H film), whereas the thickness of Ni superimposed films range between 20 and 550 nm, but most between 100 and 200 nm. Consequently, we chose 10 nm for the a-C:N and 150 nm for the Ni film, to be as close as possible to the most widely published conditions with similar film architecture but without nitrogen. According to Koh et al.47, for the formation of graphene from PLD, a Ni catalyst is preferable, due to the adequate combination of carbon solubility and diffusion rate, compared to the other metals Cu, Co and Fe. The a-C(:N)/Ni films were further annealed in vacuum at 780 °C for 30 minutes and cooled down naturally to room temperature. Whatever the nature of the original a-C and a-C:N films, Fig. 48, our process is consistent with a three-step growth synthesis involving (i) dissociation of solid carbon thin film, (ii) dissolution and diffusion of carbon/nitrogen in the metal during heating at high temperature, and (iii) segregation and/or precipitation of carbon/nitrogen atoms at the surface of the metal either at the growth temperature when the solid solution has been saturated, or during cooling because of the decrease in carbon solubility of the metal.A 10 nm thick amorphous carbon nitride (a-C:N) thin film was prepared by focusing the femtosecond laser beam on a high purity graphite target, with a constant energy density. Nitrogen was incorporated in the carbonaceous films by introducing nitrogen gas at pressures of 0.5, 1 and 10 Pa during laser irradiation. An additional nitrogen pressure of 5 Pa was coupled with a substrate bias of −250 V to increase the nitrogen content in the film through the reactivity of the plasma. An increase in nitrogen pressure from 0.5 to 10 Pa without bias assistance increases the nitrogen content in the a-C:N films from 4 to 16 at.%. Additional bias associated with the nitrogen gas pressure of 5 Pa makes it possible to reach a nitrogen content of 21 at.%. An increase in nitrogen gas pressure of more than 5 Pa with bias assistance will not increase the nitrogen content in the film higher than the previous value. The present set of experiments thus allowed us to explore a-C:N films as N-doped graphene precursors, with an initial nitrogen content ranging from the 4–21 at.%. Following deposition of the carbon film, a 150 nm thick nickel film was deposited by thermal evaporation on top of the a-C(:N) film. The thicknesses of 10 nm for a-C:N and 150 nm for Ni were fixed based on previous published works, including ours, on the synthesis of graphene on a “substrate/a-C/Ni” of similar architecture, followed by thermal heatingThe investigation of the chemical forms of carbon and nitrogen in N-doped graphene is critical for the control of the film properties. The nitrogen concentration in the N-doped graphene films, as deduced from XPS, ranged from 2.0 to 2.9 at.%, see summary in Table Indeed nitrogen dissolution and/or diffusion in the nickel layer could be much lower than for carbon. Thus, the variability of nitrogen concentration in the a-C:N films cannot be considered as a key to obtaining a wide range of nitrogen contents in N-doped graphene, using the experimental parameters investigated here.Gr) and depicted in Fig. Gr . Two other contributions, labelled CB  and CDis  were also detected.Figure 49. CGr is related to graphitic (Csp2 hybridized) carbon. CB is related to deleterious (Csp3 hybridized) carbon on carbon at the periphery of the graphene domains. The origin of the CDis corresponds to residual carbon dissolved in solid solution in the Ni catalyst. Such a contribution can be attributed to the “transparency” of the graphene layers (4 layers represent a thickness of less than 2 nm) to C1 photoelectrons emitted by carbon atoms dissolved in the nickel catalyst close to the Ni/graphene interface, and/or to residual areas of the surface not fully covered by the graphene film. The C1 contributions in the four N-doped graphene films were similar, and only the case of the NG3 films is depicted in Fig. Gr/CB ratio decreased from 2.38 for the pure graphene to an average of 1.09 (standard deviation 0.1), due to the presence of N atoms scattered over the graphene sheets. Ten percent of the carbon atoms were bonded to nitrogen  and a residual 2–3% was bonded to oxygen  which was not detected in the pure graphene. Wang et al.26 reported similar results, indicating that oxygen may be chemisorbed in the presence of pyrrolic and pyridinic nitrogen, which could be an advantage for some applications, such as fuel cells. Concerning the XAS investigations, Fig. 50. They These peaks were attributed to the sp2 hybridization of graphitic carbon, in agreement with the graphitic component (CGr) quantified by XPS. These peaks dominate in HOPG. The XAS spectra of both graphene and NG3 also showed a significant increase in two other small features located in the C1s→π* region (286.8 and 288.6 eV), corresponding to interlayer states, whose interpretation is still under debate in the literature. They are frequently attributed to functionalization  or to the dispersion of three dimensional unoccupied bands in graphite51. It is interesting to note that the contribution of these interlayer states is higher in graphene than in HOPG, and in NG3 than in graphene, at the expense of a decrease in the C1s→π* and C1s→σ* peaks. Thus, the interlayer states may can be attributed to the CB carbon localized at the periphery of graphene domains, as detected by XPS . Thus, the interlayer states mainly detected at 286.6 and 288.6 eV can both be attributed to edge carbon or carbon bonded to nitrogen or oxygen, without being able to distinguish their respective contributions more precisely at the present stage of investigation. By comparing the structure of carbon spheres with and without nitrogen concentrations in the same range as our graphene films (2.5–3.5%), using XAS, Ray et al.52 recently observed interlayer states at 287.6 and 288.6 eV they attributed to C-H, C=O and C=N bonds, in agreement with our observations. The XAS and XPS N1s spectra revealed even more precise information on the type of bonding between C and N. As the N1s spectra for the four different nitrogen concentrations of N-doped graphene films were similar, only the case of the NG3 films is depicted in Fig. Their assignments are based on previous interpretations of graphene films obtained using metallic catalystsXPS Fig. . The conons Fig. . Thus, t53 and by XAS analysis57, a predominant pyridinic contribution (35–41% deduced from XPS) was detected at 398.6 ± 0.5 eV by XPS, at 398.9 ± 0.5 eV by XAS. The relative preponderance of pyridinic nitrogen is particularly interesting for highly active and stable electro-catalysts dedicated to oxygen reduction activity32. A contribution centered at 401.0 ± 0.5 eV (XPS) and 400.9 ± 0.5 eV (XAS) may correspond to N bonded to C in amine/amide groups, or in various types of quaternary N incorporated in six-fold aromatic cycles, including pyrimidine. The XPS peak may be split into two contributions, as observed by Wang et al.12, with a lower contribution at 400.7 ± 0.5 eV corresponding to pyrrolic N, and a higher contribution at 401.4 eV ± 0.5 eV corresponding to quaternary N. Another contribution centered at 404.3 eV ± 0.5 eV (XPS) and 405.0 ± 0.5 eV (XAS) may correspond to either amino groups including saturated heterocyclic amine (up to 3 N incorporated in the six fold ring), or to pyridinic oxide. Since our concentration of nitrogen in N-doped graphene was rather low and considering the detection of oxygen by XPS, the presence of pyridinic oxide was suspected. The XAS contribution at binding energies higher than 407 eV corresponds to the continuum of the XAS spectrum of nitrogen. The complete XPS N1s results and interpretation related to all films are reported in Table XPS and XAS spectra are depicted in Fig. As a primary investigation tool for graphene film architecture, RAMAN spectra, obtained at an excitation wavelength of 442 nm (2.81 eV), are shown in Fig. −1, 1580–1582 cm−1 and 2650–2669 cm−1 ranges, respectively. Such narrow ranges for each RAMAN band are consistent with strong similarities between the graphene films, and the low nitrogen content of the four N-doped graphene films did not have a significant impact on the general shape of the Raman spectra The G band originates from the first order Raman scattering process and corresponds to the doubly degenerate E2g phonons at the Brillouin zone center. The rather low intense D band originates from the breathing mode of graphitic clusters, and corresponds primarily to the presence of defects in the graphene. This band, characteristic of defects , is located at half the frequency of the 2D band. Additional RAMAN investigations were conducted at an excitation wavelength of 633 nm (1.96 eV). Whatever the film, the G band remained in the same position compared to 442 nm, whereas both the D and 2D bands underwent a significant blueshift. These average blueshifts, at 633 nm compared to 442 nm, of the D and 2D bands from all synthesis conditions, were respectively +38 and +82 cm−1. The dependence of the frequency of both D and 2D bands on excitation energy is consistent with dispersive behavior due to double resonance. According to Malard et al.58, the D and 2D band frequencies upshift linearly with increasing excitation energy, which is about 50 cm−1/eV for the D band and about 100 cm−1/eV for the 2D band. Considering the difference of 0.85 eV between our two excitation energies (2.81 and 1.96 eV), such an upshift in energy dependence leads to a blueshift of +42 cm−1 for the D band, of +85 cm−1 for the 2D band. This is in agreement with our experimental observations of blueshifts of +38 cm−1 and +82 cm−1, related to our D and 2D bands, respectively. Compared to undoped graphene, nitrogen incorporation led to higher frequencies (blueshift) of the G band (+3–7 cm−1), D band (+10–12 cm−1) and 2D band (+8–12 cm−1). In agreement with Zafar et al.59, we observed both G and 2D blueshifts, the latter being interpreted as a possible effect of both electron n doping and compressive strain in the graphene sheets, probably due to different thermal expansion of Ni and graphene, as observed by other authors who used copper for graphene synthesis60. Additionally, the I(D)/I(G) ratio was not significantly affected by the nitrogen doping: the ratio was 0.298 in the undoped graphene film, and increased slightly from 0.310 to 0.339 with the increase in N content. These ratios are rather low compared to nitrogen doped graphene obtained by other methods61, but are consistent with crystallite sizes in the 27–30 nm range, according to the Tuinstra-Koenig relation,All spectra displayed three main G, D and 2D bands in rather similar positions with similar shapes, within the 1331–1341 cm62. The significant 2D band corresponds to the second order of zone-boundary phonon. The 2D band is sensitive to lattice defects and doping in graphene63. In bulk graphite, the 2D band consists of two contributions  whose height is roughly ¼ and ½ the height of the G peak, forming a dissymmetric 2D band. In pure single sheets of graphene, the 2D peak exhibits only one sharp contribution and can be up to four times more intense than the G band. In the films investigated here, the I(2D)/I(G) intensity ratio started from 0.303 and pure graphene, with a progressive decrease from 0.265 to 0.208 with an increase in N content. This range of I(2D)/I(G) ratios is consistent with the formation of few-layer graphene54, as detailed in the following section. Since the intensity of 2D is depends to a great extent on the electron/hole scattering rate, which is affected by lattice defects as well as by charge carrier doping, our lower I(2D)/I(G) ratio together with higher I(D)/I(G) ratio is consistent with an effect of the charge carrier doping by nitrogen, with no significant effect on the number of lattice defects or disorders. However, the observed decrease in the I(2D)/I(G) ratio and the increase in the I(D)/I(G) ratio are much less than those observed with N-doped graphene obtained by segregation, for a similar range of nitrogen content21. The shape of the 2D band of our pure graphene and N-doped graphene films was rather symmetric, which is consistent with a few-layer graphene architecture with weak interlayer coupling. Deconvolution of the 2D bands is known to be a powerful way to quantify the number of graphene sheets, from one monolayer up to about five layers64 Such a deconvolution is depicted in Fig. 65. However, many of these different processes have very close energy separations, and it was experimentally shown that the number of Lorentzian functions necessary to correctly fit 2D mode of trilayer graphene is six, each with a FWHM in the 30 cm−1 range67. In the studies cited, the graphene investigated was obtained by mechanical cleavage. However, the deconvolution of the 2D bands is also performed in a similar way for graphene films deposited by other methods, including CVD process. For example, Fang et al.68 also observed a 2D band with a FWHM of 28 cm−1 for a single monolayer of graphene, of about 64 cm−1 for a bilayer AB stacking, with a decrease in the 2D/G ratio in the latter case. Wei et al.17 also observed a similar dependence between the 2D band FWHM and the number of layers, with nitrogen doped graphene obtained by CVD. In the present work, the 2D band of all investigated graphene films was successfully deconvoluted into six contributions, each of which with a FWHM of 33 cm−1. Thus, we conclude that RAMAN investigations are consistent with a pure graphene and N-doped graphene films constituted of a three-layer architecture, which was confirmed by the AES mapping depicted below. The trilayer graphene films show a rather symmetric 2D peak, which is consistent with Bernal (ABA) stacking, rather than rhombohedral (ABC) stacking, in agreement with the observations reported in69.where λ is the Raman wavelength. The rather stable I(D)/I(G) ratio versus nitrogen doping showed that the nitrogen doping range we investigated did not significantly modify the bonding disorder and vacancies in the graphene sheets whose size remained in the same order of magnitude as that of pure graphene. Thus, the crystallite size of the nitrogen-doped graphene remains rather stable compared to pure graphene. This appears to contradict some previous published works on nitrogen doped graphene, except that is should be recalled that in such studies, the pure graphene used as reference is much more ordered than our filmset al.70 from angular resolved XPS (ARXPS). These authors showed that ARXPS can be used to accurately determine the average thickness of the graphene films, as long as the growth proceeds layer-by-layer. Obviously, their CVD process is not exactly the same as our PLD process, in so far as the carbon species come from the surrounding atmosphere in the former process, and from the Ni catalyst layer in the latter. However, that may be, the methodology, summarized in the Supporting Information, enables determination of the thickness of the graphene, and hence estimation of the number of graphene layers. This approach was compared with the previous RAMAN conclusions obtained by fitting the 2D band. From the ARXPS intensity of a graphene monolayer sample with respect to a highly-ordered pyrolytic graphite (HOPG) sample (which can be approximated as an infinite number of graphene layers), Tyagi et al.70 quantified the attenuation length of the C1 photoelectrons, depending on the photoelectron emission angle. A stepwise model for the C1 photoelectron intensity was then developed by the authors, which uses the experimentally derived attenuation length, to determine the graphene thickness of a film of arbitrary thickness. Assuming the theoretical thickness of one graphene monolayer (0.335 nm), the method applied to our ARXPS measurements enabled us to deduce the number of graphene layers for each N-doped graphene film with a few percent deviation versus the emission angle, as depicted in Fig. Another way to probe film architecture is based on the approach proposed by Tyagi ayer 0.33 nm, the The Raman 2D/G mapping and D/G mapping (@442 nm) of both samples are depicted in Fig. 2 surface was scanned to record 56 × 56 AES spectra per sample, from which the intensity ICKLL (from graphene) and INiLMM  were extracted. By using bulk Ni and HOPG references, the intensity ratio of ICKLL to INiLMM was correlated with the number of graphene layers. The resulting AES maps shown in Fig. The 10 × 10 μm41. This robust synthesis route provides a constant and reproducible nitrogen content in doped-graphene films, within 2–3 at.%, whatever the concentration of nitrogen in the a-C:N precursor film, certainly due to the reduced diffusion of nitrogen in the nickel catalyst compared to that in carbon. The introduction of such a low concentration of nitrogen charge carrier does not significantly affect the number of lattice defects and disorders in the graphene sheets compared to pure graphene. It is interesting to note that there is a slight increase in the number of graphene layers with an increase in the concentration of nitrogen in similar thermal annealing conditions. If diffusion of carbon and nitrogen occurs within the grain boundaries of nickel, followed by rapid diffusion onto the surface, probably a slight increase in nitrogen is responsible for the positive co-segregation that enhances the kinetics of formation of the graphene layers. These, to the best of our knowledge, never previously observed results will require investigation in further studies related to the synthesis and characterization of doped graphene. Our experimental analytical investigations represent a significant new methodology to explore the 2D distribution of graphene layers. Auger electron spectroscopy mapping of the N-doped graphene films is an original new way to quantify the number of graphene layers in 2D probed areas. AES mapping was shown to be more quantitative and to have a higher lateral resolution than Raman mapping. AES mapping showed that distribution of the number of layers of the N-doped graphene, synthesized by the thermal annealing of an a-C:N carbon thin layer covered by Ni catalyst, was between 1 and 6, centered around the tri-layer Bernal ABA configuration. Combining ARXPS and XAS quantified four chemical configurations of nitrogen. Although quaternary, pyridinic and pyridinic-oxide nitrogen functions are distributed throughout the whole graphene layer system, pyrrolic nitrogen is predominant in the top layer. The exploration of N-doped graphene synthesis from solid carbon source precursors deposited by femtosecond pulse laser ablation, as well as the analytical investigations focused in particular on AES mapping, extends the perspectives of doped graphene films exploration towards varied functionalities. In particular, our previous studies41 showed that the performance of textured few-layer pure graphene films represent a robust SERS platform for chemical detection, without the need to transfer the film. The present NG films were synthesized using the same route as the pure graphene films, with a similar textured few-layer architecture. One of the next steps in our research will be to advance in SERS probing by incorporating our NG films.Femtosecond pulsed laser deposition of solid carbon in an atmosphere of gaseous nitrogen, optionally combined with plasma assistance, gives rise to 10 nm thick amorphous carbon nitride a-C:N films with a nitrogen content of ca. 20 at%. Vacuum heat treatment of this solid source containing carbon and nitrogen, in the presence of a superimposed nickel catalyst film, allows diffusion of carbon and nitrogen into the Ni catalyst, which, after cooling, this leads to the synthesis of self-organized N-doped graphene sheets by precipitation and/or segregation of carbon and nitrogen species on the top surface of the nickel catalyst, in agreement with the diffusion and segregation mechanisms already discussed for graphene synthesis by pulsed laser deposition (PLD)2 substrates were introduced in a vacuum chamber pumped at a base pressure of 10−4 Pa. Amorphous carbon films were deposited by femtosecond pulsed laser deposition at room temperature. A femtosecond oscillator at the 800 nm wavelength, with a pulse duration of 60 fs and a repetition rate of 1 kHz delivered a laser beam focused at an angle of 45° onto a high purity graphite target (99.9995% purity). The energy density (fluence) of the laser beam was kept constant at 5 J/cm2. The ablation time was adjusted to keep an a-C and a-C:N film thickness of 10 nm. The SiO2 substrates were mounted on a sample holder placed at a distance of 36 mm from the graphite target. During laser ablation, nitrogen gas (99.9995% purity) was used as reactant gas to deposit a-C:N films, and the N2 pressure was carefully controlled during deposition using a mass flow controller. Nitrogen pressures were kept constant at 0.5 Pa, 1 Pa and 10 Pa, as listed in Table Ultrasonically cleaned (in acetone then in ethanol baths) SiOFollowing deposition of the carbon film, a thin nickel film 150 nm thick was deposited by thermal evaporation on the top of the a-C and a-C:N films. High purity (99.99%) Ni was melted thermally in a tungsten nacelle and evaporated towards the substrate. The deposition rate was set at 1.5 nm/minute to minimize residual stress in the growing film, thereby limiting film delamination.2 and a-C:N/Ni/SiO2 films were heated from room temperature to 780 °C at a heating ramp rate of 4 °C/s, then maintained at 780 °C for 30 minutes in a vacuum pressure of 10−4 Pa. The vacuum pressure was maintained during natural cooling to room temperature. The vacuum was broken a minimum of 5 hours after the end of the heating stage.The different a-C/Ni/SiO7/2, Ag3d5/2 and Cu3p3/2 were positioned at binding energies of respectively 83.98, 386.26 and 932.67 eV. In the case of XPS analysis, for all the samples analyzed, narrow scans were recorded for C1s, O1s and N1s with a step size of 0.1 eV and pass energy of 50 eV. This pass energy gives a width of the Ag3d5/2 peak measured on a sputter clean pure Ag sample of 0.55 eV. Components in C1s and N1s peaks were adjusted using line shapes consisting of a convolution product of a Gaussian function (75%) and Lorentzian function (25%), except for Csp2 hybridized and Csp3 hybridized components of C1s peak for which asymmetric line shapes were used and adjusted on HOPG and graphene synthetized samples. The C1 and N1s components related to the various films are listed in Table X-Ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) were performed with a Thermo VG Thetaprobe spectrometer (Thermo Fisher Scientific). XPS analysis was carried out with a focused monochromatic AlKα source  while a field emission electron gun with 150 nm spotsize operating at 10 kV accelerating voltage and 5 nA beam current was used for AES analysis. Electrons were analyzed using a concentric hemispherical analyzer operating in the constant ∆E mode for XPS analysis and fixed retard ratio mode for AES analysis. The energy scale was calibrated with sputter-cleaned pure reference samples of Au, Ag and Cu such that Au4fThe Auger mapping procedure is detailed in Supporting Information.et al.70. It is worth noting that our measurements were acquired using a type of spectrometer that simultaneously collects several photo-electron emission angles over a 60° range without tilting the sample. The step-wise growth model proposed by Tyagi et al. is based on two assumptions: (i) the graphene film covers the entire surface, (ii) the growth mode is assumed to be layer-by-layer. The procedure is detailed in Supporting Information.The average thickness of graphene films was determined with angle-resolved X-ray spectroscopy measurements using the formalism of Tyagi XANES spectra were recorded at the ANTARES beam line specially designed to perform complementary photoemission and X-ray soft absorption, at the SOLEIL Synchrotron . The ring operating conditions were 2.5 GeV electron energy, with injection currents of 500 mA and “Top-up” mode. Radiation was monochromatized using a plane-grating monochromator (PGM), which is characterized by a slitless entrance and the use of two varied linear spacing (VLS) gratings with variable groove depth (VGD) along the grating lines. All measurements were performed at 20.0(2) °C for C K-edge and N K-edge over the range 280–315 eV and 380–420 eV, respectively, with a step size of 0.2 eV to enable correct normalization of the XANES spectra. The absorption data were acquired in the partial electron yield (PEY) mode by collecting X-ray electron emissions from the sample with a Scienta R4000 analyser. The XAS spectra of the samples were normalized to the signal from a gold covered grid recorded simultaneously. The resolution of the beam line at the C and N K-edge was 50 meV.−1. The laser beam was focused on the sample with a 100x objective and the laser power was kept below 3 mW whatever the excitation wavelength, to avoid damaging the surface of the film. The diameter of the laser beam was estimated to be near 1 micrometer, near the diffraction limit at this wavelength. RAMAN maps were built from the acquisition of each 1 micrometer spectrum, over probe surfaces 10 × 10 micrometers in size. The Raman signals were acquired by a spectrometer equipped with a charge coupled device (CCD) camera. Raman spectra were deconvoluted by symmetric Lorentzian functions. Only the peak positions and intensities were kept free by the fitting process.Raman spectroscopy was performed using an Aramis Jobin Yvon spectrometer at both 633 nm (1.96 eV) and 442 nm (2.81 eV), with a spectral resolution of 2 cmSupplementary Information


The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline.CO pred 35.6 ± 17%.Six hundred twenty-three IPF patients with available QoL data  were analysed. Mean age was 69.6 ± 8.7 years, 77% were males, mean disease duration 2.0 ± 3.3 years, FVC pred was 67.5 ± 17.8%, DLp < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity . Multivariate analyses showed a significant association between QoL  and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment.Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms .The INSIGHTS-IPF registry is registered at Clinicaltrials.gov (The online version of this article (doi:10.1186/s12931-017-0621-y) contains supplementary material, which is available to authorized users. Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial lung disease associated with a high symptom burden, significant comorbidities and early death –3. MediaA number of patient-reported outcome (PRO) measures have been used in IPF research . HoweverIn the present study, we aimed to summarize QoL data collected in a nationwide, “real-world”, observational registry of patients with IPF and to examine associations between QoL and several other clinical variables.Clinicaltrials.gov (NCT01695408). The protocol [INSIGHTS-IPF  is an investigator-initiated, multicenter , observational registry study of data collected, within the confines of routine clinical care, from patients with IPF since November 2012. The study materials were approved by the Ethics Committee of the Medical Faculty, Technical University of Dresden, and by further local ethic committees as per local requirements. INSIGHTS-IPF is registered at protocol  and a deprotocol ) based oEnrollees complete PROs at enrolment and yearly thereafter. PROs include the University of California San Diego Shortness of Breath Questionnaire (UCSD SOB), the St. George’s Respiratory Questionnaire (SGRQ), World Health Organization-5 Well-Being Index (WHO-5) and the EuroQol five-dimensional questionnaire (EQ-5D).This questionnaire includes 24 items, each with a response scale 0  to 5 . The total score ranges from 0 to 120, with a higher score indicating more severe dyspnea .The SGRQ was originally developed for patients with chronic obstructive pulmonary disease or asthma , howeverThe 5 items of the questionnaire tap mood, vitality, and general health. Each item is scored 0 to 5. The total ranges from 0 to 25, with higher scores connoting better well-being.The EQ-5D taps 5 domains  and is commonly used in cost-utility evaluation. Based on domain scores, a sum utility score is calculated ranging from negative values (−0.59 worse than death) to 1 (perfect state). Respondents also rate their current health on a 20-cm vertical visual analogue scale (VAS) scored from 0 to 100 .Data were collected using an internet-based case report form (eCRF) with automated plausibility checks. On-site monitoring, with source data verification, was performed in the majority of centers (currently 70%).Summary statistics were generated for baseline data. Pearson product-moment correlation coefficients and univariate linear regression were used to examine associations between variables. Backward selection was used to generate multivariable models using the following candidate variable: disease duration, long-term oxygen therapy, physician’s judgment on IPF behavior , NYHA stage, duration since first symptoms in years, GAP index , number Data for QoL were available for 623 of a total of 737 patients (84.5%). Baseline characteristics are presented in Table Patients were treated with antifibrotic therapies (49.5%), oral glucocorticoids (23.7%); N-acetylcysteine (33.7%), and long-term O2 therapy (32.3%). Most (90.0%) had definite IPF, 5% probable IPF, and 5% possible IPF. At enrolment, treating physicians rated IPF as stable in 36.3%, slowly progressing in 30.9% and rapidly progressing in 11.2%.Baseline values for PROs and their inter-correlations are shown in Table p < 0.001; SGRQ: -0.26, p < 0.001; UCSD: -0.22, p < 0.001) or %FVC  were moderately strong. Patients without comorbidity had a mean SGRQ total score of 44; those with 2 comorbidities 47; and those with ≥4 comorbidities 59  . The WHO-5 was associated with LOT, and NYHA class III and IV. Finally, the UCSD SoB was associated with LOT, and NYHA class and %FVC.Idiopathic pulmonary fibrosis (IPF) is not only a severe life-shortening disease; it also significantly impairs patients’ quality of life. In this study, we present data from a large cohort of IPF patients. To our knowledge, this is one of the first-presentations of such data collected under real-world conditions. Overall, impairment in QoL and symptom burden were immense.Compared to a very recent report from the Australian IPF registry, QoL impairment was very similar with a SGRQ total score of 46.6 (and 48.3 in our registry). Similarly, to the data presented here, an association between QoL and dyspnoea and physiological data were reported. Yet, in contrast to our analyses also cough and depression were major contributors to diminished QoL – reasons for this may be explained by different tools used to assess depression (HADS) and a structured tool to assess cough severity . AnotherTo our knowledge, this is the first time, investigators have assessed the association between the presence of specific comorbid conditions and QoL. We observed that comorbid conditions contribute greatly to QoL impairment. However, additional research is needed to determine if therapeutic targeting comorbidities will improve QoL in these patients. Although other investigators have assessed QoL in IPF patients under real-world conditions, they found no correlation between various baseline characteristics and QoL . This maLike other investigators, we found that QoL was more impaired in patients on LTOT than in those not on LTOT. In fact, LTOT was an independent predictor of QoL even with adjustment for disease severity , 26. ThiIn several studies, investigators reported correlation coefficients between the SGRQ and one or more other patient-related assessment of health related quality of life, health status or symptoms including the Borg Dyspnea Index , 28, CouIn IPF patients, a major challenge is how to improve QoL impairment. Currently, only sildenafil, pulmonary rehabilitation or specialized, multi-modality treatment programs may have a role –38. UnfoThere are limitations to our study. The QoL assessment tools we used were not originally developed for IPF, but they do have data to support their validity in this disease. Instruments such as the K-BILD  or A TooHealth related quality of life is substantially impaired in patients with IPF, and drivers of this impairment include symptoms, comorbidities, LOT and disease severity. While current treatments improve the course of the disease and perhaps survival, additional investigation is needed to identify interventions that durably to improve this important outcome in IPF patients.


T-P phase diagram, there indeed exists a structural anomaly region, which encloses density anomaly but not diffusivity anomaly. This is consistent with that of SW Si and BKS SiO2 but different from that of SPC/E water. Two-body excess entropy anomaly can neither capture the diffusivity, structural, and density anomalies, as it can in a two-scale potential fluid. In structural anomaly region, tetrahedrality order qtetra  and translational order ttrans  are not perfectly correlated, which is different from that in SW Si and renders it impossible to use the isotaxis line to quantify the degree of structural order needed for water-like anomalies to occur. Along the isotherm of critical temperature Tc, ttrans/qtetra is approximately linear with pressure. With decreasing pressure along the isotherm below Tc, ttrans/qtetra departs downward from the line, while it is the opposite case above Tc.The relationship between structural order and water-like anomalies in tetrahedral liquids is still open. Here, first-principle molecular dynamics are performed to study it in metastable liquid Si. It is found that in  Although the interactions between atoms or molecules are different, including ionic, metallic, covalent and hydrogen bonding, they share a preference for forming tetrahedrally coordinated configurations at the micro level and displaying water-like anomalous behaviour at the macro level, such as the well-known density maximum 23457891011121314151617Tetrahedral liquids, in which the anisotopic bonding gives rise to a three-dimensional, liquid-state network with an energetic bias towards local tetrahedral order, are ubiquitous in everyday life, such as water, SiOttrans)qtetra)qtetra at low densities and minimum ttrans at high densities along the isotherm, qtetra and ttrans decrease on compression, in contrast to what is observed for simple fluids. Therefore, this region was identified by the authors as a structurally anomalous region, which in turn encloses the regions of diffusivity anomaly and density anomaly in the T-ρ phase diagram. Moreover, the two orders were found to be strictly coupled in this region, i.e., a particular value of qtetra is associated with a unique value of ttrans, and so the isotaxis lines  can be used to quantify the degree of structural order needed for these anomalies to occur. Soon after that, using the Beest-Kramer-van Santen (BKS) model potential, a similar analysis in liquid silica was carried out by Shell et al.qtetra and ttrans are not strictly coupled in this region. Therefore, they concluded that qtetra and ttrans can not anticipate the occurrence of the diffusivity anomaly and hence can not provide a satisfactory microscopic picture of the anomalous behaviour in liquid silica. The later results of liquid BeF2 with the transferable rigid ion model (TRIM) by Agarwal et al.2, but that of the Oeffner-Elliot (OE) model of GeO2 by Jabes et al.2 and BeF2), and liquids characterised by the Stillinger-Weber (SW) potential (including Si)242526qtetra and ttrans exists only in rigid-body model potentials for water and SW liquids , but not in ionic melts. In addition, to obtain a more general picture of the origins of these anomalies, the excess entropy has also been attempted to understand these anomalies and has been tested to be able to predict the regions of anomalies in the phase diagram22232425262728In recent years, much effort has been expended to understand the relationship between the atomic level structure and the water-like anomalies. In 2001, Errington and Debenedettiet al.et al.It should be noted that the water-like cascading of anomalous regions in the phase diagram has been observed not only in systems having directional interactions but also in the simulation studies of spherically symmetric potentials29303132sp3-hybridization LDL and a white-tin-like HDLAlthough so many computer simulation studies of tetrahedral liquids have focused on the relationship between structural order and water-like anomalies, they all depended on different model potentials or empirical potentials. To our knowledge, first-principle computer simulations have not been performed to study this question so far. It is well-known that the first-principle force neither makes assumptions such as empirical model nor includes fitting parameter to experimental data, so it is expected to give more realistic results. In the past few decades, first-principle simulations had achieved great success in investigating structural and dynamic properties of liquids. Based on first-principle calculations, we have studied the inherent structures of high-density liquid (HDL) and low-density liquid (LDL) Si and found that the first-order LLPT in metastable liquid Si is a transition between a ρ-T isobar lineT-P phase diagram, the line of density maxima tends to pass through the LLCP, located at Tc ~ 1420 ± 10 K and Pc ~ −30.5 ± 1.0 kbarTc ~ 1120 K and Pc ~ 0.60 GPa). We speculate that such a difference maybe origins from the different potentials adopted. Although the LLPT is proved to exist for SW liquid Si, it has been reported that it strongly depends on the parameters of the potential and an arbitrary variation, albeit small, of the parameters may even lead to its disappearanceThe density anomaly and the first-order LLPT have been shown in our previous workD as a function of pressure along eight different isotherms ranging from 1032 to 1800 K. Along each isotherm, the pressure is gradually decreased to the stability limit of HDL and an obvious maximum can be found in the whole temperature range studied here, which marks the upper bound of diffusivity anomaly region. Along each isotherm below Tc, the locus of diffusivity minimum, which marks the lower bound of diffusivity anomaly region, can not be found and is expected to be located in LDL, where system’s dynamics is slow and there is considerable error in computing D and locating the diffusivity minima. So we have not attempted to find this locus in our study. Above Tc, the diffusivity minimum is expected to be located at the HDL-V spinodal because of the larger D in vapor than that in liquid.In ttrans and qtetra) with decreasing pressure along the isotherm. From qtetra increases with the decrease of pressure in the simulated temperature range from 1032 to 1800 K, which is in contrast to what is observed for simple fluids and so is termed as structural anomaly. Below Tc, we do not find a maximum of qtetra in our simulated pressure range, which marks the lower bound of structural anomaly region and is expected to be found in LDL. At temperatures above Tc, the maximum of qtetra is expected to be located at the HDL-V spinodal, such as for T = 1532 and 1800 K. In ttrans decreases with decreasing pressure and goes through a minimum, which marks the upper bound of structural anomaly region as suggested by Errington and DebenedettiT = 1800 K, the minimum cannot be found until the HDL-V spinodal is encountered.Sex is defined as the entropy of the liquid relative to that of the ideal gas at the same temperature and pressure and can be expressed in terms of an expansion of n-body correlation functions. The first term, namely the two-body contribution S2, accounts for a large proportion, such as 80–90% in Lennard-Jones fluidsSex characterizes the reduction in the number of states  accessible to a system due to translational interparticle correlations, it can also be thought of as a metric for translational order. Errington and co-workersSex or S2 anomaly region in the T-ρ phase diagram, where Sex or S2 anomalously increases with increasing pressure. In this work, we calculated S2 as a function of pressure along eight different isotherms, shown in The excess entropy DR* = aDexp(bDSE)38Dz* = a0exp(S2)DR* = Dρ1/3/(kBT/m)1/2, m is the mass of the particle, and ρ is the number density. In the later, Dz* = DΓ−1σ−2, Γ is the collision frequency and equals 4σ2g(σ)ρ(πkBT/m)1/2, σ is the hard-sphere diameter, and g(σ) is the value of radial distribution function at the constant distance. In DR* and S2. The relation between Dz* and S2 is similar to that presented in DR*) and S2 is not linear, showing a different behaviour from that of Rosenfeld and Dzugutov. Based on the results in S2 versus pressure, which is different from the results in ref. 42It is known that there is a strong connection between transport properties of fluids and excess entropy, such as the Rosenfeld scaling relation T-P phase diagram, shown in 2S2 maxima line going across the density maxima line. So S2 anomaly can not be used as a criteria of structural anomaly to capture the region of diffusivity and density anomalies. This may origin in the fact that the relation between ln(DR*) and S2 shows an anomalous behaviour, presented in Based on the above results, now we turn to discuss the relationship of these anomalies in Sex anomaly lies much deeper than that obtained from the approximate S2 anomaly. This means that the structural anomaly calculated from the Sex criterion may be inside the density anomaly shown in SexSex lies much deeper than that obtained from S2 for the two-scale potentialSex anomaly is the same with that of S2 anomaly and at lower temperatures the former is even slightly larger than the latter  in ref. Recently, it has been shown for the two-scale potential that different criteria of structural anomaly can lead to completely different resultsqtetra and ttrans exists in rigid-body model potentials for water and SW liquids , but not in ionic melts. Here, we also present the correlation between qtetra and ttrans, shown in qtetra, low-ttrans quadrant. In other words, for any given value of ttrans, there is a maximum value of qtetra that the system can attain. Likewise, for any given value of qtetra, there is a minimum attainable ttrans. However, in the structural anomaly region, qtetra and ttrans do not collapse onto a single line, as is the case for water, suggesting that qtetra and ttrans are not perfectly correlated. With the decrease of temperature, the correlation becomes weaker and weaker. These results are different from those observed in SW Si2526qtetra and ttrans are perfectly correlated in the structural anomaly region. This degree of independence renders it impossible to use the isotaxis line to quantify the degree of structural order needed for the water-like anomalies to occur.As mentioned above, in the structural anomaly region, a strong correlation between ttrans/qtetra as a function of pressure. It can be found that at higher pressure above 20 kbar, ttrans/qtetra is independent of temperature and is linear with pressure. Along the isotherm of Tc, ttrans/qtetra can be approximately expressed as a linear relationship with pressure, ttrans/qtetra = 0.0015P + 0.494. With decreasing pressure along the isotherm below Tc, ttrans/qtetra departs downward from the straight line until the LLPT is encountered, while it is the opposite case above Tc until the liquid-vapor transition occurs.To obtain the relationship between structural order and the LLPT, in T-P phase diagram, there indeed exists a structural anomaly region, which encloses the density anomaly but not the diffusivity anomaly. This is consistent with that of SW Si and BKS SiO2 but different from that of SPC/E model of water. Two-body excess entropy anomaly can neither capture the diffusivity, structural, and density anomalies, as it can in a fluid interacting through a two-scale potential. Moreover, in the structural anomaly region, qtetra and ttrans are not perfectly correlated, which is different from that in SW Si and renders it impossible to use the isotaxis line to quantify the degree of structural order needed for water-like anomalies to occur. Along the isotherm of critical temperature Tc, ttrans/qtetra is approximately linear with pressure, ttrans/qtetra = 0.0015P + 0.494. With decreasing pressure along the isotherm below Tc, ttrans/qtetra departs downward from the line until the liquid-liquid phase transition occurs, while it is the opposite case above Tc.In summary, first-principle molecular dynamics are performed for the first time to study the relationship between structural order and water-like anomalies in metastable liquid Si. Our results show that in ab initio simulation package (VASP)4850The simulations are performed by the Vienna 3/atom, is heated up to 2000 K. After a run of 20 ps with constant temperature 2000 K, the system arrives at an equilibrium liquid state. The temperature is then gradually reduced to the desired temperature with a cooling rate of 0.5 × 1015 K/s and a subsequent run of 15–20 ps is performed at this temperature. Then, the simulations are performed with a series of successively larger volumes along the isotherm up to the stability limit of HDL. At each simulation point, we performed a simulation about 15–30 ps. It is found that for HDL 5 ps is enough to equilibrate and the statistical averages are collected for the rest of the simulation. Along each isotherm, the end point of the previous simulation is scaled to obtain the initial conditions for the next.The initial configuration, a diamond cubic crystal structure with the volume of 17.2 ÅD in liquids was obtained by fitting the long time mean square displacement (MSD). MSD is defined asThe self-diffusion coefficient i, t0 is an arbitrary origin of time. The diffusion coefficient D can be calculated bywhere ttrans is defined asThe translational order parameter ξ = rρ1/3 is the distance r between two Si atoms divided by the mean separation between a pair of atoms at the given number density ρ; g(ξ) is the pair correlation function, and ξc is a cutoff distance beyond which the system’s pair correlation function cannot be distinguished from its asymptotic value of 1. In this work, ξc is chosen to be 9.0 × ρ1/3. Scaled coordinates are used so that the above integral sums over an equivalent number of coordinate shells at each density. For an ideal gas, since g(r) = 1.0, ttrans is zero and for a crystal, it has a finite value depending on the cutoff distance. In the liquid phase, ttrans will have a value in between that of the ideal gas and a crystal. The tetrahedrality order parameter qtetra is defined aswhere ψjk is the angle formed by the lines joining a reference atom i and its nearest neighbours j and k. The average qtetra varies between 0  and 1 .where SE is defined as SE = S − Sid, where S is the total entropy of the system and Sid is the entropy of an ideal gas system. In present work, we calculate the two body approximation (S2) to SE from the pair correlation function, and is given byExcess entropy ρ is the number density.where g(r) is the pair correlation function, and How to cite this article: Zhao, G. et al. Relationship between structural order and water-like anomalies in metastable liquid silicon: Ab initio molecular dynamics. Sci. Rep.7, 39952; doi: 10.1038/srep39952 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer.Here, we applied functional genomics to analyze global mRNA expression changes associated with chromosome 9p gains. Using the TCGA data set, we identified a list of 75 genes that were strongly up-regulated in tumors with chromosome 9p gains across many cancer types.As expected, the gene set was enriched for chromosome 9p and in particular chromosome 9p24 (36 genes and 23 genes). Furthermore, we found enrichment of two expression programs derived from genes within and beyond 9p: one implicated in cell cycle regulation (22 genes) and the other implicated in modulation of the immune system (16 genes). Among these were specific cytokines and chemokines, e.g. CCL4, CCL8, CXCL10, CXCL11, other immunoregulatory genes such as IFN-G and IDO1 as well as highly expressed proliferation-related kinases and genes including PLK1, TTK, MELK and CDC20 that represent potential drug targets.Collectively, these data shed light on mechanisms of immune escape and stimulation of proliferation in cancer with PD-L1 CNG and highlight additional vulnerabilities that may be therapeutically exploitable.The online version of this article (10.1186/s12920-017-0308-8) contains supplementary material, which is available to authorized users. PD-1)/PD-ligand1 (PD-L1) checkpoint inhibition has emerged as a promising treatment strategy in different advanced and often otherwise untreatable tumors in a growing number of cancer types. In this context immunohistochemical (IHC) evaluation of PD-L1 protein expression has been proposed as a biomarker that predicts treatment efficacy. However, different IHC-antibody clones used for PD-L1 detection and different evaluation methods including different cutoff values to distinguish ‘positive’ from ‘negative’ tumors introduce a substantial variance in the determination of PD-L1 status. These ambiguities and the complex interplay of cancer-cell-inherent, microenvironment-associated and host-related factors [Programmed cell death 1 (PD-L1 copy number gains (CNG) are prevalent in significant subsets of different cancers including triple negative breast cancer [PD-L1 CNG were reported to exhibit increased PD-L1 expression and to respond well to immune checkpoint inhibition [PD-L1 CNG were abundant in many cancer types with both focal and non-focal gains typically occurring at frequencies between 2% and 10% [PD-L1 in more than 80% of tumors with focal PD-L1 gains across 22 cancer types. The core amplified region includes the genes PD-L1, PD-ligand 2 (PD-L2) and Janus kinase 2 (JAK2). Following up on these findings, we here show that chromosome 9p copy number gains are associated with specific mRNA expression changes enriched for genes implicated in cell cycle regulation and immune cell response.t cancer , Hodgkint cancer , cancer t cancer , NSCLC [t cancer , SCLC [6t cancer . In parthibition . Adding  and 10% . In thisPD-L1 copy number alteration (GISTIC) and genome-wide mRNA expression data (RNAseq v2) of the following 21 cancer types profiled in the TCGA project were obtained from the cBioPortal [https://cancergenome.nih.gov/publications/publicationguidelines).ioPortal : BladderPD-L1 copy numbers alterations were evaluated using the calls reported by the TCGA consortium based on Affymetrix SNP 6.0 array data and the GISTIC 2.0 algorithm [PD-L1 status was assessed as “loss” for calls −2 and −1, as “normal” for call 0, and as “gain” for calls 1 and 2. Copy number calls and upper quartile normalized RSEM estimates of mRNA expression were obtained from the cBioPortal . Expression values were log2(x + 1) transformed prior to statistical analysis and visualization. Differential expression between tumors with and without PD-L1 gains as well as between tumors with and without PD-L1 losses was assessed using Welch’s t-test. Hierarchical clustering was performed using Pearson correlations as similarity measure and the average linkage method to determine the distance between clusters. Non-significant fold changes were set to one before clustering. In a genome-wide mRNA expression analysis, a list of 75 strongly and recurrently up-regulated genes was identified by filtering for genes showing significant (p < 0.05) and at least 1.5-fold enhanced mRNA expression in tumors with PD-L1 gains across at least 6 cancer types  annotations obtained from msigdb v5.2 C5 (http://software.broadinstitute.org/gsea/msigdb) with significance assessment by Fisher’s exact test , bladder cancer (fold change = 4.1), head and neck cancer (fold change = 2.9), cervical cancer (fold change = 2.7) and cutaneous melanoma (fold change = 2.2). Furthermore, we explored the global mRNA expression pattern of chromosome 9p using hierarchical clustering and heatmap visualization  located on chromosome 9p were found to be differentially expressed. Comparing tumors with and without PD-L1 loss, we identified 14 cancer types with significant PD-L1 mRNA expression changes and 167 to 415 genes (20% to 51%) with modulated mRNA expression. Genes showing frequent up-regulation in tumors with PD-L1 gains included PD-L1, PD-L2, JAK2, and B4GALT1. Genes showing frequent down-regulation in tumors with PD-L1 losses included PD-L1, PD-L2 and IFNB1.Comparing tumors with and without PD-L1, PD-L2 and JAK2), the remaining 39 genes (52%) were located in other genomic regions. In particular, 21 genes were located in the core amplified region in chromosome 9p24 that we described in [ASPM, CDC20, CDCA8, CDKN2A, CENPA, CENPF, CENPI, CLSPN, FAM83D, GTSE1, HAUS6, IFNG, KIF18B, KIF2C, MELK, MYBL2, NUF2, PLK1, SPC24, TPX2, TTK, UHRF2). The vast majority of these genes play a role in the coordinated regulation of microtubule assembly and chromosomal segregation during mitosis. Sixteen strongly up-regulated genes belonged to the GO category ‘immune system process’ . Most of these genes encode cytokines and chemokines but also link immune response with tumor metabolism, such as IDO1 encoding indoleamine-2,3-dioxygenase 1. Enrichment of the both GO categories was highly significant . Interestingly, as shown in Fig. Taking a more comprehensive approach, we analyzed the setting ‘chromosome 9p gain’ in a genome-wide context and identified 75 top genes that were strongly and recurrently up-regulated , while the other half of PD-L1 CNGs frequently co-occurs with gain of a 38-gene core amplified region located in chromosome 9p24  [PD-L1 CNG tumors. The gene set was enriched for the biological motives ‘cell cycle’ and ‘immune system process’ and included known drivers of tumor growth and drug targets.Functional genomics analysis of PD-L1 CNG is a powerful predictive biomarker in patients with relapsed or refractory Hodgkin lymphoma who were treated with nivolumab [PD-L1 amplification accompanied by overexpression can also be used to identify patients with solid tumors who benefit from PD-1 blockade [PD-L1 CNGs could help to predict response to checkpoint inhibitors in solid tumors. Testing for PD-L1 amplifications could be easily implemented in a routine setting using in situ hybridization based assays such as FISH or using targeted DNA sequencing [PD-L1 CNGs in solid cancer types.A recent study showed that ivolumab . In keepblockade . These dquencing . HoweverJAK2 . The set of 75 genes was enriched for the chromosomal regions 9p13 to 9p24 (36 genes) as well as the biological processes ‘cell cycle’ (22 genes) and ‘immune system process’ (16 genes). (XLSX 34 kb) Gene list of 75 top up-regulated genes identified in a genome-wide transcriptome analysis across 22 cancer types. The list was obtained by filtering for genes harboring significant and at least 1.5-fold enhanced mRNA expression in tumors with PD-L1 gains across at least 6 cancer types. Pan-cancer Additional file 2: Table S2. Enrichment analysis of GO categories in the 75-gene list. (XLSX 240 kb)