Though idiopathic pulmonary fibrosis (IPF) is characterized by single-organ involvement, many comorbid conditions occur within other organ systems. Patients with IPF may present during evolution different complications and comorbidities that influence the prognosis and modify the natural course of their disease. In this chapter, we highlight common comorbid conditions encountered in IPF, discuss disease-specific diagnostic modalities, and review the current treatment data for several key comorbidities. The diagnosis and treatment of these comorbidities is a challenge for the pulmonologist specialized in interstitial lung diseases (ILDs). We will focus on pulmonary emphysema, lung cancer, gastroesophageal reflux, pulmonary hypertension, obstructive sleep apnea (sleep disorders), and acute exacerbation of IPF. Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and unpredictable disease with few useful treatments and a poor survival.Although the appearance of new treatments, such as nintedanib and pirfenidone, has given new hope to these patients, its management is complex and is influenced by the coexistence of several comorbidities. The presence of these comorbidities may decrease patients’ survival and quality of life and might accelerate the progression of the disease. Some comorbidities might coexist with IPF because of a common risk factor for both diseases  or, in other cases, they could be a consequence of IPF itself . There is increasing evidence that the early diagnosis and treatment of comorbidities is as important as the treatment of idiopathic pulmonary fibrosis itself.Smoking is a common risk factor for both emphysema and pulmonary fibrosis ,2,3. NotThe syndrome of combined pulmonary fibrosis and emphysema (CPFE) has been proposed as an important phenotype of pulmonary fibrosis and is defined by the presence of emphysema and parenchymal pulmonary fibrosis in the same patient . In thisIt has been suggested that cigarette smoke is the main causal factor, given the fact that a history of smoking is constant in all the published cohorts . SeveralKaolinite or aluminium silicate, for example, is an inorganic substance with industrial use which is present in tobacco smoke and has been isolated in the alveolar macrophages of smokers with pulmonary fibrosis and emphysema ,3,5.Usually, individuals with CPFE tend to be males with an extensive smoking history and increased oxygen requirement ,2,3,4. The coexistence of emphysema and fibrosis determines a characteristic functional profile that contrasts with the degree of dyspnea manifested by these patients. Pulmonary mechanics are altered by emphysema and pulmonary fibrosis. In emphysema, elastic forces are reduced, and both lung compliance and pulmonary volumes are increased. Pulmonary fibrosis leads to increased lung elastic recoil, decreased compliance, and reduced lung volumes . The sim1), and the total pulmonary capacity (TLC) are usually within normal values or only slightly decreased, while the diffusing capacity of carbon monoxide (DLCO) is disproportionately reduced , the forced expiratory volume in the first second (FEV reduced  6]. The. The1), These physiologic hallmarks of CPFE likely reflect the opposing impact of parenchymal fibrosis and parenchymal destruction on airflow and lung volumes, along with their additive impact on gas exchange. High-resolution computed tomography (HRCT) is part of the routine diagnostic evaluation of all patients with suspected IPF , and rouThe recognition of CPFE has potential management implications. Some studies suggest that CPFE is associated with reduced survival , but othRegarding therapy, nintedanib and pirfenidone seem to have a similar effect in CPFE patients as that produced in subjects with IPF alone. The ASCEND (Pirfenidone) and INPULSIS (Nintedanib) studies recruited patients with emphysema. However, the whole spectrum of severity of emphysema was not represented in those studies, because those patients who presented an obstructive ventilatory pattern or a very severe reduction of DLCO on lung function testing were excluded. It is unclear whether patients with IPF and CPFE can benefit from treatments with inhaled drugs, such as long-acting beta-agonists, long-acting muscarinic antagonists, and inhaled corticosteroids ,6,7,8. WGastroesophageal reflux (GER) is another common comorbidity in patients with IPF ,10,11, aIf GER is severe, it may imply pulmonary aspiration of gastric fluid, which may have a role in the natural history of IPF, as it might be a trigger of alveolar damage.Esophageal pH monitoring remains the gold standard for diagnosis of acid GER, with a reported sensitivity and specificity over 80% ,15. ReceThe survival of IPF patients might be reduced if GER is left untreated. Medications to treat GER are a predictor of better survival in subjects with IPF. Reflux has also been related to exacerbations in patients with pulmonary fibrosis. It has been demonstrated that bronchoalveolar lavage (BAL) pepsin levels are raised in 30% of the cases with acute exacerbation of IPF (AE-IPF) . These fOn the other hand, it has been found that the presence of reflux occurs more frequently when pulmonary fibrosis is asymmetric, with one lung more affected than the other, and this finding suggests a relationship between these diseases .In patients in whom both diseases occur, reflux is often silent and associated with preserved esophageal function but with slow clearance of gastric acid, and it is usually present in the supine position. There is a need for further investigation of the association between GER and IPF and the effect of anti-acid therapy in patients with this disease. Although the effectiveness of anti-reflux surgery is controversial, and, thus, this treatment should not be performed routinely, it should be considered for selected IPF patients.Compared to the general population, individuals with IPF have a nearly five-fold increased risk of developing lung cancer, with 3–22% of cases affected, and an estimated incidence of 11 cases per 100,000 person-year ,20,21.The strong link between IPF and cigarette smoking  likely eSome studies show that squamous cell carcinoma predominate over adenocarcinoma , while aThe survival among those patients with IPF and comorbid lung cancer is poor ,23, and While surgical resection of early-stage lung cancer may be curative, IPF severity and disease evolution must be taken into consideration, because of the increased risk of postoperative morbidity and mortality. These patients have a higher mortality associated with the surgical treatment, usually due to the development of an acute exacerbation (5–15%), which leads to a short-term mortality of approximately 50%. Exacerbations may also occur after treatment with radiation therapy or chemotherapy  . The strRecent studies suggest that the anti-proliferative effects of pirfenidone and nintedanib may synergize with concurrent chemotherapeutic oncologic agents, but additional research is needed to confirm this hypothesis ,23,24,252  ≥25 mmHg, a pulmonary artery wedge pressure ≤15 mmHg, and elevated pulmonary vascular resistance >3 wood units with a cardiac index <2.5 L/min/m2  26]. An. An2 , which estimates the right ventricular systolic pressure (RVSP) by the systolic tricuspid regurgitation velocity at Doppler as a surrogate for mPAP, is the first and most widely used test to search for PH . Althoug 80 mmHg . When th 80 mmHg . Unfortu 80 mmHg . Therefoclinicaltrials.gov NCT02951429, NCT02802345) that are currently enrolling participants. Nowadays, there is not an effective specific therapy for PH associated with IPF. Furthermore, several trials have demonstrated that pulmonary vasodilators might increase the v/q mismatch, which could result in a worsening of the hypoxemia and disease progression in IPF patients.In addition to enhance the non-invasive detection of PH, there is a need to evaluate new treatments that might improve either the hemodynamic or the clinical parameters in patients with IPF-PH. Therapies used to treat group 1 pulmonary arterial hypertension, such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, guanylate cyclase stimulators, or prostacyclin analogues, have not been effective to treat the underlying PH in the setting of IPF. Raghu et al. reported negative results for ambrisentan, an endothelin receptor type-A selective antagonist, for the treatment of IPF in patients with RHC-proven PH . The triWith the approval of pirfenidone and nintedanib, a new scenario is open for the role of these drugs in PH associated with IPF. A tyrosine kinase inhibitor as imatinib has been reported to improve exercise capacity and hemodynamics, but serious adverse events led to a high rate of study discontinuation in the active treatment arm, precluding definitive conclusions. The antiproliferative and anti-inflammatory activity of pirfenidone could theoretically be beneficial in the treatment of PH associated to IPF, but presently there is no definitive data that support this hypothesis. Thus, the possible beneficial role of nintedanib in PH due to IPF remains an open area of investigation . Although hypoxemia correction confers a survival advantage in patients with COPD, the role of long-term oxygen therapy in PH-IPF has not been clearly established. Moreover, it has been suggested that long-term oxygen therapy for this disease does not result in either improvement of PAP or reversal of pulmonary vascular remodeling. Nevertheless, the only therapeutic approaches to PH in the setting of IPF currently recommended by the European Society of Cardiology/Eureopean Respiratory Society (ESC/ERS) guidelines are to correct hypoxia with supplemental oxygen therapy, to treat the underlying interstitial lung disease, and to refer the appropriate candidate for lung transplantation . PulmonaIn conclusion, research in PH-IPF can be considered an emerging field. Further prospective studies are required to determine the best methods to detect PH in patients with IPF. In addition, and more importantly, current strategies for treating PH in IPF are far from perfect, and this fact should stimulate investigators to explore whether PH-IPF patients might benefit from novel therapies.In healthy people, sleep is a state of restoration which covers approximately one-third of human life. Overall across studies, sleep is reported to be markedly disturbed in patients with IPF . In fact1 and FVC percentages. These findings suggest that obese IPF patients with decreased pulmonary function might have an increased risk for OSA, especially during REM sleep [Recent studies have revealed that moderate-to-severe obstructive sleep apnea (OSA) syndrome, defined by an apnea–hypopnea index (AHI) > 15 events per hour, is frequent in patients with IPF . MoreoveEM sleep . MermigkEM sleep . HoweverEM sleep . InvestiEM sleep .2) had greatest sleep-related desaturation, especially during REM sleep. Thus, nocturnal hypoxemia seems to be common between patients with IPF , and this also has a negative impact on the quality of life and daytime function [Anyway, most studies have agreed on the finding of disturbance of sleep architecture. The abnormal sleep macroarchitecture in patients with IPF is characterized by abnormal sleep stage distribution with reduced slow-wave and REM sleep, increased stage 1 sleep, multiple awakenings, decreased percentage of total sleep time, low sleep efficiency, and increased wake time after sleep onset. These patients also have an altered microarchitecture, as they present with an increased number of sleep microarousals resulting in sleep fragmentation. Therefore, these disorders in sleep architecture and the resulting poor quality of sleep impair the quality of life in patients with interstitial lung diseases (ILD) . Anotherfunction . These fThere is also some evidence that REM-associated sleep-related breathing disorders (SRBD) in IPF patients might play an important role, not only in the quality of sleep and life, but also in the mortality associated with ILD. The sleep-related desaturation in these patients might contribute to pulmonary vascular disease development, with PH as one of the possible consequences. Therefore, it might be a risk factor for increased mortality. It must be noted that, in the study by Corte et al., nocturnal oximetry was not able to distinguish those patients with ILD who desaturated because of concomitant OSA . Hence, Since SRBD in IPF patients seem to be so prevalent, even in the initial phase of IPF, and are likely to be underdiagnosed, it is important for physicians to recognize the clinical phenotype of these patients. Early detection and referral to a sleep center for evaluation is essential to promptly initiate treatment. The therapy for SRBD in patients with IPF is decided on an individual basis, although the optimization of sleep and quality of life through SRBD treatment should be recognized as a primary goal .In this sense, available tools for treating patients with IPF and underlying SRBD are oxygen therapy for REM-related SRBD and continuous positive airway pressure (CPAP) for the overlap of IPF and OSA. Oxygen administration is reasonably well tolerated and recommended for advanced forms of IPF. Nevertheless, long-term home oxygen therapy in IPF patients did not improve survival when respiratory failure had been established. Moreover, only one study was carried out to analyze the use of CPAP in patients with IPF and OSA. This investigation found that these patients had a significant improvement in quality of life and sleep, daily living activities, and survival . The stuIn conclusion, alterations in sleep architecture, breathing pattern, and desaturations in IPF patients, especially during REM sleep, as well as coexisting OSA, might have a significant negative impact on the sleep quality of these patients. Physicians should ask the patient for symptoms during the night and should maintain a high degree of clinical suspicion for the presence of possible comorbid sleep disorders. As IPF is a progressive and life-threatening disease, the role of the poor quality of sleep as a significant comorbidity must be reconsidered. The effective treatment of comorbidities in IPF patients, such as sleep disorders, should be a field of future research.Idiopathic pulmonary fibrosis is a progressive disease that can present different types of evolution overtime. Some patients may progress slowly, while others experience a rapid progression, with fast decline of the lung function. Other subjects, however, may suffer episodes of sudden deterioration. These episodes are defined as acute exacerbations (AE-IPF) .Traditionally, AE-IPF have been defined as acute, clinically significant episodes of respiratory deterioration without an identifiable cause. In recent years, the International Working Group in AE-IPF has reviewed this definition as well as its diagnostic criteria . The lasThe incidence of these episodes varies between 2% and 16% per year. Results from clinical trials of nintedanib and pirfenidone suggest that IPF therapies may help to prevent the development of AE-IPF .The aetiology of AE-IPF remains unknown. It is thought to have similarities with the aetiology of acute lung injury (ALI), so that experimental models of ALI have been used for the study of AE-IPF. AE-IPF is most likely triggered by an acute event that leads to widespread acute lung injury . There iAE-IPF is more common in patients with physiologically and functionally advanced disease . Other identified risk factors are younger age, coronary artery disease, and high body mass index .The presence of AE-IPF not only implies a high mortality during the event (up to 50%), but also a significant decrease in short-term survival after the episode. IPF patients who suffer an exacerbation have a subsequent average survival of three to four months. Mortality reaches 90% in cases in which the patient needs mechanical ventilation .Given the lack of knowledge on the pathogenesis of AE-IPF, it is understandable that there is no current effective therapy available. Treatment with corticosteroids is a recommendation based on weak-strength, very low-quality evidence. The evidence available is based on isolated case reports, and there are no controlled clinical trials that endorse the benefits of their use . The exaThe use of mechanical ventilation is also controversial because of the high mortality observed when this therapy is employed, so it is usually reserved as a life-supporting procedure for those patients who will undergo a lung transplantation. Anyway, the decision to initiate mechanical ventilation must be carefully considered on an individual basis .Several potential therapies for AE-IPF have been described over the last decade, but these studies are mostly small and uncontrolled: cyclosporine, rituximab, tacrolimus, azithromycin, and intravenous thrombomodulin are some examples .


This distinction does not imply no role for purely salience-driven, or bottom-up, attention, but the latter topic is less crucial here. The term selection history alludes to the fact that the history of selection episodes, both from the recent and more distant past, can elicit lingering selection biases that are unrelated to top-down control or to the physical salience of objects. One further claim is made in the review, namely, that signals pertaining to the current goals of the individual (top-down), the intrinsic stimulus salience (bottom-up) and selection history biases all converge onto the same priority map(s) of space, wherein the compound signal will determine within a winner-take-all architecture which particular stimulus/location will be selected first.The review article by Jan Theeuwes  mainly fIn our commentary to this interesting and stimulating review paper, we want to draw attention onto three specific points that might fuel discussion, as briefly outlined below.experience-dependent attentional control, since previous encounters with a given object and/or a given location must not have involved specific attentional operations  to exert an influence on ongoing attentional deployment. In line with this notion, some of the studies carried out over recent years to study the influence of reward on attentional control  propagation of signals from control regions to target areas responsible for visual processing of the retinal input  plastic changes in critical neural substrates.Second, we think that a neurophysiological perspective might be of help to better define the different forms of attentional control the author illustrates. Within this perspective, we propose to define: i) sm e.g., , that fosm e.g., ; ii) Topal input ; and, fiThird, we would like to make some comments regarding the schematic illustration shown in Figure 1 of the review article by Theeuwes, depicting the integration of three sources of bias within the same priority map(s) of space. Our reflection on this point is threefold. On the one hand, we remark the possibility that different sources for attentional control, or biasing signals, rather than being merged through a simple computation , as suggested by the author, might be weighted differently depending on the given context and task demands. For instance, one might conceive the possibility that, depending on the given circumstances, one or the other source will exert greater influence on the priority map, therefore being the primary determinant of attentional deployment; in other words, as recently suggested by Todd and Manaligod, a context-dependent weighting of different biasing signals for AC might be at place . On the


In other words, several TADs may belong to the same 3D community. (ii) CTCF proteins—a loop-stabilizing protein that is ascribed a big role in TAD formation—are well correlated with community borders only at one level of organization. (iii) TADs and A/B compartments are traditionally treated as two weakly related 3D structures and detected with different algorithms. With our method, we detect both by simply adjusting the resolution parameter. We therefore argue that they represent two specific levels of a continuous spectrum 3D communities, rather than seeing them as different structural entities.Several experiments show that the three dimensional (3D) organization of chromosomes affects genetic processes such as transcription and gene regulation. To better understand this connection, researchers developed the Hi-C method that is able to detect the pairwise physical contacts of all chromosomal loci. The Hi-C data show that chromosomes are composed of 3D compartments that range over a variety of scales. However, it is challenging to systematically detect these cross-scale structures. Most studies have therefore designed methods for specific scales to study foremost topologically associated domains (TADs) and A/B compartments. To go beyond this limitation, we tailor a network community detection method that finds communities in compact fractal globule polymer systems. Our method allows us to continuously scan through all scales with a single resolution parameter. We found:  Rather, across cell types and organisms, Hi-C experiments reveal that chromosomes are built up by a network of three dimensional (3D) compartments.Experiments that detect the physical contacts between DNA loci in the nucleus, such as Hi-C6)-base-pair scale, two types of coexisting structures stand out. In one, all chromosome loci belong to one of the two so-called A/B compartments, where the chromatin in one compartment is generally more open, accessible, and actively transcribed than the other. In the second type, linear subsections of the genome assemble into topological domains4, often referred to as topologically associated domains (TADs)4. Plotting Hi-C data as a heat map, TADs show up as local regions with sharp borders with more internal than external contacts. The positions of these borders are correlated with several genetic processes, such as transcription, localization of some epigenetic marks, and DNA-binding profiles of several proteins–most notably CTCF and cohesin4.At the mega . However, there are some limitations in their approach. For example, they binarize the Hi-C data (‘no connection’ or ‘connection’ with a rather arbitrarily chosen thresholds) thereby discarding contact frequency variations in the Hi-C data. Furthermore, there is no comparative study connecting their communities to biological factors or any mechanistic models. Wang et al.8 takes a step in this direction, but the method to detect the TADs itself relies on biological factor data and nontrivial threshold criteria.Some network approaches are based on community detection methods that are related to what we use here. In Cabreros 1. This goes beyond previous Louvain-like studies15 that treat the Hi-C data as a network with random connections.To overcome some of these problems, we start by acknowledging that the chromosomes have a richer 3D organization than simply TADs and A/B compartments. These are just two examples. To capture this, we develop network-based method that allows us to scan through 3D structures on all scales with a resolution parameter. In particular, our approach is based on the GenLouvain method, originally designed for network community detection. For a specific value of the resolution parameter, the method finds the optimal community structure with respect to a null model of the network that has to be specified beforehand. Based on the physics of compact polymer globules, we put forward a null model that is consistent with the average contact probabilities in real Hi-C dataet al. and Norton et al.15, treat TADs as linear contiguous sequences of chromatin. This restriction overrides the GenLouvain algorithm’s ability to find the (not necessarily contiguous) optimal community structure in the data set20. We remove this restriction in our study. Therefore, to reduce confusion, we will not use the term TAD, but rather the 3D community for the cluster of nodes that comes out of the GenLouvain algorithm since they are not necessarily linear contiguous sequences.Furthermore, most studies, such as Yan 21 to detect communities in the Hi-C maps . This algorithm offers the possibility to find communities at several scales with a single resolution parameter γ. Contrasting other methods with similar features, the spectrum of communities that we detect is not necessarily hierarchical or nested, as in e.g. Wang et al., Fraser et al., and Bianco et al.24. Instead, two different values of γ give two different collections of communities, and these do not necessarily have anything to do with each other.We use the GenLouvain algorithmQ. This function quantifies by how much more dense the connections are within the communities compared to what they would be in a particular type of network, say a random network. GenLouvain’s modularity function isAij is the number of contacts between all node pairs i and j (Aij is the adjacency matrix in standard network terminology). The resolution parameter γ controls the overall scale of communities we would like to detect, where larger values of γ correspond to smaller communities. Furthermore, i and j are connected in the real network, compared to how strongly we expect them to be given δ is the Kronecker delta that is unity only if nodes i and j belong to the same community (otherwise it is zero), and m is a normalization factor so that Q goes between −1 and +1.To find the communities, the GenLouvain method tries putting the nodes into different communities to maximize the so-called modularity function 25. For a unweighted network where Aij is either zero or one, ki and kj are the number of links for nodes i and j .One of the most popular choices for et al.1, and many papers thereafter27, the contact probability between two nodes i and j decays as a power-law with the linear distance between them, that is However, the NG null-model is too rough an approximation to find communities in Hi-C maps, because it does not obey the well-established contact patterns that we know exist in DNA, or in fact any polymer system. For example, DNA is a long polymer where nodes are arranged in a linear sequence and then folded in 3D. This sets limitations for how frequently two pieces of DNA, or nodes, can join in 3D space . As was first discovered in Lieberman-Aiden α is debatable, but we use α = 1. There are two main reasons. First, at the mega-base-pair scale of human DNA, the Hi-C data suggest that it is close to one1 . Second, in the next section we will study community detection in the fractal globule polymer . This is a compact polymer that mimics the large scale structure of human chromosomes, in particular the scaling relations of the end-to-end distance and contact frequency1. The advantage of this approach is that we have the explicit 3D coordinates for every part of the polymer (because we made it), which allows us to visualize and analyze the 3D structure of the communities that we detect. For the Hi-C map, we only have pairwise contact frequencies.Before we investigate the human Hi-C data, we wish to better understand the types of 3D structures that our community detection method picks up. To do this, we use computer-generated fractal globule polymers  model28. In a nutshell, this is a Monte Carlo method that produces a fractal globule by simulating a biased random walk on lattice where the propagation probability depends on the entire walk’s trajectory over the lattice28. This yields on-lattice space-filling polymers. To generate off-lattice fractal globules, the structure is randomized with simulated annealing where the position of a monomer is randomly displaced under the constraint of a fixed inter-monomer distance. With properly chosen parameters, the CDP method produces a fractal globule with contact frequency (probability) that decays as ~s−1 (as it should29), where s is the contour distance along the polymer. To use the notation from Tamm et al.28, we use the relation p ∝ (1 + An) with A = 104 for an unoccupied site and p to an occupied site is given by ε = 10−4. This result is consistent with the Hi-C data for the human genome at the mega-base-pair scale1. We show a realization of a CDP in Fig. As introduced in an articlei and j. The contact refers to the case where the Euclidean distance between two beads are shorter than three lattice spacings. To obtain good statistics, we first generate an on-lattice polymer, and then during the annealing stage we register all contacts in 103 random variations of the on-lattice structure. In addition, we have confirmed that different threshold values for what we consider as a contact do not qualitatively alter our results presented below. Just as in the Hi-C experiments, in the final step we normalize the contact map with the KR-norm35 so that each row and column sums to unity.From every simulated CDP polymer, we construct a contact map by counting the number of contact events between polymer beads As a reference case, we use the equilibrium globule. This is a self-avoiding polymer in a closed spherical volume. When we generate equilibrium globules, we contain it in a volume with the same diameter as the fractal globules’ radius of gyration.γ, we detect communities on various scales. On top of the contact map in Fig. γ = 0.4 (b), γ = 0.6 (c), and γ = 0.8 (d), where the boxes represent community boundaries. Based on these, we ask what the 3D structure of these communities is, and if and how they are different from the polymer as a whole.Figure γ = 0.6). In Fig. Contrasting current views on TADs, we find that 3D communities do not have to be a contiguous polymer segment. Rather, linearly distant parts of the polymer can fold in 3D to form a community. We show this in Fig. s.Furthermore, because of the above-average contact frequencies inside a community, we would like to quantify how its 3D structure differs from the fractal globule polymer as a whole. To do this, we examine the scaling relation of the end-to-end distance–the Euclidean distance between the two boundary monomers defining that (contiguous) community–with respect to the subchain length s1/3, as is expected for a space-filling curve (deviations for large-s comes from finite-size effects and insufficient statistics). For the communities, we notice that the end-to-end distances are systematically smaller than for a randomly chosen subchain. Our simulations even suggest that the scaling exponent is smaller than 1/3. Consistent properties are crosschecked in Fig. 2. For comparison, we made the same analysis for the equilibrium globule (EG). In Fig. s1/2 for s0 for N monomer ideal chain. Concurrently, the end-to-end distance normalized by the radius of gyration . We find that the community subchains in FGs tend to be more sphere-like than the FG itself, and the subchains in EGs. This leads to enhanced contact frequency between monomers within a community . The data is available in various resolutions, from 103 base pairs (1 kbp) to 106 base pairs (1 Mbp), but we used 100 kbp which is the scale where both TADs and A/B compartments can be detected2.Based on our community detection approach, we now proceed to analyze Hi-C data from human cellsγ. Similar to the simulated data, it is clear that several TADs form 3D communities. To investigate how these TADs correspond to TADs defined in other studies, we compared the border locations of each contiguous block to TAD borders defined by Rao et al.2 (the group that produced the dataset we use in this study) in Fig. γ ≈ 0.7, about 70% of the borders overlap. Moreover, several studies have shown that binding sites for the insulator protein CTCF are strongly correlated with TAD borders . We therefore check the overlap between CTCF binding sites (mapped by ENCODE36) and all borders at different γ values. We note that CTCF has the highest overlap also at γ ≈ 0.7 . Interestingly, for γ < 0.6, the chromosome consists of only two communities .We next investigate properties of the 3D communities. First, we count the number of communities and average number of TADs within each community at different γ Fig.  as well γ Fig. . The hig36 (GEO Acc. Nr: GSE88583). In Figs. γ. At small γ values where only two communities are defined, one community is clearly more active than the other. The active and less active communities are then split up into smaller communities as γ increases. Already in the original Hi-C paper by Lieberman-Aiden et al.1, they used principal component analysis on the Hi-C data to partition the chromosomes into two classes. Denoting them by A/B compartments, they found that the A compartment contains transcriptionally active chromatin, whereas the B compartment is less active.Second, we map gene activity within each community using RNA-seq data from ENCODE38 to see what types of chromatin states are enriched in different communities at different γ values  starts to split up into smaller compartments and then the less active parts of the genome (B) also start to split into smaller communities. It is clear that the genome does not split up into evenly sized sub-compartments, but rather the 3D space is dominated by a few large communities. It is striking and unprecedented that by tuning a single parameter, we detect both TADs and A/B compartments with the same algorithm. We therefore argue that TADs and A/B compartments are not two conceptually different organizational structures in the nucleus, but rather different ends of the same organizational spectrum.We took one step in this direction by looking at different types of chromatin. We use 15 chromatin states defined by ENCODE3)-base-pair sized loops to mega(106)-base-pair sized 3D structures. This pattern is consistent across organisms and cell types. To let researchers scan through the spectrum of 3D compartments, we have tailored the GenLouvain community detection method to find 3D communities in fractal globule polymer systems. Apart from verifying our method on computer-generated polymers, we have applied it to analyze human Hi-C data. First, we have found that chromatin segments belonging to the same 3D community do not have to be in next to each other along the DNA. In other words, several TADs can belong to the same 3D community. Second, we have found that CTCF proteins–a loop-stabilizing protein that is ascribed a big role in TAD formation–are only correlated well with community borders at one level of organization. It remains to find what other factors are important at higher or lower levels. Third, just by adjusting a single parameter (γ), our method picks up the two most prominent 3D compartments, TADs and A/B compartments, which are traditionally treated as two weakly related 3D structures and detected with different algorithms. Rather than seeing them as different, our work put them on an equal footing, and we argue that they represent two ends of a continuous spectrum of 3D communities of different sizes.From Hi-C experiments, it is clear that inter-phase chromosomes are built up by a network of 3D compartments on various scales–from kilo(10Supplementary Information


Liver cancer is the second leading causes of cancer-related death globally. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays a critical role in metabolic profiles of tumors. Therefore, it is necessary to explore the mechanisms of PYCR1 on cell growth and survival in hepatocellular carcinoma (HCC).Protein and mRNA expression levels of PYCR1 in 140 pairs of tumor and adjacent normal liver tissues of HCC patients were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Expressions of PYCR1 were inhibited in BEL-7404 cells and SMMC-7721 cells using gene interference technology. The cell proliferation was detected by Celigo and MTT assay. The colony formation assay was also performed. The cell apoptosis was measured by flow cytometric assay. The effect of PYCR1 interference on tumor growth was observed by xenograft nude mice assay in vivo. The downstream pathway of PYCR1 interference was searched by microarray and bioinformatics analysis, and validated by qRT-PCR and western blot.P < 0.01). In vitro, the cell proliferation was significantly slower in shPYCR1 group than shCtrl group in BEL-7404 and SMMC-7721 cells (P < 0.001). The colony number was significantly smaller after PYCR1 interference (P < 0.01). The percentage of apoptosis cells significantly increased in shPYCR1 group (P < 0.01). In vivo, PYCR1 interference could obviously suppress tumor growth in xenograft nude mice. The volume and weight of tumors were significantly smaller via PYCR1 interference. The c-Jun N-terminal kinase (JNK) signaling pathway significantly altered, and insulin receptor substrate 1 (IRS1) were significantly down-regulated by PYCR1 interference in both mRNA and protein levels (P < 0.001).PYCR1 levels were significantly up-regulated in HCC tumor tissues than adjacent normal liver tissues in both protein and mRNA levels (PYCR1 interference could inhibit cell proliferation and promote cell apoptosis in HCC through regluting JNK/IRS1 pathway. Our study will provide a drug target for HCC therapy and a potential biomarker for its diagnosis or prognosis. Liver cancer is the second leading causes of cancer-related death globally . 90% of Growing tumors alter their metabolic profiles to meet the biosynthetic and bioenergetics demands of increased cell growth and proliferation . Many stIn this study, we aim to analyze the relationship between PYCR1 and HCC, explore the role of PYCR1 regulating c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathway, and clarify the mechanisms of PYCR1 affecting HCC cell growth and survival. The achievements will probably provide us a potential drug target for therapy or a biomarker for diagnosis and prognosis.http://cancergenome.nih.gov).The tumor and adjacent normal tissues used for immunohistochemistry were collected from 90 HCC patients who underwent surgery at Shanghai Seventh People’s Hospital between 2007 and 2009. The informed consent was obtained from every study participant. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Institutional Research Ethics Committee in 2007 (No. 2007-019). The mRNA profiles used in the study were obtained from the Cancer Genome Atlas (TCGA) database , supplemented with 10% fetal bovine serum , 100 U/ml penicillin and 0.1 mg/ml streptomycin  at 37 °C in 100% air.5/well for RNA interference. According to the results of preliminary experiment, HCC cells were infected with a certain amount of control lentivirus and shPYCR1 lentivirus. At 72 h post-infection, the expression of reporter gene GFP was observed by the fluorescent microscope. The fluorescence rate was the positive infective rate. If the infective rate was larger than 70% and the state of cells was normal, the further study could be continued.The sequences for RNA interference were 5′-TTCTCCGAACGTGTCACGT-3′ for control, and 5′- CAGTTTCTGCTCTCAGGAA-3′ for PYCR1 . The sequences were inserted into Age I and EcoR I points of GV115 vector. The shRNAs of GV-NC-GFP-shRNA and GV-PYCR1-GFP-shRNA were constructed as control lentivirus and shPYCR1 lentivirus, and positive clones were screened and identified. Subsequently, HCC cells were seeded in a 6-well plate at a density of 2 * 10Total RNA from HCC cells was extracted using TRIzol Reagent . RNA concentration was determined by NanoDrop 2000 spectrophotometer . A total of 20–100 ng RNA was reverse-transcribed using First-Strand cDNA Synthesis kits  according to the manufacture’s protocol. qRT-PCR was performed on ABI 7500 System  and used to analyze the expression levels of mRNA. Relative expression level of genes was calculated using GAPDH as the internal control. Each sample was run three times. The primer pairs used in the study are listed as follows. PYCR1 forward: 5′-GGCTGCCCACAAGATAATGGC-3′; reverse: 5′-CAATGGAGCTGATGGT GACGC-3′; GAPDH forward: 5′-TGACTTCAACAGCGACACCCA-3′; reverse: 5′-CACCCTGTTGCTGTAGCCAAA-3′.The cells were first washed with cold PBS three times, then lysed in RIPA lysis buffer  containing a complete protease inhibitor cocktail , and cell lysates were collected. Concentrations of proteins were then determined by bicinchoninic acid (BCA) protein assay kit . About 20–50 μg of proteins were separated by 10% SDS-polyacrylamide gel and then transferred to a polyvinylidene difluoride (PVDF) membrane. Subsequently, the membrane was incubated with primary antibodies against PYCR1 (1:200) , JUN (1:500) , IRS1 (1:500)  and GAPDH (1:2000)  overnight at 4 °C, and appropriate secondary antibodies (1:2000)  for 1 h at room temperature. Signals were detected by gel imaging system . The ratio of interested proteins to GAPDH was analyzed by FluorChem FC3 software. Western blot experiments were performed in triplicate.8 TU/ml) and shPYCR1 lentivirus  were seeded in 96-well plates at a density of approximately 2–5 * 103/well in quintuplicate. Cell proliferation was performed at specific times, such as 1st day, 2nd day, 3rd day, 4th day and 5th day. The fluorescence was measured to access cell counts using Celigo Imaging Cytometer . In addition, for MTT assay, 20 μl of MTT solution was added to each well. After 4 h incubation at 37 °C, the solution was removed and DMSO was added to dissolve the formazan crystals formed. The absorbance at 490 nm was measured Glomax-Multi + Detection System . At least three independent experiments were performed.HCC cells infected with control lentivirus  after 14 days, then colonies were visualized by fluorescence microscope and quantitated. At least three independent experiments were performed.Apoptosis assay was performed using FITC-Annexin V Apoptosis Detection Kit  according to the manufacture’s instruction. Briefly, the cells were collected by trypsin, washed twice with ice-cold PBS and resuspended in 1 * binding buffer. Then, 10 μl of annexin V-FITC and propodium were added into 100 μl of cell suspensions. After incubation for 15 min, the samples were analyzed using the Beckman Counter flow cytometer.6) stably expressing control lentivirus and shPYCR1 lentivirus, respectively. After the diameter of tumor was larger than 5 mm, tumor volume was determined twice per week. The tumor volume was calculated as V = (width2 * length)/2. The bioluminescence imaging was detected before sacrifice. Tumor was obtained and weighed after sacrifice. All animal studies were approved by the Ethics Committee of Shanghai Seventh People’s Hospital.A total of twenty female BALB/C nude mice  were purchased from Shanghai Lingchang Biotechnology (SCXK2013-0018). All of them were randomly separated into two groups, NC group (n = 10) and KD group (n = 10). They were subcutaneously inoculated with SMMC-7221 cells  and a core biologic pathway analysis was performed to identify molecular pathways.Total RNA was extracted from HCC cells using Trizol reagent in shCtrl group (n = 3) and shPYCR1 group (n = 3). The qualified samples were analyzed on Affymetrix GeneChip primeview human gene expression array. Differentially expressed genes were selected with a cut-off P < 0.05 was considered statistically significant. All results were confirmed by at least three independent experiments.Statistical analysis was performed by SPSS 16.0 . The data were expressed as mean ± standard deviation and analyzed using Mann–Whitney test because of abnormal distribution or heterogeneity of variance. P < 0.001, Fig. P < 0.01). Both our data and TCGA data proved that PYCR1 was over expressed in HCC tumor tissues.To find out whether PYCR1 was dysregulated in HCC patients, we determined PYCR1 protein expression levels in tumor and adjacent normal liver tissues of HCC patients by IHC. Our data revealed that PYCR1 levels were higher expressed in tumor tissues than adjacent normal ones . After sacrifice, the tumors were weighed, and obvious tumors were formed in NC group while no tumors were observed in KD group  for SAPK/JNK signaling pathway was highest , implying that PYCR1 might influence HCC cells proliferation and apoptosis by regulating JNK/IRS1 pathway.To explore the mechanisms of PYCR1 interference inhibiting cell proliferation and promoting apoptosis in HCC cells, we detected the gene expression profiling of shCtrl group and shPYCR1 group in SMMC-7721 cells. Compared with shCtrl group, 173 genes were up-regulated in shGINS2 group, and 379 genes were down-regulated. As shown in Fig. est Fig. b. Subseq+ [In this study, we investigated the role of human PYCR1, so-far a poorly studied protein. PYCR1 is one of three human PYCR isoenzymes. PYCR catalyzes the final step in the conversion of Δ1-pyrroline-5-carboxylate (P5C) to proline with concomitant oxidation of NAD(P)H to NAD(P)+ . In clinFurther investigation found that SAPK/JNK signaling pathway was significantly altered after PYCR1 interference Fig. b. C-Jun-JNK was reported to drive insulin resistance via direct phosphorylation of insulin receptor substrate (IRS) , a familMany researchers thought that amino acid concentrations were associated to insulin resistance . In the In conclusion, we report here that PYCR1 interference could inhibit cell proliferation and promote cell apoptosis in HCC, and the mechanisms might be involved in the regulation of JNK/IRS1 pathway Fig. . Our stu


High and low temperature direct CVD growth of graphene on these substrates including growth mechanism and morphology is discussed. Detailed discussions are also presented for Si and Ge substrates, which are necessary for next generation graphene/Si/Ge based hybrid electronic devices. Finally, the technology development of the metal‐catalyst free direct CVD growth of graphene on these substrates is concluded, with future outlooks.To fabricate graphene based electronic and optoelectronic devices, it is highly desirable to develop a variety of metal‐catalyst free chemical vapor deposition (CVD) techniques for direct synthesis of graphene on dielectric and semiconducting substrates. This will help to avoid metallic impurities, high costs, time consuming processes, and defect‐inducing graphene transfer processes. Direct CVD growth of graphene on dielectric substrates is usually difficult to accomplish due to their low surface energy. However, a low‐temperature plasma enhanced CVD technique could help to solve this problem. Here, the recent progress of metal‐catalyst free direct CVD growth of graphene on technologically important dielectric (SiO Owing to its excellent characteristics, 2D graphene sheet is regarded as a next‐generation transparent conductive electrode for applications in various electronic devices.FigureEf(Gr)) and lightly doped Si (Ef(Si)) at thermal equilibrium (dark condition) is shown in Figure Vfbias, which brings the Fermi level downward with respect to its “unbiased” condition. In this way, the Fermi level comes into close proximity to the quasi Fermi level for holes in Si, and thereby the number of accessible states for photoexcitation is significantly reduced. When reverse bias is applied, Ef(Gr) shifts to higher value and generates a large number of available energy states for holes to inject .2, ZrO2, HfO2, h‐BN, Al2O3, Si3N4, quartz, MgO, SrTiO3, TiO2, AlN, glass, and mica, and semiconducting substrates such as Si, Ge, GaN, and SiC. Merits and demerits of using high and low temperature CVD processes including growth mechanism and morphology of the graphene on these substrates have been discussed. Detailed discussions are presented for Si and Ge substrates, as they are important semiconductors, and suitable for next generation graphene/(Si/Ge) based hybrid electronic devices. Important results have been summarized in tables, and finally conclusions and outlook have been presented.Through the above discussion, it is evident that these inventions pave a way toward the production of graphene, in‐depth knowledge of the correlation among products, microscopic processes, and experimental conditions. This motivates the research for the metal‐catalyst free direct CVD growth of graphene on various dielectric and semiconducting substrates. Herein, we present a comprehensive review focused on the recent progress made toward the metal‐catalyst free direct CVD growth of graphene on technologically important dielectric substrates such as SiO22.14) on bare SiO2/Si substrates via oxygen aided atmospheric pressure chemical vapor deposition (APCVD) process.2 substrates could be achieved by using PECVD.Figure2/Si substrate was cleaned and then heated in H2  atmosphere at 1000 °C for 15 min. Three kinds of seeds were prepared onto the substrates, which include 1) mechanical exfoliation using scotch tape peel‐off graphene; 2) graphitic clusters nucleated by C2H4 (99.9%) + H2 plasma CVD  or CH4 (99.9%) + H2 plasma CVD ; and 3) patterning of nanoislands graphene by oxygen plasma etching and electron beam lithography. The position of the substrate with the seeds was at the center of the furnace. H2 plasma (H2: 250 mTorr) was generated upstream to activate the edge of the seeds at 500 °C. C2H4+H2 plasma CVD  or CH4+H2 plasma CVD  was then used for graphene growth. The PECVD growth mechanism of graphene on SiO2/Si substrate is shown in Figure 2 content, the pressure, and the growth temperature decided the growth at the edge   was found 1 nm min−1 and increased about 4.5 nm min−1 at 48 mTorr.A low temperature growth leads to compatibility and minimizes energy consumption along with cost effectiveness for bulk production in the industry. Therefore, in order to deposit a clean high‐quality graphene directly on dielectric substrates, a controllable, low‐cost, and reliable mode is important at low temperature. The catalyst‐free direct growth of polycrystalline graphene was achieved by the pyrolysis of methane  direct growth of micrometer‐scale graphene crystals on SiO2 substrates could be achieved by using PECVD technique. These graphene crystals can be directly embedded to fabricate electronic devices, thereby eliminating the conventional postdeposition transfer process. Lack of transfer process, good control of the method, excellent quality of grown graphene, and the compatibility of this process with the current microelectronics technology make it a facile approach for future use in graphene electronics.In addition to this, the metal‐catalyst free direct CVD growth of graphene on SiO2.22 substrates can be achieved at a temperature lower than 480 °C as reported by Scott et al.2 substrates using acetylene (C2H2) as a precursor. As soon as the substrate was placed, the reaction chamber was evacuated followed by the flow of Ar. The substrate was heated to a temperature of 325–650 °C. The flow of Ar was maintained for 10 min and then C2H2 was introduced into the chamber. X‐ray photoemission spectroscopy (XPS) confirmed the formation of zirconium oxide being present in the form of monoclinic baddeleyite, and being slightly oxygen deficient. The low temperature enables catalytically active oxides to form sp2 carbon. Wang et al.2 substrate using either CH4 or ethanol (C2H5OH) as a precursor via thermal CVD. First, the substrate was mounted to the central region of the quartz tube, and heated from room temperature to 1130 °C in 50 min with 50 sccm H2 and 50 sccm Ar. Second, the substrate was annealed for 20 min at 1130 °C, and then a certain flow rate of CH4 or C2H5OH vapor was introduced into the chamber to initiate graphene growth. 2D or 3D growth of graphene could be controlled by altering feedstock concentration and reaction time  plane  = 86 cm−1), D , and 2D  bands  analysis which in turn was conducted through Moiré pattern region of 0.55 nm  image confirmed the presence of a graphene/h‐BN film having a thickness of 2 nm Figure f. The im4 as a precursor via metal catalyst free CVD technique. Stacked‐layers on h‐BN substrate using hexane (C6H14) (vapor) as a precursor via APCVD technique was demonstrated by Liu et al.Similarly, Ding et al.2.54 as a precursor via near equilibrium CVD technique. Quartz having smooth face toward the downward side was placed in a high‐temperature horizontal silica tube furnace. The furnace was heated at 1180 °C and stabilized for about 30 min in 250 sccm H2 and 300 sccm Ar. During entire growth, a gas mixture (CH4:H2 = 1.9–2.3:50) was taken as the carbon source. AFM phase image of graphene grain on quartz substrate is shown in Figure4 as a precursor via remote (r)‐PECVD technique. Nanographene films having good uniformity were grown on 4 inch wafer. By controlling the growth duration, the value of transmittance on quartz was found to be greater than 92%, whereas it exhibited a low resistance of 40 kΩ sq−1 at 550 nm. The direct growth of VGs on quartz substrate can also be achieved using either CH4 or ethanol (C2H5OH) as a precursor via thermal CVD, as demonstrated by Wang et al.Owing to the high melting point along with structural stability, quartz has a flat surface having roughness about 0.414 nm. Chen et al.2 (20 sccm) and then CH4 (10 sccm) was introduced for 15, 25, 35, and 45 min, respectively. Figure Recently (2018), Chen et al. demonstrated direct growth of graphene on vertically placed quartz substrates via APCVD.2.63N4) substrates can be achieved by a two‐stage CVD process.3N4 surface, and at a later stage merged together to form a polycrystalline graphene film. These graphene films can be used to fabricate field‐effect transistors (FETs). A clean Si3N4/SiO2/Si substrate was kept into a quartz furnace at high‐temperature   . The graphene film was observed to be clearly separated from Si3N4 substrate, and formation of wrinkles took place along the boundary of the sheets  was found to be three times higher than those grown on SiO2/Si substrates as well as better than graphene grown using metal catalyst.3N4 substrates via two‐stage metal catalyst‐free CVD process where the detrimental effects of the substrate were minimized. In addition, the graphene sheets were successively grown along rough Si3N4 surface followed by merging together to form a high quality polycrystalline graphene film. The difficulties that arise during postgrowth transfer method can be eleminated by adopting two‐stage metal‐catalyst‐free‐growth technique, which finds its compatibility with current Si processing technology.The film was not distinguished properly from the underlying Sis Figure h. It wass Figure i. The grs Figure l–n. Figun Figure o illustrn Figure q confirm2.72/H2 mixture was used as the carrier gas. A rotational disorder along with wrinkles was formed onto the graphene films grown on AlN/Si. Here, temperature played an important role to improve the structural quality of the film. Again, high temperature growth might have influenced rough surface, but there was no impact on the structural quality of the graphene film as determined by Raman analysis. Moreover, the temperature for optimum growth might be higher (1350 °C), which suggests the growth of high‐quality graphene on bulk AlN substrates. Furthermore, during processing, AlN etching was minimized by the growth of graphene compared to the annealing , which enabled the growth of AlN at 1250 °C for 6 min without etching effects. It may be mentioned here that thermal treatment of nitrides films finds an ease with this method to enhance the quality of crystal, and favors the activation of doping at the time of ion implantation.Aluminum nitride (AlN) is a promising material due to its versatile applications such as microelectronic and optoelectronic devices, short wavelength emitters, electronic packaging, and acoustic wave resonators.2.8FigureMgO is considered to be advantageous for the growth of nanographene and few‐layer nanographene (nFLG) directly using CVD technique. However, calibration of the reaction time or temperature needs to be undertaken to grow nFLG and nanographene. The growth can be done at temperatures of 325 °C using acetylene as a precursor.2H4 as a precursor via free radical assisted CVD. Zhao et al.Ferrari2.92) leads to better gate modulation, improved gate capacitance, and reduced gate leakage.2 are carrier scattering due to charge fluctuations and surface roughness. These results are obstruction for further integration of FETs based on SiO2‐gated graphene.3 (STO), a transparent, high‐k perovskite dielectric may have great thermal stabilities and potentials.2/CH4:100/50/2.5 sccm).Figure−1, respectively. However, the 2D peak of graphene grown on the STO substrate did not appear due to the substrate screening effect . XPS analysis  sites on the surface  values at infinity due to the insufficient graphene growth  was demonstrated by many researchers. Chen et al.4 as a precursor via near equilibrium CVD technique, whereas Song et al.4 as a precursor via metal catalyst‐free APCVD. Zhang et al.4 as a precursor by PECVD technique. A study pertaining to graphene crystal onto sapphire substrate was accomplished using C2H4 as a precursor using PECVD technique.The graphene is considered to play a pivotal role in optoelectronic devices as a transparent conducting film (TCF). However, the manufacturing process available in the literature utilizes graphene as a TCF which follows transfer procedures. These steps are time‐consuming and sometimes chemical contaminations are encountered during processing which may impose detrimental effects to optoelectronic devices. Therefore, the metal‐catalyst free direct CVD growth of graphene on crystalline Al2.114 as a precursor.4 into different species such as CHx, C2Hy, C3Hz, and atomic hydrogen. These radicals could play a pivotal role during nucleation followed by the growth of nanographene. Apart from the above discussions in Sections The metal‐catalyst free direct growth of graphene on glass and mica substrates can be achieved via r‐PECVD system at a substrate temperature of ≈550 °C using pure CH2.122) has gained tremendous research interest due to its green impact on environment.2 surface results in the contamination free graphene‐TiO2 interface. Liu et al.2 surfaces such as (001) and (100) faces. Both substrates were cleaned using wet chemical etching followed by flattening into atomic smoothness.Figure2/Si substrate, the sharp G‐bands and D‐bands of the graphene became prominent  plane for the same growth parameter. Similarly, Bansal et al.2 substrate using CH4 as a precursor via APCVD/LPCVD technique. Moreover, graphitic nanostructures were grown on titania nanowire aerogel at 750 °C via CVD using ethylene. Three layer thick graphitic nanostructures gave a clear indication that titania nanowire surface enabled the graphitization to few‐layer graphene. The growth mechanism of few‐layer graphene on nanostructured metal oxides paved a way toward facile and controllable processing of metal oxide‐nanocarbon fiber–shell composites.TableRecently, photocatalysis effect based on titania (TiO001) and 0 faces. 001) and 0 faces. 001) and 0 faces. 001) and 0 faces. 3Apart from Ge, there are only few reports available on the metal‐catalyst free direct CVD growth of graphene on important semiconducting substrates such as Si, GaN, and SiC. To the best of our knowledge, there are no reports avalaible on the metal‐catalyst free direct CVD growth of graphene on other important arsenide and phosphide based semiconductors. Therefore, in the successive sections, direct CVD growth mechanism and morphology of graphene on Si, Ge, GaN, and SiC substrates will be discussed. Detailed discussion is being presented for Si and Ge, as they are important semiconductors for the next generation graphene/Si and graphene/Ge based hybrid electronic devices.3.13.1.12 substrates by using photoemission‐assisted plasma enhanced CVD system.4. Particles were closely connected to each other, and shared some graphene sheets between them. The advantage of using this system is that the DC discharge plasma assisted by photoelectrons emitted from the substrate under ultraviolet (UV) light irradiation could be generated close to the substrate with a controllable volume. Similarly, Zhang et al. reported the catalyst‐free direct graphene growth on various substrates including Si and SiC.r‐PECVD system at a relatively low temperature of ≈550 °C by using pure CH4. This graphene growth process was quite unconventional as compared to high temperature (≈900–1000 °C) CVD graphene growth.4), for 3 h under the plasma power of 100 W. Figure4 can dissociate itself into various reactive radicals, such as CHx, C2Hy, C3Hz, and atomic H2. These species play a key role during the nanographene nucleation and growth stages. The carbon‐containing radicals continuously get adsorbed onto the substrate surface, and bonded with each other by diffusion and collision to form graphene nanoclusters with H‐terminations. Nucleation on the as‐grown graphene was much easier as compared to clean substrates. Moreover, due to atomic H2, strong etching effect was there which helped in the suppression of formation of amorphous carbon. Similarly, some other low temperature (500 and 780 °C) direct CVD growth of multilayer graphene films and graphene nanowalls on Si substrates with the help of microwave surface wave plasma CVD and PECVD were reported by Adhikari et al. and Zhou et al., respectively.Takami et al. reported the catalyst‐free direct growth of networked graphite on Si and SiO3.1.22H2 and Ar with flow rates of 25 and 50 sccm, respectively, were introduced. Graphene growth at different temperatures was carried out by maintaining the pressure in the range of 2–100 Torr for 1 h. Figure −1. This was higher than the typical large scale graphene or graphite (1580 cm−1), which confirmed the growth of NG.Kim et al.2 atmosphere with a flow rate of 6 sccm at 300 mTorr and then kept for 20 min to activate the substrate surface, followed by 35 sccm of CH4 for 30 min at desired growth temperatures (870–970 °C). After growth at 920 °C, two kinds of surface features were observed: 1) the rectangular black dots highlighted by the solid red box, and 2) the large white area highlighted by the dashed blue box , but they were in the form of small dots and patches instead of continuous uniform graphene films.ox Figure12a. Fi2 was not necessary to grow graphene on SOI and just replaced 6 sccm of H2 with 50 sccm of Ar at 920 °C. Small black dots were observed and the SOI surface seemed to be less reactive. When the growth was carried out at 970 °C, the size of the black dots increased and stronger graphene bands were observed. Based on the above results, they proposed a growth mechanism for graphene on nonmetal or semiconducting surfaces as surface reaction, adsorption, decomposition, and accumulation  domains, concave BLG domains, and bulging FLG domains on the upside‐down placed single crystalline Si substrates at 900–930 °C for 1 h using the composition of CH4 or ethanol as the carbon feedstock in a conventional thermal APCVD system. It was also established that the concentration of active carbon species in CVD system exerts significant impact on the growth mode of graphene. The carbon precursor flow rate and reaction time during the CVD process controlled the growth dynamics, which ultimately led to a well‐controlled morphology of the obtained carbon material, such as 2D graphene film or VAGNs. The growth morphology was found to be independent of substrate as well as carbon source precursor. This growth strategy suggested that VAGNs can be fabricated on variety of substrates using different carbon precursors in a thermal APCVD system without using plasma, and offers a new insight for intrinsic growth mechanism. System was heated to 1130 °C in 50 min with 50 sccm H2 and 50 sccm Ar. The substrates were annealed for 20 min at 1130 °C, and then CH4 or ethanol (vapors) was introduced into the chamber to initiate graphene growth. The graphene growth morphology could be controlled by varying the precursor concentration and/or reaction time. The VAGNs growth process is schematically depicted in FigureRecently, Wang et al. demonstrated the direct synthesis of uniform VAGNs on Si substrates via catalyst‐free thermal CVD for the first time.4 flow rate between 7 and 14 sccm, whereas planar growth was observed for less than 7 sccm CH4 flow rate. The carbon precursor decomposition under low CH4 flow rate synchronized with the adsorption of carbon atoms on active sites and the growth of graphene. Therefore, the diffusion of carbon species to edge of graphene proceeded under a thermodynamic equilibrium condition, and had enough time to reach the desired positions with minimum energy to form stable crystalline phases.4 flow rates, the effective diffusion of carbon species was limited on the substrate or graphene surface. Therefore, a multiple graphene nucleation and simultaneous enlargement took place, which was induced by the supersaturation of active carbon species concentration, and finally led to the shrinking of available surface on the substrate into narrow channels. In this way, surface diffusion of carbon species reduced drastically and the direct deposition of carbon species started at the graphene edges. Hence, the edge reaction occurred very fast, and led to the vertical growth instead of boundary coalescence when two graphene domains approached each other.Initially, graphene flakes were randomly nucleated on the substrate surface and enlarged to form continuous film, as time progressed. Once a buffer layer formed, initial planar graphene growth eventually altered to upward growth. Consequently, the carbon atoms from precursor thermal cracking were continuously incorporated into the open edges to make the unique vertical growth proceed. VAGNs were obtained with the CH3.1.3Figure2 and SF6 in an ICP reactive ion etching system. Second, the VG was directly grown on the SNCs using CH4, H2, and Ar in the ratio of 1:5:45 at 1000 °C for 3 min. The chamber pressure was maintained at 2.5 kPa, and a bias voltage was applied between the filament and the substrate to facilitate the growth of graphene. Finally, SNC‐ PG electrode was fabricated by patterning the SNC‐G electrode with the help of UVL and RIE techniques. The tilted angle SEM images of the SNC electrode and SNC‐G electrode are shown in Figure Instead of using flat Si surfaces for the metal‐catalyst free direct CVD growth of graphene, researchers have used textured Si substrates to grow graphene.−1 belongs to Si, whereas the characteristic peaks of few‐layered graphene marked as D, G, and 2D were observed for the SNC‐G electrode.2 (2.04%) was due to the surface oxidation. The SNC‐G electrode contained carbon along with Si, and a very small amount of O2 (0.79%). Similarly, Son et al.4, CO2, and H2. CO2 was used as a mild oxidant which helped in achieving robust and uniform growth of MLG around each Si nanoparticle by generating catalytic sites.It was observed that the graphene nanosheets (GNs) were vertically grown on the SNCs and resembled to petaloid clusters. The average height and half‐width of the vertically aligned SNCs were found to be 2 µm and 100 nm, respectively, and the average half width of the SNCs with VG coating was 200 nm. The GNs grew vertically after covering the SNCs surface and formed 3D petaloid structures due to the internal stress and the applied bias voltage.3.22 determines the number of grown graphene layers, as H2 balances the production of reactive hydrocarbon radicals and etching of graphitic carbon during a CVD process. Therefore, the optimized graphene growth was carried out with H2:CH4 = 50:0.1 sccm at 910 °C for 100 min to obtain single‐layered graphene. Figure−1  at 900–930 °C for 5–120 min. Initially, the graphene islands were uniaxially aligned along theCatalytic growth of a single‐crystalline graphene on a solid substrate surface can be achieved by growing a single grain to a size as large as possible from a single nucleation site. Recently, a centimeter‐sized single‐crystalline graphene was obtained from a single nucleus.ID/IG ratio of the single‐crystal graphene (<0.03) was much smaller than that of the polycrystalline graphene (≈0.4), which indicated that the extended grain boundary defects in the single‐crystal graphene on Ge (110) were absent. Hence, it can be inferred that the hydrogen‐terminated Ge (110) surfaces are an ideal substrate for the catalytic growth of single‐crystalline monolayer graphene. On the other hand, Dai et al. also demonstrated the metal‐catalyst free direct CVD growth of graphene on Ge (110) wafers instead of Ge (110) buffer layers on Si (110).However, 2O (18 MΩ cm) at 90 °C for 15 min. The cleaned substrates were loaded into a horizontal tube and the system was evacuated to ≈10−6 Torr. It was filled to atmospheric pressure with a mixture of Ar (99.999%) and H2 (99.999%) at a constant total flow rate of 300 sccm. The Ge (001) samples were annealed for 30 min at 910 °C, and then CH4 (99.99%) was introduced to initiate the growth for 1–18.25 h. The GNRs were found to be self‐aligned 3° from the Ge 〈110〉 directions, and self‐defined with smooth armchair edges. They were having tunable width to <10 nm and aspect ratio to >70. It was also observed that, to obtain highly anisotropic GNRs, the growth rate in the width direction should be very slow (<5 nm h−1).After the successful direct CVD growth of single‐crystalline and polycrystalline graphene monolayer, the direct CVD growth of graphene nanoribbons (GNRs) on Ge was reported by Jacobberger et al. for the first time.It was inferred that the energy barrier associated with the graphene nucleus rotation significantly increased, as it became larger, which resulted in fixing the orientation of the NR lattice during the subsequent growth.4, H2, and Ar at 3.6–4.6, 100, and 200 sccm, respectively. After ultra high vacuum (UHV) annealing to 700 °C, both the Ge (110) and the Ge (111) surfaces restructured into domains, and exhibited in‐plane ordering underneath. The Ge(111)/graphene interface was strongly affected by UHV annealing. STS analyses revealed significant differences in electronic interactions between graphene and Ge (110)/Ge (111). Raman spectra indicated that the graphene was considerably strained after the growth with more point‐to‐point variation especially on Ge (111). Finally, the extreme strained case was observed for graphene/Ge (001), which resulted in the reorganization of the Ge surface intoKiraly et al. studied the metal‐catalyst free direct CVD growth of graphene on differently oriented Ge substrates in order to understand the nature of the graphene–Ge interfaces.4 gas at 900–930 °C2/CH4 flow ratio, and the growth time in order to understand the growth mechanism and morphology.2 and Ar, respectively, whereas the CH4 flow rate varied between 1 and 10 sccm. Once the growth temperature reached to 930 °C, CH4 was introduced into the chamber, and the total pressure was set to 100 mbar. It was possible to tune the growth in order to obtain different graphene structures, such as GNRs, monolayered and multilayered graphenes by simply varying the CH4 flow and growth time. At a flow rate of CH4 (F) = 1 sccm, GNRs oriented along the 〈110〉 directions on the surface  concentration led to strong supersaturation. The formation of carbon growth species was much faster as compared to their total consumption, which allowed the further nucleation of graphene domains.4, poorer quality graphene films with absence of the Ge nanofaceting were obtained. The time dependent growth at F = 2 sccm and H2/CH4 = 100 for 60 min was carried out several times. The growth proceeded in a layer‐by‐layer regime, as the carbon adatom species (CHx) concentration before nucleation was just above the critical supersaturation level. The adsorbed carbon species depleted as the nucleation and growth of graphene grains started. Eventually, their concentration was reduced to a level where the nucleation rate could be negligible and only monolayered domain enlargement could take place. Moreover, the initial supersaturation condition was restored and the second graphene layer formation started to take place. These results can be attributed to the similarities between the C–Cu and C–Ge alloy systems.Despite the fact that the direct CVD growth of graphene on Ge (100) results in highly strained graphene overlayers, Pasternak et al. demonstrated the direct LPCVD growth of large area high‐quality graphene films on Ge (100) overlayers supported on Si (100) substrates by using CHce Figure17a sim4 and Ar/H2 mixtures, while the total system pressure was maintained at 700 mbar.In continuation to the metal‐catalyst free direct CVD growth of graphene on Ge substrates, Lukosius et al. and Lupina et al. reported a complementary metal oxide semiconductor (CMOS) technology compatible good quality graphene on 200 mm Ge(001)/Si(001) wafers, respectively.ID/IG ratio (≈0.1), which was the indication of a low concentration of defects. Thus, a good quality, uniform, and large area graphene was obatined. Graphene‐induced Ge faceting was also observed in this case  surfaces without grain boundary defects.2/Si or HfO2/Si wafers to fabricate FETs.4 and rest of the process was same as described in ref. 2 (15 nm)/Si or HfO2 (15 nm)/Si substrates to fabricate FETs.Dabrowski et al.FigureLch) of 25–120 nm were defined via e‐beam lithography. Cr/Pd/Au (0.7/10/8.3 nm) contacts were thermally evaporated and patterned at random locations across the substrate so that the ribbons could be perpendicular to the source and drain electrodes. A schematic diagram of the FET architecture is shown in Figure Lch of ≈25 nm. The direct CVD growth of aligned, narrow, and semiconducting GNRs on Ge (001) could overcome many challenges, like control over the polydispersity in ribbon width, length, and location. Thus, it may enable significant advances in state‐of‐the‐art semiconductor electronics.The GNRs were peeled off with the help of a sacrificial multilayer stack of Au/poly(methyl methacrylate) (PMMA)/thermal release tape, and stamped onto the desired substrate Figure18a–e. 3.32H2 and 1000 sccm NH3 for 5 min, while the total pressure was maintained at 750 mbar. As GaN can dissociate at high temperatures, an overpressure of NH3 was maintained to protect the GaN surface. NH3 plays a dual role, as it compensates the loss of nitrogen from GaN during growth as well as releases H2, which is helpful in graphene‐CVD process. The thickness of the grown carbon thin films was in the range of 2–4 nm and they were continuous, uniform, and scalable.Silicon carbide (SiC) and gallium nitride (GaN) are two important wide bandgap semiconductors which can be integrated with graphene for electronic and optoelectronic device applications. There are only few reports available on the metal‐catalyst free direct CVD growth of graphene on SiC and GaN substrates. Unfortunately, no reports are available on direct CVD growth of graphene on other wide bandgap semiconductors. Direct CVD grown graphene‐based coatings as transparent electrodes can be utilized in optoelectronics, especially for fabricating GaN‐based light emitting diodes. So far, this has been achieved by transferring CVD grown graphene from metal substrates to GaN surface.4 (2 sccm) and H2 (20 sccm) with the total pressure maintained at 10 mTorr. The power for discharging the gas mixture was 50 W, and CH4 was effectively dissociated into various species, such as CHx, C2Hy, H, and H2. The dissociation rate was about 34%, which was much higher as compared to ≈0.0002% in thermal CVD,Ea ≈ 2.0–2.6 eV) in thermal CVD.2‐hybridized carbon atoms in as‐grown graphene , G (≈1580 cm−1) and 2D (≈2680 cm−1) confirmed the formation of graphene film with structural disorder. Figure Since PECVD is a low temperature process, therefore direct growth of uniform graphene films on GaN via PECVD seems to be an ideal option to fabricate optoelectronic devices in order to prevent thermal degradation of GaN and other active layers. Kim et al. demonstrated the direct integration of polycrystalline graphene into GaN‐based light emitting diodes (LEDs) via PECVD.Hence, GaN‐based blue LEDs were fabricated with directly grown graphene through a batch process for centimeter‐scale LED substrates, and their schematic diagram and a scanning TEM image with a graphene electrode are shown in Figure 4 were demonstrated by Zhang et al. and Ghosh et al., respectively.2 (4–32 sccm), and CH4 (0.5–8 sccm) for 1–6 min. Before each sample growth, substrates were heated to 1600 °C for 3 min under a 100 mbar pressure to sublimate the Si from top of the SiC surface, which exposed the inner carbon and provided the spontaneous nucleation site for external carbon species. All the important results on low and high temperature metal‐catalyst free direct CVD growth of graphene on Si, Ge, GaN, and SiC are summarized in TableSimilarly, low‐temperature direct PECVD growth of island type nanographene and vertical graphene nanosheets on SiC substrates using CH42, ZrO2, HfO2, h‐BN, Al2O3, Si3N4, quartz, MgO, SrTiO3, TiO2, etc., and semiconducting substrates, such as Si, Ge, GaN, and SiC. It was observed that direct CVD growth of graphene on dielectric substrates is difficult to achieve because of their low surface energy. Also, it is difficult to obtain good quality uniform graphene films on dielectric substrates via high‐temperature CVD methods. However, a low‐temperature PECVD technique could solve this problem. Apart from Ge, there are limited reports available on the metal‐catalyst free direct CVD growth of graphene on other important semiconducting substrates including wide bandgap semiconductors, such as Si, GaN, and SiC. Extremely low carbon diffusivity on Si surface and relatively high carbon solubility at high temperatures could hamper direct CVD growth of high‐quality monolayer graphene on Si substrates. Less low‐temperature direct CVD growth of graphene films on Si using different PECVD systems was attempted. However, the quality of grown graphene was not good, and large area uniform films could not be obtained. These PECVD methods mostly yielded island type growth and vertical graphene nanosheets (VGNs). The temperature of Si substrate should be lower than 1000 °C for a high‐temperature direct CVD growth of graphene. The high temperature (>800 °C) direct growth on Si substrates was attempted by using thermal APCVD, LPCVD, and HFCVD, respectively. These methods also yielded different morphologies of graphene, such as triangular nanographene, SLG, and FLG domains as well as VGNs. VGNs were grown on flat and textured Si substrates, respectively, but high quality and large‐area uniform graphene films could not be obtained. On the other hand, Ge substrate is far better than Si substrate due to its high catalytic activity and surface diffusivity, and a very low carbon solubility at its melting point (<108 atoms per cm3). Hence, direct CVD growth of graphene on large Ge wafers was carried out by using thermal CVD. Large area, high quality, and uniform graphene films were successfully produced. Single‐crystalline Ge substrates are also available for direct CVD growth of single‐crystalline monolayer graphene to fabricate graphene/semiconductor heterostructures based electronic devices. Furthermore, epitaxially grown large‐area single‐crystalline Ge layers on Si wafers are also available for direct CVD growth of graphene. Moreover, direct growth of uniform graphene films on GaN via PECVD seems to be an ideal option to fabricate optoelectronic devices in order to prevent thermal degradation of GaN and other active layers. As GaN can dissociate at high temperatures, therefore an overpressure of NH3 must be maintained to protect the GaN surface. NH3 plays a dual role and compensates the loss of nitrogen from GaN during growth as well as releases H2, which could be helpful in high‐temperature graphene‐CVD process. Direct CVD growth of graphene on Si and wide bandgap semiconducting substrates further needs to be explored to directly integrate graphene on these substrates for graphene/semiconductor based hybrid electronic and optoelectronic device applications. Attempts could be made toward growing high quality and large area graphene films on these substrates  by exploring new carbon precursors, and by designing novel CVD units. These growth methods exhibit great potentials pertaining to technology and scientific aspects, as some of the facile growth techniques have already been adopted. A detailed understanding of the metal‐catalyst free direct CVD growth mechanism of graphene on dielectric and semiconducting substrates is pivotal to achieve a controlled graphene growth on them, which is crucial for graphene based electronic and optoelectronic device fabrication.Recent progress made toward the metal‐catalyst free direct CVD growth of graphene on various dielectric and semiconducting substrates is summarized in this review. The focus was on the metal‐catalyst free direct CVD growth of graphene on technologically important dielectric substrates, such as SiOThe authors declare no conflict of interest.


The composition and structure were studied using a range of material characterization techniques. No covalent bonds were observed between molecules, and the self-assembled driving force was the only intermolecular interaction: Van der Waals’ force in the intra-layer and π–π interactions between layers. The arranged-rearranged structures provided a range of lithium ion shuttle channels, including the space between layers and diffusing through the nanosheets, which decrease the diffusion distance of lithium ions remarkably and reduce the irreversible capacity of the battery.This study examined the characteristics of small molecular structure nano-graphene in a dynamic hierarchical self-assembly and found that graphene is rearranged under its own pressure during dynamic aggregation and water ripples are formed by the The online version of this article (10.1186/s11671-019-2903-4) contains supplementary material, which is available to authorized users. The development of green alternative energy sources has received considerable interest. Recently, nano-graphene and graphene composites attracted interest for used as lithium ion anodes –3. In ad2 carbon atoms. Each layer has a hexagonal honeycomb structure called a nano-graphene sheet  is a representative example of nano-graphene that has been well studied –30. The eet Fig.  31]. Wh. Wh2 card-spacing generated via the dynamic self-assembly at the molecular level and the relationship between the clusters of nano-graphene, an in-depth analysis of the formation factors inside of nano-graphene was analyzed further.This paper introduces the dynamic hierarchical self-assembly structure–function relationship of hexabenzocoronene. By observing the n-butylammonium perchlorate (TBAP). Deionized water is used for all experiments.Hexabenzocoronene was synthesized according to a previously reported procedure –35. All The morphology and lattice fringe were observed using a scanning electron microscope , transmission electron microscope , and high-resolution transmission electron microscope .n-butylammonium perchlorate and 0.1 mM ferrocene electrolyte solution were scanned at a scan rate of 0.1 mV s−1.Electrochemical measurements were performed on the Shanghai Chenhua CHI660e system. A three-electrode system is used, a platinum wire for the counter electrode, a platinum plate with a fixed of electrode, and a saturated calomel electrode for the reference electrode. The concentration of the supporting electrolyte TBAP was 0.1 mol/L, and the analytical pure solvent was acetonitrile (ACN). Firstly, polish the platinum carbon compound electrode vertically on the circular gauze on the glass brick ; secondly, rinse off the white aluminum with distiller water and then use ultrasonic for 1 min by acetone; and finally, use ear ball washed and blown dry. Then, the suspension of the hexabenzocoronene sample was dropped on the surface of the glassy carbon compound electrode, and the solvent was naturally evaporated to dryness. Then 0.1 M tetra-Hexabenzocoronene is carbon–carbon material combined with significant π–π conjugate chemical bonding. A procedure for the preparation for hexabenzocoronene consisted of a series of reactions, such as Sonogashira, Diels-Alder reaction, Lewis catalyst-based cycle reaction, and deprotonation under basic conditions to give intermediates in unsatisfactory yields –38. The HBC has been widely used, but in the study of self-assembled system, it needs to be further understood. Although studies of the same or similar anode materials have been mentioned in the reported literature, the HBC study is still insufficient. Therefore, the focus of the work is on the detailed research of the self-assembly system, and put it on one by one to understand the internal dynamic distribution of aggregation and the induction and to improve the supplement of the lack of content anode materials.The small-molecule nano-graphene self-assembled dynamically to form regular thin sheets, which were sequentially and systematically stacked to form intermittent sheet nano-graphene fragments that were held tightly to each other . On the To explain the abovementioned rearrangement/change caused by its own weight and whether it will affect the material properties, scanning electron microscopy (SEM) was performed to determine if the particle size had changed. As shown in Fig. d-spacing between the layers highlight the performance of LIB anode materials.Transmission electron microscopy (TEM) showed that the hexabenzocoronene molecule exhibits structural features with a coherent layer spacing and a molecular layer spacing from 0.34 nm. High-resolution TEM (HRTEM) indicated that nanoparticles bind to each other  was further undertaken to understand the lithium storage behavior. The CV curves hexabenzocoronene were measured at the same scan rates (0.1 mV s−1) and display redox peaks with slight shifts with increasing scan rates, thereby showing a rectangular shape with increasing scan rates, as shown in Fig. V) can be separated into oxidation increases (V1), standard oxidation effects (V2), and standard reduction effects (V3) (Eq. (Cycle voltage (CV) was performed at the high potential of the lithium-ion batteries to determine the long-term stability and potential energy Fig. a. Accord rates 0. mV s−1 a+ incorporated into the hexabenzocoronene. The charging process (Li+ transfer) in hexabenzocoronene anodes requires stabilization. The calculated stabilization HOMO energy of the hexabenzocoronene radical anode ranges from 5.592 V, as shown in Fig. The anion/radical anion with an electron donating functional group leads to a homogeneous/uniform electron distribution throughout the flake, which is beneficial for maximizing the number of Lid-spacing between the layers for hexabenzocoronene was examined. This paper revealed a multi-diffusing process of lithium ions as the dynamic structure providing dynamic diffusion paths. TEM showed that lithium diffuses between the layers and has the ability to pass through the sheets, which greatly increases the lithium ion (yellow spot) diffusion efficiency; the Additional file Va/cm3 (STP) g−1 value is 110.47 and 96.62. According to adsorption-desorption isotherm, there is no hysteresis loop in the isotherms of HBC. Moreover, Additional file Vm is 18.647 cm3 (STP) g−1, and as,BET is 81.16 m2 g−1. The TEM image revealed self-assembled structures that were disorganized in the center of the fingerprint, and then they were arranged more regularly into a fingerprint-like structure. In the process of the self-assembly of graphene sheets, graphene sheets arrange in a stacked manner and self-assemble into a layered two-dimensional structure in a head-to-head manner. Moreover, the bonding force between molecules is weak with no strong chemical bonds. The self-assembled structure is a dynamic process involving the angular-rearrangement of self-assembled layers of graphene nanosheets under the action of energy. Moreover, TEM image showed that lithium ions have different diffusion modes between the graphene sheets, which can diffuse between the layers and pass through the layers, from the inner layer to the outer layer diffusion. Therefore, nano-graphene exhibits strong lithium ion diffusion properties and surprising lithium ion storage capacity.The inset in Fig. d-spacing in the self-assemblies led to a significantly enhanced LIB anode charge capacity and cycling stability. These results revealed a structure–property correlation between the nature of functional groups and Li storage capacity. Nevertheless, identifying the mechanism for how nano-graphene hierarchically assembles and dominates the overall battery performance will be an important research topic. Through these studies, a more rational and effective application of nano-graphene will be realized. Observing the characteristics of the internal architecture from a microscopic perspective and analyzing the dynamic hierarchical self-assembly properties of a nano-graphene sheet one by one will be the subjects of a future study.HBC shows good structure durability and stability. The electron density with the optimal Additional file 1:Supporting information (DOCX 436 kb)


N = 1,098 participants  without a diagnosed autism spectrum disorder, most of whom were university students. The IRI scale “Perspective Taking” and the EQ were negatively related to the AQ in male and female participants, while the IRI scale “Empathic Concern” was negatively related to the AQ in females only. Moreover, the AQ was positively related to the SQ-R in females only. Lastly, the SQ-R and a number of the empathy scales were significantly associated: For example and surprisingly, the EQ correlated weakly and positively with the SQ-R in both male and female participants. The results from this study illustrate how standard self-report measures of empathy, autistic tendencies, and systemizing tendencies are associated with each other in a large sample not diagnosed with an autism spectrum disorder. Additionally, some potential gender-specific effects are revealed.The aim of the present study was to investigate associations between four highly used self-report measures assessing empathy , autistic tendencies, and systemizing tendencies. Participants in this study completed the following self-report measures: The Interpersonal Reactivity Index (IRI) and the Empathy Quotient (EQ) to measure empathy, and the Autism Spectrum Quotient (AQ) and the Systemizing Quotient–Revised (SQ-R) to assess autistic and systemizing tendencies, respectively. The final sample consisted of  Empathy can be understood as an important concept contributing greatly toward successful human social interaction –3. HowevIn line with the various definitions of empathy, a range of self-report measures assessing individual differences in empathy exist . ThesInternational Classification of Diseases 11th Revision (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). It is—among other things—characterized by deficits in social functioning and communication . ASD is/will be classified (including diagnostic criteria) and divided into various subtypes in the nication , 19. Accnication –24. Howenication , 25, 26.nication , 24, 27.nication .Aside from reporting lower levels of empathy, samples of participants diagnosed with an ASD also show higher systemizing tendencies compared to control samples , 21, 24.Although higher autistic tendencies are robustly associated with both lower empathy and higher systemizing tendencies, empathy and systemizing tendencies are not robustly correlated with each other. Correlations between scores in different EQ and SQ(-R) versions have been reported to lie between −0.06 and −0.21 in general population samples, and at around −0.29 in a sample of people diagnosed with an ASD , 30, 31.Taken together, the aim of the present study was to investigate the relationships between empathy, autistic tendencies, and systemizing tendencies. Previous studies investigating these relationships typically used versions of the EQ, AQ, and SQ(-R). The findings previously shown with these scales should be replicated. In addition to this, the present study also sought to examine these relationships using the IRI, which, contrary to the EQ , assesses empathy as a multidimensional construct. In line with results from previous studies, we expected the following associations:Positive correlations between the EQ and the IRI scales PeT and EmCNegative correlations between the AQ and both the EQ and the IRI scales PeT and EmCPositive correlations between the AQ and the SQ-RPositive correlations between the AQ and the IRI PeD scaleNo significant correlations between both the EQ and the IRI scales with the SQ-Rhttps://osf.io/q2arp/. Data will be made available upon reasonable request.This study is registered at https://www.ckannen.com/). The data collection took place at Ulm University, Ulm, Germany. Therefore, most participants tended to be younger and were students. More specifically, 1,249 participants took part online in the present study, which is part of the Ulm Gene Brain Behavior Project (UGBBP). However, 11 participants were excluded due to missing data. Hence, 1,238 participants  were retained for subsequent analyses. One participant reported suffering from Asperger syndrome. This participant was excluded from further analyses, as he/she was identified as an outlier in terms of the AQ score.Participants took part in an online study including various self-report questionnaire measures presented using the SurveyCoder-Tool (th-Quantil − (1.5x(75th-Quantil − 25th-Quantil))] or higher than [75th-Quantil + (1.5x(75th-Quantil − 25th-Quantil))] on at least one of the scales under investigation, or for age, were treated as outliers and excluded from further analyses , 140 participants were excluded due to their categorization as an outlier on at least one of the scales under investigation, or because of their reported age. All participants who scored lower than Consistent with most of the literature, the EQ correlated most strongly with the IRI scales PeT and EmC for both males and females , 16, 17.The AQ was significantly and negatively related to the EQ and the IRI scale PeT for both males and females with medium effect sizes . Additior = 0.18) could only be considered small to medium . Some of the IRI scales were also significantly related to the SQ-R depending on the sample . This is in contrast to previous results and assumptions indicating that empathy and systemizing tendencies are (weakly) negatively related and therefore potentially distinct and independent phenomena  and the Affective Neuroscience Personality Scales (ANPS), including its FEAR scale (assessing facets of anxiety using a trait approach) –45. The Next, the sole use of self-report questionnaires as measures for the constructs could be criticized. Clearly, this methodology has several disadvantages . The speIn conclusion, the results from this study provide insights into the relationship between empathy, autistic tendencies, and systemizing tendencies in a large, mostly student, sample not diagnosed with an ASD. The results generally support the notion that autistic tendencies are negatively related to empathy, but positively related to systemizing tendencies, although in males the association between autistic and systemizing tendencies was weak and nonsignificant. Therefore, the results suggest that future studies should report findings with these measures separately for males and females, and also support the notion that future studies should focus on facets of autistic tendencies and empathy to examine these relations in more fine-grained detail.All subjects gave electronic informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the local ethics committee of Ulm University, Ulm, Germany.CS and CM planned and implemented the study and collected the data. CS implemented the statistical analyses and wrote the manuscript. CM worked over the manuscript to improve it. AC gave helpful advice and also worked over the manuscript to improve it.The position of CM is funded by a Heisenberg grant awarded to him by the German Research Foundation .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.