We have previously analysed serum autoantibody levels in patients with idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), and healthy controls and identified the autoantibody against anti-myxovirus resistance protein-1 (MX1) to be a specific autoantibody in iNSIP. We found that a higher anti-MX1 autoantibody level was a significant predictor of a good prognosis in patients with non-IPF idiopathic interstitial pneumonias. In this retrospective study, we sought to clarify the prognostic significance of the anti-MX1 autoantibody in IPF.  We measured anti-MX1 immunoglobulin (Ig) G, IgA, and IgM autoantibody levels by enzyme-linked immunosorbent assay in serum collected at the time of diagnosis from 71 patients with IPF diagnosed according to the 2018 IPF guideline. The gender-age-physiology (GAP) index was calculated in each case. p < 0.05). Univariate Cox proportional hazards regression analysis did not identify an elevated anti-MX1 IgG, IgA, or IgM autoantibody level as a significant prognostic factor; however, a higher anti-MX1 IgA autoantibody level heralded significantly poorer survival after adjustment for GAP stage (p=0.030) and for percent forced vital capacity and modified Medical Research Council score (p=0.018). Neither the anti-MX1 IgG autoantibody nor the IgM autoantibody could predict survival after these adjustments.  The study population (59 men and 12 women) had a median age of 67 years. Serum anti-MX1 IgG and IgA autoantibody levels correlated positively with GAP stage ( The serum anti-MX1 IgA autoantibody level is a significant prognostic factor in IPF. Further studies are needed to clarify the pathophysiological role of this autoantibody in IPF. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology –3 with aThe ATS/ERS/JRS/ALAT guideline for IPF highlights the importance of serum markers for diagnosis, predicting the prognosis and assessing the response to treatment . Krebs vα and IFN-β and are involved in the control of intracellular pathogens [We have previously identified anti-myxovirus resistance protein (MX) 1 to be an autoantibody specific for idiopathic nonspecific interstitial pneumonia (NSIP) using protein microarrays . MX protathogens . Humans athogens . MX1 is athogens  via its athogens  and cellathogens .We have also found that a positive anti-MX1 autoantibody test for at least one of the three subclasses of antibody (immunoglobulin (Ig) G, IgA, and IgM) in serum  predictsAt our institution, bronchoscopy is performed in most patients suspected to have IIP provided that they are able to tolerate pulmonary function tests (PFTs). We retrospectively reviewed the National Hospital Organization Kinki-Chuo Chest Medical Center (KCCMC) database  and idenIPF was diagnosed based on high-resolution computed tomography (CT) scans with/without pathological findings in surgical lung biopsy specimens in addition to clinical findings . Most ofThe retrospective study was approved by the KCCMC Ethics Committee on May 5, 2014 . The need for informed consent was waived because all subjects had consented to collection of blood for measurement of markers in serum and to use their clinical information for research purposes at the time of diagnosis of IPF .We retrospectively reviewed the demographic and clinical findings for each patient at the time of diagnosis of IPF, including age, gender, body mass index, smoking status, modified Medical Research Council (mMRC) score , PFTs, aThe serum anti-MX1 autoantibody level was measured in each case by enzyme-linked immunosorbent assay (ELISA) as previously described  using prSerum KL-6 and SP-D levels were measured using commercial ELISA kits .  The cuto2 by more than 10 Torr compared with previous measurements. (2) Exclusion of an obvious cause of acutely impaired respiratory function, such as infection, pneumothorax, cancer, pulmonary embolism, or congestive cardiac failure. Apparent infections were excluded by measuring antibodies for Mycoplasma pneumoniae and Chlamydia pneumoniae in paired sera, β-D glucan, and cytomegalovirus antigen tests, and bacterial cultures of blood and sputum. Congestive heart failure was excluded by echocardiography and pulmonary embolism by contrast CT and/or echo Doppler examination.AE of IPF was diagnosed according to the Japanese Respiratory Society criteria , 21 as fp value <0.05 was considered statistically significant.Data for continuous variables are shown as the median and interquartile range (IQR) and those for categorical variables as the number and percentage. Associations between various markers of disease severity were evaluated by Spearman rank correlation. The clinical significance of each parameter, including the serum anti-MX1 autoantibody level, as a predictor of survival and occurrence of AE at the time of diagnosis of IPF was determined by Cox proportional hazards regression analysis. All statistical analyses were performed using SPSS version 26 for Macintosh . A The patient demographics are given in p < 0.001). AE occurred significantly more frequently in IPF with higher levels of serum anti-MX1 IgA autoantibody (>0.312) than in IPF with lower levels (≤0.312) (p=0.035). Higher serum levels (>0.237) of anti-MX1 IgG autoantibody were not associated with survival and incidence of AE in IPF patients .Median survival time was 2079 days , and medp=0.016) and with the percentage of neutrophils in BAL (p=0.028). There was also a significant relationship between the serum anti-MX1 IgA autoantibody level and the percentage of lymphocytes in BAL (p=0.013). High-resolution CT patterns were not associated with serum anti-MX1 IgG and IgA autoantibody levels  and mMRC score (p=0.006) to be significant prognostic factors.In univariate analysis, a higher mMRC score (≥2), lower %FVC and %DLco values, GAP stage II or III, higher KL-6, and SP-D levels, and a higher percentage of neutrophils in BAL fluid were identified to be significant poor prognostic factors . Multivap=0.018 and p=0.003, respectively) after adjustment for mMRC and %FVC  and a higher mMRC score (p=0.012) were significant predictors of AE  in association with genetic factors and secondary stimulation is a fundamental event . Pulmonaα for IPF also suggests a reduced type I IFN response in IPF [MX1 is induced in response to stimulation by type I IFN, and increased MX1 expression in IPF suggests elevation of the type I IFN response. However, in vitro , 25 and e in IPF , althouge in IPF , 29 binde in IPF . The enge in IPF  was repoe in IPF . ELMOD2 e in IPF . Hence, e in IPF  in IPF mOrtiz et al. reported that the endoplasmic reticulum (ER) stress response increases MX1 mRNA and induces apoptosis in prostate cancer cells . It is aβ coupled with interleukin (IL)-10 has been reported to induce production of IgA antibodies [β and IL-10 in lung biopsy specimens is upregulated [β and IL-10 concentrations. Thus, IPF with higher levels of anti-MX1 IgA autoantibody might show more local production of TGF-β and IL-10, more apoptotic AECs in the lung, and progression of pulmonary fibrosis that is more rapid than would be found with lower levels of this autoantibody. Hence, as shown in our study, higher anti-MX1 IgA autoantibody levels in IPF resulted in a poor outcome. Predominance of the IgA autoantibody over the IgG autoantibody as a predictor of survival is consistent with that of IgA antibody against citrullinated protein antigen in IPF [Hamano et al. defined anti-MX1 autoantibody-positive cases based on IgG, IgA, or IgM autoantibody positivity . In our tibodies . In IPF,egulated . Hence, n in IPF .Hamano et al. reported that patients with non-IPF IIP (including NSIP) who were anti-MX1 autoantibody-positive survived for longer than those who were anti-MX1 autoantibody-negative after adjustment for GAP stage . These iThis study has some limitations. First, it had a retrospective, single-center design. Second, it included only four patients with IPF and an anti-MX1 IgA autoantibody level >0.312, so the predictive significance of a higher level has yet to be confirmed. However, the absolute anti-MX1 IgA autoantibody level was a significant prognostic factor.We conclude that the serum anti-MX1 IgA autoantibody level is a significant predictor of the prognosis and AE in patients with IPF. Further studies are needed to confirm this finding and the pathophysiological role of anti-MX1 autoantibodies in IPF.


Since the very first landmark report by Geim and Novoselov in 2004 on graphene , the intWorks on the fabrication of graphene, nanomaterials have appeared; for example, the electrochemical synthesis of highly oxidized graphene oxide (GO), by Díez-Pascual and co-workers , who aimSome published papers in this Special Issue focus on the performance peculiarities of graphene-based nanomaterials in specific contexts. For example, Torres and co-workers have studied the effect of the reduction temperature in the electrochemical performance of reduced-GO-based nanofibers obtained by a hydrothermal method . The aut2 uptake, with a view to future CO2 capture technologies. If cryogels are a good example of an assembled graphene-based scaffold, and given the high interest for such 3D ensembles, the readers cannot miss the review paper presented by Bellet et al. [In this Special Issue, there is also room for chemically modified or assembled graphene nanomaterials, such as those presented by La et al. , who havt et al. . It deal2 heterostructures with excellent catalytic activity towards H2 and O2 evolution reactions) [However, the most reported field of application in graphene-based materials within this Special Issue, nearly half of the total contributions, has definitely been the nanocomposites one. Different nanocomposite studies for structural applications are reported, such as that authored by Sánchez-Romate et al. , dealingactions) , or the actions) . The greactions) , and thaactions) .Last, but not least, this Special Issue contains a unique review paper on the properties and applications of Graphyne derivatives , emergin


Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ , with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease . FibrosiMechanisms of fibrosis progression can be self-sustaining once established, without the need for ongoing inflammatory signaling. As reviewed by Herrera et al. , in the To date, nintedanib and pirfenidone are the only approved treatments for IPF, yet they only slow disease progression. Nintedanib is known to inhibit the receptor tyrosine kinases of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) ,9. HowevThe relatively high incidence of systemic side effects warrants the development of more efficient, preferably localized, treatments. For this aim, an inhaled version of nintedanib was recently described. Using two animal models ,13, it wIn the current work, we used RNA-sequence analysis from the IPF-CM model to explore the underlying signaling pathways and characterized nintedanibs’ involvement in this process. Results were validated using IPF patient samples and bleomycin-treated animals. n = 5) were subjected to RNA-seq analysis. A total of over 20,000 genes were discovered, with 234 significantly upregulated targets. Wong et al. recently published a combined list of “Known Pulmonary Fibrosis Genes”, which consists of human genes associated with pulmonary fibrosis from several datasets [p < 0.0001, FDR = 0.003) using WebGestalt [p = 8.3 × 10−5). KEGG pathway analysis showed that the “HIF1α signaling pathway” was the most significant . The upregulated genes related to the HIF1α pathway are listed in FLT1, VEGFA, SERPINE1 and TIMP1). These targets were previously implicated in fibrosis [p < 0.05, GAPDH levels were elevated in the analysis, it was previously shown not to be significantly altered by western blot [HPRT1 and beta-actin (ACTB)) were added, based on the sequencing results that showed no change following IPF-CM exposure (fold change (FC) 0.98, p = 0.95 and 1.02, p = 0.69, respectively). In addition, HIF1α was also significantly elevated following exposure to the IPF-CM at the mRNA and the protein levels  were elevated  showed that IPF tissues expressed significantly higher HIF1A, TIMP1, SERPINE1 and VEGFA mRNA levels  and VEGFA mRNA levels  and short term  nintedanib exposure, including inhibition of αSMA and COL1A  that werin-vivo model, which included rats exposed to bleomycin, followed by treatment with oral or inhaled vehicle/nintedanib [p < 0.0001, p < 0.05, These findings were tested in an ntedanib . ResultsThe pathogenesis of IPF is still incompletely understood, and is thought to involve recurrent injury to the alveolar epithelium inducing an aberrant wound healing response, characterized by activation and proliferation of fibroblasts and myofibroblasts . With thHIF1α, a key transcriptional factor in response to this chronic hypoxia, is involved in many fibrotic diseases ,22 and wHIF1α was shown to promote the fibrotic phenotype of alternatively activated macrophages through increased cell differentiation profibrotic mediator production, such as IL-6 . Data frGAPDH is slightly elevated following IPF-CM exposure, we added HPRT1 and ACTB to our data, as they showed no change. Since performing sequencing for every experiment is not optional, this point should be carefully addressed in future experiments. Another interesting observation from our analysis was regarding the housekeeping genes. The notion of housekeeping genes has been in use in the literature for nearly 50 years. In particular, several genes have been widely used as internal controls in experimental expression studies, such as GAPDH, tubulins and 18S . In our When analyzing IPF patient samples, HIF1α was expressed at lower levels in fibroblastic foci, and at higher levels in collagenous “old fibrosis” areas. Supported by other works, HIF1α has also been observed to be highly expressed in various cell types throughout the lung tissue, especially within the fibrotic areas . In the TGFβ and hypoxia signaling appear interrelated wherein Smad3, the major TGFβ-responsive transcription factor, can be up-regulated by hypoxia  and collSERPINE1, VEGFA and TIMP1) were significantly overexpressed in the IPF-CM-exposed N-HLFs. As previously described by McMahon et al. [Nevertheless, Goodwin et al. suggested that fibroblast-specific HIF1α signaling is a critical component of pulmonary fibrosis . Similarn et al. , factorsn et al. . HIF1A mRNA levels [Preclinical and clinical studies show that the fibrotic process correlates with the expression of HIF1α target genes, such as TIMP1 and PAI-1 ,40. AmonA levels . These fVEGFA mRNA expression was significantly blocked by nintedanib, which is known to inhibit the VEGF receptor [VEGFA, another HIF1α target was also elevated following HLF exposure to the IPF-CM, as well as in tissue lysates of patients with IPF. These findings support other works proposing that VEGFA might facilitate fibrogenesis ,43. Howereceptor ,9. SinceIn the last part of this work, the in-vivo impact of both oral and inhaled nintedanib on bleomycin-induced HIF1α expression was studied. Similar to the histopathologic findings, both routes of nintedanib administration inhibited HIF1α to a similar extent, with the inhaled high dose being most effective. However, PAI-1 differed where the higher inhaled dose showed elevated levels. One explanation could be that the high dose inhibited the progression of disease, and thus the high amounts represent a slower timeline of disease. To test this theory, earlier sections (from days 7–14) are needed that might show reduced PAI-1 expression with the high doses. Alternatively, the higher dose may have initiated additional signaling pathways, such as signal transducer and activator of transcription 3 (STAT3). STAT3 was previously shown to non-canonically activate Smad3 and therefore, possibly, PAI-1. In our recent work we showed that nintedanib can elevate pSTAT3 levels in HLFs . TIMP1 was specifically observed in mast cells within the fibrotic areas. These findings correlate to a recent study by Overed-Sayer et al.  that shoStabilized HIF1α under hypoxic conditions can trans-activate target genes involved in metabolic reprogramming into anaerobic glycolysis . In factIn conclusion, once formed, IPF-ECM sets up a pro-fibrotic feedback loop that is capable of sustaining progressive fibrosis. This loop was shown to include the HIF1α signaling pathway. To our knowledge, we are the first to show the inhibition of this pathway by nintedanib. Although the complete mechanism was not fully elucidated, nintedanib was shown to reduce HIF1α levels and to block the pro-fibrotic process propagated by the ECM. 2 at 37 °C.Primary HLFs were isolated from IPF  tissues and control samples  at the time of biopsy, as described . Followi4OH and N-HLFs were added for further culture. Nintedanib  was diluted in DMSO and added an hour prior to the addition of N-HFs to the culture. Experiments were performed as previously described . BrieflyWestern blot was performed as previously described . AntibodRNA was extracted by RNeasy kit  and converted to cDNA using GeneAmp . Reactions were performed with SYBR Green . Primers are listed in ftp://ftp.ensembl.org/pub/release-89/fasta/homo_sapiens/dna/Homo_sapiens.GRCh38.dna.primary_assembly.fa.gz) accessed on 20 May 2020, using Tophat2 version 2.1.0 , with up to 2 mismatches allowed per read. The minimum and maximum intron sizes were set to 70 and 500,000, respectively, and an annotation file was provided to the mapper. Only uniquely mapped reads were counted to genes, using ‘HTSeq-count’ package version 0.6.1 with ‘union’ mode (http://www.ncbi.nlm.nih.gov/pubmed/25260700?dopt=Abstract), accessed on 20 May 2020. Normalization and differential expression analyses were conducted using DESeq2 R version 1.18.1 package.RNA libraries were generated using CEL-Seq protocol, and sequenced on Illumina HiSeq2500, 15/50 paired-end run. Reads were trimmed using trim galore (cutadapt version 1.10) and mapped to the Human genome . Slides were incubated overnight at 4 °C with primary antibodies , and devwww.graphpad.com, accessed on 20 May 2020) and by SPSS . ANOVA was performed to compare differences between multiple cohorts. Student’s t-tests were employed to analyze differences between two groups. An effect was considered significant for p < 0.05. Analysis was done using GraphPad Prism . Informed consent was obtained from all patients. All animal experiments were performed in accordance with the UK Animals (Scientific Procedures) Act, 1986, under the authority and controls of a project license held at the Charles River Edinburgh facility.


Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition . Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes  GRN and C9orf72 as the most common defects in addition to other rarer genetic forms with mutations in TARDBP, TBK1, VCP, OPTN, and UBQLN2 (fused in sarcoma (FUS) in ∼5% of familial ALS (ALS-FUS)  is the most frequent neuromuscular disease characterized by the predominant loss of first and second motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and death generally within 1–5 years . Frontotd UBQLN2 . This waALS-FUS)  and the ALS-FUS) ,c.TDP-43 and FUS the acronyms improve readability are ubiquitously expressed DNA/RNA binding proteins with a physiologically predominant nuclear localization, involved in multiple steps of RNA metabolism, including transcription, splicing, transport, and stabilization . The mecHere, we review the neuropathological and genetic evidence of oligodendrocyte impairment in TDP-43/FUS-proteinopathies, summarize current insights into the roles of TDP-43 and FUS in oligodendrocytes, and discuss the potential impact of altered oligodendroglial functions in ALS/FTLD pathogenesis.C9orf72, TARDBP, and OPTN (C9orf72 mutations) from other FTLD—TDP types  and in the vast majority of cases of ALS (ALS—TDP). Neuronal TDP-43 pathology presents as compact or diffuse neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, dystrophic neurites, and thread and dot pathology. Based on the morphology, amount, and distribution pattern of cortical neuronal inclusions, at least five distinct subtypes of FTLD—TDP pathology can be delineated (types A–E), each with relatively specific clinical and genetic associations and recognition that cortical pathology in ALS—TDP most closely resembles FTLD—TDP type B . The preand OPTN . In the and OPTN , and in and OPTN . Moreoveand OPTN . Notablyand OPTN , 2014. IDP types . MoreoveDP types . Thus, oDP types , it is tFUS mutations and three conditions presenting with FTD and/or a movement disorder, including atypical FTLD-U, neuronal intermediate filament inclusion disease, and basophilic inclusion body disease. GCI pathology is a common feature in all distinct FTLD—FUS entities (FUS, two broad distinct neuropathological patterns based on the frequency, morphology, and distribution pattern of distinct FUS-positive inclusion types can be delineated that correlate with the clinical phenotype and severity of the functional consequence of specific FUS mutations (FUS proteinopathies include ALS cases with entities . For ALSutations . Notablyutations .Although the origin of cells with GCI in TDP-43 and FUS proteinopathies as oligodendroglia has been validated in several studies using various markers for immature and mature oligodendroglial lineage cells, including Olig2 , TPPP/p2MOBP as a risk factor for ALS (MOBP to be associated with more severe white matter degeneration and a clinically more aggressive form of FTD (In addition to neuropathological findings, further evidence for a role of oligodendroglia in ALS/FTD is provided from genetic studies that have identified the oligodendrocyte-specific gene  for ALS  and a rim of FTD . Howeverm of FTD . More rem of FTD .Although oligodendrocyte biology has been extensively reviewed elsewhere , some keBecause cells with TDP-43 or FUS-positive GCI displays a noticeable depletion of the physiological nuclear immunoreactivity, one can speculate that affected oligodendrocytes develop a pathological phenotype resulting from the combined action of the loss of nuclear/cytoplasmic functions and the gain of toxicity induced by the abnormal cytoplasmic expression. However, crucial questions to be resolved are as follows: What are the functional consequences, and how might oligodendroglial dysfunction contribute to degeneration? What causes/triggers TDP-43/FUS aggregation in oligodendrocytes?Different aspects are discussed in the following and illustrated in Tardbp and Fus are highly expressed in OPCs, and their expression decreases with oligodendrocyte maturation (1, prompting the speculation that TDP-43/FUS might play important roles in those cells. Neural progenitor cells derived from an ALS patient with a TARDBP mutation differentiate in vitro to mature oligodendrocyte as efficiently as cells derived from non-ALS cases or other sALS and fALS patients, including those with C9orf72 mutation, whereas mutant FUS carriers were not investigated (in vivo information as to how the loss of TDP-43/FUS might regulate OPC functions and their ability to differentiate into mature oligodendrocytes. This is of outstanding importance because the generation of new oligodendrocytes not only occurs physiologically in response to neuronal activity and it is important for learning and memory (In mice, both turation 1, promptstigated . Howeverd memory , but it d memory .in vivo, Tardbp (Fus (Fus ablation does not lead to oligodendrocyte death (To investigate the role of TDP-43 and FUS in mature oligodendrocytes , Tardbp  or Fus (dbp (Fus  was depldbp (Fus . In contte death , thus suPlp1, Mbp, Mog, and Mag (MBP (Mal (Mobp alternative splicing (Mag exon 8 (Mbp mRNA in translationally silent RNA granules (Mbp transport is a tightly regulated process that requires the distinct action of several RNA binding proteins, including hnRNPA2B1 (Mbp transport. To this end, it is worth mentioning that FUS and TDP-43 regulate the alternative splicing and the stability of Mapt (Mbp mRNA transport as well as for the correct maturation and myelination process of oligodendrocytes (Q331K knock-in mice can be stratified into two populations on the basis of their behavioral impairment and affected mice display altered Mapt splicing pattern, whereas unaffected animals upregulate genes regulating myelination (Mbp could be a contributor to TDP-43 and FUS proteinopathies. In line with this, a recent paper reports that the relative protein expression of MBP versus PLP1 is reduced in spinal cord corticospinal tract white matter of ALS patients (TDP-43 and FUS are likely implicated in several aspects of myelination. Firstly, cross-linking immunoprecipitation sequencing experiments discovered that TDP-43 binds to the mRNAs from key genes for myelination such as  and Mag , whereasMag (MBP  and Mal MBP (Mal . Secondlsplicing , whereasg exon 8 , althouggranules , membrangranules . As sevegranules , one counRNPA2B1 , hnRNP KnRNPA2B1 , and franRNPA2B1 . IntrigunRNPA2B1 , hnRNP KnRNPA2B1 , 2017, anRNPA2B1 , which inRNPA2B1 . In addi of Mapt , the gendrocytes . Intrigulination . Taken tpatients .In addition to myelination, oligodendrocytes provide trophic support to neurons , a task ad hoc investigations: which is the cellular source of TDP-43 and FUS containing exosomes? Are exosome biogenesis and release impaired? Is the composition of exosome payload perturbed in oligodendrocytes derived from ALS and FTLD patients? Finally, oligodendrocytes protect axons from the depolarizing effect of extracellular potassium accumulation by expressing the potassium channels Kir4.1 (Mechanistically, oligodendrocytes support neurons by releasing lactate , and reds Kir4.1 . Intrigus Kir4.1 . Becauses Kir4.1 , it woulTardbp in astrocytes switches their transcriptome and that of the surrounding microglia toward an inflammatory status in mice (Complementary, oligodendrocyte dysfunction in ALS/FTLD might not be exclusively cell-autonomous, but it could arise from aberrant signaling coming from other glial cell populations. In particular, the genetic ablation of  in mice . Further in mice .Mbp (The neuropathological analysis showing that TDP-43 or FUS aggregates are restricted to subsets of neurons and oligodendrocytes prompts the question as to why these cell types are exquisitely vulnerable to the formation of inclusions. Although this topic is still under-investigated, one can speculate that oligodendrocyte susceptibility might arise from their high energy demand required for myelination  and actiMbp , and areMbp . IntriguMbp .A complementary hypothesis might be that oligodendrocytes have a reduced proteostatic capacity because they display increased vulnerability to proteasome impairment when compared with other glial cells . MoreoveIn summary, investigations so far have provided substantial evidence for a potential role of oligodendroglial dysfunction in ALS/FTLD. However, more detailed studies on the physiological roles of TDP-43 and FUS in the complex functions of oligodendroglial lineage cells and the determination of molecular changes during the disease process are required to further dissect the significance of specific alterations in disease pathogenesis. This might pave the way for new therapeutic approaches in ALS/FTLD by, e.g., boosting oligodendrocyte metabolism and functions.CV and MN researched literature, conceived the presented concepts, and wrote the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Ammonium polyphosphate (APP) was modified with a silane coupling agent , and then the synergistic flame retarding effect of graphene and surface-modified APP (APP@Si-171) on high-impact polystyrene (HIPS) was investigated. Surface modification and thermal stability characterization of APP were analyzed by Fourier transform infrared spectroscopy (FTIR), energy dispersive spectrometer (EDS), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). The results showed that surface-modified APP (APP@Si-171) exhibited significantly better dispersion and less agglomeration tendencies compared with pure APP. A series of target HIPS composites containing different mass fractions of the two flame retardants were prepared by melt blending. TGA and cone calorimeter tests (CCT) were conducted to quantitatively investigate the thermal and flammability properties of the composites, respectively. Results from TGA and CCT demonstrated that the addition of the flame retardants delayed the onset and peak temperatures in differential thermogravimetry (DTG) curves and weakened the peak heat release rate (PHRR) and total heat release (THR). Moreover, the synergistic effect index (SE) was employed to quantify the synergistic behavior between the two fillers, and the results showed that APP@Si-171 and graphene had a synergistic effect on improving the thermal stability and flame retardancy of HIPS. High impact polystyrene (HIPS) is a widely used thermoplastic copolymer in both engineering and household applications, which is synthesized by grafting a small amount of elastomer polybutadiene into the polystyrene matrix, due to its excellent rigidity, ease of coloring and processing, good dimensional stability, high impact strength, etc. . HoweverAmmonium polyphosphate (APP) is one of the most common flame retardants because it has the advantages of environmental protection, low cost and good flame retardancy. However, since the shortcomings, such as water solubility and poor compatibility in polymers, limit the application of APP, it is necessary to improve the compatibility of APP to meet the corresponding requirements. Currently, treating APP with a coupling agent is an effective way to solve the shortcomings ,8. In ad2 hybrid orbital [Graphene is a kind of two-dimensional material with a thickness of only one carbon atom, which consists of carbon atoms and SP orbital . Graphen orbital ,15. Furt orbital . TherefoRecently, to further improve the flame retardancy, two or more flame retardants had been added simultaneously into the polymer matrix to achieve the optimization purpose. Amani et al.  studied In this paper, silane coupling agent Si-171 (vinyltrimethoxysilane) was firstly used to surface modify APP to produce APP@Si-171, and it was added to HIPS in different proportions with graphene. A series of HIPS/APP@Si-171/graphene composites were prepared by melting blending method. The dispersion of the fillers was investigated by scanning electron microscope (SEM), and the thermogravimetric analysis and cone calorimeter tests were conducted to examine the synergetic effect of APP@Si-171 and graphene on thermal and flammability properties of the HIPS composites.HIPS-622  pellets were purchased from Shanghai SECCO Petrochemical Co. Ltd. . Multilayer graphene was obtained from Suzhou Tanfeng Graphene Technology Co. Ltd. . APP  was purchased from Hangzhou JLS Flame Retardants Chemical Co., Ltd. . Silane coupling agent Si-171 , purchased from Nanjing Chemical Reagent Co. Ltd. , was used to modify APP. Analytical grade ethanol was purchased from Wuxi Yasheng Chemical Co. Ltd. .To modify APP, 1.5 g Si-171 liquid and 50 mL anhydrous ethanol were added into a 100 mL beaker and mixed by a magnetic stirrer for about 10 min until they were evenly mixed. Then, the solution was transferred into a 500-mL three-port flask equipped with a reflux condensing device, and the temperature was raised to 85 °C and maintained for 1 h under the stirring condition. Fifty g APP was dispersed in 200 mL anhydrous ethanol, which was fully stirred by an electric mixer for about 30 min to achieve uniformity. Then, the anhydrous ethanol solution of APP was added into the three-port flask with a reflux condensation device, and the reaction system temperature was kept at 50 °C for 2 h under stirring condition until the reaction was complete. Finally, the product was filtered and dried in a vacuum drying oven at 80 °C for 4 h. The dried product was grinded, crushed and filtered with a 300-mesh screen to obtain the modified product as fine powder.The melt blending method was employed to prepare the target HIPS/APP@Si-171/graphene composites. HIPS pellets were blended with APP, APP@Si-171 and graphene , respectively, at 180 °C and 50 rpm for 20 min using a torque rheometer . After the blending, the composites were pressed at 190 °C under the pressure of 10 MPa for 10 min to obtain 4 mm sheets, which were subsequently cut into a suitable size for further analysis. The mixing weight fractions of HIPS and fillers are given in −1 and the resolution was 4 cm−1.Fourier transform infrared spectroscopy (FTIR) was performed with a Nicolet iS50 spectrometer . The range of test wavenumber was 4000–400 cmThe energy dispersive spectrometer (EDS) tests were conducted with a tabletop microscope  and energy dispersive spectrometer .The composites were sputter-coated with gold and then the dispersion of the composites was examined with EVO-18 SEM .The static contact angle tests were conducted on a contact angle equipment  based on the sessile drop method, i.e., depositing a drop of test liquid onto the sample surface. The contact angle values of the samples in this study were the average values of at least five repetitive tests on the same sample. The average and standard deviation of the contact angle values were calculated as less than ±2.2 in size, were horizontally exposed to the conic heat radiator with an external heat flux of 50 kW/m2. Each test was replicated at least three times to guarantee the reproducibility.The cone calorimeter tests (CCT) were conducted with a CC-2 cone calorimeter  to investigate the flammability of HIPS and its composites according to ISO5660 . The samples, 100 × 100 × 4 mmThermogravimetric analysis (TGA) tests were performed with a 3+1100LF TGA sync analyzer  operating in nitrogen atmosphere. Each test, containing 6–8 mg of sample, was carried out in a 70 μL alumina crucibles from 25 to 1000 °C at a heating rate of 10 °C/min under a purge gas flow of 40 mL/min. Additionally, each test was repeated at least three times.x and y are the mass fractions of the two additives, respectively, H is HIPS and G is grarphene. When the SE value is greater than 1, the two additives show the synergistic effect; when the SE value is equal to 1, the two additives show the superposition effect; when the SE value is less than 1, the two additives show the antagonistic effect.Dittrich et al.  defined −1, 2900 cm−1 and 2980 cm−1. The peaks at 2900 cm−1 and 2980 cm−1 corresponded to the stretching vibration of C-H on the -Si-CH- group, and the peak at 1050 cm−1 was attributed to the stretching vibration of Si-O [FTIR was used to explore the surface modification of APP. As shown in  of Si-O . FTIR te4 in APP molecule loses NH3 to form -OH under heating condition [3 in Si-171 molecule hydrolyzes to form -OH, and both Si-OH and P-OH groups are dehydrated and condensed to form the Si-O-P structure, which connects the Si-171 molecule to the APP molecule. CH2=CH- in the Si-171 molecule enhances the dispersion and compatibility of APP@Si-171 in HIPS, and improves the moisture absorption of the APP molecule.In combination with the results of the FTIR test, the reactions that may occur during the modification process are listed in ondition , -OCH3 iAs can be seen from According to the test analysis of the electron energy spectrum weight and atomic percentage of APP@Si-171 in As seen in 2 atmosphere are presented and compared in 3 as well as a small amount of H2O, while the mass loss of APP is about 10.2% in this temperature range. While in the second stage, about 400 to 600 °C, further temperature rise causes thermal decomposition of superphosphoric acid, which lead to the release of NH3 and considerable H2O as well as the formation of phosphoric acid, pyrophosphate, polyphosphoric acid and crosslinked P2O5 [To characterize the improved thermal stability of modified APP@Si-171, the measured TG and DTG curves of APP and APP@Si-171 in Nked P2O5 . The masE is the activation energy, e is the Euler number, A is preexponential factor, R is the ideal gas constant, maxT is the peak temperature, initm is the initial mass at the onset of the peak and θ is the ratio of mass at end temperature of peak to initm. The calculated values are also listed in The kinetics of overall thermal decomposition in the third stage, reflected by Arrhenius parameters, can also be quantitatively estimated by the corresponding equations ,32:(2)E=In order to intuitively observe the dispersion of the filler in the HIPS matrix, the SEM images of the cross section of the composites are studied. As shown in The single peak presented in HIPS4-9 curves in A phenomenon that should be noticed is that the difference of TG curves at 400–800 °C is not obvious in Td, onset, Tmax, MLRmax, Residue yield, A and E are summarized in Utilizing the same analysis method demonstrated in Td, onset and Tmax. Specifically, compared with pure HIPS, the addition of 15 wt% filler would delay the Td, onset of composite materials by 4.9 (15 wt% APP@Si-171), 17 (7.5 wt% APP@Si-171 + 7.5 wt% graphene) and 2.2 °C (15 wt% graphene). The gaseous products of NH3 and H2O during APP@Si-171 thermal decomposition could slow down the pyrolysis reaction of HIPS by diluting free radicals, and therefore, delay Td, onset. Moreover, all the Tmax of the composites are delayed, which can be attributed to the fact that the added graphene advances the third stage of decomposition in HIPS3 to the main peak stage of the composite. Less APP@Si-171 in composite would directly lead to the reduction of mass loss caused by its thermal decomposition, increase Tmax and decrease MLRmax.The data in Compared with pure HIPS, the char residue of HIPS3 was increased from 0% to 4.4%. This is due to the promotion of char formation by APP@Si-171 and its thermal decomposition products, so that adding APP@Si-171 to HIPS3 can increase the residue yield. Moreover, the char residues of HIPS4-HIPS9 were increased gradually. As discussed above, the sheet-like structure of graphene, which blocks the volatile penetration and heat transfer in solid is credited for the increased char residue as more graphene is added. For pure HIPS, the single-step thermal decomposition with almost no residue is considered to be depolymerization and cyclization .E of HIPS is remarkably increased as the two fillers are added, revealing that the addition of fillers makes the decomposition of HIPS more difficult to occur, thus improving its thermal stability. Moreover, with the increase of the content of graphene, E increases first and then declines. The viscosity of the composite increases with the increase of graphene content, which affects the intumescence of APP and causes the decrease of E.As shown in Td, onset, Tmax, residue yield (SERE) and E of HIPS/APP@Si-171/graphene composites. The calculation results are listed in max of HIPS composite as demonstrated in In addition, in order to study the synergistic effect of APP@Si-171 and graphene in HIPS matrix, Equations (4)–(7) are used to quantify the synergistic effect index of 2 and residue yields are listed in Bench-scale cone calorimeter tests (CCT) were carried out to investigate the interaction between the two additives in the matrix and the overall thermal behaviors of relatively large samples during the combustion process. The obtained flammability properties of neat HIPS and its composites, including PHRR, THR , CO2 yield (SEC) of HIPS/APP@Si-171/graphene composites, shown in 2 and residue yields in some cases are lower than 1, they are subordinate parameters in evaluating fire safety compared with that of PHRR. Furthermore, from 2 production while graphene is significant in increasing char residue.In addition, the synergistic effect of APP@Si-171 and graphene in HIPS matrix can also be assessed by Equations (8)–(10) following the similar method of Equation (1) by calculating the synergistic effect indexes of PHRR, residue yield and CO3 and H2O generated by the thermal decomposition of APP@Si-171 dilute the gaseous small molecular products evolved by pyrolysis of HIPS. Meanwhile, the produced gases by APP@Si-171 can combine with phosphoric acid, another pyrolyzate of APP@Si-171, through foaming and promote cross-linking and char formation to form a barrier carbon layer, which hinders heat transfer and volatilization of gas products, delays the HRR rise rate of HIPS/APP@Si-171 composite and ultimately reduces its PHRR and THR. With the increase of the content of graphene, the PHRR of the composite decreases monotonously, whereas the THR declines first and then increases. This is mainly because the lamellar carbon layer formed by the interaction of graphene and APP@Si-171 blocks the heat transfer in solid and the volatilization of gaseous thermal decomposition products when the amount of graphene is small. As the amount of graphene increases, the viscosity of the condensed phase is enhanced [enhanced , which sRE of residue yield of HIPS7 and HIPS8 are larger than 1, indicating that APP@Si-171 and graphene synergistically facilitate the generation of char residue of HIPS composites.To better understand the flame retardancy mechanism, SEM experiments were also performed to investigate the microstructure of char residues of HIPS4, HIPS5, HIPS6, HIPS7, HIPS8 and HIPS9, and the results are shown in Td, onset, Tmax as well as residue yield and reduced the PHRR, THR and CO2 yield. On the one hand, APP@Si-171 and its thermal decomposition products slowed down the thermal decomposition process and benefited the formation of char residue; on the other hand, graphene was the main component of the carbon layer, and the sheet of graphene stacked layer by layer served as a barrier to prevent the volatilization of HIPS thermal decomposition products and heat transfer. The synergistic effect between APP@Si-171 and graphene was investigated by calculating the synergistic effect index. The results showed that the synergistic effect index of Td, onset, Tmax, residue yield and E of HIPS4-HIPS8 composites were all greater than 1, and the MLRmax of HIPS composite was decreased by the addition of fillers, which implied that APP@Si-171 and graphene had a synergistic effect on enhancing the thermal stability and flame retardancy of HIPS. This work hopefully provides some guidance for designing or choosing a suitable flame retardant for engineering applications.In this work, surface-modified ammonium polyphosphate (APP@Si-171) was prepared by surface-modifying APP with Si-171, and the surface modification of APP was explored by FTIR, EDS, SEM and the static contact angle tests. FTIR and EDS results showed that APP@Si-171 was successfully modified, the SEM images of APP and APP@Si-171 showed that the microscopic particles of APP@Si-171 were well modified and the hygroscopicity and compatibility of APP were improved. The result of static contact angle tests further confirmed that the hydrophobic properties of APP@Si-171 were significantly improved. Moreover, it can also be inferred that the distribution of Si in APP@Si-171 sample was relatively uniform through EDS analysis. APP@Si-171 and graphene were individually and jointly incorporated into HIPS to prepare a series of improved composites, respectively. The results from SEM test on studying the dispersion of filler showed that APP@Si-171 was relatively uniformly dispersed and the agglomeration was also improved. Similarly, graphene was well dispersed in the HIPS matrix because the added multilayer graphene formed many sheet structures in the HIPS matrix. Subsequently, the thermal and flammability properties were explored by TGA and cone calorimeter tests. The results showed that APP@Si-171 and graphene increased the


This paper presents the results of investigations of the effect of graphene oxide and surface shot peening on the mechanical properties and fatigue life of bolts made of austenitic 304 steel. An innovative method for the uniform deposition of graphene oxide on screws is presented. The process involved activating the surface using plasma and then performing graphene oxide deposition using centrifugal force and vacuum drying. The screw specimens prepared in this way were subjected to a surface peening process. Comparative studies have shown that the combination of graphene oxide deposition and shot peening processes results in an increase in fatigue life of approximately 42 ÷ 275% (depending on the stress amplitude level) compared to the as-delivered samples. The results presented are promising and may provide a basis for further research on the application of graphene and its derivatives to increase fatigue life and improve the mechanical properties of machine components. Modification of the surface layer of machine components can have a significant effect on improving their mechanical properties ,4,5,6,7.They showed that the surface crushing created by surface peening leads to compressive stresses in the subsurface layers affecting crack development. In non-surface-strengthened specimens, crack initiation usually occurs at the bottom of structural or geometric notches, whereas the introduction of a state of subsurface compressive stresses can shift the crack initiation site to the point of maximum material stress below the surface ,15 and, The current technological challenge is to combine the strengthening process occurring during surface shot peening with the introduction into the surface layer of a material having different properties than the native material to improve its mechanical and fatigue properties.The combination of graphene and its derivatives with metal can significantly improve the mechanical properties ,16,17. AThe literature contains information on composites in which graphene has been bonded to the base material directly ,25 or viThe aim of this research was to analyze the effect of graphene oxide deposition and surface shot peening on mechanical and fatigue properties. The tests were conducted on a structural element, such as a screw, which had a surface geometry that had numerous geometric notches making the uniform deposition of graphene oxide more complicated.p < 0.045; S < 0.015; n < 0.11; Fe = bal. For static strength and fatigue life testing, the bolt head was removed.The tests were performed on M12x50 bolts a made of2SO4, Chempur, Poland) and phosphoric acid . Next, potassium permanganate  was slowly added to this mixture. The oxidation process was performed for a few hours and stopped by the addition of deionized water and hydrogen peroxide . The graphite oxide water suspension obtained was left for sedimentation. Then, the purification and exfoliation processes were performed. The concentration of graphene oxide water dispersion was 10 g/L [Graphene oxide (GO) flakes dispersed in water b were obs 10 g/L ,32. The Shot peening media  were selected so that during peening, the balls could move freely to reinforce the bottom of the geometric notch without carrying shot material other than the bolt’s parent material. The transfer of material other than the bolt’s parent material could result in the initiation of corrosion and, therefore, geometric and structural weakening of the structural component during its service life. Thus, an austenitic steel shot was used which had an elemental composition similar to the bolt’s parent material which was C~0.17%; Cr~18%; Ni~10%; Fe = bal. c.BM—base material   Figure a;BM+SP—base material  and shotBM+GO—base material  and withBM+GO+SP—base material  and withTests on the structural, mechanical, and fatigue properties were carried out for bolts made of austenitic 304 steel according to the following designations:The graphene oxide deposition process was performed for a part of the bolts in the delivery state (BM+GO) and bolts in the delivery state intended for subsequent shot peening (BM+GO+SP). The process consisted of plasma cleaning and surface activation a, graphe2 atmosphere  in an Nmosphere a.The cleaning and activation of the sample’s surface by RF plasma is crucial in the deposition of graphene oxide, because it promotes the hydrophilicity of the steel. As a result, the graphene oxide aqueous suspension  b. To sepp = 5 bar, and an exposure time of 15 min. The diameter of the shot was selected to strengthen the bottom of the thread. The intensity of peening measured on Almen-type NI plates was Nf = 0.24 mm. The distance of the nozzle assembly from the shot peened surface was l = 420 mm.The surface peening process was carried out for the bolt parts in the delivery state (BM+SP) and with a deposited graphene oxide layer (BM+GO+SP). A special workstation for shot peening type PEEN—IMP (proprietary peening station in Institute of Precision Mechanics) (patent PL 204718) was used, which enabled the smooth regulation of the energy of the shot impact on a strengthened surface. The shot pellet granulation and process parameters were selected experimentally so that the shot peened surface coverage was 100%. During the shot peening process, the specimen rotated in a rotary motion, and the shot hit perpendicularly to the surface of the specimen. The following peening parameters were selected: stainless-steel shot with diameters of 0.4 and 0.6 mm, air pressure of Graphene oxide was deposited on screws investigated by scanning electron microscopy  and scanning transmission electron microscopy  using a Quanta 250 FEG SEM, FEI, Hillsboro, OR, USA. SEM images were acquired using a backscattered detector  with an accelerating voltage of 2–5 kV for GO and 5–10 kV. The Raman spectra were acquired using a Renishaw InVia Raman microscope equipped with an Andor EMCCD detector . The Raman signal was collected using laser radiation with a wavelength of 532 nm and a laser excitation power of 2.5 mW. The laser beam was directed to the sample through a 20× objective lens, and the laser spot size was approximately 5 μm in diameter.Microhardness measurements were performed using the Vickers method according to the requirements of PN-EN ISO 6507-01:2018-05. The tests were carried out on a Shimadzu M microhardness tester with a load of 100 g (HV0.1) and a load time of 5 s. Microhardness was determined according to the analytical relation using the averaged diagonal of the resulting imprint. Prior to the basic measurements, the measuring system was checked using the 43722 HV0.1 hardness standard No. 4480. The variation in the microhardness of the materials tested was determined based on linear microhardness distributions from the surface of the tested material to a depth of 2 mm.Static tensile tests and fatigue tests were performed using a servo-hydraulic testing system  with a load cell range equal to ±250 kN and an LVDT sensor range of ±80 mm. Specimens as screws without heads were mounted in fixtures which allowed for their axial loading.An application toolset supplied by the machine producer was used for static tensile tests—MultiPurpose TestWare Software 793 (MPT). Tests were carried out at room conditions (23 ÷ 25 °C and 40 ÷ 60% RH) with a constant speed of actuator movement, that is to say 1 mm/min (displacement rate) and with a preload of 100 N. f = 20 Hz and a load ratio of R = 0.1. Tests were performed on three levels of loads: maximum force values in the load cycle corresponded to 0.8, 0.7, and 0.6, respectively, of the tensile strength obtained during the tests of the base screw material. The data, which were recorded during tests, included the number of cycles and peak and valley values of force and displacement. Fatigue tests were designed and conducted using another producer application, 790.20 Cyclic Fatigue under force control. The control signal had a sine wave form at a frequency of Analysis of the surface morphology of the bolts made of austenitic 304 steel showed a visible development of the surface after shot peening. The surface morphologies of the screw fragments in the delivery state (BM) a, shot pAs a result of the plasma surface activation, the centrifugal force of the graphene oxide suspension on the screw, and the vacuum drying process, a uniform distribution of graphene oxide flakes was observed. This was not only on the outer surface but also in the bottom of the geometric notches, meaning the bottom of the rounded root. The deposited graphene oxide had characteristic thin folds a,b locat−1, G—1600 cm−1, and 2D—2920 cm−1, typical for graphene oxide, were observed on the surface of tested BM+GO and BM+GO+SP  not subjected to ennobling treatment.The study shows that under the influence of the graphene oxide deposition process, the microhardness at a distance of 0.08 ÷ 0.2 mm from the front of the sample remains below 400 HV. This is due to the activation of the surface because of the high plasma temperature in the first step of graphene oxide deposition.Shot peening of the screw’s surface caused an increase in the HV microhardness of the samples (BM+SP) and those subjected to graphene oxide deposition (BM+GO+SP) . The chaSamples with a deposited graphene oxide layer were subjected to plasma cleaning treatment, during which the surface layer was tempered. This resulted in lowering their microhardness to 0.06 mm, which can be clearly seen in the graph for the BM+GO samples compared to the BM material in the delivery state . The micThe increase in the microhardness of the shot peened samples with a deposited graphene oxide layer (BM+GO+SP) in comparison to shot peened samples without a graphene oxide deposition (BM+SP) occurred at a depth of 0.08 ÷ 1 mm and was >17%. The microhardness equilibration for all samples occurred at a depth of the subsurface layer of approximately 2 mm.anσ, and type of samples considered  are presented in The results of fatigue life tests (averaged from three tests) for each level of stress amplitude, Analysis of the static tensile test results showed that the scatter of the results for the different samples was within 5% of the statistical error. No significant increase in tensile strength Rm was observed for the graphene oxide deposited and shot peened (BM+GO+SP) samples compared to the other samples tested. The results of the tensile strength limit Rm were as follows: BM—885 MPa, BM+SP—878 MPa, BM+GO—887 MPa, and BM+SP+GO—893 MPa.an  samples exhibited a 122% higher fatigue life compared to the shot peened (BM+SP) samples.The use of combined treatment of graphene oxide deposition and shot peening increased the fatigue life depending on the level of stress amplitude, σan . For exaDeposition of graphene oxide on the surface of bolts in the as-delivered condition (BM+GO) resulted in a reduced fatigue life compared to the untreated bolts (BM). This was caused by the partial temperability of the surface layer during plasma interaction in the graphene oxide deposition process.The crack initiation in all of the samples in the delivery condition (BM) and subjected to the treatments analyzed  occurred at the bottom of the geometric notches, that is to say at the bottom of the rounded root thread a.It was observed that the front-line fractures in the graphene oxide deposited and shot peened samples (BM+GO+SP) a,b compaObservation of the fatigue fracture microfractography in the crack initiation areas showed the occurrence of brittle cracks a. As a rExamples of material decohesion and surface layer separation were observed in the bottom of the notch b and on The peened samples with deposited graphene oxide BM+GO+SP exhibited subsurface secondary cracks with the crack front perpendicular to the main crack front line f.Microfractography of the fatigue fractures of all specimens revealed fatigue stripes g, a tranThe innovative process developed combining surface cleaning and activation, graphene oxide application, and vacuum drying resulted in permanent deposition of graphene oxide on the surface of screws;The collected Raman spectra confirmed that graphene oxide flakes were still present on the surface after the shot peening process;The graphene oxide deposition process combining plasma interaction and graphene oxide deposition resulted in a decrease in the microhardness of the subsurface layer of approximately 15–20% compared to the samples in the delivery state;For samples with a deposited graphene oxide layer and shot peened (BM+GO+SP) compared to shot peened samples without a deposited graphene oxide layer (BM+SP), an increase of more than 17% in microhardness up to a <0.2 mm depth of the subsurface layer was observed. This was the effect of graphene oxide being introduced into the surface layer during the shot peening process;At a depth of approximately 2 mm of the subsurface layer, the microhardness of all samples tested  was the same;Samples (BM+GO+SP) had the highest fatigue life after graphene oxide deposition and shot peening;The use of the combined techniques of surface activation treatment, graphene oxide deposition, vacuum drying, and shot peening resulted in an increase in fatigue life by 42–275% (depending on the stress amplitude).A comparative study of samples in the delivery condition (BM), shot peened (BM+SP), with a deposited graphene oxide layer (BM+GO), and with a deposited graphene oxide layer and shot peened (BM+GO+SP) showed that:The results of the fatigue life tests are promising and provide a basis for further research on the effect of graphene oxide and its interaction after shot peening on increasing the fatigue life of materials in machine components.hybrid graphene treatment and is presented in patent application P. 438715.The processing of elements presented in this work consisting of plasma cleaning and surface activation, application of graphene oxide, vacuum drying, and mechanical shot peening is called


Turn sections represent the second largest part of total race time in 1500 m freestyle races and may substantially affect race results. Therefore, the aim of the study was to investigate individual race strategies and compare the effect of start, swim, and turn performances between short-course and long-course races. Video footages were collected from all 16 male finalists at the 2018 short and 2019 long-course World swimming championships  for subsequently analysis of start, turn, and swim performance.p = 0.004), but slower mean turn times compared to long-course races (p < 0.001). Total race velocity closely correlated with swim and turn but not start section velocity in short-  and long-course races . Analysis of individual race strategies showed that turn performance affected race results in 6 (75%) and 3 (37.5%) of the 8 world-best 1500 m swimmers in short-course and long-course races, respectively. Medal standing was improved for 1st, 3rd, and 4th ranked short- as well as 1st and 2nd ranked long-course finalist. Coaches, athletes, and performance analysts may carefully consider the importance of turn performance additionally to free-swimming skills.The larger number of turns in short-course races resulted in significantly faster race times ( Performance analysis has become routine procedure in high-performance sports, in order to evaluate the training process, discover potentials, and investigate key performance indicators , 2. As pWhile parameters related to free-swimming have been extensively investigated , 15–17, In long-course races (50 m pool length), the effect of turn performance on race results increased with race distance, hence number of turns involved –10, 18. Video footages were collected from 8 male finalists of the 1500 m freestyle events at the Hangzhou 2018  (short-course) and Gwangju 2019  (long-course) World championships for subsequent analyses of start, turn, and swim sections. All participants of the FINA World swimming championships provided written informed consent to the organizer that all video material collected during competition can be used for television broadcasting and race analyses by the participating nations. All data were anonymized before the analysis. The study was approved by the Ethical committee of the Palacký University of Olomouc (Registration-Number: 77/2020) and in accordance with the Declaration of Helsinki.For the short-course World championships, a camera  was positioned on top of the stands 30 m above water level and about 100 m from the side of the pool. The camera was placed perpendicular to the direction of swimming and exactly in the middle of the pool (12.5 m apart from both pool ends). The camera zoom was set before the races to assure clear vision across the entire pool. To ensure same conditions for the long-course World championships (50 m pool length), two cameras of the same type used before, were positioned 12.5 m apart from both ends of the pool. Cameras were synchronized via wireless LAN connection and recorded half to the pool each. Video footages were recorded as mp4 format with 50 frames-per-seconds and an image qualify of 1920 × 1080 full HD.Split times for start, swim, and turn sections were analysed using Dartfish . The light flash of the timing system that was synchronized to the starting signal was used to synchronize video footages for the race analysis. Race results were obtained from the official electronical timing system .Based on mean breakout distances of 10.69 ± 1.18 m and 10.11 ± 1.25 m for short- and long-course races, respectively, start section was determined by the time from the starting signal until top of the swimmer’s head passed the 10 m mark visible on the lane ropes. Based on previously reported breakout distances between 4.64 ± 0.23 m and 5.48 ± 0.87 m in 1500 m freestyle races , turn sepost-hoc test. A one-way ANOVA was used to compare total race time between short- and long-course races. To investigate accuracy, 50% of all races were analyzed by another experienced race analysts. Inter-rater reliability was assess using Intraclass-correlation coefficient (ICC) between the repeated measures and showed an ICC of 0.988–0.989 and 0.991–0.992 for short-course and long-course World championships, respectively. Statistical analysis was performed using the STATISTICA software version 13.4.0.14. .The data are presented in mean ± standard deviation (SD). Normality was verified with Shapiro-Wilks test and alpha-level of 0.05 indicated statistical significance. Spearman’s correlation coefficient was applied, to assess relationship between mean velocities and ranking in all race sections. For Spearman’s correlation, a critical value of 0.643 with an alpha level of 0.05 was reported to a data sample of eight participants . Analysip = 0.004). Additionally, in short-course, swimmers spent significantly less time in the swim  and more time in the turn sections  compared to long-course, respectively. However, mean turn times were significantly faster for long-course compared to short-course .The times for start, swim, and turn sections are presented in Table p = 0.381). Thereafter, turn times became significantly slower for the short-course (p < 0.001) but remained stable for the long-course races (p = 0.732).Analysis of variance (ANOVA) revealed that mean turn times of the first 500 m section were not different between short-course and long-course  and long-course . Additionally, total race velocity correlated with swim and turn section velocities in short-  and long-course . Start performance was not related to final ranking or total race velocity  and in 3 (long-course) out of 8 World championships finalists. Coaches, athletes, and performance analysts should carefully consider the importance of turn performance in addition to free-swimming skills.Analyses in top-elite athletes, i.e. the eight world best 1500 m swimmers in the short- and long-course championships, naturally come with a low number of participants. Although the current results of such a low number of world-class swimmers cannot be translated to a general population of competitive swimmers, such analyses provide unique insights into individual race strategies. Marginal differences should not be neglected as they may provide the distinguishing factor for final ranking. Therefore, further studies need to verify these findings based on data collections across finalists of multiple World championships. Additionally, individualized distances measurements of underwater phase and breakout distances after the turn would allow further insights and a detailed analysis of turn strategies .


In this study, we proposed a waveguide structure consisting of multilayer graphene metamaterials (MLGMTs). The MLGMTs support the fundamental volume plasmon polariton mode by coupling plasmon polaritons at individual graphene sheets over a silicon nano-rib structure. Benefiting from the high conductivity of the MLGMTs, the guided mode shows ultralow loss compared with that of conventional graphene-based plasmonic waveguides at comparable mode sizes. The proposed design demonstrated propagation lengths of approximately 20 µm (four times the current limitations) at an extremely tight mode area of 10−6A0, where A0 is the diffraction-limited mode area. The dependence of modal characteristics on geometry and material parameters are investigated in detail to identify optimal device performance. Moreover, fabrication imperfections are also addressed to evaluate the robustness of the proposed structure. Moreover, the crosstalk between two adjacent present waveguides is also investigated to demonstrate the high mode confinement to realize high-density on-chip devices. The present design offers a potential waveguiding approach for building tunable and large-area photonic integrated circuits.Manipulating optical signals in the mid-infrared (mid-IR) range is a highly desired task for applications in chemical sensing, thermal imaging, and subwavelength optical waveguiding. To guide highly confined mid-IR light in photonic chips, graphene-based plasmonics capable of breaking the optical diffraction limit offer a promising solution. However, the propagation lengths of these materials are, to date, limited to approximately 10 µm at the working frequency  Significant enhancements achieved in light–matter interactions, nonlinear optical effects, chemical and biological sensing sensitivities, and resolution in imaging and spectroscopy can further benefit from the localization of light waves in deep subwavelength sizes. To date, the most promising approach to achieve this goal is to excite surface plasmon polaritons (SPPs)  by couplmA); the propagation length (pL = λ/[4πIm(en)]), where λ is the working wavelength in free space and Im(en) is the imaginary part of the effective refractive index; and the figure of merit (FoM), which indicates the ratio between pL and mode size. For a dielectric loaded GPW, Xu et al.  determines the length required to completely transfer power from one waveguide to another, where sn and an are the en of the symmetric and asymmetric modes, respectively. For a lossy waveguide system such as plasmonic waveguides, we adopted a more suitable criterion, the normalized coupling length cL/aveL [aveL is the average pL of the symmetric and asymmetric modes. The maximum transfer power ρmax between waveguides is only a function of cL/aveL, and the adjacent waveguides can be considered as nearly isolated (ρmax = 0.33%) if cL/aveL > 10 is reached. This is because the transfer power from one channel to the other is relatively weak at the distance of aveL. At the frequency f = 30 THz and the geometry parameters of gw = 180 nm, rw = 20 nm, rh = 30 nm, tSi = 25 nm, and dt = 25 nm, the results of cL/aveL along with ρmax versus s at µ = 1 m2/V.s for several FEs are shown in FE = 0.4 eV are shown in µs. The results show that decreasing FE or µ leads to weaker coupling strength, and the dependence of coupling strength on FE is stronger than that on µ. We observe that the separations for negligible couplings between waveguides are s = 0.52, 0.64, and 0.72 µm for FE = 0.35, 0.40, and 0.45 eV, respectively  make the proposed waveguide capable of building high-density graphene-based photonic-integrated circuits operating in the mid-infrared range.According to the coupled mode theory (CMT) , energy  Lc/Lave , which cvely see a, and arvely see b. The regw = 200 nm, rw = 10 nm, rh = 30 nm, tSi = 5 nm, dt = 5 nm, FE = 0.6 eV, and N = 10. All the results in f = 30 THz, µ = 1 m2/V·s, and FE = 0.6 eV, except the results in ref. [FE = 0.8 eV. If FE = 0.8 eV is decreased to 0.6 eV, mA and pL will be further reduced. Liu et al. [mA = 8.0 × 10−7, by adopting a symmetrical HPW. Teng et al. [mA of the single GCNW [pL. Liu et al. [2 layers and roll it into a cylindrical waveguide. It can be inferred that the two-layer graphene structure effectively improves the pL but at the cost of a larger mA. Last year, Teng et al. [pL = 3.5 µm and mA = 2.0 × 10−6. In comparison with these published results [pL = 19.4 µm and mA = 2.6 × 10−6, thus obtaining an extremely high value of FoM = 10,612.To demonstrate the superior waveguiding performance of the proposed design, we compared the reported results ,36,38,39 in ref.  with EF u et al.  achievedgle GCNW  by one ou et al.  to add a results ,36,38,39k SPP modes supported by monolayer graphene; (2) high-efficiency coupling between the nanoscale mode sizes of high-k SPP modes and submicron-scale dielectric waveguide modes or micron-scale optical fiber modes; (3) sufficient long propagation length beyond hundreds of micrometers or even millimeters. To relieve the first obstacle, employing multilayer graphene structures can efficiently control the field localizations and effective refractive index by varying the number of the graphene layers, thus overcoming the difficulty of exciting the high-k SPP modes. Next, the coupling efficiency can be improved by designing perfectly adiabatic metallic gratings, reducing field scattering during the coupling process. The final one is a common limit, as the SPP modes supported by general noble metals operating in the near-IR and visible light bands. In addition to discovering new low-loss materials, designing a novel waveguide structure by combining multiple guiding mechanisms together has been the most effective solution to decrease the propagation losses.Currently, the obstacles for experimentally fabricating integrated graphene waveguides include three major points, despite the mature developments of both silicon photonics and graphene industries. (1) Excitation of extremely high-2 layer. By coupling the low-loss fundamental VPP mode of the MLGMTs, which is formed by coupling the SPP modes at individual graphene sheets and the dielectric mode of a Si nano-rib, the hybrid mode of the present design achieves an ultralong propagation length pL = 19.4 µm with mA = 2.6 × 10−6 at FE = 0.6 eV operating at f = 30 THz. Compared with the reported results, the pL of our structure is five times greater than those reported at a comparable mA. Even for the looser mA, previously reported pL values at FE = 0.6 eV and f = 30 THz were still limited to below 10 µm. The MLGMTs provide a high-conductivity graphene structure that significantly increases pL with an increasing number of graphene layers. Therefore, the increased degree of pL is mainly restricted by the modern fabrication technique. In addition, the crosstalk between two adjacent waveguides demonstrates that the proposed structure is beneficial in realizing high-integration photonic devices operating in the mid-IR band. Our design is expected to pave the way for potential applications in building ultralow loss and compact and tunable mid-IR photonic devices and can be extended to other extraordinary 2D materials.This work reported a mid-IR waveguiding structure based on MLGMTs on a Si nano-rib waveguide structure covered by a porous SiO


To understand the photoconductive mechanism, the perovskite’s passivation and the graphene photogating effect are proposed to contribute to the device’s performance. This study provides new routes for the application of perovskite film in photodetection.Due to their outstanding optical properties and superior charge carrier mobilities, organometal halide perovskites have been widely investigated in photodetection and solar cell areas. In perovskites photodetection devices, their high optical absorption and excellent quantum efficiency contribute to the responsivity, even the specific detectivity. In this work, we developed a lateral phototransistor based on mesoscopic graphene/perovskite heterojunctions. Graphene nanowall shows a porous structure, and the spaces between graphene nanowall are much appropriated for perovskite crystalline to mount in. Hot carriers are excited in perovskite, which is followed by the holes’ transfer to the graphene layer through the interfacial efficiently. Therefore, graphene plays the role of holes’ collecting material and carriers’ transporting channel. This charge transfer process is also verified by the luminescence spectra. We used the hybrid film to build phototransistor, which performed a high responsivity and specific detectivity of 2.0 × 10 Graphene, nicknamed “miracle material”, a typical two-dimensional film was well explored experimentally, as well as theoretically and computationally, which provided an attractive platform for broadband visible-infrared photodetection ,2,3. Man3NH3PbX3 (X = Cl−/Br−/I−) [3NH3PbI3 nanowire photodetector possessed a high detectivity and polarization sensitivity characteristics [Due to the properties of high absorption coefficient, long charge carrier diffusion length, and excellent mobility, the organic–inorganic halide perovskites are extensively studied, which can be described by the formula CH/Br−/I−) ,10. Besi/Br−/I−) ,12,13,14eristics . Furthereristics . Meanwhieristics . Compareeristics ,19.5 A/W, with a graphene-perovskite phototransistor [3NH3PbI3 nanowire/graphene, gold plasmonic-enhanced graphene/perovskite photodetectors, and even fully inkjet-printed graphene/perovskite/graphene photodetector have been investigated [By combining the graphene’s high carrier mobility with the perovskites’ good light-harvesting capability, high-performance graphene/perovskite photoelectric devices have been widely demonstrated ,24,25,26ansistor . Other wstigated ,22. A kestigated ,23. Graphene nanowalls’ (GNWs) structure in a nanoframework is vertical oriented and possessed many unique properties, such as mechanical stability, high in-pane conductivity, and high surface-to-volume ratio ,28. Cons2 (300 nm) substrate, using the radio-frequency plasma-enhanced chemical vapor deposition (RF-PECVD) method. Before growth, the substrate was cleaned in acetone, ethanol, and distilled water, respectively. A mixture gas of methane and hydrogen (6:4) was introduced as the reactant. The growth temperature was about 800 °C, with a chamber pressure of 50 Pa. During growth, the radio frequency power was set as 200 W, maintaining for 45 min for graphene growth.Graphene nanowalls were fabricated on a Si/SiO3NH3PbIxCl3-x perovskite was synthesized according to the method reported previously [2 , 0.14 M PbCl2 , and 1.3 M CH3NH3I  were mixed in co-solvent, at 60 °C, with stirring, that comprised of dimethyl sulfoxide  and γ-butyrolactone , with a ratio of 3:7. After coating, chlorobenzene was quickly added to the substrate, to induce crystallization, and the film was annealed at 100 °C, for 10 min. The synthesis, coating, and annealing process of perovskite were finished in a glove box.The CHeviously . Raw mat2 square by an oxygen plasma. Then, electrodes were deposited, using magnetron sputtering technique. At last, with another metal mask, perovskites were coated on the graphene nanowalls. Finally, the device was packaged in N2 atmosphere, as a prototype transistor.With a metal mask, the grown graphene nanowalls were etched into a 2 × 2 mmAt first, Raman spectra of GNWs were obtained by using Renishaw inVia Reflex  with a 532 nm laser. Scanning electron microscopy (SEM) and Transmission Electron Microscope (TEM) images were obtained by using JSM-7800F  and JEM-2100F , respectively. The crystal structure of the film was investigated by XRD measurements, with a PANalytical-X’Pert Powder  diffractometer equipped with Cu-K radiation (0.154056 nm wavelength). Excited at 532 nm laser, the luminescence spectra of perovskites samples were determined on a FLS 980 spectrometer  detected by red sensitive PMT. The decay curves at 770 nm were measured by using a 472.0 nm EPL-470 laser with a pulse width of 95.9 ps. In addition, the UV−visible excitation spectra were recorded on an Edinburgh FLS980 spectrometer equipped with a 450 W xenon lamp. To evaluate its photo-detective property, a solar simulator (XES-50S1-EI) and several laser sources  were used as the irradiation light, and a Keithley 2450 and Keithley 4200  were used to record the electrical results, respectively. At last, we measured, directly, the noise spectral density of the dark current by using an FFT spectrum analyzer . All the measurements were performed at room temperature.2 substrate, which presents a porous structure and a large number of graphene edges. The graphene edges can also be testified by the Raman spectra in −1) requires a defect for its activation and the G peak (1580 cm−1) corresponds to the doubly degenerate zone center E2g mode, we can see that, the longer the growth time of GNWs used, the larger the intensity ratio of the D to G (ID/IG), which means more graphene edge defects and a higher degree of disorder shaped [At first, the GNWs were grown by the RF-PECVD technique. r shaped ,31. Howe2, which is less conductive and accumulates more charges. This phenomenon indicated that a PbI2 phase was formed, which is referred to as the passivation effect [2 phase can be confirmed in the XRD pattern , the transistor presented an obvious photo-responsive property. With a switch-on and switch-off process, the I–t curves presented good stability (At first, the device’s photoelectrical response was tested under a solar simulator, as shown in tability b. In add3 A/W measured with an incident power of 40 μW of 635 nm laser. Considering the noise spectral density of the dark current, ni = 5.5 × 10−9 A/Hz−1/2 at the frequency of 1 Hz, the specific detectivity was calculated to be 7.2 × 1010 Jones. As listed in The maximum responsivity of was 2.0 × 10For the highly performance hybrid photodetector based on graphene/perovskite film, a key theoretical hypothesis is that photo-excited holes in perovskites transfer to graphene, and therefore electrons in graphene transfer to a proximal perovskite layer . Compare2 crystals separate from perovskite. These PbI2 crystal layers reduced the carrier recombination in the absorber superficies, as well as the grain boundary; therefore, they promoted the device performance [Moreover, the passivation effect and photogating effect must be pointed out. Since the passivation process, PbIformance . In brie3 A/W and 7.2 × 1010 Jones, respectively. In addition, it achieved faster rise and fall times than that of the perovskite hybrid with single-layer graphene. Comparing with the with monolayer graphene hybrid with perovskite, this device based on graphene nanowalls showed a much high performance in photodetection. The hybrid phototransistor described here is expected to contribute to the development of lateral devices based on perovskite, such as the photodetection and solar cell applications.In summary, we have fabricated the first graphene/perovskite phototransistor. It is lateral structured and easy to be fabricated. By the spin-coating method, perovskites were infiltrated in the porous graphene nanowalls. In the device, graphene acted as the hole collecting and transfer layer, and mesoscopic heterojunctions formed in the graphene/perovskite interface. At room temperature, photoelectrical measurements show that it has a responsivity and specific detectivity of 2.0 × 10


While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area. Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable condition defined by the radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) in the absence of an identifiable cause or exposure . With a Parenchymal fibrosis is proposed to originate from prolonged or perpetuated alveolar epithelial injury . This evThe clinical features of IPF provide very limited insight into associated immune factors. Diagnostic criteria for IPF are essentially the presence of a pattern consistent with Usual Interstitial Pneumonia on chest imaging or lung biopsy in the absence of an identifiable cause. Compared to other ILDs, IPF lungs contains fewer inflammatory cells and chest imaging contains very little of the ground glass opacities that are typically reflective of inflammation . FeatureImmune responses are dichotomized into innate and adaptive processes. The former component, which is the focus of this review, is currently understood as a rapid and programmed response to chemical or physical stimuli and the latter being a specific response to a particular antigen. While abnormalities in both components have been described in IPF, the available evidence suggests a pathogenic contribution of innate immunity whereas the role of adaptive immunity is less clear. Thus, this review will focus on the innate immune processes that could contribute to IPF.Fibrotic immunopathology has been reported in the context of pattern recognition receptor (PRR) activation. PRRs respond to the physical or chemical structure of their respective ligands to initiate and in some cases perpetuate host defense. PRR-activating structures derived from microorganisms are termed “pathogen associated molecular patterns,” or “PAMPs” and substances generated by tissue injury are called “danger associated molecular patterns,” or “DAMPs” . AnotherPathogen associated molecular patterns. While not viewed as an infectious process, several lines of evidence derived from animal and human studies support a connection between IPF and microbes. The contribution of viral and bacterial PAMPs has been explored as follows  fluid and lung tissues   inflammasome activation in IL-1β associated fibrosis in the bleomycin mouse model . Recent 9 (TLR9)  which al9 (TLR9) . In fact9 (TLR9)  and exce9 (TLR9) . The inf9 (TLR9) , heighte9 (TLR9)  and it iAs the first line of defense against invading pathogens, cells of the innate immune system have important roles in host defense and tissue homeostasis. The best studied cells in the context of IPF are macrophages and neutrophils, though more recently described populations such as fibrocytes, myeloid-derived suppressor cells (MDSCs), and innate lymphoid cells (ILCs), may also be involved. It is worth noting that stromal populations such as fibroblasts and epithelium also demonstrate innate immune functions  but becaMacrophages are both the major antimicrobial phagocytes in the lungs and central mediators of fibrotic lung disease , is increased in IPF BAL . The invFinally, an additional fibrogenic neutrophil function is the formation of extracellular neutrophil traps. These highly inflammatory aggregates of chromatin and neutrophils regulate activation of immune cells  and fibrTo summarize, neutrophils could participate in IPF through their production of soluble mediators, regulation of epithelial injury, control of ECM turnover, and formation of NETs. . HoweverFibrocytes are bone marrow-derived cells displaying characteristics of leukocytes, hematopoietic progenitor cells, and fibroblasts. Viewed as originating from monocytes, they are found in the systemic circulation from which they migrate to areas of tissue injury and participate in wound repair  are a heterogenous population of myeloid origin first observed in cancer patients. Despite their reported heterogeneity, MDSCs share the common function of contributing to regulatory T cell (Treg) expansion and, subsequently, suppressing T cell activation and proliferation. Pathologically, there is an increasing evidence of MDSCs being involved in non-malignant inflammatory diseases including fibrotic disorders (isorders . Specifiisorders . Along tisorders . The vasisorders . The recisorders .Innate Lymphoid Cells are recently identified lymphoid cell populations distinguished by their lack of recombination activating gene (RAG) and classical T or B cell receptors (eceptors . The laceceptors ; ILC2, ieceptors . ILCs ineceptors . In the eceptors . While Ieceptors , their dBox 1Is innate immunity protective or pathogenic in IPF?Are PRRs that recognize DAMPs or PAMPs protective or pathogenic in the setting of pulmonary fibrosis?Does the altered microbiome cause PAMP driven innate immune activation in IPF?Does perpetuated microinjury cause DAMP driven innate immune activation in IPF and are therapies targeting DAMPs and their receptors efficacious in IPF?Can immune events detected in the circulation be used to guide personalized therapies in IPF?via the regulation of epithelial cell activation?Do macrophages participate in pulmonary fibrosis Does production of lipid mediators in macrophages contribute to pulmonary fibrosis?Can therapies targeting macrophage activation stabilize or restore lung function in patients with IPF?Are NETS an important part of IPF pathogenesis?Can fibrocytes be a therapeutic target or biomarker in IPF?Do myeloid-derived suppressor cells or ILCs participate in IPF?in situ?How do circulating myeloid cells, other than monocytes, contribute to the increased pool in the lung? Do they invade the lung and provide “transitory or permanent” populations The connection between innate immunity and IPF continues to evolve and now encompasses a contribution from numerous processes and cell populations enacting competing and overlapping functions. The presence of these processes in fibrotic conditions affecting numerous organs frames innate immune dysfunction as a convergent molecular feature of divergent clinical states. The detection of these mediators in both diseased organs and the systemic circulation could represent a more significant hematologic contribution than previously believed. Conversely, it could represent the nonspecific and intrinsic nature of the response. When compared with epithelial cells and fibroblasts, whose proposed role in fibrosis is relatively well defined, the more heterogeneous contribution of innate immunity is nuanced and unlikely to respond to a single intervention which may make it challenging to target. Additional challenges include critical aspects of host defense and tissue homeostasis both in the lung and in distant organs. Because some of these limitations may be overcome by the relative ease of isolating immune cells and mediators from bronchoalveolar lavage and blood, innate immunity is an attractive area for the development of personalized therapies based on easily accessible biomarkers. Areas of particular interest and important questions in this context that would benefit from concerted efforts performed in large scale multicenter recruitment efforts, leveraging of existing datasets and registries, and the generation of improved modeling systems that more faithfully recapitulate the complex microenvironment of the fibrotic human lung and improve the understanding and treatment of IPF on a global scale are shown in