These mutations typically affect the major splicing pathway, which excises more than 99% of all introns in humans. However, approximately 700-800 human introns feature divergent intron consensus sequences at their 5' and 3' ends and are recognized by a separate pre-mRNA processing machinery denoted as the minor spliceosome. This spliceosome has been studied less than its major counterpart, but has received increasing attention during the last few years as a novel pathomechanistic player on the stage in neurodevelopmental and neurodegenerative diseases. Here, we review the current knowledge on minor spliceosome function and discuss its potential pathomechanistic role and impact in neurodegeneration.Pre-mRNA splicing is an essential step in eukaryotic gene expression. Mutations in  Pre-mRNA splicing is an essential step in eukaryotic gene expression. It is predominantly a co-transcriptional process during which the non-coding introns are excised from precursor mRNA (pre-mRNA) molecules and the flanking exons are joined (spliced) together resulting in translation-competent mature mRNA molecules. In most metazoan organisms, pre-mRNA splicing is carried out by two separate spliceosomes that function in parallel, specializing in distinct intron types 23Table 1). Specifically, the major spliceosome is composed of U1, U2, U4 and U6 unique snRNAs, while the respective snRNAs in the minor spliceosome are U11, U12, U4atac and U6atac. U5 snRNA is shared between the two spliceosomes. In either spliceosome the U4 and U6 as well as their functional analogues U4atac and U6atac snRNPs form a trimeric structure with the U5 snRNP called U4/U6.U5 or U4atac/U6atac.U5 tri-snRNP, respectively. In these complexes U4 and U6 or U4atac and U6atac snRNAs are extensively base-paired with each other 911The key difference between the two machineries is in the composition of the small nuclear ribonucleoproteins (snRNPs), and at a functional level, in the initial intron recognition steps. Both machineries are composed of five small nuclear RNAs (snRNAs) that associate with a large number of protein components to make up snRNPs 7Table 1) 24In contrast to the divergent snRNA composition, most of the protein components are thought to be shared between the two systems. All snRNPs except U6 and U6atac are associated with a seven-membered ring of Sm-proteins necessary for snRNP function and biogenesis Figure 1), the main difference is in the mechanism of intron recognition. With major introns, the individual U1 and U2 snRNPs independently bind to the 5’ss and BPS sequences, respectively. Additionally, the U2AF1/2 protein dimer recognizes a polypyrimidine track (PPT) found upstream of the 3’ splice site (3’ss) as well as the terminal AG dinucleotide in major but not minor introns. In contrast, the recognition of the 5’ss and BPS of minor introns takes place via cooperative recognition by U11 and U12 of the di-snRNP, respectively 33031Both the U1 and U2 and the analogous U11/U12 function in the initial recognition of introns and it is this step of splicing where the two systems show most differences. In addition to the significant differences in the extent of U11/5'ss vs U1/5'ss and U12/BPS vs U2/BPS base-pairing  and Spinal Muscular Atrophy (SMA), both of which are characterized by the degeneration of motor neurons. However, a feature that remains enigmatic is the tissue-specific phenotype observed in patients, regardless of the spliceosomal component or accessory factor affected. Here, we discuss the two currently known minor spliceosome-associated neurodegenerative diseases, emphasizing the points of convergence that illuminate the possible role and involvement of the minor spliceosome in cellular differentiation and function.SMN1 gene 64SMN2 gene that humans have acquired by gene duplication SMN2 harbours a silent C to T transition in exon 7 which disrupts an exonic splicing enhancer and converts it to an exonic splicing silencer 67SMN2 further downstream in intron 7, that creates an hnRNPA1 binding site acting as an additional splicing silencer, result in a splicing pattern where exon 7 is predominantly skipped. This leads to the production of a C-terminally truncated protein that is rapidly degraded  697071SMN2 produces only a fraction of full-length SMN mRNA, resulting in severely decreased SMN levels. The SMN protein is ubiquitously expressed and shows bimodal localization in both the cytoplasm and the nucleus, where it is enriched in biomolecular condensates termed Gemini of Cajal Bodies (GEMs) 63778077Spinal Muscular Atrophy (SMA) is the most common motor neuron disease in children with an estimated incidence of 1 in 6’000 to 1 in 10’000 live births. Pathological hallmarks include the degeneration of motor neurons in the anterior horn of the spinal cord and brain stem and concomitant muscle atrophy 61Amyotrophic Lateral Sclerosis is the most common motor neuron disease in adults with an estimated incidence of 1 - 3 per 100’000 and a prevalence of 3-7 per 100’000 indivi-duals worldwide 85858788899495979899101102103104105C9orf72 gene 113116FUS and SOD1 mutations, which cause aggregation of FUS and SOD1, respectively, most ALS cases display ubiquitinated TDP-43 inclusions 113118While most ALS patients suffer from the apparent sporadic form of the disease (sALS), about 10 % of the patients have clearly inherited the disease 96109111, minor tri-snRNP formation is impaired in SMA patient-derived lymphoblasts 124125ALS and SMA are both neurodegenerative diseases that lead to the loss of motor neurons and consequently voluntary muscle movement. Despite the differences in age of onset, disease progression and etiology, FUS-linked and TDP-43-linked ALS and SMA converge with each other 120122In the context of ALS, depletion of TDP-43 has a direct effect on the minor spliceosome components with various minor snRNAs being misregulated in a cell-line specific manner. In SH-SY5Y cells the levels of U4atac and U6atac snRNAs are reduced by depletion of TDP-43, while in U87MG cells the levels of U12 snRNA are reduced and U11 are increased. In contrast, HeLa cells show no significant changes in the level of minor spliceosome in response to TDP-43 depletion 127127Similar observations were made with FUS. Primary cultured hippocampal neurons from knock-out FUS mice and HeLa cells with a FUS knock-down failed to form GEMs 128130131128132132134While a direct function of TDP-43 in minor intron splicing remains to be elucidated, FUS preferentially interacts with minor intron containing mRNAs and with the minor spliceosome 113137138Summarized in Figure 3). But is there evidence that further links such defects to motor neuron pathology? In contrast to major introns, minor introns are neither present in housekeeping genes nor evenly distributed throughout the genome but mainly present in genes related to information processing 34126135140141142143144Myo10 gene encoding a member of the myosin-family of motor proteins that has been associated with axon outgrowth and neuronal development 146Stasimon gene (TMEM41b in humans), which is required for motor neuron development and function has been reported to be aberrantly spliced in Drosophila, Zebrafish, and Mouse models of SMA 12545143148Cacna1a, Cacna1b, Cacna1c, Cacna1e and Cacna1h 2+ homeostasis and axonal defects in both SMA and ALS 150151152et al. Together, SMA and ALS with FUS/TDP-43 pathology have both been associated with defects in minor intron splicing and/or abnormal cellular distribution of minor spliceosome components (However, while there is growing evidence for a contribution of the minor spliceosome to the pathomechanism of neurodegenerative disorders, most of the data are correlative and the specific mechanism or the other contributions are not yet fully elucidated. For example, SMN, FUS and TDP-43 all have other axonal functions that are impaired in SMA and ALS, such as control of genes that are involved in neuritogenesis and axonal outgrowth that could further contribute to the neurodegenerative phenotype 15515615715892160161


Idiopathic pulmonary fibrosis (IPF) occurs primarily in older adults and the incidence is clearly associated with aging. This disease seems to be associated with several hallmarks of aging, including telomere attrition and cellular senescence. Increasing evidence suggests that abnormalities involving telomeres and their proteome play a significant role in the pathobiology of IPF. The aim of this study is to summarize present knowledge in the field, as well as to discuss its possible clinical implications. Numerous mutations in genes associated with telomere functioning were studied in the context of IPF, mainly for Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC). Such mutations may lead to telomere shortening, which seems to increase the risk of IPF, negatively influence disease progression, and contribute to worse prognosis after lung transplantation. Some evidence indicates the possibility for the use of telomerase activators as potential therapeutic agents in pulmonary fibrosis. To sum up, increasing evidence suggests the role of telomere abnormalities in the pathobiology of IPF, natural history and prognosis of the disease. There are also possibilities for telomerase targeting in the potential development of new treatment agents. However, all these aspects require further research. Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial pneumonia of unknown etiology. The prevalence of this rare disease is estimated at 2–29 cases per 100,000 in the general population ,4,5. TheAnother interesting clinical issue is the familial occurrence of IPF, termed familial interstitial pneumonia (FIP). From 2 to 20% of patients with IPF have a positive family history. Inheritance appears to be autosomal dominant; however, with variable penetrance ,11,12. SIPF is limited to the lungs and is defined by the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). UIP’s histopathological image is described as patchy dense fibrosis that causes remodeling of the lung architecture, often resulting in honeycombing, and alternates with areas of less affected parenchyma. Honeycombing can be also seen in high-resolution computed tomography and is obligatory for definite radiological diagnosis of UIP .However, UIP is not a pattern that occurs only in IPF and can be observed in other diseases, e.g., connective tissue diseases and drug-induced interstitial lung disease. Therefore, the diagnosis of IPF is rather by exclusion and we have to exclude other known causes of UIP pattern.The fibrotic zones in UIP contain dense acellular collagen and scattered fibroblastic foci. Honeycomb is the end stage of fibrosis and is composed of cystic fibrotic airspaces frequently lined by bronchiolar epithelium and filled with mucin.The other cells engaged in fibrosis are smooth muscle cells, which in this lesion are commonly hyperplastic ,15.IPF occurs primarily in older adults and the incidence is clearly associated with aging , which iA telomere is a region of tandem repeats of short DNA sequences at the ends of chromosomes, which are important for their stability and allow the complete replication of the ends ,22. TeloAll names of genes and proteins were unified and presented following Gene Nomenclature Committee Guidelines .IPF seems to be associated with several hallmarks of aging, including genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, telomere attrition, and cellular senescence ,29.Tert−/− or Terc−/− mice [TERT and TERC genes in the human population. Notably, heterozygous mutations in TERT/TERC were reported in ∼15% of patients with familial interstitial lung disease, as well as, but rarely in sporadic IPF (<3%) [TERT or TERC no coding mutation, with 23% of the cases in this study showing said mutation. Such patients presented telomere lengths less than the 10th percentile when compared with control subjects. Even after controlling for age, sex, and ethnicity, suffering from pulmonary fibrosis was significantly associated with restriction of telomerase fragments. Overall, 25% of sporadic cases of pulmonary fibrosis had telomere lengths less than the 10th percentile [TERC mutations are associated with the shortest telomere lengths [Incomplete DNA replication causes the loss of small amounts of sequences which form telomeres at each S phase of the cell cycle; however, the enzyme telomerase compensates for this loss by the de novo addition of TTAGGG repeats . Telomer−/− mice ,33; howe−/− mice ,35. TherPF (<3%) ,37,38. Arcentile . It is a lengths ,41,42.Sui et al.  reportedAn increasing body of evidence supports the epithelial-mesenchymal hypothesis of IPF, which suggests that this disease is the result of successive injuries to the alveolar-capillary membrane with ineffective reconstitution of normal epithelium. The core of this hypothesis is that type II alveolar epithelial cells fail to repair the damaged epithelium as a result of ineffective proliferation, migration, and/or differentiation, and this leads to interstitial scarring . This hyShort telomeres are not specific for IPF only. This pathology was described also in other interstitial lung diseases. However, it seems that telomeres in IPF are shorter than in other diseases from this group .We should also highlight that the prevalence of interstitial lung diseases in carriers of telomere-related gene mutations increases with age .TERT or TERC was 10 years earlier than that of the nonsmokers [Smoking is considered one of the risk factors of IPF . There insmokers . Additionsmokers .TERT mutations from 21 unrelated families. The authors concluded that there appears to be a significant association between smoking and/or fibrogenic exposures with pulmonary fibrosis in TERT mutation carriers who are ≥40 years of age [Diaz de Leon et al. identified 134 individuals with heterozygous According to Dressen et al., among self-reported ever-smokers with IPF and controls, both age and smoking status were associated with telomere length. Among all patients, in a model of telomere length by age, IPF diagnosis, and smoking status, IPF status was associated with telomere length, whereas a weaker association was observed between telomere length and smoking status .+) oxidase, inhibiting sirtuin 3 expression and inactivating nuclear erythroid 2-related factor (Nrf-2) [Telomere length is a function of its length at birth and its rate of attrition. The latter is a result of history of replication, in addition to reflecting various factors such as chronic inflammation and cumulative oxidative stress, acting on progenitor cells . Increas (Nrf-2) .One of the endogenous sources of ROS is mitochondrial respiration. Mitochondrial electron transport chain even under normal conditions, may ‘leak’ 1–2% of all electrons as ROS. When mitochondria are damaged, ROS levels increase and begin to damage mtDNA. The damaged mtDNA continues to dysfunction the electron transport chain, which results in the enhanced generation of ROS, forming a kind of vicious circle . DysfuncAnother issue is the coexistence of insufficient antioxidant defense, which result in the inability to keep ROS below a toxic threshold. In IPF, significant reductions, e.g., in heme oxygenase (HO)-1 in broncho-alveolar lavage (BAL) alveolar macrophages, as well as downregulation of extracellular superoxide dismutase and pathways such as Nrf-2 in fibroblastic foci were reported ,68.Additionally, a significant part of oxidation processes occurs in the sulfhydryl group in proteins, resulting in protein misfolding. The accumulation of misfolded proteins in the endoplasmic reticulum is enhanced under conditions of oxidative stress and results in endoplasmic reticulum stress, which, together, leads to the malfunction of cellular homeostasis .On the other hand, excessive and unsolved endoplasmic reticulum stress and mitochondrial dysfunction enhances an apoptotic response of the alveolar epithelial cells, which, due to the abnormal shortening of telomeres, have a deficient regenerative capacity. These processes, together with other aging-related changes, seem to be critical for the development of IPF .Epidemiological data show that males suffer from IPF more frequently than women . AdditioAlthough there are no direct studies on human subjects in this field, prevalence and annual incidence of IPF increasing with age  intriguiThe above mentioned lacks in knowledge, indicating a strong need for further research in this field.TERT or TERC was found, had telomere lengths less than the 10th percentile when compared with control subjects. Overall, 37% of familial cases of pulmonary fibrosis in this study had telomere lengths less than the 10th percentile [TERT and/or TERC mutations was also reported by Tsakiri et al. Heterozygous carriers of TERT/TERC mutations had shorter telomeres than age-matched family members with wild type [Telomere abnormalities seem to contribute to the development of FIP. Cronkhite et al. observed the significantly higher proportion of probands with familial pulmonary fibrosis (24%) in which no coding mutation in rcentile . The assild type .TERT or TERC. Mutant telomerase resulted in short telomeres. Moreover, asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. Authors also concluded that telomere length may serve as a surrogate marker for the identification of patients at greatest risk for carrying mutant telomerase genes, whereas longer telomeres appeared to predict the absence of a telomerase mutation. However, these observations require verification in larger samples.On the other hand, Armanios et al.  reportedTelomere abnormalities seem to be associated not only with the risk of pulmonary fibrosis, but also contribute to the natural history of the disease.TERT mutations was progressive, with reduced life expectancy [TERT compared with 7% of 464 non-risk allele carriers . Subsequent analyses identified enrichment of rare protein-altering variants in Poly(A)-Specific Ribonuclease (PARN), Regulator of Telomere Elongation Helicase 1 (RTEL1), and rare variations in TERC in patients with IPF compared with controls. The proportion of patients with at least one rare variant in TERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls. Patients with IPF who had a variant in any of the four identified telomerase component genes had telomeres that were shorter than patients without a variant in any of the four genes and had an earlier mean age of disease onset than patients without one or more variants. Moreover, in the placebo arms of clinical trials, shorter telomeres were significantly associated with faster disease progression [In the context of pulmonary fibrosis, telomere shortening has been described as a negative prognostic factor . Diaz depectancy . Similargression .Although an increasing body of evidence shows undisputable benefits from using antifibrotic drugs ,81,82,83TERT, two subjects had mutations in TERC, and one fulfilled clinical telomere syndrome criteria, a positive history of thrombocytopenia, a family history of pulmonary fibrosis, but no detectable mutation in TERT, TERC or DKC1. Hematological complications were the most prevalent morbidity in this group and required significant adjustment of the immunosuppressive regimen in all patients. Other complications reported by authors were the high rate of acute renal failure and acute tubular necrosis, gastrointestinal bleeding that required red blood cell transfusion support, infectious complications in several subjects, and one patient presented defective healing at the anastomotic site. In addition, in some patients there was impaired functional recovery, with three individuals developing critical illness polyneuropathy and myopathy. Despite the high frequency of complications, seven of the eight patients were alive with a median follow-up of 1.9 years, and one subject died 10 months post-transplant after a prolonged hospitalization.Silhan et al.  describeAnother important issue discussed by Silhan et al.  is the rTERT or TERC mutations with a median age of 52 years at the time of lung transplantation. The authors observed the following post-transplant complications: myelodysplasia and/or bone marrow failure, anemia and neutropenia. The median survival after lung transplantation was 214 days.Borie et al.  reportedOn the other hand, Newton et al. analyzed 82 patients and reported that having telomere length <10th percentile was independently associated with worse survival as well as a shorter time to onset of chronic lung allograft dysfunction with more frequent grade three primary graft dysfunction. On the contrary of previous reports, there was no difference in the incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction among short telomere patients.To sum up the above presented evidence, we can conclude that telomere shortening seems to be associated with increased medical complications. This may be justified by the overall pathobiological landscape of this particular disease group, notably, their multi-systemic manifestation. Multiple organs and tissues are affected, including different epithelia and bone marrow. This characteristic manifestation includes IPF patients and may well explain the origin of the complications presented after lung transplantation. Although, there is a piece of evidence about worse survival and shorter time to onset of chronic lung allograft dysfunction, which would justify screening IPF patients for telomere length prior to qualification, routine implementation of such examination requires further research.There are only data on pirfenidone treatment in the context of telomere length. Dressen et al. observed a significant interaction between telomere length and treatment on lung function decline. Shorter telomeres at the study baseline timepoint predicted more rapid forced vital capacity (FVC) decline in patients with IPF than did longer telomeres, and treatment with pirfenidone had benefit regardless of telomere length status .Additionally, a recent study showed that neither pirfenidone nor nintedanib modulated the expression of senescence markers .Tert therapy resulted in improved lung function and lower inflammation and fibrosis at 1–3 weeks after viral treatment, and improvement or disappearance of the fibrosis at eight weeks after treatment. AAV9-Tert treatment led to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence [As of now, there is no such treatment registered for use in the human population; however, Povedano et al. presented an interesting perspective in this field . The autnescence .Elsewhere, Le Saux et al. used a GRN510 molecule (derived from cycloastragenol) to activate telomerase. The authors observed that GRN510 can reduce fibrosis following bleomycin administration in animal models, suggesting that GRN510 may prove effective as a potential therapeutic agent for IPF .To sum up, increasing evidence suggests the role of telomere abnormalities in the pathobiology of IPF, natural history, and prognosis of the disease. There are also possibilities for telomerase targeting in the potential development of new treatment agents. However, all these aspects require further research.


U-shaped graphene domains have been prepared on a copper substrate by chemical vapor deposition (CVD), which can be precisely tuned for the shape of graphene domains by optimizing the growth parameters. The U-shaped graphene is characterized by using scanning electron microscopy (SEM), atomic force microscopy (AFM), transmission electron microscopy (TEM), and Raman. These show that the U-shaped graphene has a smooth edge, which is beneficial to the seamless stitching of adjacent graphene domains. We also studied the morphology evolution of graphene by varying the flow rate of hydrogen. These findings are more conducive to the study of morphology evolution, nucleation, and growth of graphene domains on the copper substrate. Graphene, an ideal 2D versatile carbon material with a combination of the honeycomb-like arrangement, has drawn extensive attention in the research field, due to its good properties, such as high carrier mobility , mechaniNowadays, on the one hand, using the CVD method for preparing large-area graphene on a copper foil surface is a synthetic way with great potential for industrial development, but the growth of graphene is accompanied by crystal imperfections and boundaries ,14. ThisIn this work, we report for the first time the growth of large-sized “U” shaped graphene domains on a solid-Cu substrate by using ambient pressure CVD. These U-shaped graphene domains also run parallel to each other as well as along the gas flow direction. Evidently, the U-shaped graphene has a smooth edge, which is of importance to seamlessly stitching of the adjacent graphene domains. Moreover, the U-shaped graphene size could change when the methane flow rate was adjusted, and the morphology of the graphene domain could be different when the hydrogen flow rate was adjusted.2 and the clean Cu foil was placed into the quartz tube. The Cu foil was heated to 900 °C under a flow rate of 100 standard cubic centimeters per minute (sccm) for Ar, and 75 sccm for H2. After being annealed for 20 min at 1020 °C, CH4 with a flow rate of 20 sccm was introduced to the chamber for 90 s, then the flow of CH4 and H2 are turned off while maintaining a flow rate of 100 sccm for Ar, and the reactor is quickly moved to the other side to bring the temperature of the reaction zone down to room temperature. The whole process is illustrated in An atmospheric pressure CVD system was used with a quartz tube which was 6.5 feet in length and has an inner diameter of 2 in. as illustrated in The graphene-covered Cu substrate surface was spin-coated with a polymethylmethacrylate (PMMA). After 2 h, the Cu foil was etched by using a 0.5 M ammonium persulfate solution. In the meantime. The PMMA/graphene was transferred to deionized water for the removal of chemical residues. Then, PMMA/graphene was pasted on to a target substrate and then immersed into acetone to remove the PMMA layer. Finally, the substrate was placed in a vacuum drying oven and then dried by heating.Scanning electron microscopy (SEM) , atomic force microscopy (AFM) , Raman spectroscopy  with a 100× lens, and transmission electron microscopy  were used to characterize the graphene film.4 flow rate in an ambient pressure CVD on Cu foil, which was never reported before. Each U-shaped graphene domain has the same growth direction, the domains are parallel to each other, and the domain direction is consistent with the reaction’s gas-flow direction. The graphene domains display differences in size, indicating the nucleation and growth of graphene domains are different. Considering the total gas flow rate was relatively high in the reactor, it is possible that the reaction gases were in an unstable condition, which is difficult to achieve an even distribution of carbon species in such a short growth time [As illustrated in wth time . TherefoAs shown in 4 flow rate increases, more methane molecules can be absorbed on the copper surface and are decomposed to create more free carbon atoms, and therefore the number of possible nucleation sites increases, resulting in the shortage of carbon species around the edges of the graphene domains, which limited the growth in size for an individual graphene domain in our case. The formation of the graphene domain is closely related to the experiment parameters , such as−1 and ~2691 cm−1, corresponding to the G-peak and the 2D peak, respectively. Moreover, the weak D-peak (~1360 cm−1) in the Raman spectra indicate the high quality of graphene film. The I2D/IG ratio is about 2.2 for the black curve, which indicates a monolayer graphene region. For the red curve the I2D/IG ratio is about one, and for the blue curve the I2D/IG intensity ratio is below one, indicating the few layer region of graphene. In order to further study the layer number and the defects of graphene, the graphene was transferred to a copper grid for TEM observation. As shown in In CVD, the evolution of the graphene domain shape is related to many growth conditions, including the surface treatment of substrate, the flow rate of gas, the annealing time and so on. In this work, we found that the hydrogen flow rate can significantly influence the final shape of graphene domains. A series of graphene domains with different shapes are formed on a copper foil at a high flow rate of methane (20 sccm) and a short growth time (90 s) by varying the hydrogen flow rate as shown by the typical SEM images in It is possible that the morphology evolution of the graphene domain is caused by the destruction of the dynamic equilibrium mechanism . TherefoIn summary, we have controlled the growth of U-shape graphene domains on a copper foil by using CVD at atmospheric pressure. The change in methane flow rate has a great influence on the nucleation density and the size of the U-shaped graphene domain. Besides, different domain morphologies of graphene have been formed, such as semi-circle-shaped graphene and heart-shaped graphene, through varying the flow rate of hydrogen, which indicates the important role of hydrogen in the morphology evolution of graphene domain. This study may provide a new way to fabricate the novel morphology of graphene domains and may contribute to an understanding the growth mechanism of graphene.


The composites together with the individual analog of Ag/CNT and Ag/graphene were characterized by means of XRD, TEM-SAED, N2 sorptiometry, Raman, FTIR, UV-Vis, and photoluminescence spectroscopy. These nanomaterials were then tested for the catalytic reduction of 4-nitrophenol (4-NP) to the technologically beneficial 4-aminophenol (4-AP). The Ag2O@Ag@CNT-graphene composite calcined at 400°C has shown fascinating reduction performances for 4-NP either in the dark (k = 0.014 s−1) or under visible light illumination (k = 0.039 s−1) in the presence of 5 mM NaBH4 compared to Ag/CNT (0.0112 s−1) and Ag/graphene (0.010 s−1) catalysts. This was chiefly because Ag2O@Ag@CNT-graphene comprises the highest pore volume (0.49 cm3/g) and involves three types of pores in the margin from 1.8 to 4.0 nm in front of only one modal type of pores for the rest of the catalysts and thus maximizes the adsorptive capacity of the reactants (4-NP and NaBH4). Moreover, the former composite exhibits the highest concentration of the Ag2O component as established by numerous techniques in addition to the cyclic voltammetry, proposing it's facile reaction with 4-NP along with the simultaneous transfer of surface hydrogen and electrons from NaBH4 ions to produce 4-AP. The promotion of the p-n junction evaluated using the Mott-schottky equation on Ag2O@Ag@CNT-graphene assisted by charges separation and surface plasmon resonance bands of Ag and Ag2O are found to be advantageous for 4-NP reduction. The latter composite delivers a specific capacitance of 355 F g−1 at 1.0 A g−1 exceeding those of Ag/CNT (230 F g−1) and Ag/graphene (185 F g−1). The EIS study establishes the high electronic conductivity of the metallic Ag and Ag2O moieties, low internal resistance of CNT-graphene as well as the marked ionic transfer facilitated by the composite porous nature.A simple hydrothermal route assisted by a triblock copolymer was used to synthesize Ag Undeniably, silver nanoparticles have attracted lots of attention in different areas of application; however, the agglomeration and the consequent separation processes prohibit its usage. This can be minimized by affixing the Ag nanoparticles on CNT-graphene composite. Indeed, the functionalized CNT is going to show a p-type transfer that can be converted after graphene incorporation and with the deposited Ag into n-type compensated by the p-type Ag2O formed species. The formation of the p-n junction between oxygen functionalized CNT/Ag2O (as p-type) and Ag/graphene (as n-type) hetero-structure [CNT/Ag2O/Ag/graphene] is expected to enhance the reduction activity based on enhancing the conductivity, electron mobility and lifetime of photo-generated electron-hole pairs. This work inspects the relationships between the photocatalytic activity and structure alterations in view of metal (oxide)–support interaction, average metal size and dispersion, charge transfer, role of surface texturing, and functionalities of Ag2O/Ag/CNT-G on the reduction efficiency of nitrophenols. The supercapacitance performances of the catalysts is estimated and well correlated with the photocatalysts structure as well as their photo-reduction effectiveness.Oxygen-containing CNTs are desirable rather than pristine CNTs since the former are considered as anchoring sites for diverse semiconductors and metal nanoparticles via forming covalent, electrostatic and hydrogen bonds  and 0.5 g of the as-fabricated graphene oxide (according to the modified Hummer method) are dissolved in 10 ml of the synperonic F108 (Triblock copolymer of an average Mn 2800-Sigma Aldrich), formed as a result of dispersing 1 g/100 ml distilled water. To the latter suspension, an aqueous AgNO3 solution (to from 4 wt%Ag) dissolved in 10 ml distilled water was well mixed and kept under stirring for 30 min followed by sonication for another 3.0 h. During the latter sonication process, an addition of NaBH4 (0.1 M) is began till the yellow color is formed. Later on, this suspension is autoclaved at 180°C for 12 h followed by washing, filtering and drying at 100°C for 5 h. This catalyst was finally annealed at 400°C, and to be denoted as 4%Ag/CNT-graphene400. Similarly, the individual analog 4%Ag/CNT400 and 4%Ag/graphene400 catalysts are prepared in a typical way to that mentioned for the hybrid CNT-graphene.0.5 g of the as-obtained multi-walled carbon nanotubes  and mean pore radius (r) were determined from N2 adsorption isotherms measured at 77 K after out-gassing the samples at 473 K for 3 h under a reduced pressure of 10−5 Torr. Diffuse reflectance ultraviolet–visible spectroscopy (UV–vis DRS) of the samples was carried out at room temperature using UV–vis JASCO spectrophotometer (V-570) in the of 200–1,000 nm range using BaSO4 as a standard. The band gap energy (Eg) of the samples is estimated using the equation: αhν = A(hν-Eg)n/2 and determined by finding the intercept of the straight line of the plot of (αhν)1/2 or (αhν)2 against hν for both indirect and direct transitions, respectively  was measured at room temperature using a Philips diffractometer (Model PW-3710). The patterns were progressed with Ni-filtered copper radiation (λ = 1.5418 Å) at 30 kV and10 mA with a scanning speed of 2θ = 5°/min. The Fourier transform infrared (FT-IR) spectra were monitored via a single beam using Thermo scientific Nicolet iS10 instrument thorough which the samples were grounded with KBr (1:100) to form tablets, and to record the measurements in the 4,000–400 cm4. The solution was subjected to a constant stirring. With the addition of NaBH4, the yellow color of the solution was darkened due to the formation of the phenolate ions. The desired amount of catalysts was added (0.025 g); while stirring was continued at room temperature. The dark yellow color of the solution was progressively vanished, demonstrating the reduction of 4-NP. The reaction progress was checked via withdrawing samples from the reaction mixture at normal time intervals. The catalyst/4-NP+NaBH4 suspension was also exposed to the visible light irradiation of a 160 W Hg lamp, to investigate the effect of light on the reduction activity of the catalyst. The conversion of 4-NP to the corresponding amino (4-AP) was checked by UV-Visible spectroscopy (a Perkin Elmer Lamda-900) by measuring the absorption maxima corresponding to the reactant 4-NP as well as the product 4-AP compounds. For the recycling measurement, the used catalyst was separated by filtration and then used without any treatment for further six times under the same conditions. The effect of additives on the catalysts performances toward 4-NP reduction was performed by adding 100 ppm concentration of triethanol amine, isopropyl alcohol, benzoquinone and Na2CO3.To investigate the catalytic reduction of 4-nitrophenols (4-NP), 100 ml of 0.1 mmol aqueous solution of 4-NP was inserted in a 100 ml beaker together with a 12.5 ml of 0.5 M of NaBH2O phase (JCPDS card no. 41-1104) exhibited via the main diffraction plane (111) at 32.8°; beside some others at 2θ = 36.2° and 19.7°, shows an enhancement mostly on the 4% Ag/CNT-graphene400 catalyst. Graphitic peaks due to (002) and (100) planes were only shown on the CNT sample; when compared with the mother CNT-graphene pattern, indicating that the deposition of Ag NP can prevent the stacking of graphene when interconnected with CNT into multilayers , with an average diameter of 7 nm. The HRTEM shows a little deterioration for the CNTs networks as a result of the high calcination temperature. The TEM image of 4%Ag/graphene400 exhibits an agglomeration of Ag nanoparticles of a dimension with 23 nm. The SAED inset-image evidences the presence of lattice fringes with interplanar spacing of 2.47 and 1.40 Å due to (002) and (220) diffraction planes of graphene and Ag nanoparticles, respectively, supporting the results obtained from XRD investigation. The TEM image of the 4%Ag/CNT-graphene400 catalyst shows that graphene coated carbon nanotube and silver nanoparticles of spherical architecture are equally distributed on both of the carbon substrates. The distributed Ag nanoparticles of darker color and of average diameters of 20 nm were seen throughout the image. A lighter color is seen mainly around CNTs to ascribe the presence of the Ag2O phase; in agreement with XRD results, of a mean diameter of 15 nm. The SAED pattern of this sample demonstrates diffraction bright spots at d-spacings 2.51 and 2.04 Å corresponding respectively, to the (002) and (200) planes of graphitic carbons and Ag nanoparticles, respectively.The X-ray diffraction profiles of Ag incorporated graphene, CNT and CNT-graphene catalysts calcined at 400°C were shown in Figure 400 sample (46.8 Å) and thus showed the lowest SBET value (71.4 m2/g) if compared with Ag/CNT400 (412.7 m2/g) and Ag/CNT-graphene400 (365.1 m2/g), depicted in Table 3/g) with a median pore size of 26.9 Å. All the prepared materials exhibited a characteristic Type IV isotherm  compared to 4%Ag/CNT-graphene400 (0.74) whereas 4%Ag/graphene400 retains the ratio of 1.02 similar to that without Ag, pertaining higher graphitization purity and least disturbance. This indeed maximizes the occurred defects in former catalysts comparatively and to comprehend the strong interaction of the Ag nanoparticles within their structures. The 4%Ag/graphene400 sample shows a more diffused and splitted 2D band  with higher wavenumber than those exhibited on the former ones , proposing an extra contribution of the inner double-resonance scattering due to layers of graphene sheets. The appearance of a Raman peak at 594 cm−1 solely on 4%Ag/CNT-graphene400 confirms the existence of Ag-O stretching modes  of the fabricated CNT-graphene, shown as inset in Figure −1 beside peaks at 2,919 and 2,850 cm−1 due to asymmetric and symmetric stretching of the C–H bond; in CH2, and 1,565 cm−1 with 1,451 cm−1 to the aromatic C = C stretching, confirming the hexagonal structure of the graphitic carbons and indeed indicative of the intact structure of CNT and graphene without disruption following the hybridization process  vibration but with a significant decrease in intensity. This catalyst also provokes the evolution of Ag-O moieties as diagnosed via the peak at 560 cm−1. In case of 4%Ag/graphene400, vanishing of the free OH band is attained together with reducing the intensity of all the bands correlated to C = O, C-O, C-OH, and C-O-C functional groups, those suffer blue shifting compared to the Ag free sample to simply comprehend the Ag involvement. The presence of bands at 943, 825, 700, and 615 cm−1 never seen in the hybrid spectrum can be correlated to the involvement of Ag and Ag-O bonds within graphene structure 2 and (hν)  spectra were measured following an excitation at 320 nm  Figure  were 1.5m Figure . All the400, Ag/graphene400 and Ag/CNT-graphene400 electrodes at a scan rate of 100 mV s−1 in the potential window range from −0.4 to 0.5 V in 6.0 M KOH solution. The CV of CNT-graphene400 indicates a cathodic peak at 0.015 V and an anodic one at 0.07 V. Ag incorporation has stimulated shifting both of the peaks into lower potentials elucidating beside its good encapsulation the higher conductivities and ions charge transfer. Conclusively, the CV curves indicate the presence of quasi-capacitance current with an extended potential window in case of the Ag/CNT-G catalyst. This is a good indicative to stability and strong interaction of Ag within CNT-G hybrid than in case of Ag/CNT and Ag/G where the dissolution of Ag is attained at 100 mV  >4%Ag/CNT400 (300 s) >4%Ag/graphene400 (370 s). Accordingly, the calculated kinetics seen as inset in Figure −1>0.0112 s−1 >0.010 s−1. The time dependent ultraviolet-visible spectra of the reaction mixture in the presence of 4%Ag/CNT-graphen400 showed a gradual decrease in the peak intensity (at 400 nm) of 4-nitrophenolate ions with a gradual increase in the peak intensity (at 300 nm) of 4-AP. The yellow color of the solution completely fades within 3.5 min reaction time, specifying the over-all conversion of 4-NP to 4-AP. This enhanced activity of the composite CNT-graphene containing Ag is primarily related to increasing the pore volume of this specific catalyst (0.49 cm3/g) and to the presence of three types of pores in the margin from 1.8 to 4.0 nm in front of only one modal type of pores for the rest of the catalysts. This indeed maximizes the adsorptive capability toward the reactants 4-NP and NaBH4 and thus helps the facile reduction-capability. It seems also that the particle size decrement was not the main factor affecting the reduction process since 4%Ag/CNT400 presented the lowest domain (7 nm) and was not the most reactive catalyst. However, the high disperse-ability of the Ag nanoparticles with the appreciable surface area the composite own helps much in improving activity, as TEM and N2 adsorption explores. Exposing the lattice plane (200) on Ag/CNT-graphene400 in front of (220) for rest of the catalysts might advocate higher binding energy between 4-NP and the former plane facilitating the reduction process.To confirm thephotocatalytic activity of the catalysts, a nitrophenol (NP) reduction in the presence of 0.5 mmole NaBHm Figure , showed 400 toward 4-NP reduction under visible light irradiation  for all catalysts in comparison with the Ag free hybrid were determined via the extended linear part of the Mott-Schottky (M-S) plots FB of the samples are −0.018 V, −2.2 V, and −0.05 V for 4% for Ag/CNT-graphene400, 4%Ag/CNT400, 4% Ag/graphene400, respectively in front of 1.4 V (vs. Ag/AgCl) for CNT-graphene400. Thus, the values determined for the CB are −0.22, −2.4, −0.25, and 1.2 V for the above sample sequence (CB ≈ EFB −0.2 V)  was rather larger than 4%Ag/CNT-graphene400 (2.5 × 1018 cm3) under dark condition, manifesting that the depletion of electrons in the latter was faster in favor of Ag2O formation and indeed confirm the p-n interface formation and the role of the latter in achieving high reduction performance.To affirm the latter interface, the flat-band potentials  isopropanol (IPA), and benzoquinone (BQ) were selected as the main scavengers for the holes, (h+), hydroxyl radicals (∙OH), and superoxide radicals  in capturing some electrons (from CNT due to differences in work function) and thus prolonged the distances between electrons and holes to give enough space for facilely perform the reduction process. Rising the activity on the 4%Ag/CNT-graphen400 catalyst might also highlight the necessity of the positively charged Ag2O p-type in stimulating strong interaction with the -NO2 group of 4-NP, through the coulombic interaction forces. In addition, the components of Ag2O can acquire efficient electrons via a transfer process from metallic Ag to efficiently inhibit the recombination of the photo-excited pairs of the latter. Undeniably, few of photo-generated electrons can be captured by the O2 moieties embedded on CNT and graphene surfaces; established via FTIR, to form O2O or OH− to form OH∙ upon light illumination; as scavengers study confirm, those affect the activity via degradation consequences. Accordingly, the marked decrease in the activity during the addition of IPA and BQ is attributed to the abstraction of H+ ions from borohydride to ∙OH and OFor investigating the catalytic mechanism and to unravel the effect of some organics on the reduction consequences of 4-NP, several scavengers were utilized to determine the primary active species responsible for the reduction performances of 4%Ag/CNT-graphen400 catalyst can be proceeded by the diffusion of BH2O@Ag interface is expected. Evidently, lowering the work function of Ag (4.26 eV) than that of CNT-graphene (~4.95 eV) rearranges the charges distribution to be around the CNT-graphene composite and thus enhances the reduction efficacy due to the absorption ability of the composite     , and Ag/manganese dioxide films (225 F g−1 at 2 mVs−1) -activities of the different catalysts, PL results and to the synergistic interaction between Ag2O/Ag/CNT-graphene ternary heterostructure is proposed, as strongly illustrated in Scheme 2O components (p-type) occurs, by exciting electrons (e−) from the VB to the corresponding CB, leaving holes (h+) in the VB. Immediately, the electrons are instantly captured by CNT-graphene to rapidly transferred to the O2 dissolved in the reaction medium or those on the composite surfaces; established via FTIR, to produce superoxide radicals ; emphasized from the scavenger study. Such processes occurred over Ag2O can retard the e−-h+ recombination and indeed prolong their life time to result in an enhanced catalytic performance of the Ag2O/Ag/CNT-graphene heterostructure. Furthermore, the intimate interfacial contact among the hybrid in assembling P-n units in conjunction with their cooperative synergy also contributes to the enhanced (photo)catalytic performance of the ternary hetero-structure.Based on the above methodical exploration, a conceivable photocatalytic mechanism of the Ag2O/Ag/CNT-graphene400 catalyst toward 4-NP reduction was tested via performing 6 successive runs under visible light illumination and without any treatment between the runs. Figure 4 and under illumination. It also dictates the stabilization of both the metal oxide and the NPs via considerable interaction with composite of CNT and graphene preventing them from leaching during the reaction.The durability of the 4%Ag2O@Ag@CNT-graphene has shown fascinating photo-reduction performances for 4-NP with a rate constant of 0.039 s−1 exceeding many in literatures and indicates a magnificent specific capacitance value of 355 F g−1 at 1.0 A g−1. Although this photocatalyst does not reflect the highest number of charge carriers it exposes appreciable amounts of Ag2O (p-type) that played a unique role toward the reactants adsorption and to contribute with the metallic Ag in enhancing the mentioned applications. This study also highlights the synergistic effects prompted by the constructed 3D-like array via 1D CNT (as spacer) and 2D graphene in dispersing Ag2O and Ag nanoparticles. The electronic conductivity of latter moieties, the porous nature of the composite, the p-n junction interface and delaying of e−-h+ recombination together with decreasing the internal resistance are all competes in enhancing the photoreduction and energy storage reactions.The established heterostructure Ag2O@Ag@CNT-graphene catalyst with varied amounts of Ag2O@Ag and compared with the individual analog of Ag/CNT and Ag/graphene. He participate in discussion and writing of this search. MK participate in discussion, writing of this search and preparation of substances under study. AI participate in synthesize of materials and analysis of materials by XRD, TEM, Raman, FTIR, UV-Vis Diffuse reflectance, N2 adsorption beside electrochemical techniques such as cyclic voltammetry (CV), galvanostatic charge-discharge, and impedance spectroscopy (EIS).MM suggest synthesize of AgThe 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.


Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain associated with this condition. Recently, novel therapeutic agents have been shown to control the progression of IPF. However, these drugs do not improve lung function and have not been tested prospectively in patients with IPF and coexisting lung cancer, which is a common comorbidity of IPF. Optimal management of patients with IPF and lung cancer requires understanding of pathogenic mechanisms and molecular pathways that are common to both diseases. This review article reflects the current state of knowledge regarding the pathogenesis of pulmonary fibrosis and summarizes the pathways that are common to IPF and lung cancer by focusing on the molecular mechanisms. Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which results in irreversible distortion of the lung’s architecture. Although its cause remains to be elucidated fully, advances in cellular and molecular biology have greatly expanded our understanding of the biological processes involved in its initiation and progression . It is wAlthough knowledge of the pathogenesis of IPF remains incomprehensive, numerous research papers have contributed to the understanding of this disease. In particular, some environmental and microbial exposures have been associated with the initiation of IPF. Various individual genetic and epigenetic factors have also been related to the development of fibrosis, and potential contributions of variants and interactions with putative external factors have been presumed but not clarified. Repeated microinjury to alveolar epithelial tissues has been revealed as the first trigger of an aberrant repair process in which several lung cells develop abnormal behaviors that promote the fibrotic process. IPF is currently considered an epithelium-driven disease wherein dysfunctional aging lung epithelia are exposed to recurrent microinjuries that sabotage regeneration and lead to aberrant epithelial–mesenchymal crosstalk, creating an imbalance between profibrotic and antifibrotic mediators. Concurrently, environments that are supportive of elevated fibroblast and myofibroblast activities are maintained, and the normal repair mechanisms are replaced with chronic fibrosis. This review article details the current evidence of molecular contributions to the pathogenesis of IPF. The currently accepted mechanisms of pulmonary fibrosis are shown in It is assumed that fibrosis advances over long periods of time in patients with IPF. Thus, at the time of diagnosis, modifications of lung structure have already been established by the disease and pathological features, such as various stages of epithelial damage, alveolar epithelial cell (AEC) 2s hyperplasia, dense fibrosis, and abnormally proliferating mesenchymal cells, are found. At this time, it is not possible to determine the course of events that have led to lung damage; however, it is accepted that dysfunctional epithelia are key to the pathogenesis of IPF .Under normal conditions of lung injury, AEC1s are replaced with proliferating and differentiating AEC2 cells and stem cells, which restore alveolar integrity by stimulating coagulation, the formation of new vessels, activation and migration of fibroblasts, and synthesis and proper alignment of collagen. Chemokines, such as transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF), are central to these processes. Conversely, continued lung injury or loss of normal restorative capacity invokes an inflammatory phase of the wound healing process. The associated increases in the expression levels of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) create a biochemical environment that favors chronic flaws of regeneration and tissue remodeling .TGF-βs are multifunctional cytokines that are present as three isoforms: TGF-β1, TGF-β2, and TGF-β3. Although the biological activities of these isoforms are indiscrete, TGF-β1 plays a predominant role in pulmonary fibrosis . The thrTGF-β1 is considered the most important mediator of IPF. AEC2s produce TGF-β1 following actin–myosin-mediated cytoskeletal contractions that are induced by the unfolded protein response (UPR) following ανβ6 integrin activation. The αvβ6 integrin/TGF-β1 pathway is a constitutively expressed molecular sensing mechanism that is primed to recognize injurious stimuli. TGF-β1 is a strong profibrotic mediator that promotes the epithelial–mesenchymal transition (EMT); epithelial cell apoptosis; epithelial cell migration; other profibrotic mediator production; circulating fibrocyte recruitment; fibroblast activation and proliferation and transformation into myofibroblasts; and VEGF, connective-tissue growth factor, and other pro-angiogenic mediator production .PDGF is a potent chemoattractant for mesenchymal cells and induces the proliferation of fibroblasts and the synthesis of ECM. Activated homologous A and B subunits of PDGF can form three dimeric PDGF isoforms. Alveolar macrophages with IPF produce higher volumes of PDGF-B mRNA and protein ,26. AEC2bFGF is a stimulator of fibroblast and endothelial cell proliferation that has been correlated with the proliferative aspects of fibrosis. In particular, bFGF expression is up-regulated at various periods of wound healing, and recombinant bFGF has been shown to accelerate wound healing. Accordingly, anti-bFGF antibody inhibited the formation of granulated tissue and normal wound repair. Alveolar macrophages are a predominant source of bFGF in intra-alveolar fibrotic areas following acute lung injury . In a stTGF-α induces proliferation in endothelial cells, epithelial cells, and fibroblasts, and is present in fibrotic areas . In prolKGF is produced by mesenchymal cells, and the KGF receptor is expressed in the epithelial tissues of developing lungs. In rats, KGF accelerated the functional differentiation of AEC2s, and the intratracheal instillation of KGF significantly improved bleomycin-induced pulmonary fibrosis . These dHGF is produced by mesenchymal cells and has been identified as a potent mitogen for mature hepatocytes. The HGF receptor is a c-Met proto-oncogene product that is predominantly expressed in various types of epithelial cells. HGF levels are higher in bronchoalveolar lavage fluid and serum from patients with IPF than in serum from healthy people ,40. HGF Repetitive exposures of alveolar epithelium to microinjuries, such as infection, smoking, toxic environmental inhalants, and gastroesophageal reflux, contribute to AEC1 damage. AEC2s normally regenerate damaged cells, but when dysfunctional, their ability to reestablish homeostasis is impaired. This condition is considered indicative of the pathogenesis of IPF ,45.High cellular activity leads to protein over-expression, and if unchecked, it can cause endoplasmic reticulum (ER) stress. The correcting protective pathway is stimulated by the imbalance between cellular demand for protein synthesis and the capacity of the ER to dispose of unfolded or damaged proteins. This protective pathway is known as UPR, and it re-establishes ER homeostasis. To this end, this pathway inhibits protein translation, targets proteins for degradation, and induces apoptosis when overwhelmed. The activation of UPR stimulates the expression of profibrotic mediators, such as TGF-β1, PDGF, C-X-C motif chemokine 12 (CXCL12), and chemokine C-C motif ligand 2 (CCL2), and thus, can lead to apoptosis .EMT is a molecular reprograming process, and in AEC2s, it is induced by UPR and enhanced by profibrotic mediators and signaling pathways. Under these conditions, epithelial cells express mesenchymal cell-associated genes, detach from basement membranes, and migrate and down-regulate their typical markers. The most used marker of these transitioning cells is alpha smooth-muscle actin (αSMA). However, EMT occurs during development and in cancerous and fibrotic tissues, but it is not involved in the restoration of tissues through wound healing processes .Other key pathways of IPF are related to the deregulation of embryological programs, such as Wnt-β-catenin signaling, which has been associated with EMT and fibrogenesis following activation by TGF-β1, sonic hedgehog, gremlin-1, and phosphatase and tensin homolog. Deregulation of these pathways confers resistance to apoptosis and offers proliferative advantages to cells .Damage to alveolar structures and the loss of AECs with basement membranes involves alveolar vessels and leads to increased vascular permeability. Wound clots form during this early phase of wound healing responses, and sequentially, new vessels are formed through the proliferation of endothelial cells and endothelial progenitor cells (EPCs). Patients with IPF with failure of re-endothelization have significantly decreased numbers of EPCs, likely resulting in dysfunctional alveolar–capillary barriers, profibrotic responses, and compensatively augmented VEGF expression. This series of endothelial changes could stimulate fibrotic processes and abnormalities of vessel functions, contributing to cardio–respiratory declines and advanced disease. Furthermore, endothelial cells may undergo a mesenchymal transition with similar consequences as those of EMT .Endothelial and epithelial damage also activates coagulation cascades during the early phases of wound healing. Coagulation proteinases have several cellular effects on wound healing. In particular, the tissue factor-dependent pathway is central to the pathogenesis of IPF and promotes a pro-coagulation state with increased levels of inhibitors of plasminogen activation, active fibrinolysis, and protein C. Under these pro-coagulation conditions, degradation of ECM is decreased, resulting in profibrotic effects and the induction of fibroblast differentiation into myofibroblasts via proteinase-activated receptors .The pathobiology of IPF is led by aberrant epithelial–mesenchymal signaling, but inflammation may also play an important role because inflammatory cells are involved in normal wound healing from early phases. Initially, macrophages produce cytokines that induce inflammatory responses and participate in the transition to healing environments by recruiting fibroblasts, epithelial cells, and endothelial cells. If injury persists, neutrophils and monocytes are recruited, and the production of reactive oxygen species exacerbates epithelial damage. The resulting imbalances between antioxidants and pro-oxidants may also promote apoptosis of epithelial cells and activation of pathways that impair function. Finally, monocytes and macrophages produce PDGF, CCL2, macrophage colony stimulating factor, and colony stimulating factor 1. These proteins may also have direct profibrotic effects ,49.The roles of lymphocytes in IPF are still unclear. However, some lymphocytic cytokines are considered profibrotic due to their direct effects on the activities of fibroblast and myofibroblast. Th-1, Th-2, and Th-17 T-cells have been clearly associated with the pathogenesis of IPF. The Th1 T-cell subset produces IL-1α, TNF-α, PDGF, and TGF-β1 and has net profibrotic effects. Th2 and Th17 responses appear more important in the pathogenesis of IPF. In particular, the typical Th2 interleukin IL-4 induces IL-5, IL-13, and TGF-β1 expression, leading to the recruitment of macrophages, mast cells, eosinophils, and mesenchymal cells and the direct activation of fibroblasts. Additionally, fibroblasts from patients with IPF are hyperresponsive to IL-13, which has a positive effect on fibroblast activity and enhances the production of ECM. The Th17 T-cell subset indirectly promotes fibrosis by increasing TGF-β1 levels. Th17 cells are also positively regulated by TGF-β1, suggesting the presence of a positive feedback loop . NumbersContributions of mesenchymal cells, and particularly fibroblasts and myofibroblasts, are crucial for the pathogenesis of IPF. These cells are recruited, activated, and induced to differentiate and proliferate in the abnormal biochemical environments that are created by activated epithelial and endothelial cells. Although the initial trigger and source of mesenchymal cell recruitment remain unclear, the current published consensus defines fibroblasts and myofibroblasts as the key cell types for IPF. Circulating fibrocytes, pulmonary fibroblasts, and myofibroblasts have also been identified among mesenchymal cells that are involved in IPF . The mosMultiple studies compare IPF with cancer to provide insights into the pathogenesis of both diseases, for which survival rates are low. Arguments against the similarities of cancer and IPF include the presence of homogeneity, metastases, and laterality in cancers. However, cytogenetic heterogeneity has been shown in myofibroblasts, which do not metastasize to other organs. In addition, simultaneous involvement of both lungs is a definitive indication of IPF. However, this is primarily based on the generally accepted assumption that tumors are almost always monoclonal and grow in only one lung before metastasizing and invading other organs. From an anatomical viewpoint, patients with IPF mainly exhibit fibrosis in the lung periphery and in the lower lobes, which are sites of lung tumors in a high percentage of cases . AdditioThy-1 gene may restore Thy-1 expression, suggesting a new therapeutic approach for this disease. Specific gene mutations have also been considered important to the origin and progression of cancer [Hypomethylation of oncogenes and methylation of tumor suppressor genes are established pathogenic mechanisms for most tumors. Epigenetic responses to environmental exposures, including smoking and dietary factors, and aging have recently been identified in patients with IPF. Recent studies also demonstrated changes to global methylation patterns in patients with IPF that are reciprocal to those in patients with lung cancers . Under tf cancer . Similarf cancer ,61,62,63f cancer ,65,66. Rf cancer . In thesf cancer . In addif cancer ,70,71. Rf cancer ,73,74. AIntercellular channels provide metabolic and electrical coupling of cells and are formed by proteins of the connexins (Cxs) family. Cxs are necessary for the synchronization of cell proliferation and tissue repair . Among tThe Wnt/β-catenin signaling pathway regulates molecules that are related to tissue invasion, such as matrilysin, laminin, and cyclin-D1. However, arguably, the most important function of Wnt/β-catenin pathway is to mediate crosstalk with TGF-β. This pathway is abnormally activated in some tumors, as shown in lung cancer and mesothelioma . Wnt/β-cTyrosine kinases are key mediators of multiple signaling pathways in healthy cells with demonstrated roles in cell growth, differentiation, adhesion, and motility and in the regulation of cell death. Tyrosine kinase activity is controlled by specific transmembrane receptors that mediate the activity of various ligands. Conversely, abnormal activities of these kinases have been associated with development, progression, and spread of several types of cancer . RecentlTGF-β, PDGF, VEGF, and FGF are common mediators of carcinogenesis and fibrogenesis. Among them, VEGF may directly or indirectly promote cell survival and proliferation by activating ERK1/2 and PI3K. Accordingly, elevated expression levels of VEGF mRNA were shown in EPCs from patients with IPF. Furthermore, antifibrotic strategies using multiple inhibitors of tyrosine kinase receptors have been evaluated in a rat model of bleomycin-induced fibrosis; PDGF, VEGF, and FGF inhibitors produced significant improvement in fibrosis ,88,89,90TGF-β is the most important mediator of the pathogenesis and carcinogenesis of IPF. In tumor microenvironments, TGF-β, predominantly from cancer-derived epithelial cells, induces myofibroblast recruitment at the invasive front of the cancer tissue and protects myofibroblasts from apoptosis. These cells encircle tumor tissues and produce TGF-β. With inflammatory mediators and metalloproteinases, myofibroblasts break basement membranes of surrounding tissues to facilitate tumor invasion ,92. LikeIn cancer cells, the capacity to invade surrounding tissue strongly correlates with the expression of various molecules, including laminin, heat shock protein 27, and fascin ,103,104.Matrix metalloproteases and integrins are strongly associated with invasion and migration of cells . IntegriInflammatory reaction is described by some reports as a promoting factor in the development and progression step of tumorigenesis . As descIn conclusion, cancer and fibrosis are both severe lung diseases, and they share biological pathways. Although the specific genetic and cellular mechanisms are not yet fully understood, several signaling pathways and microenvironments have been shown to disrupt tissue architecture and lead to dysfunction. Conversely, it is clear that lung tumorigenesis and fibrosis display highly heterogeneous behaviors, warranting personalized therapeutic approaches. Lung fibrosis may eventually be attenuated by therapies that are developed after considering mechanisms that are common to cancer and IPF.


DMF is one the most commonly-used solvents for preparing graphene nanocomposites. Various processing variables for DMF are being used for the preparation of epoxy/graphene nanocomposites. Whilst the emphasis of all of these reported studies are on the improvements in mechanical, and other properties, of the epoxy/graphene nanocomposites, there is no study investigating how DMF affects the processing and how it is associated with the final properties of the nanocomposites. In this work, different dosages of DMF have been used to prepare nanocomposites. Mechanical testing, X-ray diffraction (XRD), dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) have been used to analyze the effectiveness of DMF dosage on the properties of processed nanocomposites. Larger dosages of DMF are not always ideal for dispersing graphene as it promotes reaggregation of graphene during the processing.  Since its discovery in 2004 , graphenEpoxy is a widely used thermoset material due to its superior mechanical properties, thermal stability, solvent resistance, and ease of processing . ApplicaFor epoxy/graphene nanocomposites, graphene can significantly improve the physical and chemical properties of the matrix at extremely low loadings , and thiThe exploration of property enhancements of epoxy/graphene nanocomposites is rapidly advancing. However, in practical terms, graphene is not suitable to disperse in epoxy just by simple mixing, as graphene tends to reaggregate in the matrix due to the strong van der Waals force even after homogenisation. Dispersing them in polymer resin with relatively high viscosity is difficult. Therefore, using solvents as dispersing media has been widely accepted and regarded as the simplest method to distribute isolated graphene homogeneously in the nanocomposite materials.N,N-dimethylformamide (DMF) at 1 g/L, with remarkable improvement in the final properties. Dispersal of graphene in DMF, ethanol, and acetone have even been demonstrated at different concentrations, such as 1 g/2 L, 1 g/3 L, or 1 g/10 L [For example, in some studies ,11,12,131 g/10 L ,33,34,351 g/10 L ,37 repor1 g/10 L ,39,40 re1 g/10 L ,42, THF 1 g/10 L ,44, buta1 g/10 L ,46, acet1 g/10 L ,48, and 1 g/10 L , have al1 g/10 L  using co2/g, the average lateral size and thickness are 4.5 μm and 12 nm, respectively. The epoxy matrix used in this study consists of EPOPHENTM EL5 bisphenol A based liquid epoxy (EP) and EPOPHENTM EHA57 diamine hardener (HD), purchased from Polyfibre UK Ltd.  This epoxy system is a multi-purpose resin offering good all-round properties with the epoxy group content of 4.76–5.25 mol/kg. The viscosities of the liquid epoxy and hardener at room temperature are 12,000–15,000 and 45 cps, respectively. To prepare the epoxy material (EP + HD), 100 parts by weight of liquid epoxy were mixed to 50 parts by weight of hardener. Graphene nanoplates were purchased from Graphene Laboratories Inc.  (product name: AO-3). The graphene nanoplatelets, according to the manufacture’s technical datasheet, have a specific surface area of 80 mFive sets of nanocomposites filled with 0.3 wt % graphene were prepared. One set of samples was prepared as a reference using neat epoxy only, marked as G-0.3. Another four sets were prepared with different dosages of DMF. To understand the relationship among solvent dosage, graphene dispersion state, and the properties of the nanocomposites, 0.3 wt % epoxy/graphene nanocomposites were prepared by using different dosages of DMF. The dosages prepared were 100, 300, 500, and 1500 mL. Graphene (0.45 g) was first dispersed in a specified dosage of DMF  and bath sonicated for 0.5 h. Epoxy monomer was then added to the dispersion and sonicated for another 0.5 h. To remove the DMF solvent, the mixtures were heated to 150 °C with stirring. The mixture with 100 mL of DMF was only heated for 4 h, the mixtures with 300 and 500 mL DMF were heated for 8 h, and the mixture with 1500 mL DMF was heated for 16 h to evaporate the solvent. All mixtures were weighed to ensure full removal of DMF. The mixtures were then cooled to room temperature and the hardener was added with hand stirring for 5 min, followed by 5 min bath sonication. Vacuum degassing was then carried out to remove the entrapped air bubbles. Subsequently, the mixtures were mold-cast and cured at room temperature for 6 h, followed by 6 h post-curing at 80 °C. K1C) according to ASTM D5045. The specimen dimensions were 3 mm × 6 mm × 36 mm with a crack length of 3 mm. The notch was made at the middle of the sample and tapped to sharpen by a razor blade. The K1C was calculated using Equation (1):maxP is the maximum load of the load-displacement curve, f(a/w) is constant related to the sample geometry and was calculated using Equation (2), B is sample thickness (mm), W is sample width (mm), and a is crack length (kept between 0.45 and 0.55 W). The critical strain energy release rate (G1C) was evaluated using Equation (3) where E is the Young's modulus obtained from the tensile tests (MPa), and v is the Poisson's ratio of the polymer, taken to be 0.35.Tensile, three-point bend, and fracture toughness tests were conducted with a universal testing machine , and the crosshead speed was kept at 2 mm/min for all tests. Tensile properties were measured according to ASTMD638 (Type V geometry). The three-point bend test was conducted according to ASTM D790 with specimen dimensions of 3 mm × 12.7 mm × 48 mm. A single-edge-notch three point bending (SEN-TPB) specimen was used to test mode-I fracture toughness (E’) and loss factor tan δ. All tests were conducted by using the temperature sweep method (temperature ramp from 30 to 150 °C at 5 °C/min) at a constant frequency of 1 Hz. Thermogravimetric analysis (TGA) of the nanocomposites was carried out with a TA Instruments Q500 thermal analyzer . The temperature range was from room temperature to 600 °C at a ramp rate of 5 °C/min under N2 atmosphere. The structure of the epoxy/graphene nanocomposites was examined using X-ray diffraction (XRD) carried out with a Siemens D-5000 diffractometer  using a Cu Kα radiation source (λ = 0.15406 nm) with step size of 0.02°. Scanning electron microscopy (SEM) analysis was carried out using a FEI Quanta 200 microscope  to examine the fracture surfaces of nanocomposites. The fractured surfaces were cut from the specimens and a layer of gold was applied using an Emscope sputter coater, model SC500A . For tensile, flexural, fracture, and hardness tests, six specimens were tested for each set of conditions and mean values were then reported.A dynamic mechanical analyzer (DMA)  was used to determine the storage modulus  as a function of temperature for epoxy/graphene nanocomposites. As can be seen from the figure, the storage modulus of G-0.3 is 2.35 GPa. With the increasing dosage of DMF, D-100, D-300, and D-500 samples show increased storage moduli of 2.45, 2.52, and 2.60 GPa respectively. However, with the further increase of the DMF dosage, D-1500 shows a decreased storage modulus with the value of 2.31 GPa. This is the lowest value among all of the samples.gT) characterizes the segmental motion of polymers and was taken as the temperature value at the peak of the tan δ curves, as shown in gT shifted to a higher temperature. This can be ascribed to the fact that the uniformly-dispersed graphene restricted molecular mobility of the epoxy matrix, thus leading to the increased gT values. Among all of these increments, 500 mL DMF-prepared nanocomposites showed the highest gT of 75.57 °C, which is more than 6 °C higher than that of G-0.3 samples, while a 5 °C increment in gT was observed for D-100 and D-300 samples. The reason for this improvement can be explained by the effect of graphene on the cross-linking structure of the nanocomposites. Generally, the cross-linking density means the concentration of cross-linked bonds per volume. As for a typical polymer nanocomposite, the higher the cross-linking density, the stronger the polymer chains bond to each other, therefore leading to a higher gT of the nanocomposites. However, samples prepared with 1500 mL DMF show the lowest gT value of 65.78 °C. The likely reason for this decrease is that graphene, in a liquid matrix, tends to reaggregate over time, especially in a low viscosity medium. As a larger dosage of DMF requires a longer time for complete evaporation, the reaggregation of graphene is more likely to occur. Comparing with the structures of well-dispersed epoxy/graphene nanocomposites, the non-uniformly-dispersed graphene decreased the gT.The glass transition temperature (To summarize the mechanical properties, it has been described in the previous published research that due to the strong van der Waals force on dispersed graphene sheets, graphene tends to reaggregate in liquid matrix with the passage of time ,55,56. FThe fracture surfaces of nanocomposites were examined by SEM and are shown in Finally, XRD was used to characterize the structure of epoxy/graphene nanocomposites. As shown in This graphitic structure could only be caused by the agglomeration of graphene during processing. This result clearly shows that the use of a large dosage of DMF has induced reaggregation of graphene, which leads to the decrements in the properties.In summary, polar solvents, like DMF, are responsible for providing a low-viscosity medium, which is an ideal environment for fullerenes to agglomerate . It is aDMF was used to investigate the effects of solvent dosage on the preparation and properties of epoxy/graphene nanocomposites. This research provides guidelines for the usage of DMF solvents in the preparation of epoxy/graphene nanocomposites, and could also be a reference for other polymer composites where the use of solvents is required in the processing. Mechanical properties, TGA, DMA, SEM, and XRD were tested in this work. The results show that large dosage of solvents are responsible for decreasing the final properties of the nanocomposites. The long processing time, higher temperatures, and low viscosity of solvents are responsible for the promotion of the reagglomeration of graphene. These findings will have profound implications in nanocomposites manufacturing, as large amounts of solvents could be avoided from economic and health and safety perspectives. The processing time could be shortened causing less environmental pollution by reducing the amount evaporated solvents. These results help in optimisation and are having positive implications on the practical processing technology of nanocomposites. However, although the relationship between solvent dosage and the consequent processing of epoxy/graphene nanocomposites has been demonstrated here for the first time, it has not given the critical value for the best condition of dispersibility and processability. Therefore, more work needs to be conducted to fully understand the best usage of solvents.


In addition, the a-Si:H solar cells present notable flexibility whose power conversion efficiencies show little degradation when the solar cells are bent to a radius as small as 14 mm for more than 100 times. The application of this unique flexible substrate can be extended to CuInGaSe and CdTe solar cells and other thin-film devices requiring high-temperature processing.Flexible thin-film solar cells with high weight-specific power density are highly desired in the emerging portable/wearable electronic devices, solar-powered vehicles, etc. The conventional flexible metallic or plastic substrates are encountered either overweight or thermal and mechanical mismatch with deposited films. In this work, we proposed a novel substrate for flexible solar cells based on graphene paper, which possesses the advantages of being lightweight and having a high-temperature tolerance and high mechanical flexibility. Thin-film amorphous silicon ( Mechanically flexible and lightweight thin-film solar cells can be attached to objects with curved surfaces, making them suitable as a source of electricity supply units for portable/wearable electronic devices and unmanned aerial vehicles –5. By co3 vs 7.9 g/cm3 of stainless steel) [−6/K) [Because of the superior thermal stability and coefficient of thermal expansion (CTE), metallic foils are widely used as substrates for flexible solar cells , 15–17. s steel) , 22. How) [−6/K) , 24 and ) [−6/K) , 25. Cel) [−6/K) . Our rec) [−6/K) , 13. HowGraphene, with many unique properties such as high strength and electrical and heat conductivity –30, has a-Si:H) solar cells on smooth graphene papers which were achieved by a filtration method using porous anodic aluminum oxide (AAO) filter. The device depicts a distinct weight-specific power density of 8.31 kW/kg, which is 415 and 4.5 times higher than the previous reports on glass and PI substrates, respectively [a-Si:H is used as the model material in this work with the overall processing temperature below 250 °C, the graphene paper substrates can be extended to other flexible (opto-)electronics, especially suitable for the devices requiring high-temperature processing.As a derivate of graphene, graphene papers have been demonstrated by the solution-phase assembly, electrophoretic deposition, and chemical vapor deposition . The excectively , 38. Mor2·2H2O, and 100 ml deionized water to remove the remaining aluminum substrate and achieve the AAO film supported by PMMA  layer as a spacer layer was then deposited by radio frequency (RF) magnetron sputtering of a 2 wt% AZO ceramic target (99.99% purity) at 250 °C. Subsequently, the n-i-p a-Si:H layers were deposited in a multi-chamber plasma-enhanced chemical vapor deposition (PECVD) system under 250 °C. The n, i and p-type layers were 30-, 280-, and 10-nm thick, respectively. After sputtering an 80-nm indium tin oxide (ITO) thin film, Ag grids were thermally evaporated as the top electrode using a contact mask  curves of thin-film a-Si:H solar cells were carried out under 25 °C using a Xe lamp solar simulator  coupled with an air mass 1.5 global (AM 1.5 G) filter, and the external quantum efficiency (EQE) measurements were characterized by a commercial spectral response system (PV Measurement Inc. QEX10). The thermal stability of the graphene paper substrate was monitored by thermal gravimetry (TG) on a TG instrument (SDTA851 Switzerland-Mettler Toledo) from room temperature up to 1000 °C at a heating rate of 10 K/min. The reliability of solar cells under multiple bending cycles was performed with a home-built automatic bending setup [The surface morphologies were characterized by Hitachi S4800 scanning electron microscope (SEM). All the current density-voltage  as a function of annealing process Fig. c, where a-Si:H solar cells. Its thickness and weight are 53 μm and 5.73 mg, respectively. The device deposited on a rigid glass substrate is also fabricated as a reference. Figure J-V) characteristics of the devices on both GP-3A and glass substrates measured under AM 1.5-G irradiation. A power conversion efficiency (PCE) of 5.86% is obtained on the GP-3A substrate, with an open-circuit voltage (VOC) of 0.87 V, a short circuit current (JSC) of 11.96 mA/cm2, and a fill factor (FF) of 0.57. Compared with the device on glass substrate, the Jsc is improved by 17%, which is further confirmed by EQE measurements  of devices on different substrates. The PW is defined as the ratio of the output power under standard solar irradiation  to the mass of the solar cell per unit area as expressed by following equation:As the thickness of md is the mass of the solar cell per unit area.where the a-Si:H solar cells were successfully fabricated on the patterned PI flexible substrates [a-Si:H solar cells based on GP-3A and the counterpart substrates are summarized in Table Compared with the devices deposited on the glass substrate, the thickness and weight of solar cells on graphene papers are reduced by ~ 20 times and ~ 350 times, respectively. Meanwhile, the power density reaches as high as 8.31 kW/kg, which is 415 times higher than that of its counterpart. In our previous work, bstrates . The GP-J-V curves of the a-Si:H devices after encapsulation. Unfortunately, the energy conversion efficiency of the device was decreased from 5.86 down to 4.14% after the encapsulation. It may be because the copper wire electrodes generate additional contact resistance and slightly damage the device. Thus, elaborate encapsulation strategies would be developed for such GP-based ultra-light devices in future work. After encapsulation, the J-V curves under various bending angles are characterized with a homemade setup [Graphene paper, which possesses superior flexibility, is lightweight, and has high-temperature tolerance, is expected to be an alternative choice for portable device application. Figure de setup . The flede setup , 8, 13. a-Si:H solar cells based on graphene papers were successfully achieved with better photocurrents and comparative energy conversion efficiencies (5.86%) over the counterparts on flat glass substrates. The thickness and weight of solar cells on graphene paper are reduced by ~ 20 and ~ 350 times, respectively. Meanwhile, the power density reaches as high as 8.31 W/g, which is 415 times higher than that of the counterparts. Moreover, the devices based on graphene paper presented an excellent performance with a marginal drop even after 100 bending cycles under 14-mm radius due to ultrathin thickness and excellent mechanical flexibility of graphene paper substrates. Although the work was conducted on a-Si:H material, our proposed scheme can be extended to other material systems that may lead to a new era of flexible optoelectronic devices.In this work, we developed a carbon nanotube-enhanced graphene paper substrate which delivered higher thermal stability, is lightweight, and has excellent mechanical flexibility over traditional flexible substrates. The


We also demonstrate that HCl-induced doping is governed by dissolved O2 and pH in accordance with the Nernst equation. The nanoscopic electrochemistry anatomized in this work sets an ambient limit to material properties, which is universal to not only 2D but also other forms of materials.Controlling extra charge carriers is pivotal in manipulating electronic, optical, and magnetic properties of various two-dimensional materials. Nonetheless, the ubiquitous hole doping of two-dimensional materials in the air and acids has been controversial in its mechanistic details. Here we show their common origin is an electrochemical reaction driven by redox couples of oxygen and water molecules. Using real-time photoluminescence imaging of WS Manipulation of charge carriers is promising for tuning electronic, optical and magnetic properties in two-dimensional materials, but mechanistic details are not fully understood. Here, the authors report that ambient redox reactions govern charge transfer doping in graphene and tungsten disulfide. Such chemical modification of the electronic structure allows detection of even a single molecule that adsorbs on graphene in a transistor form5. The charge exchanges can be described by a simple donor–acceptor model by assuming a significant difference in their electron affinities. Despite the apparent simplicity, however, there is a clear lack of understanding in the ubiquitous chemical interactions of 2D materials. The first graphene transistor was reported to be doped with hole carriers originating from unknown chemical entities6. Optical confirmation soon followed this observation, but with no complete mechanistic understanding7. While various acids were exploited to inject hole carriers in graphene, their exchange mechanism is not clear8. All of these underline that the spontaneous charge transfer between 2D materials and the environment is far from being understood, which hampers both fundamental research and application of 2D materials. In this work, we elucidate that the charge exchange is driven by redox couples of oxygen and water molecules, originally proposed for surface conduction of diamonds10, and that the redox reaction is confined within the nanoscopic space between 2D materials and hydrophilic substrates. By exploiting environment-controlled in situ spectromicroscopy, we captured molecular diffusion through the interstitial 2D space and revealed that photoluminescence (PL) of WS2 and lattice vibration of graphene, both as an indicator of charge density, are dictated by oxygen and water contents and their spatiotemporal distribution.Reduction in dimensions has seen many scientific discoveries in various metallic and semiconducting low-dimensional materials during the past four decades. Because of their high fraction of surface atoms, in particular, various material properties of two-dimensional (2D) materials are greatly affected by charge exchange with neighboring chemical entities or environments. When exposed to alkali metals2 (1LWsilica) was mechanically exfoliated onto SiO2/Si substrates (see the “Methods” section) and served as a model 2D system with precise control over gas environments  have substantial binding energy due to dimensionally restricted screening11 and interact with excess charge carriers to form charged excitons or trions (X±) with additional stabilization as depicted in Fig. 1b12. As shown in Fig. silica in the ambient air typically showed two peaks, each originating from excitons (X0 at EX0 = 2.01 eV) and negative trions (X− at EX− = 1.98 eV), the latter of which derived from defect-related native charge carriers12. By assuming that the ionization reactions of excitons into trions are governed by the law of mass action13, their PL intensity ratio (IX−/IX0) serves as a quantitative measure for the density of charge carriers that are modulated by chemical interaction between WS2 and the environments . The concomitant decrease in the total intensity (It = IX− + IX0) is due to the increasing importance of the nonradiative decay channel at higher ne14. Water vapor in the Ar gas, however, reduced ne when judged from a noticeable decrease in IX−/IX0. Exposure to dry or humid O2 led to an even more considerable decrease in the ratio, and thus further depletion of negative carriers. Time-lapse measurements in Fig. 2 atmospheres, which confirmed the molecular origin of the charge modulation. The dissociation energy of the trions (Ediss = EX0 − EX−) showed a strong correlation with the intensity ratio over the entire atmospheric conditions  exhibited a much smaller It and O2 sensitivity than 1LWsilica  of WS2  of 1L graphene/SiO2/Si (1LGsilica) were greatly upshifted and recovered by thermal annealing at 500 and 1000 °C, respectively. Based on the established Raman metrology22 of hole density (nh) and lattice strain (ε) shown in Fig. ωG and ω2D of samples that were treated at various temperatures were translated into nh and ε with high accuracy of ~1 × 1012 cm−2 and ~0.2%, respectively  . As shown in Fig. 2 also exhibited the same sensitivity toward dissolved O2 in water, and the change became more obvious at lower pH  of 2D materials and electrochemical potential  of the redox system as shown in Fig. EF,graphene = −4.57 eV and EF,redox = −5.669 + 0.0592pH − 0.0148 log[p(O2)], reduction of O2 is more favored at lower pH, which leads to increased hole doping of graphene (Supplementary Note 2). On the other hand, the CT is doubly inhibited by a reduction of the reactant and an increase in EF,redox, when the concentration of O2 is decreased. The rate of CT is proportional to the density overlap between occupied states of graphene and empty oxidized states of the redox system, the latter of which is depicted as a Gaussian distribution centered at Eox in Fig. EF,graphene, and can be well described by the Gerischer model  Fig. . Notablyted Fig. . A typic pH Fig. . Eq. 1)2 dissolv2. Redox couples of O2/H2O responsible for the CT reside at the interface of 2D materials and substrates, and their 2D diffusion was captured in real time by wide-field PL imaging. The CT reaction can be turned on and off via controlling O2 or interfacial water serving as a hydration solvent. The CT rate of 2D materials in contact with liquid water can also be tuned by varying the concentration of dissolved protons or O2 as described by the Nernst equation. The presented nanoscopic electrochemistry will pave the way toward efficient control of charge density and the related material properties in 2D, and other low-dimensional materials and devices.In this work, we have shown that the ambient oxygen reduction reaction is behind the long-standing mystery of the spontaneous and activated CT doping in graphene and WS2 (1LWsilica) and graphene (1LGsilica) samples were prepared by mechanically exfoliating bulk crystals  onto SiO2 (285 nm)/Si substrates in the ambient environment. For 1LWBN samples, single layers were first mechanically exfoliated onto polydimethylsiloxane substrates and then dry-transferred onto thin hBN crystals supported on SiO2/Si substrates. To minimize a change in spectroscopic signals induced by optical interference, hBN crystals thinner than 3 nm were selected as substrates. To remove interfacial water in 1LGsilica, we exposed bare substrates briefly to the vapor of diethyl zinc before mechanical exfoliation in a glove box. For thermal activation, samples were annealed at a target temperature for 2 h in a quartz tube furnace that was maintained at a pressure of 3 mTorr.Most of single-layer WS22. Briefly, monochromatic outputs from solid-state lasers operated at 458 and 514 nm were focused onto samples with a spot size of ∼1 μm by using a microscope objective . Backscattered PL and Raman signals were collected with the same objective and guided to a spectrometer equipped with a liquid nitrogen-cooled CCD detector. Overall spectral accuracy was better than 5 and 1 cm−1 for PL and Raman measurements, respectively. To avoid significant photoinduced effects, we maintained the average power of the excitation beam below 6 μW for WS2 and 400 μW for graphene samples.Raman and PL were performed with a homebuilt micro-Raman spectrometer setupFor wide-field PL imaging, the collimated green laser beam was focused at the back-focal plane of the objective with a plano-convex lens  after three-times expansion with a Galilean beam expander. The average power of the wide-field excitation was maintained below 1.5 mW that was illuminated onto an area with a diameter of ~100 μm. PL signals in the range between 1.9 and 2.1 eV mostly contributed to the PL images recorded with the CCD detector.−1) and O2 (5–250 mL min−1). Unless otherwise noted, flow rates for dry gases were 1000 and 250 mL min−1 for Ar and O2, respectively. Relative humidity (RH) inside the gas cell was monitored by a serially connected hygrometer and could be controlled between 5 and 90% by varying the mixing ratio of an additional Ar gas line that passed through a water bubbler  in ambient conditions. The volume of water droplets was maintained in the range of 2.5–3 μL.The hydrophilicity of SiOSupplementary InformationSupplementary Movie 1Supplementary Movie 2Supplementary Movie 3Supplementary Movie 4