P = 0.04). Moreover, high PD-L1 expression was significantly associated with poor OS  and especially in Asian populations . But it did not have an impact on disease-free survival . Further well-designed clinical studies with uniform assessment approaches for PD-L1 expression are warranted to verify its prognostic value.Accumulated evidence has shown that the programmed cell death receptor 1/programmed cell death receptor 1 ligand 1 (PD-1/PD-L1) pathway is a promising therapeutic target for cancer immunotherapy. However, the association between PD-L1 and esophageal squamous cell carcinoma (ESCC) patient survival remains unclear. We performed a meta-analysis to investigate the prognostic value of PD-L1 in ESCC. We searched PubMed, Embase, Web of Knowledge, and Cochrane Central Register of Controlled Trials databases for relevant studies that evaluated PD-L1 expression and ESCC patient survival. Fixed- and random-effects meta-analyses were conducted according to the heterogeneity of the included studies. Sensitivity analysis was performed according to Metan-based influence analysis. Publication bias was evaluated using Egger’s and Begg’s tests. Overall, 13 studies with 2,877 patients were included. Twelve studies demonstrated the association between overall survival (OS), and 6 studies described the relation between disease-free survival (DFS). PD-L1 overexpression was found in 43.7%  of the patients with ESCC. High PD-L1 expression was associated with distant metastasis in patients with ESCC ( Esophageal cancer is the sixth leading cause of cancer-related mortality and the eighth most common cancer worldwide . EsophagProgrammed cell death receptor 1 , which belongs to the B7-CD28 co-stimulatory factor superfamily, is a receptor expressed on the surface of T, B, and Natural killer (NK) cells that regulate their activation and apoptosis . Its ligPD-L1 overexpression has been observed in various types of solid tumors, including melanoma, lung cancer, breast cancer, colorectal cancer, bladder cancer, gastric cancer, hepatocellular carcinoma, renal cell carcinoma, papillary thyroid cancer, and head and neck cancer –23. A meHowever, in ESCC, the number of studies are limited and the prognostic value of PD-L1 expression still remains controversial, as some studies associate PD-L1 expression with a rather favorable prognosis, while others postulate a less favorable disease course for cancers with high PD-L1 expression –37.To address this issue, we conducted a meta-analysis to investigate the correlation between PD-L1 overexpression and ESCC prognosis.In this study, we identified a total of 257 potentially relevant articles with our search strategy. After screening the titles and abstracts of these articles, we excluded 232 studies because they were duplicate studies or were irrelevant. After reading 25 potentially eligible articles in detail, we finally included 13 studies in this meta-analysis –48. A deThe characteristics of the included studies are presented in Table All the studies performed immunohistochemical (IHC) analysis to evaluate PD-L1 expression in ESCC tissues, with PD-L1 positivity rates ranged from 18.4% to 82.8%. The hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from the original text or from the original authors. Among the 13 studies, 12 studies demonstrated the association between overall survival (OS) and PD-L1 expression, and 6 studies described the relationship between disease-free survival (DFS) and PD-L1 expression. The Newcastle-Ottawa quality assessment scale (NOS) score for study quality ranged from 6 to 8 .P = 0.04). Significant heterogeneity was observed ; therefore, a random effects model was used for the analysis . Significant heterogeneity was observed ; therefore, a random effects model was used for the analysis . However, we detected no significant associations between PD-L1 overexpression and sex , T stage , N stage , TNM stage , tumor grade , lymphatic invasion , venous invasion , and neoadjuvant treatment . Moreover, there were no significant associations between PD-L1 expression and drinking  or smoking history  of patients with ESCC. Pooled results showed that PD-L1 expression was high in patients with distant metastasis , lymphatic invasion , venous invasion , metastasis , and smoking history ; therefore, a fixed effects model was used. The other assessments were performed using a random effects model ; therefore, a random effects model was used.The studies by Chen et al., Kim et al., and Tanaka et al. included patients who had received neoadjuvant treatment , 45, 47.P = 0.07; Figure I2 = 88%, P = 0.0003); therefore, a random effects model was used.The subgroup analysis of the three studies showed that patients with high PD-L1 expression had shorter OS, compared with those with low PD-L1 expression ; therefore, a fixed effects model was used.The subgroup meta-analysis of two studies with the same PD-L1 antibody and cutoff value, the result showed OS was significantly associated with PD-L1 overexpression  was performed to evaluate the stability of the results. The results of the analysis demonstrated that no individual study significantly influenced the HRs of OS, suggesting that the results of the present meta-analysis are credible Figure . AdditioP-values for these tests were 0.822 and 0.392 (OS) and 0.917 and 0.876 (DFS), respectively . The possible reason for this finding is racial difference.Moreover, in metan-based influence analysis demonstrated that no individual study significantly influenced the HRs of OS, suggesting that the results of the present meta-analysis are credible. Moreover, removal of the only one non-Asian study by Jesinghaus et al. enhanced the association between PD-L1 expression and OS  was negatively correlated with PD-L1 expression. High PD-L1 expression in cancer cells might prevent effective antitumor immunity , “Antigens, CD274” [Mesh], “Esophageal Neoplasm,” “Neoplasm, Esophageal,” “Esophagus Neoplasm,” “Esophagus Neoplasms,” “Neoplasm, Esophagus,” “Neoplasms, Esophagus,” “Neoplasms, Esophageal,” “Cancer of Esophagus,” “Cancer of the Esophagus,” “Esophagus Cancer,” “Cancer, Esophagus,” “Cancers, Esophagus,” “Esophagus Cancers,” “Esophageal Cancer,” “Cancer, Esophageal,” “Cancers, Esophageal,” “Esophageal Cancers,” “Esophageal Squamous Cell Carcinoma,” “CD274 Antigens,” “B7-H1 Immune Costimulatory Protein,” “B7 H1 Immune Costimulatory Protein,” “B7-H1 Antigen,” “Antigen, B7-H1,” “B7 H1 Antigen,” “PD-L1 Costimulatory Protein,” “Costimulatory Protein, PD-L1,” “PD L1 Costimulatory Protein,” “Programmed Cell Death 1 Ligand 1 Protein,” “CD274 Antigen,” “Antigen, CD274,” “Programmed Cell Death 1 Ligand 1,” “B7H1 Immune Costimulatory Protein,” “B7-H1,” “PD-L1,” “B7 H1,” and “CD274.”The article language was restricted to English. To identify additional studies, we also reviewed the reference lists of relevant articles.The inclusion criteria were as follows: (1) the entire study population comprised patients with histologically confirmed ESCC; (2) PD-L1 protein expression in the primary ESCC tissue was detected by IHC analysis; (3) data regarding the correlation between PD-L1 and clinicopathological parameters were provided; and (4) sufficient survival data were provided to estimate the prognosis. Moreover, if there were multiple articles based on similar populations, only the most recent article was included.in vitro studies and animal experiments; (2) review, meta-analysis, editorial, case report, conference abstract, and expert opinion; and (3) studies on the PD-L1 level of TIL or circulating tumor cells.The exclusion criteria were as follows: (1) Eligible reports were identified by two reviewers (Wei Guo and Pan Wang), and disagreements were resolved by a third reviewer (Yibo Gao).P-value) were directly extracted from tables or text of the included studies or were obtained by contacting the original authors. When both univariate and multivariate analysis for survival outcome were provided, only the multivariate analysis was extracted since it has been more precise.Cohort level characteristics  were extracted for statistical analysis. Survival data (HR, CI, and The NOS was used, and any discrepancies in the score were resolved by discussing the findings and reaching a consensus. The maximum possible score for the NOS is 9 points, and a study that achieved a score of 6 or higher was considered to be of high quality .P-value < 0.05 was considered to indicate statistical significance. Heterogeneity among studies was tested using the chi-square test and I-Square. A P-value < 0.1 or I2 > 50% was considered to indicate significant heterogeneity among studies. If heterogeneity was identified among studies, a random effects model was used to pool the ORs, and if not, a fixed effects model was selected. The potential for publication bias was assessed using both Begg’s rank correlation method and Egger’s weighted regression method [Pooled ORs and their 95% CIs were analyzed to determine the association between PD-L1 expression and clinicopathological parameters, and HRs and their 95% CIs were used to evaluate the association between PD-L1 expression and survival of patients with ESCC. A n method , 56. All


Rsh), it increases after exposure to ambient conditions, and this problem has been considered as the biggest impediment to practical application of graphene electrodes. Here, we report an extremely stable graphene electrode doped with macromolecular acid (perfluorinated polymeric sulfonic acid (PFSA)) as a p-type dopant. The PFSA doping on graphene provides not only ultra-high ambient stability for a very long time (> 64 days) but also high chemical/thermal stability, which have been unattainable by doping with conventional small-molecules. PFSA doping also greatly increases the surface potential (~0.8 eV) of graphene, and reduces its Rsh by ~56%, which is very important for practical applications. High-efficiency phosphorescent organic light-emitting diodes are fabricated with the PFSA-doped graphene anode (~98.5 cd A−1 without out-coupling structures). This work lays a solid platform for practical application of thermally-/chemically-/air-stable graphene electrodes in various optoelectronic devices.Although conventional p-type doping using small molecules on graphene decreases its sheet resistance ( Chemical doping is a viable strategy to tune the electrical properties of pristine graphene, but suffers from stability issues. Here, the authors develop a macromolecular chemical doping approach that makes use of polymeric acid and provides high stability. Since the development of chemical vapor deposition (CVD) methods to produce high-quality and large-area graphene5, much research has been devoted to applying graphene in flexible electronics such as organic light-emitting diodes (OLEDs)16, organic solar cells19, and organic transistors22. However, pristine graphene has high sheet resistance (Rsh > 300 Ω sq−1) and low work function (WF ~4.4 eV) which are still inferior to those of ITO , so pristine graphene must be modified before it can be a practical replacement for ITO electrodes24.Graphene has outstanding electrical, mechanical, and optical properties37. Dopants used in graphene for electrodes to date have been mainly classified into two types: (1) small molecules35, and (2) transition metal oxides37; both exploit charge transfer on the graphene surface. Charge-transfer doping of graphene with small-molecule dopants such as inorganic small-molecule acids 25 and metal chlorides 29 has been widely used and developed to increase the electrical conductivity of graphene; however, graphene that is doped with inorganic small-molecule acid has serious environmental instability, which has been considered as a great impediment to practical application of graphene electrodes. Rsh of an HNO3-doped graphene gradually increases under ambient conditions due to high volatility of small-molecule acids, and high temperature accelerates significant degradation in its electrical conductivity8. After doping with metal chlorides, reduction of metal cations can produce metal particles on the graphene surface; these have two deleterious effects: they can decrease the optical transmittance (OT) of the graphene, and if they are large, they protrude and provide leakage paths for electrical current in thin-film devices29. Also, transition metal oxides are not uniformly deposited on the graphene surface because the graphene lacks dangling bonds or surface functional groups. Therefore, thermal evaporation of transition metal oxide on graphene also roughens its surface38. Ideal chemical doping of graphene for practical use as an anode in electronic devices should achieve: (1) low Rsh, (2) high WF, (3) high stability against heat, chemical, and ambient conditions, (4) smooth film surface, and (5) high OT.Various researchers had used chemical doping to control the electrical properties of pristine graphene40. Therefore, the PFSA is an ideal form of macromolecular p-type dopant for graphene electrode. Our unconventional approach of using polymeric acid may stimulate research into high-stability graphene doping, and can be a starting point in the development of polymeric-acid dopants for ideal graphene electrodes.Here, we introduce a novel approach to macromolecular chemical doping that uses a polymeric acid, which has not been used for graphene doping and demonstrated extraordinary results on all kinds of aspects of stability  and high WF; these characteristics are almost unattainable with conventional small-molecule acid doping. We use a perfluorinated polymeric sulfonic acid (PFSA) for application to flexible graphene anodes in optoelectronics. PFSA is composed of a perfluorinated carbon backbone and sulfonic acid groups. Due to the electron-withdrawing properties from electronic dipole of acidic proton in sulfonic acid groups, PFSA induces p-type doping of graphene. Furthermore, the perfluorinated carbon backbones have large ionization potential, which substantially increases the surface potential of graphene. Superior thermal and chemical stability of PFSA molecule provided outstanding stability of chemically doped graphene against high temperature heating and exposure to various chemicals including strong acids and bases3) to dope graphene  had OT = 90%, and PFSA-doped 4LG had OT = 89%  instead of volatile small-molecule acid , which indicates that high-quality graphene had been successfully grown and transferred onto the substrate with few defects. The spectrum of PFSA-doped graphene also showed a very weak D band; this result proves that solution-processed doping of the PFSA does not induce any significant structural defects in the graphene lattice. The G- and 2D-bands of the PFSA-doped graphene were up-shifted compared to those of pristine graphene ; this change indicates that PFSA causes p-type doping of graphene43.Raman spectroscopy is a non-destructive tool to identify the doping characteristics, the number of layers, and the structural disorder in grapheneSLG Fig. . The speRsh by using the EddyCus® TF map 2525SR system   on glass substrate, then performed spatial mapping of tem Fig. . Pristin−1) Fig. . This reRrms) ~0.495 nm) than that of pristine graphene (Rrms ~1.47 nm) . To verify doping stability under high temperature, each p-type doped graphene  ≤ 300 °C in ambient conditions.The thermal stability of PFSA-doped and HNORsh  at Ta = 300 °C), whereas Rsh of HNO3-doped graphene on Si/SiO2 substrate increased as Ta increased (~119.6% increase of Rsh (asD) at Ta = 300 °C)  Fig. ; this trRsh in the PFSA-doped graphene was performed after annealing at various Ta. Over the whole region, Rsh decreased as Ta of PFSA increased  of ent Fig. . The PFS3H) faces towards graphene. PFSA doping increases the WF of graphene by ~0.71 eV  cause electronic dipole interaction with graphene, thereby reducing the electron density of graphene  as well as an interface dipole formed by the electronegative perfluorinated backbone on the graphene; this dipole caused by fluorinated substituents can induce a similar vacuum-level shift in self-assembled monolayers on the electrode surface48. The increased surface WF of the PFSA-doped graphene can effectively reduce the hole-injection energy barrier from the anode to overlying organic layers in OLEDs. Thermal annealing would cause rearrangement of PFSA at high Ta49. Thermal annealing causes the perfluorinated backbone that has low surface energy to become dominant at the film surface, and sulfonic acid groups (−SO3H) in PFSA rearrange towards the underlying graphene. Therefore, high-temperature annealing of PFSA-doped graphene increases the p-type doping effect in PFSA-doped graphene.To determine the mechanism by which PFSA dopes graphene, we performed density-functional theory (DFT) calculation of PFSA-doped graphene. For ease of calculation, we used the simplest molecular form of PFSA. In the most energetically favorable configuration of PFSA-doped graphene Fig. , the aci eV Fig. , which in) by using in-depth Raman spectrum analysis and the Dirac point shift in field-effect transistors (FETs). The hole-doping effect can be differentiated from the strain effect50. To monitor changes in n and strain as a function of Ta after PFSA doping, we obtained a hundred Raman spectra for each graphene sample by raster-scanning an area of 10 μm × 10 μm, then verified the variation of G-band and 2D-band position of each spectrum ; this change can be attributed to slight thermal deformation during annealing.To quantify the p-type doping effect in PFSA-doped graphene, we calculated the charge concentration  substrate and measured electrical properties of FETs that used pristine or PFSA-doped graphene   Fig. .32Ta influences the n of PFSA-doped graphene because the number of acidic protons in the proximity of graphene increases. All measurements showed that thermal annealing caused Rsh decrease, WF increase and n increase in PFSA-doped graphene as Ta increased; these results are direct evidence that increased Ta influences the doping effect of PFSA.These results also support that rearrangement of PFSA at high Rsh changes of PFSA-doped and HNO3-doped graphene under exposure to chemicals, and ambient conditions. To demonstrate the chemical invulnerability of PFSA-doped graphene, polar protic ), polar aprotic (dimethyl sulfoxide), and non-polar solvent (toluene) were spin-coated on p-doped graphene samples, which were then gently annealed to remove residual solvents. All treatments significantly increased the Rsh of HNO3-doped graphene on Si/SiO2 substrate, but had negligible effect on Rsh in the PFSA-doped graphene , weak acid , weak base , or strong base  for 15 s. Rsh of HNO3-doped graphene greatly increased after acid and base treatments 51 which were introduced during transfer process. We measured contact angles by using deionized water and diiodomethane on pristine, HNO3- and PFSA-doped 4LG to calculate surface energies of the graphene according to p-type doping . Similarly, increased WF by PFSA doping was also stably maintained for 10 days under ambient conditions  33. The configurations between each dopant and graphene suggest that the acidic proton of HNO3 is more exposed to outer circumstances than is the acidic proton of PFSA , and S2p peak (~170 eV) , with four PFSA-related chemical bonds , C−S (~289.6 eV), −CF2 (~292.4 eV), −CF3 (~294.0 eV))55. which can be confirmed in the chemical structure of PFSA  showed weak p-type doping effect and poor ambient stability, respectively  substantial increase in surface WF, (3) high stability against high temperature, chemicals, and ambient conditions, (4) smooth and uniform surface without any defects or large particles, and (5) negligible decrease in OT.Considering all the experimental observations and further analyses of PFSA-doped graphene, we can conclude that PFSA meets all the requirements of an ideal p-type dopant to produce a graphene anode: (1) large 3 due to a ~0.8 eV increase in the surface WF and reduced Rsh  were calculated  and higher power efficiency (PE ~95.6 lm W−1) without an out-coupling structure than did the device with the pristine 4LG (~82.7 cd A−1 and ~77.6 lm W−1)  and green-emitting phosphorescent OLEDs that had anode made of pristine or PFSA-doped 4LG Fig. . BecauseRsh Fig. . Hole inode Fig. . As a re−1) Fig. . The impRsh decrease, (2) substantial increase in surface WF, (3) high stability against all kinds of circumstances , (4) smooth and uniform surface, and (5) negligible decrease in OT. The non-volatility, strong binding to graphene, and chemical and thermal stability of PFSA can explain the excellent environmental stability of PFSA-doped graphene.We used a macromolecular fluorinated acid, PFSA, as a chemical p-type dopant to give extremely stable chemical p-type doping for graphene. The PFSA-doped graphene met the requirements for ideal p-type doping of graphene anode: (1) large We also fabricated HODs and OLEDs to demonstrate the superior hole injection and electroluminescent characteristics of devices that used the PFSA-doped graphene as an anode. An HOD that used the PFSA-doped graphene showed dramatic improvement of hole current, and OLEDs that used PFSA-doped graphene exhibited increase of luminous efficiencies: this result demonstrates the possibility of practical anode application of the PFSA-doped graphene due to its improved electrical conductivity and surface WF, and confirms that our PFSA is a promising p-type chemical dopant to make more ideal flexible graphene electrodes with excellent environmental stability, high WF; simultaneous achievement of these attributes has been almost impossible using conventional doping with small molecules.This work provides a promising way to overcome the demerits of chemically doped graphene electrodes and is a significant step towards development of stable graphene electrodes for practical use in various opto-electronic devices.2 gas and annealed for 30 min. As a carbon source, 60 sccm of CH4 gas was flowed for 30 min, then the Cu foil was rapidly cooled to room temperature. After synthesis of graphene on Cu foil, PMMA was applied by spin-coating polymer solution  as a supporting polymer layer for graphene transfer. O2-plasma treatment using reactive ion etching (RIE) was performed to remove the graphene that grew on the bottom of the Cu foil. The foil was immersed in a CE100 (YMS tech) etchant solution for 1 h to etch the Cu foil, then rinsed with deionized water for several hours to remove the etchant residue. Floated SLG was transferred onto the target substrate. Before measuring the stability, we performed vacuum annealing on transferred graphene at ~500 °C. Glass substrates were used to investigate the OT, large-area uniformity, and ambient stability. To perform c-AFM, we used native Si as substrates. In other characterizations of PFSA doping effect , we used Si/SiO2 (~300 nm) substrate. The supporting polymer layer was removed by soaking in an acetone bath. 4LG was stacked by repeating this process. Then 0.1 wt.% tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-7octenesulfonic acid copolymer  in IPA was spin-cast to chemically dope the graphene, then the sample was annealed at 100 °C for 10 min to remove the solvent. Raman spectra were obtained using a home-built setup operated with a 514-nm laser50. Rsh of graphene electrodes was measured using a 4-point probe combined with a Keithley 2400 source meter. Rsh decrease of PFSA-doped graphene saturates at PFSA thickness of ~10 nm, and we used 3.4 nm-thick PFSA layer for chemical doping of graphene. Surface potential difference was measured using an SKP-5050 Kelvin Probe measurement system. OT was measured using a SCINCO S-3100 UV-Vis spectrophotometer. To probe the morphology, conducting atomic force microscopy (c-AFM) was measured using a Bruker Dimension Icon Scanning Probe Microscope equipped with TUNA module in contact mode with a 0.01−0.025 Ω·cm Antimony (n) doped Si tip . A 300-nm-thick layer of SiO2 on p-doped Si was used as substrate for graphene-based FETs. Pristine graphene was transferred onto SiO2 substrate, then Cr (5 nm)/Au (300 nm) layers were thermally deposited using a pre-patterned mask to form FETs of width 200 μm and length 400 μm. XPS and UPS measurement of pristine and PFSA-doped graphene samples were conducted using the same equipment in collaboration with the Korea Basic Science Institute.SLG was synthesized on Cu foil by CVD. The foils were heated to 1060 °C with 15-sccm flow of H2 plasma and a pre-patterned shadow mask. UV-ozone treatment was performed for 10 min to activate the graphene films and to uniformly deposit the GraHIL on the graphene anode. The polymeric hole-injection layer was composed of Poly:poly(styrenesulfonate) (PEDOT:PSS) (CLEVIOS P VP AI4083) and PFSA, and was spin-coated to give a 50-nm-thick layer on the graphene anode, then annealed on a hot plate at 150 °C for 30 min. A 15-nm-thick layer of Di-[4--phenyl]cyclohexane (TAPC) was deposited on top of the HIL as a hole transporting material. A 5-nm-thick layer of 1,1-bisphenyl]cyclohexane (TCTA) doped with green phosphorescent dopants (bis(2-phenylpyridine)iridium (III) acetylacetonate (Ir(ppy)2(acac)) (97:3 by volume), and a 5-nm thick layer of 4,4′-N,N′-dicarbazolylbiphenyl (CBP) doped with Ir(ppy)2(acac) (96:4 by volume)) were deposited successively as a green-emitting layer. Then a 55-nm-thick layer of 1,3,5-tri(phenyl-2-benzimidazolyl)-benzene (TPBI) was deposited as an electron-transporting layer. Finally, LiF (1 nm)/Al (100 nm) was deposited on top of the TPBI layer as a cathode. The devices were encapsulated using a glass lid and epoxy resin. A Keithley 236 source measurement unit and Minolta CS 2000 spectroradiometer were used to measure current-voltage-luminance characteristics of green phosphorescent OLEDs.To prepare graphene as a transparent conducting electrode in OLEDs, we formed a 4LG anode by stacking SLGs. The prepared multi-layered graphene was patterned by RIE using O56. The experimental system was modeled as one PFSA molecule doped on each 4 × 4 graphene layer; this doping density is the most appropriate for the system. To avoid the undesirable interaction from the periodic supercell images, we used a supercell as large as 9.84 Å × 9.84 Å × 35 Å within potential dipole corrections for all calculations. The plane-wave energy cutoff was 650 eV, and the Brillouin-zone sampling meshes were 7 × 7 × 1. For the geometry optimization, all the coordinates were fully relaxed until the forces were < 0.01 eV Å−1. The Tkatchenko−Scheffler Van der Waals correction57 was used to describe the dispersion interaction between the adsorbate molecule and graphene layer.All DFT calculations were performed using projector augmented wave pseudopotentials with the Perdew−Burke−Ernzerhof type of generalized gradient approximation functions, which is implanted in the Vienna Ab-initio Simulation PackageEPFSA-graphene is the total energy of PFSA-doped graphene, EPFSA is the total energy of isolated PFSA molecule, and Egraphene is the total energy of the pristine graphene layer.The adsorption energy per PFSA molecule is defined as:The datasets generated during the current study are available from the corresponding authors upon reasonable request.Supplementary InformationPeer Review File


LINE-1 (L1) is the dominant autonomously replicating non-LTR retrotransposon in mammals. Although our knowledge of L1 evolution across the tree of life has considerably improved in recent years, what we know of L1 evolution in mammals is biased and comes mostly from studies in primates (mostly human) and rodents (mostly mouse). It is unclear if patterns of evolution that are shared between those two groups apply to other mammalian orders. Here we performed a detailed study on the evolution of L1 in perissodactyls by making use of the complete genome of the domestic horse and of the white rhinoceros. This mammalian order offers an excellent model to study the extinction of L1 since the rhinoceros is one of the few mammalian species to have lost active L1.We found that multiple L1 lineages, carrying different 5’UTRs, have been simultaneously active during the evolution of perissodactyls. We also found that L1 has continuously amplified and diversified in horse. In rhinoceros, L1 was very prolific early on. Two successful families were simultaneously active until ~20my ago but became extinct suddenly at exactly the same time.The general pattern of L1 evolution in perissodactyls is very similar to what was previously described in mouse and human, suggesting some commonalities in the way mammalian genomes interact with L1. We confirmed the extinction of L1 in rhinoceros and we discuss several possible mechanisms.The online version of this article (10.1186/s13100-018-0117-4) contains supplementary material, which is available to authorized users. The LINE-1 or L1 retrotransposon (Long Interspersed Nuclear Element 1) is found in virtually all vertebrate genomes but it is only in mammals that it has accumulated to extremely large numbers, accounting for the large genome size typical of this vertebrate class . L1 is bThe availability of complete genome sequences across the entire tree of life has led to a better understanding of the biology of L1 in a wide diversity of eukaryotes , 32–41. Among the lineages that could best illuminate the evolution of L1 and the cause(s) for loss of activity are the Perissodactyls, a mammalian order that includes horses and rhinoceroses, and belongs to the laurasiatheria super-order. The horse genome is known to harbor active L1 s  whereas Equus caballus 2007 (EquCab2) and Ceratotherium simum simum 2012 (cerSim1) genome assemblies using GPS [genome.ucsc.edu website. First, GPS conducted a BLAST type-search (WU-tBLASTn) of each genome using the conserved Reverse Transcriptase (RT) domain of ORF2 as a query motif. GPS then extracted 7000 bp upstream and downstream of the RT domain yielding fragments roughly 14,000 bp in length. A second WU-tBLASTn was then performed on each fragment to identify other motifs characteristic of FL mammalian L1 inserts . In this analysis, GPS did not search for sequence identity at the promoter region since L1 has been documented to frequently undergo recruitment of novel sequences as 5’ UTRs. A file containing FL fragments and their 3000 bp upstream regions was generated for each genome. In addition, we collected all FL elements that were already annotated in these two genomes to insure we didn’t miss any L1 subfamily.Full-length (FL) elements were collected from the sing GPS . These tFL sequences were categorized into families based on their phylogenetic relationships along the entire length of each sequence. A family is defined as a collection of inserts that result from the amplification of a highly homogenous group of progenitors that are easily identifiable by their unique combination of characters. We used neighbor joining trees to compare the global relationships of elements as a first step in our phylogenetic analysis. Distinct clusters of elements were considered to be families and were validated by a second round of phylogenetic analysis on the 5′ promoter region to confirm the existence of distinct families that originated from the replicative activity of highly similar progenitors. FL consensus sequences were derived for each family and are available as Additional file NJ and maximum likelihood (ML) trees were calculated for each region and domain of L1. Phylogenetic trees were calculated using the MEGA 6.06 package. The RDP4.0 program (Recombination Detection Program 4.0) was used to detect events of recombination between families of L1 . RDP sofhttp://www.datamonkey.org/ web server were used [To test for evidence of selection, several methods from the ere used . PARRIS ere used . A ω ratere used . To deteere used . The datTandem Repeat Finder  was usedHippomorpha/Ceratomorpha at 56 Myr, which is consistent with molecular and paleontological studies [The age of each family was estimated by calculating the average pairwise divergence based on the 3′ end of each family of elements. Since the 3’ UTR in perissodactyla is short (~ 100 bp), a 500–600 bp region of the end of ORF2 and the 3’UTR was used to estimate family age. CpG dinucleotides and the highly mutable polypurine tracts located in the 3’UTR were removed from alignment. The average distance between copies, as well as the standard error, was calculated using the maximum likelihood parameter distance (using the MEGA 6.06 suite). Divergences were converted to time assuming a divergence of  studies , 72, 73.Ceratotherium simum and Equus caballus. Since L1 elements tend to decay with time because of internal deletions [Family copy numbers were estimated using a locally installed copy of the RepeatMasker software. A custom library was constructed using our consensus sequences and used as a query to identify genomic L1 inserts in the complete genome sequences of eletions , 74–76, E. caballus chromosomes 1,2,3,5,7,9 and X as a reference genome to available C. simum contigs. These regions were chosen based on the higher quality of reference genome sequence available. The alignments were then analyzed using a locally run build of RepeatMasker using our consensus sequences as a custom library to identify L1 inserts located within these specific regions. Insertions, deletions, and divergence from consensus was calculated for 500 loci each, for two subfamilies of L1 that amplified and went extinct before the split of the Hippomorpha and Ceratomorpha suborders: L1_Perissodactyla4_II and L1_Perissodactyla6_I.Whole genome alignments were constructed using E. caballus and C. ceratotherium reference genomes, respectively. L1 elements were then aligned along the full length of the inserts and grouped based on their 5’ UTRs. Elements showing homology in their 5’UTR regions were then aligned along the full length of the insert and further categorized into families using a phylogenetic analysis of their 3′ terminus regions. A family here is defined as a collection of elements that result from the activity of a highly homogenous group of progenitors, which are classified by a unique combination of distinct characters. Neighbor joining trees of these elements were then constructed using different regions and functional domains of L1 to ensure that the homogeneity of the families extended over the entire length of the element. Using this approach, we identified 30 families and consensus sequences were derived for each of them  L1 inserts were recovered using GPS or the RepeatMasker tables from the The length of the consensus sequences varies between 5518 to 7914 bp, depending on the length of their 5’UTRs and, to a lesser extent, the length of the intergenic region between ORF1 and ORF2. In general, older families are represented by much fewer FL elements in comparison to younger families, which is expected since L1 inserts decay over time due to the accumulation of internal deletions , 74. We We performed a phylogenetic analysis using the longest non-recombining region of ORF2 (2207 bp) Fig. . The topThe phylogeny and timing of amplification of L1 families reveals that multiple lineages have coexisted over extended periods of evolutionary time in both horse and rhinoceros. In horse, the lineages with the 5’UTR of type 1 (L1_Ec1_I to X) and 2 (L1_Ec2_I to VII) have coexisted for the last 40 million years of horse evolution, and until ~13my they coexisted with the ancestral lineage carrying type 4 (families L1_Ec4_I to III). The rhinoceros-specific lineage (L1_Cs2_I to III) also coexisted with the ancestral L1_Perissodactyla4_I family since before the split from horse until L1 went extinct in the rhinoceros less than 20my ago. Similarly, the genome of the ancestors of both rhinoceros and horse harbored multiple families that were simultaneously active. Thus the evolution of L1 in perissodactyls is characterized by the long-term coexistence of a small number of lineages. Different types of 5’UTRs typically characterize these lineages and we observe no or little branching within those lineages, the only possible exception being families L1_Ec1_VII and VIII, that are branching of lineage 1, yet did not persist for a long period of time. Thus it appears that the diversification of L1 in perissodactyls was driven by the acquisition of novel 5’UTRs. Our analysis indicates that novel promoters, sharing no homology with their predecessor family, were recruited a minimum of six times in the past 60 Myr , the dynamics of L1 amplification could not be more different in these two species. The majority of the amplification in rhinoceros almost 29,000) result from the continuous activity of the ancestral L1_perissodactyla4_I family after the split from horse, the four rhinoceros-specific families (L1_Cs2_I to III and L1_Cs3_I) contributing an additional ~ 14,000 copies. In contrast the three lineages that have been simultaneously active in horse for the last 56 my have each contributed ~ 13,000 copies, although they diversified into 20 recognizable families and for two of them maintained activity until present. Since L1 has been extinct in rhinoceros for less than 20my, these data suggests that, until its extinction, L1 was much more prolific in the rhinoceros than in the horse genome. The last three families to amplify in rhinoceros  were in fact very successful  domain that mediates the formation of ORFIp trimers, a RNA-recognition motif (RRM), and a C-terminal domain (CTD) –79. In gDespite this high level of conservation at the amino acid level, we observed substantial structural variation in the perissodactyla CC domain Fig. . PreviouInterestingly, we found that the region that separates the two ORFs, the IGR, differ greatly in length among families and was evolutionarily very dynamic. In ancestral families (L1_perissodactyla7_I and L1_perissodactyla6_I), the IGR was about 280 bp long. It then increased in length to about 500 bp in lineage 4, and more moderately in lineage 2, where it ranges from 476 to 328 bp. In the two oldest families with a 5’UTR of type 1, it was about 375 bp long but it shrunk to ~ 50 bp in family L1_Ec1_VIII and all its descendants.p = 8.46*10∧-13; L1_Perissodactyla4_II: mean divergence in horse = 13.07%, in rhinoceros = 11.58%, p = 1.34*10∧-9) and indicate that rhinoceros evolve on average 12% slower than horses.Since the majority of L1 insertions evolved at the neutral rate, the number of differences they accumulate through time can be used to test if the rate of molecular evolution is the same across genomes. We tested this hypothesis in perissodactyls by comparing the divergence from consensus for 500 orthologous inserts in horse and rhinoceros belonging to families that amplified before the split between these species  92 my ago . We founAdditional file 1:Full-length consensus sequences. (FAS 193 kb)Additional file 2:Consensus sequences of the 5’ UTRs. (FASTA 29 kb)


High-speed light emitters integrated on silicon chips can enable novel architectures for silicon-based optoelectronics, such as on-chip optical interconnects, and silicon photonics. However, conventional light sources based on compound semiconductors face major challenges for their integration with a silicon-based platform because of their difficulty of direct growth on a silicon substrate. Here we report ultra-high-speed (100-ps response time), highly integrated graphene-based on-silicon-chip blackbody emitters in the near-infrared region including telecommunication wavelength. Their emission responses are strongly affected by the graphene contact with the substrate depending on the number of graphene layers. The ultra-high-speed emission can be understood by remote quantum thermal transport via surface polar phonons of the substrates. We demonstrated real-time optical communications, integrated two-dimensional array emitters, capped emitters operable in air, and the direct coupling of optical fibers to the emitters. These emitters can open new routes to on-Si-chip, small footprint, and high-speed emitters for highly integrated optoelectronics and silicon photonics. Integrating graphene with existing silicon technologies may pave the way to compact light sources for optoelectronics and photonics. Here, the authors fabricate graphene-based arrays of blackbody emitters integrated on a silicon chip, operating in the near-infrared region at high speed. Recently, carbon nanotube (CNT)-based light emitters, where CNTs are directly formed on silicon substrates, have been reported as light sources, based on electroluminescence by electron-hole recombination8 and blackbody radiation by Joule heating11. It is a great feature that these devices work as on-chip and small-footprint light emitters in the near-infrared (NIR) region, including telecommunication wavelength11. In addition, the high-speed light emission with a response time of ~100 ps has been recently demonstrated for CNT-based blackbody emitters, where the high-speed emission is explained by the extremely fast temperature response of CNT films, due to unique thermal properties of its one-dimensional structure12. Recently, optical communications are also demonstrated by using CNT emitters on silicon chips11.Nanocarbon-based optoelectronic devices are promising candidates for the high-speed, uncooled, and on-chip optical communication devices, such as light sources13, optical15, and thermal properties16, which have been applied for optoelectronic devices. Graphene-based blackbody emitters (gray-body emitters for thin graphene due to the low emissivity of 2.3 % per layer22) are also promising light emitters on silicon chip in NIR and mid-infrared region, just like CNT-based blackbody emitters27. In addition, the significant advantage of the emitter with graphene instead of CNTs is the planar, uniform, and bright light emission due to its two-dimensional geometry20. However, although graphene-based blackbody emitters have been demonstrated under steady-state conditions or relatively slow modulation (100 kHz) in large area devices26, the transient properties of these emitters under high-speed modulation have not been reported to date. Also, the optical communications with graphene-based emitters have never been demonstrated.Graphene, which is another nanocarbon material, has unique two-dimensional properties in electronic34. Moreover, we experimentally demonstrate optical communications at 1 and 50 Mbps based on eye-pattern analysis and real-time waveform detection by using multi- and few-layer graphene, respectively, integrated two-dimensional array emitters with a chemical vapor deposition (CVD) grown graphene, capped emitters operable in air, and the direct coupling of optical fibers to the emitters.Here, we report a highly integrated, high-speed, and on-chip blackbody emitter based on graphene in NIR region including telecommunication wavelength. Under a rectangular voltage, a fast response time of ~100 ps, corresponding to ~10 GHz modulation, has been experimentally demonstrated for single and few-layer graphene, and the emission response properties are strongly affected by the degree of graphene contact with the substrate, which depends on the number of graphene layers. The mechanisms of the fast modulation in this emitter are elucidated by performing theoretical calculations of the heat conduction equations considering the thermal model of emitters including graphene and a substrate. The simulated results indicate that the fast response properties can be understood not only by the classical thermal transport of in-plane heat conduction in graphene (dominated by hot spots) and heat dissipation to the substrate, but also by the remote quantum thermal transport via the surface polar phonons (SPoPhs) of the substrates11. Graphene was formed at the termination of the transmission lines. In this study, few-layer and multi-layer (≳5) graphene has been prepared by the mechanical exfoliation method with a scotch tape, and single-layer graphene has been prepared by CVD growth35. DC bias voltage dependences of the current for these emitters are shown in Supplementary Note 22. The graphene temperatures, which are obtained from these fittings, depends linearly on the applied voltage due to electron scattering with optical phonons caused by Joule heating37 and can reach about 750 K at Vds = 8 V  under a rectangular bias voltageIn these devices, the emission responses consist of two components: an initial fast response with a rise time of ~100 ps and a second slow response of the temperature rise. Figure 2 substrate under bias voltages by solving the simultaneous heat conduction equations of one-dimensional graphene and two-dimensional SiO2 substrate , where κgr is the thermal conductivity of graphene, the formation of a hot spot can contribute to the faster temperature response  of graphene emitters. However, the existence of a hotspot by itself is insufficient to explain the fast response of the experimentally observed emission ), the response speed of the initial region becomes high because the temperature relaxation time τ is simply given by ρC/g47. However, for a high g, the degree of the temperature rise in the initial fast region is suppressed by high heat dissipation to the substrate and its degree in the second slow region is emphasized by high thermal coupling between graphene and the substrate; consequently, the overall emission response is dominated by the second region with a slow temperature response. In contrast, with decreasing g, the dominant mechanism of the temperature response in the initial fast region crosses over from heat dissipation toward substrate (g(T − T0)) to the SPoPh and in-plane heat conduction of graphene (κ(∂2T/∂x2)). The degree of the temperature rise in the initial fast region increases and the influence of the substrate temperature in the second slow region is suppressed; that is, the shape of the overall temperature response approaches the shape of the rectangular input voltage. In this condition, the temperature response time of the initial fast region is in the order of 100 ps. We note that the experimental results  in principle, the contribution of the hot spot generation to the fast temperature response is not that high from the numerical calculation as shown in Fig. g condition, because both the increase of the speed of the initial temperature rise and the suppression of the subsequent slow region can be realized by SPoPh remote thermal transport due to the long propagation length of surface phonon polaritons and the suppression of the temperature rise of the substrate beneath the graphene.To understand the detailed mechanisms of the emission responses in Fig. 2 exhibit a clear rectangular emission response under a rectangular input. This quick rectangular response can be qualitatively understood by the temperature response for the emitter with low thermal conductance g 45. Our results imply that the direct measurement of the transient temperature is an effective method to precisely elucidate the in-plane and out-of-plane thermal transport in the graphene devices, and the time-resolved emission measurement, demonstrated in this study, is one of the effective method for the transient temperature investigation.These simulated results can explain the experimental emission response depending on the number of layers. As shown in Fig. e g Fig. , becauseput Fig.  because 11. Figure 51. A completely open eye is observed indicating that the optical commutation is possible at 1 Mbps. The relatively slow and asymmetric response observed in the eye pattern corresponds to the slow emission response in multi-layer graphene as shown in Figs To investigate the practical applications of these graphene emitters for optical communications, we demonstrate the real-time detection of the modulated light from the graphene emitters by using a conventional photoreceiver with a normal-mode APD2 on the silicon wafer, it is a great advantage that many light emitters can be directly integrated at any positons on silicon chip35. We fabricated two-dimensional array of graphene emitters, which are high dimension and density by using unsuspended graphene compared with earlier work20. Figure 52.As mentioned above, the high-speed blackbody emitters can be fabricated by using CVD-grown graphene as well as exfoliated graphene. Since the CVD-grown single-layer graphene can be uniformly transferred with the large size of >1 cm2O3 insulator. Such encapsulation technique was previously demonstrated by using hexagonal boron nitride (h-BN), and this technique allowed the operation of large area devices for more than 1000 h in air21. We grew the Al2O3 capping layer by an atomic layer deposition (ALD) method, which is used in a conventional silicon-based semiconductor process. The conductance of the device was decreased to ~50 % by the deposition of Al2O3 due to charged impurity scattering and SPoPh scattering by the capping layer53. As shown in Fig. 2O3-capped emitters can operate in air for more than 100 h. Furthermore, by using this Al2O3-capped emitters, we also demonstrated the direct coupling of this capped light emitter to a multimode optical fiber in air owing to their small footprint and planar device structure  at NIR wavelength including telecommunication wavelength. The 100-ps response time of this graphene emitter is faster than that of the conventional semiconductor light emitting diodes (~MHz) and is comparable to that of the laser diodes (~GHz). In addition, we have reported the application of graphene-based emitters for optical communications via optical fiber with the real-time signal transmission (1 and 50 Mbps) by using multi- and few-layer graphene, respectively. The high-speed modulation can be understood by the fast thermal relaxation dominated not only by the classical thermal transport of the in-plane and out-of-plane heat conduction, but also by the remote quantum thermal transport via the SPoPhs of the substrates. These findings suggest that the emission intensity and modulation speed of a graphene emitter can be controlled by the number of layers of graphene and the physical contact between graphene and substrate, indicating that the emission properties can be designed by the device structure. Since SPoPhs can be excited in the polar substrate, such as HfO2, Al2O3 and h-BN54, the effect of SPoPh can be modified by changing the substrate. In particular, two-dimensional materials such as h-BN have recently attracted attention owing to their unique properties of their flat surfaces55, anisotropic structure, and two-dimensional polariton transport56, and these unique properties are applicable to the graphene light emitters26. Graphene light emitters are greatly advantageous over conventional compound semiconductor emitters because they can be highly integrated on silicon chip with simple lithography processes by using large scale CVD graphene. In addition, it has been reported that the optoelectronic devices with nanocarbon materials are compatible with integrated silicon photonics and three-dimensional integrated circuits8. Hence, graphene-based emitters can be directly combined with the silicon platform with three-dimensional integrated electronics and integrated silicon photonics, and they can open new routes to highly integrated optoelectronics, e.g., optical interconnects.We have demonstrated graphene-based blackbody emitters, which have a high modulation speed (100-ps response time) and small footprint (~1 μm2/Si substrate using poly(methyl methacrylate) (PMMA)35. The number of graphene layers are derived from the intensity ratio of 2D and G peaks in Raman spectroscopy for single- and few-layer graphene and from the thickness measured by an atomic force microscope for multi-layer graphene. The graphene on the substrate was patterned by e-beam lithography and O2 plasma etching with a Ni mask, which is subsequently removed by hydrochloric acid solution. Ti/Pd electrodes were deposited as source and drain electrodes on the graphene. The graphene sizes of device channels were 5 × 5 μm for the device with single-layer graphene, 6 × 9 μm for the device in Fig. 11. A gate bias cannot be applied because of the use of an undoped substrate. The capped emitters for the air operation  silicon substrate Fig. . We used11. The Al2O3-capped emitters were measured in air. Two-dimensional emission images and emission spectra of the emission was detected by an InGaAs CCD camera and an InGaAs linear detector with a spectrometer, which has the wavelength range from 0.9 to 1.6 μm, respectively. The relative spectral response of the measurement system including the optical path and the detector was measured with a standard light from a blackbody furnace, and all spectra were corrected accordingly. Bias signals were applied through a signal line of the coplanar device using a DC voltage source, a signal generator, a function generator and a pulse generator for steady-state emission, time-resolved high-speed emission measurement, real-time optical communications, or pulsed light generation, respectively. In the time-resolved emission measurements based on a single-photon counting method, the emitted light was guided to the Geiger-mode InGaAs APD (wavelength range: 0.9–1.7 μm) through a fiber coupler and a multimode graded-index optical fiber, and the time-resolved emission intensity was obtained using a time-correlated single-photon counting module , in which the detected signal from the APD was amplified by a transimpedance amplifier and a pre-amplifier (100 MHz bandwidth), and was measured using a digital oscilloscope Peer Review File(PDF 638 kb)


Attentional bias toward sleep-related information is believed to play a key role in insomnia. If attentional bias is indeed of importance, changing this bias should then in turn have effects on insomnia complaints. In this double-blind placebo controlled randomized trial we investigated the efficacy of attentional bias modification training in the treatment of insomnia.n = 67) or a placebo training group (n = 70). Both groups received eight training sessions over the course of two weeks. All participants kept a sleep diary for four consecutive weeks (one week before until one week after the training sessions).We administered baseline, post-test, and one-week follow-up measurements of insomnia severity, sleep-related worry, depression, and anxiety. Participants meeting DSM-5 criteria for insomnia were randomized into an attentional bias training group (There was no additional benefit for the attentional bias training over the placebo training on sleep-related indices/outcome measures.The absence of the effect may be explained by the fact that there was neither attentional bias at baseline nor any reduction in the bias after the training. Either way, this study gives no support for attentional bias modification training as a stand-alone intervention for ameliorating insomnia complaints. Insomnia is a prevalent disorder that affects about 10% of the general population . Indeed,Such a prevalent and impairing disorder calls for effective treatments. In general, insomnia is most effectively treated with Cognitive Behavioral Treatment for Insomnia (CBT-I). People with insomnia benefit from CBT-I, with meta-analyses reporting large treatment effects on insomnia severity –10. HoweAn additional issue with CBT-I interventions is that they tend to be time and resource intensive for both clinicians and clients. Consequently, the availability of such treatments is recognized as being low in relation to need. Thus, restricted access to treatment, problems with patient motivation and adherence, and the real or perceived costs can limit the utility and uptake of such interventions . While sOne possible approach that may hold potential benefits to the treatment of insomnia is focusing  on maladaptive automatic cognitive information processes, such as selectively attending to sleep-related cues in the environment . Theoretically, it has been argued that attentional bias toward sleep-related information is supposed to play a key role in insomnia. For instance, Harvey’s  cognitivIn another influential model, Espie and colleagues  further In line with these two models, it has been shown that people with insomnia show an attentional bias towards sleep-related stimuli –19. HoweA viable next step seems to be testing whether the maladaptive, sleep-related attentional bias can also be modified with an attentional bias modification training (ABM) and whether this affects insomnia severity and sleep indices. Over the last years, different ABM training paradigms have been developed in the field of anxiety, whereby subjects are trained to shift their attention from threatening information  toward neutral or positive information . At firsTo our knowledge, there have been two studies that have sought to examine ABM training in insomnia to date, both of which have employed experimental designs with sub-clinical samples , 30. MilOverall, these studies provide some encouraging initial findings suggesting possible benefits of ABM for insomnia. As acknowledged by the authors however, a larger scale randomized controlled trial with a clinical sample is necessary in order to establish the therapeutic potential of such an intervention. Furthermore, these studies observed no changes in sleep-related attentional bias. This could have been due to a type II error . However, the absence of a change in attentional bias and the small sample size also raises the question whether the changes in sleep-related worry and sleep onset latency resulted from ABM or were due to other processes, including the possibility of type I errors . Thus the aim of the current study was to conceptually replicate these previous findings in a larger sample. Furthermore, we sought to determine if the effects of ABM training would be demonstrated in people meeting DSM-5 criteria for insomnia opposed to having only ‘sleep problems’ such as in Clarke et al.’s study.Therefore, we set up a double-blind placebo controlled ABM study that differed from the Clarke study on a number of key aspects. Firstly, we included a sample of people with clinical levels of insomnia and also recruited a larger sample to ensure the study was adequately powered. Furthermore, a larger number of total training sessions were delivered over a longer period of time ; as suchwww.insomnie.nl). Inclusion criteria were being at least eighteen years old, meeting DSM-5 criteria for insomnia  and an Insomnia Severity Index of 10 or higher . Exclusion criteria included starting a psychotherapy in the past six months, alcohol or drug abuse, high score on depressive symptoms (CES-D score of 27 or higher)  / 2). Between-group effect sizes were calculated with: d = ([Mpre1 –Mpost1]–[Mpre2 –Mpost2]) / SDchange, in which SDchange is the pooled SD of the pre–post change score. For all the multilevel models we checked whether the residuals met the assumption of normality. Throughout the study we used an alpha level of .05 (two-sided).Within-group Cohen’s Outlying scores on the main outcome variables were removed if they had a baseline z score of 3.29 or higher. Three full diaries (baseline and post-test) in the placebo condition were deleted because participants reported in their baseline diary that they did not sleep for a full week. Furthermore, we removed the following outliers from the baseline and post-test: one attentional bias score and one number of awakenings score in the placebo condition; one anxiety, one sleep onset latency, one terminal wakefulness score, and one number of awakenings score in the experimental condition.SD = 2.05) sessions. Of the participants in the ABM-placebo condition, 62 (88.6%) completed six or more training sessions and on average they completed 7.29 session (SD = 1.76), t(135) = .56, p = .58.Of the participants in the ABM-training condition, 58 (86.6%) completed six or more training sessions and on average they completed 7.10  was not significantly lower than probe on the neutral word , t = 0.30, p = .77. This means that, contrary to our first hypothesis, there was no indication of an attentional bias towards sleep-related word cues in people with insomnia. Split half reliability of the dot-probe task at baseline was r = -.06, p = .54 and test retest reliability was r = -.09, p = .43.A paired-sample d effect size was equal to .01. In d of attentional bias scores can be found. See The multilevel regression analysis showed that there was neither significant time effect nor an interaction effect (time × condition) on attentional bias scores at post-test. This means that, contrary to our second hypothesis, the training was not more (nor less) effective in ameliorating attentional bias than the placebo training. Cohen’s d effect sizes ranged between .00 to .40. In d for attentional bias, Insomnia Severity Index (ISI), Sleep efficiency, Sleep onset latency, depressive symptoms (CESD), anxiety symptoms (HADS-A), and worry about sleep (APSQ) can be found. For the remaining variables, the completers’ sample and the multilevel regression coefficients please see The multilevel regression analyses showed that there were significant time effects at post-test for both conditions on the ISI (primary measure), the PSQI, and total sleep time. Significant time effects were found for the CESD only on the ABM condition and for the HADS-A and TWAK only for the placebo condition. For the remaining variables no time effects were observed. Furthermore, no significant interaction effects (time × group) were found on any of the variables at either the post-test or follow-up. This means that, contrary to our third hypothesis, the training was not more (nor less) effective than the placebo training. Cohen’s Of the 60 participants that filled out the post-test in the placebo condition, seven thought there was a relationship between the arrow and the words; four of these recognized the correct relationship. Of the 54 participants in the experimental condition, 12 thought there was a relationship between the words and the arrow; however, none recognized the correct relationship.There were no adverse events reported in this trial.We investigated whether a multiple-session ABM training could reduce sleep-related attentional bias and sleep complaints in a sample of 137 people with insomnia. In this placebo controlled randomized study we found no indication for the presence of a sleep-related attentional bias and no evidence that we could change the bias or the sleep complaints. We did observe a general reduction in both groups on insomnia symptoms, which is most likely due to non-specific factors such as keeping a diary and taking part in a research trial.The absence of a sleep-related attentional bias at baseline is not in line with earlier research that did evidence an attentional bias toward sleep in individuals with insomnia –19, nor At any rate, changing attentional bias is a critical issue since it is the alleged working mechanism of ABM interventions. Furthermore, only when attentional bias is changed, effects on outcome measures are observed in the field of anxiety . In the In contrast to the study of Clarke and colleagues , we did Another explanation may be that we did not succeed in manipulating the bias, whereas the studies by Clarke and colleagues , and Miln = 137 in our study, versus n = 36 in [In our view, this study had several strengths. First, as we mentioned, the study was adequately powered to find an average effect size difference ( = 36 in ); theref = 36 in . Further = 36 in ). Howeve = 36 in –61). For = 36 in  found thr = -.06. This means that the (change in) attentional bias may have been present in our sample, but the dot-probe may have failed to detect it. This poses a serious problem since now we cannot be certain whether we did not succeed in changing the attentional bias or we could not detect this change. Future studies should employ a more reliable measure of attentional bias  limitations to this study. The most important limitation regards the psychometric properties of the attentional bias measurement task (dot-probe). As we mentioned above, we detected neither attentional bias at baseline nor any change of attentional bias. Recently it was shown that the dot-probe task lacks reliability , 64. Forrch task—) or shourch task—). Howeverch task— concludeApart from this point, there were other limitations to this study. One concerns the timing of the ABM task delivery. In the present study participants were instructed to complete the training between 7 PM and 11 PM. This was designed to target the delivery of the ABM in the lead-up to sleep when biased attention to threat may begin to be problematic, while not requiring participants to complete this task at a time that could interfere with the process of falling asleep. This does however, represent a point of difference from the two earlier studies , 30 wherWhen weighing these strengths and limitations, it is difficult to give a definite answer to the question whether our study should be seen as a failed manipulation of attentional bias or as evidence against the hypotheses. Regarding the failed manipulation, we think the most serious limitation of our study (and indeed many past research) is the unreliable dot-probe task. We believe it is critical to replicate our study with a measure capable of reliably assessing attentions bias. If such study, again, does not observe (changes in) attentional bias, it can be concluded that ABM trainings are not (yet) able to change sleep-related attentional bias. If on the other hand, these changes on attentional bias are observed, but do not lead to symptom changes, this would have strong implications for the theoretical and clinical role of attentional bias (training) in insomnia research. Specifically, such a finding would suggest that attentional bias for sleep-related negative information may be a cognitive correlate of insomnia, but is not causally related to disturbed sleep. As long as no such study with adequate measurements has been reported, we think that no firm conclusions can be drawn on the role of (changing) attentional bias in insomnia complaints. Therefore, the results of the current study clearly provide no evidence for the clinical efficacy of ABM for insomnia and suggest caution in interpreting the potential applied benefits of such an intervention approach on the basis of other recent findings , 30. GivS1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.


Spaced education is a novel method that improves medical education through online repetition of core principles often paired with multiple-choice questions. This model is a proven teaching tool for medical students, but its effect on resident learning is less established. We hypothesized that repetition of key clinical concepts in a “Clinical Pearls” format would improve knowledge retention in medical residents.This study investigated spaced education with particular emphasis on using a novel, email-based reinforcement program, and a randomized, self-matched design, in which residents were quizzed on medical knowledge that was either reinforced or not with electronically-administered spaced education. Both reinforced and non-reinforced knowledge was later tested with four quizzes.Overall, respondents incorrectly answered 395 of 1008 questions . Incorrect response rates varied by quiz , but not significantly by post-graduate year . Although there was no evidence of benefit among residents , we observed a significantly lower risk of incorrect responses to reinforced material among interns .Overall, repetition of Clinical Pearls did not statistically improve test scores amongst junior and senior residents. However, among interns, repetition of the Clinical Pearls was associated with significantly higher test scores, perhaps reflecting their greater attendance at didactic sessions and engagement with Clinical Pearls. Although the study was limited by a low response rate, we employed test and control questions within the same quiz, limiting the potential for selection bias. Further work is needed to determine the optimal spacing and content load of Clinical Pearls to maximize retention amongst medical residents. This particular protocol of spaced education, however, was unique and readily reproducible suggesting its potential efficacy for intern education within a large residency program. Internal medicine residency curricula are designed around six core competencies, designated by the Accreditation Council for Graduate Medical Education, that are required for graduation, including patient care, medical knowledge, professionalism, systems-based practice, practice-based learning, and communication skills . ResidenKnowledge retention among medical housestaff remains a pervasive concern . RepetitWe sought to determine whether a modified version of SE focused on the spacing effect could be applied to a novel, email-based reinforcement program on medical facts amongst medical house-officers, using a randomized, self-matched design in which interns and residents were tested on material that was or was not further reinforced at random with electronically-administered SE.The study was conducted at a large, single urban academic medical center with approximately 649 licensed beds. The internal medicine residency program is composed of approximately 160 housestaff. As education research, the project was deemed exempt from IRB approval by the Beth Israel Deaconess Medical Center Committee on Clinical Investigations.To maximize retention, the residency program previously instituted a series of weekly "Clinical Pearls", or key learning points, from lectures and didactic sessions given throughout the week. These pearls are sent to all medical housestaff via email weekly and cover topics from major lecture series . All residents receive these “Pearls” each week, regardless of their individual rotation and attendance at conference. The Pearls document, which is drafted each week by a resident during his or her teaching elective, is typically one to two pages in length, in bullet-point format, and organized by day of week and didactic session.Prior to this study, a survey of housestaff showed that 22% of residents read these emails weekly, while 72% read a Clinical Pearls email at least monthly. More than 60% of residents never referred back to old Clinical Pearls weekly emails. We hypothesized that synthesizing this learning material every month and testing this material would increase readership and improve retention.® Word and Portable Document Format formats. The document contained reinforced Pearls from both the current and prior month .From December 2013 to May 2014, one author (JM) compiled all weekly Pearls emails over a calendar month. Each individual learning point, or Pearl, underwent simple randomization to be reinforced or not reinforced via SE. Pearls that were not reinforced underwent no further repetition . The reinforced Pearls were incorporated into a larger monthly document organized by subspecialty. This document was emailed each month to all housestaff in both MicrosoftTo test the spacing effect of the reinforced material, we sent out eight original multiple choice questions each month to the entire housestaff based directly on the Clinical Pearls. Half of these questions covered material that had been randomly reinforced by spaced learning in the weekly and monthly documents, and half covered material that had only appeared in the weekly email; these were not distinguished on the survey in any way .Each week, after each individual pearl was randomized to SE or no SE, two questions were written by either a resident on their teaching elective or by the author (JM). One question pertained to clinical information to be reinforced by SE, and another question was based on a Pearl not reinforced by SE, for a total of eight questions. This strategy was repeated for five months.The eight questions covered material from weeks one and three of the most recent month and weeks two and four of the month prior , ensurinEach monthly eight question quiz included questions from the current month and the previous month. Four questions were taken from material randomized to SE and four questions were taken from material not randomized to SE.Subjects responded anonymously to these questions. No questions were repeated across surveys, and answers were not provided until all responses to questions were collected. These multiple choice questions were written by a resident on their teaching elective or by the author (JM) based directly on the weekly Clinical Pearls emails. All questions were reviewed by two reviewers- (JM and AV) to ensure standardization of the level of difficulty, question format, and quality of the content tested. Questions were edited as necessary to meet the standards agreed upon between the two reviewers prior to study initiation. To maximize power, an incorrect response rate near but below 50% was sought.In August 2014, during the subsequent academic year, a post-study survey was sent out to junior and senior residents who were housestaff during the study . Using aBecause correct responses were more common than incorrect, we evaluated the likelihood of any given question being answered incorrectly as the primary outcome. We present the overall proportion of incorrect responses with exact binomial confidence intervals.To evaluate the effect of reinforcement on the frequency of correct answers, we used generalized estimating equations to account for clustering of questions within-resident and within-quiz. We estimated the relative risk of an incorrect response to questions that had been reinforced with SE relative to those that had not, using a log link, binomial distribution, and exchangeable correlation matrix. We adjusted for post-graduate year (in three categories) except in analyses stratified by year. We tested the effect of post-graduate year and the specific quiz given similarly using type three tests with two or three degrees of freedom, respectively.A total of four quizzes, each comprised of eight questions, were distributed to housestaff. On average, 31 (SD 6.55) house officers responded to each quiz, representing a response rate of 20%. Of these, interns comprised 47% of respondents and junior and senior residents comprised the remainder. All respondents answered all the questions on each quiz, providing an identical number of questions to reinforced and unreinforced material. Overall, respondents incorrectly answered 395 of 1008 questions . Incorrect response rates varied by quiz  but not significantly by post-graduate year (PGY) . In crude analyses, 188 of 504 questions on reinforced material were answered incorrectly, compared with 207 incorrect responses to unreinforced material .We next evaluated the relative risk of an incorrect response overall and among interns and residents. In analyses accounting for clustering and adjusted for post-graduate year, the relative risk of answering a reinforced question incorrectly compared with an unreinforced question was 0.90 . Although there was no evidence of benefit among junior and senior residents , we observed a significantly lower risk of incorrect responses to reinforced material among interns  .A total of 27 housestaff responded to the post-study survey . Of thesIn this randomized trial of a focused form of SE tied to an existing email system to reinforce key teaching points from weekly lectures, we found no statistical difference in retention of reinforced versus unreinforced material among our housestaff overall. However, retention was significantly better with reinforced material among interns.There are several reasons that interns may have been most likely to respond to this intervention. Interns may have a steeper learning curve and therefore may be more motivated to review Clinical Pearls emphasized in didactic sessions, as more of this material is likely to be new. Indeed, their rate of incorrect responses was modestly higher than that of junior and senior residents, although residents of all years appeared to find the questions challenging (as intended). In addition, interns may be less likely to suffer from email fatigue, a common problem with this type of intervention in an increasingly digitalized housestaff environment. A post-survey from this project concluded that many interns and residents were turned off by the reinforcement of Clinical Pearls due to the frequency of emails.Repetition of clinical material has been shown to improve retention over time in other studies as well. A 2012 study of CPR skills and knowledge similarly showed that recertification status blunted the deterioration of knowledge-based skills (i.e. scene safety and EMS activation) over time. However, components requiring specific skills, such as chest marking, declined over time despite recertification status .In traditional models of SE, when students submit an answer, the student is immediately presented with the correct answer and an explanation of the topic . In addiOur study has both strengths and weaknesses. A particular strength of this study was its method of randomization. We did not randomize house officers; in our experience, substantial crossover can occur in novel interventions that only some residents receive. Instead, the subject matter was randomized, thereby allowing the entire housestaff to participate in the program. This eliminated unintended crossover between groups and also allowed each quiz to serve as its own control, increasing the efficiency of the design. We studied approximately 16 weeks of reinforced material, allowing for a broad range of questions and a large sample size of questions. The SE was all administered electronically, which required 1–2 hours of organizational labor each week, although most of the effort inherent in this study was devoted to studying its effect rather than to the intervention itself. We suspect that as smartphone applications that can be harnessed for medical education before more ubiquitous, the process of SE import and extraction may simplify –16. ImpoLimitations of this study include a low response rate. The multiple choice quizzes were optional and were given online, with the link provided via email. However, the fact that each quiz included both intervention and control questions substantially minimizes the bias that a low response rate might otherwise produce. In addition, we had no means of determining who read the weekly or monthly Pearls. Therefore, it was unclear whether those who read the Pearls were the same residents who took the quizzes; if not, the benefit of this intervention may have been markedly underestimated. This study also did not use a typical SE protocol. In our study, housestaff were not given immediate feedback to their quiz responses, and questions were not repeated in a regimented program as is typically performed with SE. Our effect size may have been stronger had we used a more quintessential model, albeit with less immediate applicability to programs like ours.We have no objective measure of the quality of our assessment questions, although they were all edited by two co-authors, including an associate residency program director. Two observations suggest that these questions achieved their desired aims. First, we aimed for a correct-response rate similar to that measured, suggesting that our calibration of difficulty was accurate. Second, the fact that we observed an effect of SE using these questions, albeit only among interns, suggests that the questions were sufficiently sensitive to change; had they been substantially easier or more difficult, it would have been impossible to detect such an effect.In summary, in this randomized trial, we found that reinforcement of learning material statistically improves medical retention among medical interns, but not medical residents. SE appears to be a promising and readily incorporated modality for improving retention when added to low-cost, highly-accessible electronic reinforcement systems.S1 FigClinical Pearls Assessment Survey.(TIFF)Click here for additional data file.S2 FigIRB determination email.(MSG)Click here for additional data file.S3 FigIRB determination form.(DOCX)Click here for additional data file.


Further experimental works by optimizing the cleaning process, growth parameters of the present growth method, or by using other growth methods, as well, are expected to realize a high quality SiCOI structure, thereby opening up the way for a breakthrough in the development of advanced ULSIs with multifunctionalities.We report an innovative technique for growing the silicon carbide-on-insulator (SiCOI) structure by utilizing polycrystalline single layer graphene (SLG) as a buffer layer. The epitaxial growth was carried out using a hot-mesh chemical vapor deposition (HM-CVD) technique. Cubic SiC (3C-SiC) thin film in (111) domain was realized at relatively low substrate temperature of 750 °C. 3C-SiC energy bandgap of 2.2 eV was confirmed. The Si-O absorption band observed in the grown film can be caused by the out-diffusion of the oxygen atom from SiO The trachnology . They prnsistors , photodensistors  and solansistors . are also the promising materials for such purposes due to their superior properties. Graphene, a carbon allotrope, possesses high carrier mobility, up to 200,000 cm2/Vs, even at room temperature (RT) [11 cm−2. The quantum Hall effect exists in graphene at RT, owing to ballistic transport of electrons and holes [In addition to Ge and III-V materials as proposed by them, we believe that graphene and IV-IV materials ure (RT) , and thind holes , and thind holes ,10,11,12nd holes . As a nend holes , graphennd holes , GaAs-onnd holes  and SiC-nd holes  structur2/Si substrate at relatively low temperature by a homemade hot-mesh chemical vapor deposition (HM-CVD) apparatus. There are several reports regarding to the growth of SiC film on SiO2 substrates without introduction of any buffer layer [2 substrate without a graphene buffer layer using the same procedures with this work in terms of source gas, growth temperature, and technique [2 is amorphous, all reported grown SiC films, including those from our work, show polycrystalline structures.So far, to realize high quality SiC thin film on silicon, we have studied the growth of SiC-on-SOI substrates with an ultrathin top Si layer  and alsoer layer ,21. In technique . We repo2 hybridized orbitals. This bonding structure is similar to the C plane of a hexagonal crystalline structure and (111) plane of zinc-blende structure. With this regard, the growth of (111) oriented SiC on graphene in <111> direction is feasible. Recently, graphene was also shown to be able to serve as a buffer layer for the growth of other material nanostructures on insulator such as zinc oxide (ZnO) nanorods [Based on the above results, one of major merits of using graphene as a buffer layer is the feasibility of growing highly oriented single crystalline SiC film. Large lattice mismatches between graphene and SiC is a critical problem in realizing high quality epitaxial film, but we believe such a problem can be resolved by clever growth technique. As an example, it was proved that the large density of threading dislocations resulted in the growth of GaN on sapphire due to a large lattice mismatch has been drastically reduced by the application of lateral growth technique . Graphennanorods  due to t2/Si(100) substrate, purchased from Graphene Laboratories Inc., NY, USA, is shown in + laser at incident power of 20 mW/wavelength of 514.5 nm), as shown in The schematic of graphene/SiO−1 and 2670 cm−1, respectively. The ratio intensity of the 2D and G band (I2D/IG) is about 1.6, hence it indicates that the graphene is a single layer [The sharp peaks of the G and 2D band were observed at 1580 cmle layer . In gene2 as a carrier gas with the constant flow rate of 100 sccm. This method utilizes heated tungsten wires arranged in a mesh, which promotes the high decomposition efficiency of H2 gas. The growth pressure was set to 1.8 Torr. The temperature of the substrate was set to 750 °C, while the mesh was 1800 °C. As reported, among its many polytypes, 3C-SiC is a stable phase that can be grown at low temperatures [eratures . The cry2/Si(100) substrate has been enhanced in (111) domain. These experiments have been repeated, and all samples have exhibited the same orientation of 3C-SiC (111). The full width at half maximum (FWHM) of XRD curve shown in 2 [et al. reported the graphitization process or the formation of epitaxial graphene on the 3C-SiC (111) surface by an annealing process in an ultrahigh vacuum condition [etc., also need to be determined, thus opening a lot of interesting works to be explored.2 ,21,22, sondition . Therefo−1 and 1080 cm−1 are observed. The peak at around 800 cm−1 indicates the transverse optical (TO) phonon of stoichiometric Si-C bond in 3C-SiC [−1 indicates the Si-O bond [−1 for 3C-SiC bulk. In this case, the small variation of absorption band may be due to the size effect of the precipitates/grains. The Si-O absorption band observed in the grown film can be explained by two aspects: (1) Out-diffusion of the oxygen atom from the SiO2 substrate; and (2) oxygen doping during the cleaning process. Since the gap between the mesh and substrate was just 30 mm, the surface temperature of the substrate is considerably more than 750 °C. This condition may cause the out-diffusion of oxygen from the SiO2 layer into the graphene and grown SiC film. Graphene can also be easily doped by oxygen during the organic cleaning process [n 3C-SiC  while 10i-O bond . In gene process .The local bonding distortion in an intrinsic SLG can result a π-orbital misalignment . This diIn conclusion, these preliminary results suggest that graphene can be used as a promising buffer layer for epitaxial growth of 3C-SiC thin film on insulator at relatively low temperatures. Ideally, graphene should be grown directly on the insulator prior to the growth of SiC film. However, such technology is not realized up to this date. Further experimental works by (1) utilizing large-area SLG; (2) optimizing the cleaning process; (3) optimizing the growth parameters of the present growth method, and (4) utilizing other promising growth methods as well, are expected to realize high quality SiC thin film on insulator. Graphene can not only serve as a promising buffer layer for the growth of semiconductor thin films and nanostructures on insulators in highly oriented single crystalline forms, but it also can be used to fabricate other functional devices by exploiting its superior characteristics towards the realization of advanced ULSIs with multifunctionalities.


Growth of X-enes, such as silicene, germanene and stanene, requires passivated substrates to ensure the survival of their exotic properties. Using first-principles methods, we study as-grown graphene on polar SiC surfaces as suitable substrates. Trilayer combinations with coincidence lattices with large hexagonal unit cells allow for strain-free group-IV monolayers. In contrast to the Si-terminated SiC surface, van der Waals-bonded honeycomb X-ene/graphene bilayers on top of the C-terminated SiC substrate are stable. Folded band structures show Dirac cones of the overlayers with small gaps of about 0.1 eV in between. The topological invariants of the peeled-off X-ene/graphene bilayers indicate the presence of topological character and the existence of a quantum spin Hall phase. Their low-buckled geometries with a mixing of 8, e.g., the appearance of Dirac cones near the K corner points of the hexagonal Brillouin zone (BZ). The almost zero gap, together with vanishing effective masses, indicate high room-temperature carrier mobility. The first realization of a silicene field effect transistor operating at room temperature has been reported12. Suggestions that silicene may join graphene as a wonder material13 or stanene as the next supermaterial for chip interconnects14 can be found in literature. The linearly dispersive bands of the Dirac cones give rise to a constant optical absorbance, determined by the Sommerfeld finestructure constant15. The spin-orbit interaction opens a fundamental gap in the 2D honeycomb group-IV materials18. They are quantum spin Hall (QSH) insulators19 with a quantized spin Hall conductivity18.Graphene-like group-IV, such as silicene20, which however hinder a proper decoupling of the key electronic states from the underlying substrate9. A van der Waals (vdW) epitaxy of weakly interacting monolayer films on passivated or self-passivated substrates has been predicted21. Graphite-like materials with hexagonal atomic arrangements are expected to be promising substrate candidates22. Indeed, first experimental studies, e.g. on MoS2 surfaces or 2D crystals23, have been made, in line with theoretical investigations24. Studies also suggest graphene27, or hexagonal boron nitride (hBN)29, as substrates. By means of ab initio calculations, the possibility of a vdW epitaxy of silicene or stanene on insulator surfaces, e.g. CaF2(111)30, Al2O3(0001)31, and SiC(0001)32, has been investigated. In the case of the topological insulator Bi2Te3(111)7 and non-passivated SiC(0001)33 surfaces, however, the hybridization between Sn overlayer and substrate is too strong.Silicene, germanene, and stanene, referred to as X-enes, are not found in nature, even not corresponding graphite-like layered materials. Therefore, X-enes have to be synthesized. There were trials to grow 2D group-IV materials on metallic and semimetallic substrates37. The passivation of SiC substrates due to the graphene overlayers may open a venue towards X-enes on a substrate available from the well-known graphene-on-SiC technology. Indeed, deposition of Sb2Te3 films on monolayer epitaxial graphene and quasi freestanding bilayer graphene was already achieved38. In this letter, we combine the ideas of deposition of silicene, germanene, and stanene on 2D hexagonal atomic arrangements and passivated wide-gap insulators. We investigate geometries and electronic structures of honeycomb group-IV crystals on graphene/4H-SiC(0001) and graphene/4H-SiC. On top of the uppermost Si atomic layer, a graphene layer is deposited in an optimized distance a = 3.87  Å, 2.47 Å, and 3.8 Å.The repeated slab method40. The non-primitive unit cells of the adapted 2D lattices are listed in Table In order to have almost vanishing in-plane strains, one has to extend and rotate the 2D hexagonal cells of the three materials. The stacking of the two honeycomb crystals over the hexagonal SiC surface was explicitly obtained by the coincidence lattice method41. However, for the C-terminated surface, the formation of high-quality graphene islands has been also reported with a 34. Here, because of the constraint due to the third X-ene layer, we study SiC surface cells with reasonable numbers of atoms between 12 and 19. In the case of stanene we use a 4 × 4 translational symmetry, which covers four 2 × 2 cells of the SiC(000 The cell size of the SiC(0001) surfaces is somewhat smaller than the favored  the smaller distances 25. The buckling amplitudes of the X-ene layer are practically the same as in the freestanding crystals43. The reasons for the different behavior of graphene grown on C- and Si-terminated, polar SiC surfaces have been discussed elsewhere44. The energetics and the structural results given in Supplementary Table The Gr layers deposited on C-terminated SiC, 116 meV at K (germanene), and 146 meV at K (stanene), similar as for other vdW depositions of X-enes30. The gap values are only slightly larger than those obtained for freestanding bilayers25. The exceptional case of germanene is illustrated by the hybridization of germanene- and graphene-derived states near the Dirac points. The orbital and element projections in Figs. pz and Gepz states, i.e., different atoms but the same orbital symmetry.We focus on the geometries on SiC between two time-reversal invariant momenta (TRIM) of the BZ48 and implemented in the VASP code49. The topological invariant Z2 is determined by the crossings of an arbitrary reference line modulo 2 connecting two TRIM points within the WCC phase evolution ky line47.The survival of the X-ene Dirac cones with small gaps in Fig. When the SiC by using the projector-augmented wave (PAW) method for generation of wave functions and pseudopotentials50, as implemented in the Vienna ab-initio simulation package (VASP)51. Exchange and correlation (XC) are described within the Perdew-Burke-Ernzerhof (PBE) functional52. To account explicitly for vdW interaction, the optB86b functional53 is employed. The plane-wave expansion is restricted by a kinetic energy cutoff of 400 eV, while the BZ integrations are carried out with a 3 × 3 × 1 Γ-centered Monkhorst-Pack k-point mesh.54. Its characteristic CUT parameters, the radii to model the XC self-energy for a constituting atom, have been described elsewhere43. For instance, for the excited holes in C2p states it is calculated to be 2.89 bohr. As a result, for SiC we compute an indirect gap Equilibrium geometries are found by minimizing the total energy with a stopping criterion of 0.01 meV/atom. Atomic positions are then relaxed until the Hellmann-Feynman forces become smaller than 10 meV/Å. Band structures require quasiparticle studies to account for the excitation aspect. A computation of the quasiparticle self-energies for all atomic arrangements needed is computationally too time-consuming. Moreover, spin-orbit interaction has to be taken into account. We apply the approximate DFT-1/2 methodSupporting Information