Many eukaryotic species contain two separate molecular machineries for removing non-coding intron sequences from pre-mRNA molecules. The majority of introns (more than 99.5% in humans) are recognized and excised by the major spliceosome, which utilizes relatively poorly conserved sequence elements at the 5′ and 3′ ends of the intron that are used for intron recognition and in subsequent catalysis. In contrast, the minor spliceosome targets a rare group of introns (approximately 0.5% in humans) with highly conserved sequences at the 5′ and 3′ ends of the intron. Minor introns coexist in the same genes with major introns and while the two intron types are spliced by separate spliceosomes, the two splicing machineries can interact with one another to shape mRNA processing events in genes containing minor introns. Here, we review known cooperative and competitive interactions between the two spliceosomes and discuss the mechanistic basis of the spliceosome crosstalk, its regulatory significance, and impact on spliceosome diseases. Drosophila. More recently, an investigation of the genome of slime mold Physarum polycephalum revealed an exceptional case of >20,000 minor introns in a single genome  and ligation of coding sequences (exons) in pre-cursor messenger RNA (pre-mRNA), is carried out by a dynamic and complex machinery known as the spliceosome. The majority of metazoan organisms contain two parallel but analogous spliceosomes: the major or U2-dependent spliceosome which excises approximately 99.5% of introns, depending on the organism, and the minor or U12-dependent spliceosome which excises about 0.5% of introns. The respective intron types are similarly referred to as either major or U2-type introns, and minor or U12-type introns . The nume genome . The type genome . The orie genome . Nonethee genome . Interese genome . On the e genome . These pe genome .A key distinguishing feature between U12-type and U2-type introns is the conservation of intron recognition sequences i.e., the 5′ splice site (5′ss), 3′ splice site (3′ss) and the branch point sequence (BPS). Additionally, U2-type introns distinctively contain a polypyrimidine tract (PPT) upstream of the 3′ss. Splice site sequences are relatively weakly conserved in U2-type introns, which leads to more flexible splice site choices that fuel alternative splicing processes. In contrast, splice site sequences within U12-type introns are significantly more conserved , which tEfforts aimed at understanding the functional significance of U12-type introns have suggested that the splicing of minor introns is slower or less efficient than that of major introns and could be used as a rate-limiting step to control or fine-tune mRNA levels of MIGs . AccordiInteraction between the minor and major spliceosomes during pre-mRNA processing can lead to two opposing outcomes: cooperation or competition. Cooperative interactions can facilitate mutual activation of adjacent spliceosomes during splicing through exon and intron definition mechanisms. Alternatively, the two spliceosomes can compete with one another for access to introns that harbor splice site recognition sequences for both machineries. Under normal physiological conditions, competitive interactions can be identified by the alternate use of either U12-type or U2-type splice sites, which result in different mRNA isoforms. In contrast, cooperative interactions between the two spliceosomes are more challenging to identify, as they typically do not lead to changes in alternative splice site usage under physiological conditions, except in the few cases where such interactions have been exploited for regulatory purposes. Additionally, diseases affecting minor spliceosome functions lead to a variety of alternative splicing choices in both interaction types.At the mechanistic level, mutual interactions between the major and minor spliceosomes on the same pre-mRNA are predominantly mediated by exon definition interactions, in which the initial recognition of introns takes place by pairing splice sites across exons instead of introns . Subsequin vitro, between U1 snRNP and the minor spliceosome  are the main facilitators of these interactions . These iiceosome , and in and 3′ss .SNRNP48 and RNPC3 genes. These encode the U11-48K and U11/U12-65K proteins, respectively, that are components of the U11/U12 di-snRNP. Both genes contain a conserved sequence element in non-coding regions which include a tandem repeat of the U12-type 5′ss consensus sequence. The tandem 5′ss sequences are recognized by the U11 snRNP, but are not used as splicing donors by the minor spliceosome. Instead, the binding of the U11/U12 di-snRNP activates an upstream U2-type 3′ss (SNRNP48) due to inclusion of a PTC, or are retained in the nucleus due to an export-incompetent mRNA isoform (RNPC3)  . Notablyntiation , and is ntiation .Further evidence for cooperative interactions between the two spliceosomes has emerged from global transcriptome analyses of diseases which partially compromise the function of the minor spliceosome. A typical outcome in these diseases is intron retention resulting from splicing defects. However, several studies have also demonstrated that the splicing defects are not limited to U12-type introns but can also spread to the flanking U2-type introns  in a subCompetition between the two spliceosomes represents a special subclass of alternative splicing where an individual intron can be spliced by either the minor or the major spliceosome. In these instances, competing splice sites are typically in close proximity to one another on the pre-mRNA and the resulting mRNA isoforms are also often annotated in public databases. Depending on the positioning of the splice sites, such introns have been referred to as twintrons or nested introns, which both refer to instances where either minor or major intron is located within the other intron type . Nested prospero (pro) gene in Drosophila  or longer  mRNA isoforms. The resulting pro protein isoforms differ in the homeodomain region, which may affect DNA binding specificity  that is specific for the SRSFR10 protein and is involved in SRSF10 autoregulation. Levels of the functional SRSF10 isoform spliced by the minor spliceosome correlate not only with the activity of the minor spliceosome, but also with overall levels of other SR proteins, in a tissue-specific and developmental manner. This further suggests that regulation of the SR-protein family as a group, may be linked to the activity of the minor spliceosome   . The truif (RRM) .MAPK8-9) and for TMEM87a and TMEM87b genes. Here, competition between minor and major pathways leads to mutually exclusive incorporation of alternatively spliced exons into the mRNA. In the MAPK8/9 genes, U12-type and U2-type splice sites have an interlocked configuration where mutual competition of two U2-type 3′ss and two U12-type 5′ss leads to inclusion of either the alternative exon 6a or exon 6b   family genes (ctively) . In thisctively) . The difctively) , whereasctively) . A recene intron . Competipression , indicatCCDC84 gene  by e intron .MAPK12 and CENATAC cases with a shared 3′ss, there is another, albeit undetectable functional change upstream of the 3′ss. In the major pathway this region constitutes a pyrimidine-rich PPT recognized by the U2AF2 protein present in the U2AF1/2 heterodimer. In contrast, the minor spliceosome does not use the PPT or the U2AF1/2 heterodimer for intron recognition, but rather relies on BPS recognition by the U12 snRNA. A plausible explanation for the intron 3′ end compatibility between the two spliceosomes is that the minor intron BPS is also pyrimidine-rich and can, in a suitable context, also serve as a PPT for major introns, as suggested earlier (In both the  earlier .A unique case of competition has been described for the non-productive use of components of both splicing pathways to regulate the ratio between unspliced genomic RNA and subgenomic spliced mRNA species in the Rous Sarcoma Virus (RSV). The genomic RNA of this retrovirus contains an inhibitory splicing element designated the Negative Regulator of Splicing (NRS), the function of which is to suppress all splicing of the viral RNA to ensure production of unprocessed genomic RNA, that is subsequently packaged into virions . InteresHuman diseases that compromise functions of either spliceosome can have two differential outcomes in competitive contexts between the two spliceosomes. First, in cases of competitive intron recognition that leads to a balanced expression of spliceosome-specific mRNA isoforms, such as those described above, the most likely outcome is a shift in the balance between the isoforms. This effect may vary depending on the specific mutation/spliceosomal defect, and may be combined with other outcomes, such as alterations in exon definition mechanisms or increased levels of intron retention.An alternative possibility is the activation of cryptic splice sites near introns that do not display any obvious competition between the two spliceosomes. “Cryptic” in this context refers to splice sites that are not used under physiological conditions and are predictably also not annotated or documented in public databases. Thus, cryptic splice sites can be thought of as pseudo splices sites that are weaker in strength compared to authentic sites, and as such, are not efficiently recognized by the spliceosome in a context specific manner. Such splice sites tend to be activated as a consequence of mutations in either authentic splice sites or alternatively, in spliceosome components or regulators. Both lead to defects in splice site recognition either at the level of single introns, or more broadly . While cSNRNPE, RCD8/EDC4 and SLC9A8 genes  implicated in the Peutz-Jager Syndrome    and AP4Mal palsy  both of al palsy . In contal palsy . The stuUntil very recently, the outlook on the regulatory significance of the minor spliceosome functioning in parallel with the major spliceosome has been static. The main focus in the field has been on the inefficient splicing of U12-type introns under physiological conditions and the increased intron retention events observed in minor spliceosome diseases. However, rapidly accumulating transcriptomic data from an increasing number of minor spliceosome diseases is now challenging this narrow view by providing robust evidence of widespread crosstalk mechanisms between the minor and major spliceosomes, which were previously only reported in single-gene investigations. The fact that the locations of U12-type introns are known and highly conserved, presents a unique opportunity or lens through which the parallel functioning of both spliceosomes, particularly in exon and intron definition contexts, can be examined. Importantly, under physiological conditions, crosstalk between the two spliceosomes appears mostly to function as a mechanism for reinforcing constitutive splicing patterns through exon definition interactions, and to a lesser extent, as a mechanism for regulating balanced expression of mRNA isoforms that are dependent on either spliceosome. The less studied role of this crosstalk in regulating gene expression is particularly intriguing, as the few genes described here that utilize adjacent U12-and U2-type splice sites to regulate their expression, highlight an overlooked yet significant regulatory mechanism for some MIGs. Consequently, examining such crosstalk mechanisms has the potential to contribute to current understanding of the evolutionary significance of both spliceosomes functioning in parallel. Interestingly, for genes currently known to harbor these adjacent splice sites both cooperative and competitive outcomes have been observed, with the latter being more common. Competition between splice sites is a common occurrence for U2-type introns, due to the more degenerate splice sites in these introns and has been discussed extensively within the context of alternative splicing . In contMAPK8/9 (TMEM87a/b (In disease contexts the primary splicing defect can lead to additional defects in both competitive and collaborative interactions between the two spliceosomes. The occurrence of additional mRNA isoforms as a consequence of the loss of crosstalk between the two spliceosomes also influences the interpretation of transcriptomic data derived from minor spliceosome disease patient cells. A typical transcriptome-level workflow aims to identify the affected minor introns and MIGs, and optionally, use the intron retention levels to estimate the downregulation of MIGs for downstream analyses. Thus, the presence of novel transcripts arising from cryptic splice site usage and the loss of exon definition interactions can either exacerbate the effect on expression levels or lead to formation of mutant proteins, which may contribute to the pathology of the given disease. Additionally, the MAPK8/9  and TMEMMEM87a/b  examplesMEM87a/b  have demMEM87a/b .de novo events, such as KisSplice used in the CENATAC (At a more technical level, the activation and detection of cryptic splice sites poses an additional challenge for data analysis. Most software used in alternative splicing analyses rely on existing annotations when detecting alternative splicing events . As cryp CENATAC , we docu CENATAC , which iIn summary, recent transcriptome-wide investigations have uncovered a substantial number of crosstalk interactions between the major and minor spliceosomes. An outstanding question related to these splicing events concerns the identification of true regulatory events from cases representing opportunistic cryptic splice site activations. An additional unanswered question is whether either spliceosome can be regulated individually in a manner that would influence the crosstalk. There is some evidence of specific splicing factors such as hnRNP H/F and SRSF10 being linked to regulation of the minor spliceosome , but theBoth authors contributed equally 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.


Cell proliferation is an important cellular process for physiological tissue homeostasis and remodeling. The mechanisms of cell proliferation in response to pathological stresses are not fully understood. Mitochondria are highly dynamic organelles whose shape, number, and biological functions are modulated by mitochondrial dynamics, including fusion and fission. Mitofusin-2 (Mfn-2) is an essential GTPase-related mitochondrial dynamics protein for maintaining mitochondrial network and bioenergetics. A growing body of evidence indicates that Mfn-2 has a potential role in regulating cell proliferation in various cell types. Here we review these new functions of Mfn-2, highlighting its crucial role in several signaling pathways during the process of pathological cell proliferation. We conclude that Mfn-2 could be a new mediator of pathological cell proliferation and a potential therapeutic target. Cell proliferation is a precision–control process, which is essential for embryonic and postnatal development . Under pPreviously, mitochondria have been regarded as static and isolated organelles. More recently, they are found to undergo constant changes in morphology, including fission, fusion, and network formation, and they can also relocate to different parts in cells (trafficking); all of these processes are termed mitochondrial dynamics. Mitochondrial dynamics is essential to maintain the normal function of cells such as energy metabolism, calcium homeostasis, and reactive oxygen species generation . Mitochovia various pathways.Research in the past two decades or so have revealed that the mechanisms of mitochondrial dynamics are regulated by a group of highly conserved guanosine triphosphatases (GTPase) . MitofusIn this review, we summarized recent advancements in the study of mitochondrial fusion protein Mfn-2. We focus on the link between altered Mfn-2 and pathological cell proliferation.Current evidence indicates that Mfn-2 plays various roles in many cellular processes, including cell proliferation and cell death . Chen etAtherosclerosis is the main cause of cardiovascular diseases. It has been clearly demonstrated that the development and progression of atherosclerosis involve inflammation, abnormal proliferation of VSMCs, remodeling of the vascular wall, and evolution of occlusive plaques.via the inhibition of Erk/mitogen-activated protein kinase (Erk/MAPKs) signaling followed by cell cycle arrest. Cell transition from G0/G1 phase to S phase is one of the important characteristics for proliferation. EdU assay indicated that downregulation of Mfn-2 resulted in a significant decrease of G0/G1 phase cells and a synchronous increase of the percentage of S-phase cells in homocysteine-induced VSMCs, and overexpression of Mfn-2 obtained the contrary results, suggesting that cell cycle arrest at G0/G1 phase is responsible for the anti-proliferation effects of Mfn-2  and its receptors, inducing VSMCs to transform from quiescent state to secretion and proliferation state kt, etc. . One remkt, etc. . In Fengkt, etc. , which tIn patients diagnosed with type 2 diabetes, the incidence of atherosclerosis is high, and the expression of Mfn-2 in the muscle decreased; similar results are also observed in high-fat-diet mice. In addition, increasing the level of Mfn-2 could alleviate insulin resistance  through via autophagy, considering the role of Mfn-2 in the maintenance of MAM, more studies are required to provide evidence linking Mfn-2-mediated autophagy with VSMC proliferation in the future.As mentioned above, Mfn-2 is crucial in maintaining MAM structure. MAM is the central platform for the initiation of mitophagy and the formation of autophagosome . Chen anPulmonary hypertension is another pathological condition attributed to VSMC proliferation. Pathophysiological changes involve all three layers of pulmonary arteries during vascular remodeling. For instance, endothelial angiogenesis, smooth muscle cell hyperplasia and hypertrophy, adventitial fibroblast proliferation, myofibroblast differentiation, and extracellular matrix deposition have all been reported . The excThe role of Mfn-2 in pulmonary hypertension is complicated. via targeting Mfn-2 directly. Recent studies revealed that miRNAs play an important role in the pathogenesis of pulmonary hypertension by regulating ASMC proliferation . Several2+ transfer and inhibit cell proliferation in kidney cysts  is a cellular state in which the protein folding capacity of ER is overwhelmed due to increased protein load or disruption of the protein folding environment . It has  pathway . Ngoh et pathway . DownregA study from via the N-terminus  receptors (IP3R) and ryanodine receptors (RyRs) on the ER membrane  and entevia the Wnt/β-catenin pathway in bladder cancer. Mfn-2 knockdown increased the translocation of β-catenin into the nucleus, resulting in larger tumor volumes and a higher proliferation index. Pharmacological inhibition of the Mfn-2/mTORC2/Akt pathway attenuated tumor growth via various signaling pathways, there are currently no studies that figured out whether these pathways are related to mitochondria fusion. More studies on this topic may be necessary in the future.Although some evidence indicated that, in addition to fusion reaction, Mfn-2 has been reported to regulate cell proliferation (2)Although there are many evidence about the role of Mfn-2 in neoplastic diseases, the microenvironment may change the impact of Mfn-2 in different types of cancers. In the future, a more detailed analysis of Mfn-2 may be necessary.(3)Could altered Mfn-2 act as a potential biomarker in pathogenesis?via MAM formation and mitophagy to regulate cell proliferation and cell survival/death in different tissues. Many important questions await extensive investigation. In the future, studies on the role of Mfn-2 in cell proliferation may lead to the development of new strategies for treating various diseases, such as cancer and cardiovascular diseases.The machineries of mitochondrial fusion/fission and the significance of mitochondrial dynamics in regulating mitochondrial and cellular functions have been established. The mitochondrial fusion protein Mfn-2 regulates mitochondrial morphology, metabolism, calcium homeostasis, and mtDNA stability. Mfn-2 also plays a role YX and JL draft the manuscript. WW revised and polished the manuscript. XL supervised the review and established the whole frame. All 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.


The Li−S batteries showed stabilized coulombic efficiency as high as 94% and excellent cyclic performance with an ultra low cyclic fading rate of 0.075% for the initial 280 cycles at a current density of 1.0 C. The improved electrochemical performance was ascribed to the enhanced conductivity by the connective graphene networks and the weakened shuttle effect by the special outer graphene layers. Mass production of the products was realized by the continuous FB−CVD process, which opens up new perspectives for large scale application of 3D graphene materials.Three−dimensional (3D) graphene with novel nano−architectures exhibits many excellent properties and is promising for energy storage and conversion applications. Herein, a new strategy based on the fluidized bed chemical vapor deposition (FB−CVD) process was proposed to prepare 3D graphene networks (3DGNs) with various nano−architectures. Specially designed SiC−C@graphene core/shell nanoparticles were prepared taking the advantages of the FB−CVD system, and 3DGNs with hierarchical nanostructures were obtained after removing the SiC core. The 3DGNs performed well as electrodes of lithium–sulfur batteries. The C–S cathode showed good rate performance at the current density of 0.1–2.0 C, and an initial discharge capacity of 790 mAhg Since its discovery in 2004, graphene has drawn increasing attention and has been intensively investigated due to its unique and excellent properties, such as huge specific surface area, high electrical conductivity and electron mobility, robust mechanical performance, good flexibility, high thermal conductivity, and efficient light absorption ,2,3. OveLithium–sulfur batteries are nowadays undergoing a tremendous number of investigations because of the highest theoretical capacity of elemental sulfur among cathode materials for secondary lithium batteries . However2O3 nanoparticles (NPs) have been used as templates for the catalyst−free CVD of graphene meso−sponge with monolayer graphene [Until now, several methods have been developed for fabricating 3DGNs, which could be divided into two categories: assembly of graphene sheets and direct synthesis from carbon sources . Assemblgraphene . 3DGNs pgraphene . Though To combine the construction of 3DGNs with hierarchical nanostructures in scientific perspective and the mass production in engineering perspective, we proposed a novel strategy by fluidized bed chemical vapor deposition (FB−CVD). SiC−C@graphene core/shell nanoparticles with novel nanostructures were first prepared via the FB−CVD process. After heat treated under high temperature and vacuum environment, high purity 3DGNs were obtained. The nano−architectures of the 3DGNs could be adjusted thanks to the different microstructures of SiC−C@graphene nanoparticles prepared at different experimental conditions. Sulfur with high loading was infiltrated into the 3DGNs via a melt−diffusion strategy to prepare the carbon/sulfur composite cathodes for lithium–sulfur batteries. The cathodes showed good discharge capacity, improved cyclic performance and excellent efficiency, demonstrating a great prospect of engineering application for the 3DGNs produced by the continuous FB−CVD process.−3 Pa. After heat treatment, SiC particles were evaporated and the carbon phase was remained to form 3D connective graphene net−cages. To investigate the effect of reaction atmosphere, propylene concentration and temperature on the microstructure of the products, different experimental conditions were conducted as shown in Preparation of the 3DGNs: The SiC−C@graphene nanoparticles were prepared by a fluidized bed chemical vapor deposition (FB−CVD) method. In a typical synthesis process, the reaction zone of the vertical fluidizing tube was heated at 1000 °C. Hexamethyldisilane (HMDS)  was used as the precursor to prepare SiC–C composite nanoparticles. HMDS was heated at 80 °C by a water bath to form vapor and then was carried into the furnace by argon. The other precursor of propylene was injected to the furnace at the same time. The products were collected by powder separator device which was connected to the gas outlet of the furnace. The obtained composite nanoparticles were then heated at 1950 °C for 3 h under a vacuum degree of 10Fabrication of 3DGNs/Sulfur Composites: The 3D graphene net−cages powder/sulfur composite cathodes were fabricated following a typical melt−diffusion strategy. The 3D graphene net−cages powder was firstly mixed with sulfur powder  with a mass ratio of 1:4 by milling. Subsequently, the mixture was placed in a sealed flask at 155 °C for 5 h to incorporate sulfur into the 3D graphene net−cages.−1 at room temperature. The differential scanning calorimetry (DSC) and thermogravimetry (TG) measurements were performed by a simultaneous thermal analysis apparatus  with a heating rate of 5 °C/min in different atmospheres.Characterizations: Microstructures of the product were observed by a field emission scanning electron microscope . The TEM images and corresponding selected area electron diffraction (SAED) patterns were obtained on a high resolution transmission electron microscope  at an acceleration voltage of 200 kV. The crystal structure of the samples was examined by X−ray diffraction (XRD) on a diffractometer using Cu Kα radiation . Raman scattering was excited employing a He–Ne laser (λ = 516 nm), and was collected by a micro−Raman spectrometer  in the wave number of 1000–3500 cmN−methyl−pyrrolidone dispersant by a magnetic stirrer for 24 h. The slurry was then coated onto an aluminum foil, followed by a vacuum drying for 6 h at 60 °C to obtain an areal sulfur loading of 1.1 mg·cm−2. Disks of 13.0 mm were punched as the working cathodes. A quantity of 25.0 μL electrolyte containing 1.0 M lithium bis (trifluoromethanesulfonyl)imide solution in 1,3−dioxolane/1,2−dimethoxyethane (1:1 v/v) was used to construct the Li–S cell. Lithium metal foil was used as the anode and the polypropylene membranes were used as the separators. The coin cells were tested in galvanostatic mode at various currents within a voltage range of 1.6–2.8 V using multichannel battery cycler . The cyclic performance was tested at a current density of 1.0 C. The capacities were calculated corresponding to the total mass of the cathodes slurry.Electrochemical Measurements: Li−S batteries were constructed to evaluate the electrochemical performance of 3D graphene net−cages as cathode scaffolds according to the procedure of the reference . The catThe spouted fluidized bed (FB) technology and chemical vapor deposition (CVD) method are combined to prepare C–Si based nanoparticles with hierarchical structures. Compared with conventional CVD route, the so−called spouted fluidized bed chemical vapor deposition (FB−CVD) method originally used for nuclear fuel particle coating, displays many advantages in the synthesis of nanostructured particles ,32,33,342 ratios. When 30% H2 was introduced into the furnace, which meant a decrease of the carbon content, the framework of the 3D graphene tended to open and lose the spherical shape, presenting a flower−like structure  graphene networks with novel nano−architectures were prepared by combining the FB−CVD process and subsequent heat treatment. Taking the advantages of the uneven temperature distribution of the fluidized bed and the rapid transport mechanism, core/shell structured SiC−graphene nanocomposites were prepared. The 3DGNs with different nano−architectures could be fabricated by adjusting the reaction atmosphere, temperature and precursors of FB−CVD. Novel 3D graphene net−cage nanostructures with interlaced graphene nanobelts and connected graphene shells were obtained from SiC−C@graphene nanocomposites. The 3DGNs performed well as electrodes of lithium–sulfur batteries with high sulfur loading, high discharge capacity, excellent cyclic performance and high efficiency. The hierarchical internal and external microstructures of the 3DGNs were responsible for the high electrochemistry performance by improving the conductivity, resisting the volume change and hindering the shuttle effect. This work provides a novel and effective synthesis strategy for the preparation 3DGNs with nano−architectures. These unique 3DGNs will find diverse applications in areas such as lithium−ion batteries, catalytic carriers and supercapacitors by fine structure design and integration with other functional materials. The realization of mass production by the FB−CVD process opens up new perspectives for large scale engineering application of the 3D graphene materials.


Aerogels have attracted significant attention recently due to their ultra-light weight porous structure, mechanical robustness, high electrical conductivity, facile scalability and their use as gas and oil absorbers. Herein, we examine the multi-functional properties of hybrid aerogels consisting of reduced graphene oxide (rGO) integrated with hexagonal boron nitride (hBN) platelets. Using a freeze-drying approach, hybrid aerogels are fabricated by simple mixing with various volume fractions of hBN and rGO up to 0.5/0.5 ratio. The fabrication method is simple, cost effective, scalable and can be extended to other 2D materials combinations. The hybrid rGO/hBN aerogels (HAs) are mechanically robust and highly compressible with mechanical properties similar to those of the pure rGO aerogel. We show that the presence of hBN in the HAs enhances the gas absorption capacities of formaldehyde and water vapour up to ~ 7 and > 8 times, respectively, as compared to pure rGO aerogel. Moreover, the samples show good recoverability, making them highly efficient materials for gas absorption applications and for the protection of artefacts such as paintings in storage facilities. Finally, even in the presence of large quantity of insulating hBN, the HAs are electrically conductive, extending the potential application spectrum of the proposed hybrids to the field of electro-thermal actuators. The work proposed here paves the way for the design and production of novel 2D materials combinations with tailored multi-functionalities suited for a large variety of modern applications. The GAs can also be used as reinforcing agents in composites, in sensors and nano-electronics, energy storage2, as cell growth promoters3, absorbers for the removal of food toxins4, in catalysis and biomedical applications among others1. Other materials such as hexagonal boron nitride (hBN) have also attracted significant attention for the fabrication of aerogels5 since their distinct properties as compared to GAs, pave the way for the development of new applications. For example, boron nitride based aerogels (BNAs) have been extensively used for the removal of organic and inorganic pollutants from aqueous solutions with high efficiency6. Moreover, BNAs possess high thermal conductivity and they remain stable up to 1000o C which make them attractive materials for applications required to perform reliably under harsh environments7. Besides graphene and boron nitride based aerogels, the area is highly active and other materials have also been tested, including silica9 and SnO210 based aerogels that show attractive properties and have been used in various applications.Graphene aerogels (GAs) have attracted significant attention recently since they are ultra-lightweight, mechanically robust, electrically conductive, perform well under harsh environment and as a result have found good use in various applications17. In this regard, hybrid aerogels (HAs) have started to gain attention and some efforts have already been reported in the literature for aerogels composed of combined graphene/boron nitride nano-sheets12, graphene/ boron nitride nanotubes13, graphene/MoS216 and others17. In particular, BNAs exhibit high thermal conductivity but low electrical conductivity,18 therefore, they are only suitable for applications as insulators. In contrast, reduced graphene oxide has both high thermal and moderate electrical conductivity and therefore its field of application differs than hBN. Both materials possess attractive mechanical properties, they are highly compressible and perform well as absorbers of gas and oil pollutants. It would be of great interest to create hybrid aerogels that retain the properties of the standalone materials or even develop hybrids that could outperform the efficiency of the homostructured materials.In an attempt to combine and exploit the distinct properties of dissimilar 2D materials, the fabrication of 2D hybrids could, under certain circumstances, impart new multi-functionalities and therefore has recently emerged as a very intense research field19. Bi et al.20 examined the efficiency of spongy graphene for oil absorption by floating the sample in liquid pollutants such as commercial petroleum products, fats and ketones, and the results showed high speed of absorption and efficient recovery. Similar experiments have been performed for thermally cross-linked Poly(acrylic acid)/rGO of low porosity as absorbers of various oils with high efficiency21, as well for pure graphene aerogels with density less than ~ 9 mg/cm322. An extensive discussion on the subject regarding carbon based absorbers can be found in reference19 and for hBN based materials in reference6. Boron nitride based porous materials have also been tested for the removal of substances from water. A foam like hBN structure was developed with density of ~ 30.4 mg/cm3 and proved very efficient for the removal/separation of a number of oils and chemicals by immersing the porous materials into contaminated water23. Similar experiments performed for another sponge like material made by few-layer hBN-coated melamine sponge which showed to possess very good recyclability performance24.One particular application of the aerogels is their use as volatile organic compounds (VOC) absorbers for the protection of museum artefacts such as paintings and other objects. It is worth noting that most artefacts owned by museums are often stored under hostile environmental conditions in deposits (e.g. in crates and boxes). It has been estimated that the largest museums typically display only about 5% of their collection at any time. This roughly 5% is usually rotated among the most important works the museums have, while other less significant works may never leave the storage area. Additionally, some artworks may be displayed but need preservation frequently in order that they survive, like works based on paper, which will fade if exposed to light. Both carbon and hBN aerogels have been tested as oil and organic absorbersHerein, we fabricate hybrid aerogels at various mix ratios composed of reduced graphene oxide (rGO) and hexagonal boron nitride (hBN) platelets using a freeze-drying approach. The method is cost effective and can be easily used for the fabrication of large-scale quantities, while it can be extended to the fabrication of other 2D materials as well. In this work we examine in detail the mechanical properties of the HAs as well the changes in the electrical conductivity induced by the presence of hBN. Furthermore, we investigate the efficiency of the proposed HAs as gas absorbers of formaldehyde, hydrochloric acid and acetic acid, as well their capacity for water vapour absorption. The results presented below show that the rGO/hBN hybrid aerogels possess good mechanical properties and reasonable electrical conductivities but, most importantly, certain combinations of these hybrids exhibit extremely high gas absorption capabilities.25 was followed herein for the fabrication of the rGO aerogels. Aqueous solution of GO was prepared by modified Hummer’s method27 and was subsequently diluted in water to obtain a concentration of 1 mg/mL. Hypophosphorous acid (H3PO2) and iodine (I2) of weight ratio GO: H3PO2:I2 equal to 1:100:10, were then added as the chemically reducing agents28. Subsequently the solution was placed in a furnace and heated to 80 °C for 8 h, resulting in a uniform gelation of the GO. The sample was then rinsed with water until a pH equal to 5, followed by freeze-drying for 48 h. For the fabrication of the HAs, another solution with boron nitride platelets of 1 mg/mL concentration was prepared in ethanol–water (50–50% w/w) and stirred for 10 min. Solutions with mixed GO and hBN with various concentrations of 0.9/0.1, 0.7/0.3 and 0.5/0.5 mg/mL were stirred and then the same steps as for the case of the pure GO were followed. We note that the addition of ethanol significantly stabilizes the mixed solution29 and assists to achieve uniform dispersions as seen in Fig. 13. It is noted that this approach cannot be used for the preparation of pure hBN aerogels, which points out to the crucial role of the presence of the GO which stabilizes the mixture. This is due to the gelation mechanism that involves the simultaneous reduction and self-assembly of the GO sheets, based on chemical reactions between the oxygen functional groups present at the surface of the GO and the chemical agents28. Thus, the hBN platelets that do not contain such groups on their surface simply attach to the GO sheets. The only complication is that the gelation time might be increased in the mixed solutions as discussed previously13. The density of the aerogels is found to be in the range of 13.9–23.4 mg/cm−3 without significant variation between samples.The approach presented previously by Hong et al.5/2 line. The analysed area was a spot with 3 mm diameter. The atomic ratios were calculated from the intensity (peak area) of the XPS peaks weighted with the corresponding relative sensitivity factors (RSF) derived from the Scofield cross-section taking into account the electron transport properties of the matrix,  and the energy analyser transmission function. For spectra collection and treatment, including fitting, the commercial software SpecsLab Prodigy  was used. The XPS peaks were deconvoluted with sum Gaussian-Lorenzian peaks after a Shirtey type background subtraction.The surface analysis measurements were performed in a UHV chamber (P ~ 5 × 10 − 10 mbar) equipped with a SPECS Phoibos 100-1D-DLD hemispherical electron analyser and a non-monochromatized dual-anode Mg/Al x-ray source for XPS. The XP Spectra were recorded with MgKa at 1253.6 eV photon energy and an analyser pass energy of 10 eV giving a Full Width at Half Maximum (FWHM) of 0.85 eV for Ag3d2O), hydrochloric acid or acetic acid were used as gas source each time. For the humidity measurements, vials full of water were placed similarly to the gases, while the relative humidity (RH) was measured independently and was found to be ~ 97%. All samples were initially dried at 200 °C for 2 h in order to remove their absorbed humidity and weighed into a high accuracy weight meter to measure their dried mass. Afterwards, the aerogels were loaded in a glass petri dish which was mounted inside the desiccator. The desiccator with the aerogels and the fuming gas was constantly inside a fume hood. Periodically, the mass of each sample was recorded by the weight meter, exactly next to the fume hood minimizing the exposure of the aerogels to the environment. The regeneration of the graphene and the graphene-hBN aerogels was performed by using a common electric hair dryer. During the regeneration process, the formed volatile vapour was removed with the assistance of the hood, as reported by Li et al.30.The gas absorption test was conducted in static conditions into a closed glass desiccator with an excess of pollutant, using a saturated vapour stream at room temperature. 100 mL of either formaldehyde  component concentration is calculated and from the peak intensities of C1s, O1s, P2p and N1s the (%) relative atomic ratio is obtained. Both sets of results are shown in Table 33. The C:O ratio for the 50/50 is almost the half of the pure GA which shows that the presence of hBN affects the reduction of the GO.In Fig. 34. The HAs show graphite peak at 2θ = 26° and also a clear peak at 27.3°, which are attributed to the (002) diffraction of hBN12. The position of the Raman peaks for the GO are ~ 1590 cm−1 and 1356 cm−1 corresponding to the G and D phonons, respectively35. The presence of hBN is also evident in the HA from an intense peak at 1366 cm−1 originating from the in-plane E2g phonon mode36. The intensity of the peak of the hBN is large due to the relatively large thickness (~ 2–3 μm) of the platelets.In Fig. −3 for all cases. In fact, this value is a prerequisite for classifying the 3D porous structure as an aerogel12. The structural characteristics of the integration of the rGO with the hBN, such as the attachment and wrapping of the hBN to the rGO, agrees very well with the results reported in other studies12.SEM images for all samples with various mixed ratios are given in Fig. The mechanical properties under compression for the hybrid structures of variable rGO/ hBN content were examined in detail and compared to those of the pure rGO aerogel. In Fig. −3 were tested and a compressive stress of ~ 1.5 kPa was measured at 50% of strain11. Elsewhere, rGO aerogels reinforced with boron nitride nanotubes of total density ~ 16 mg/cm−3, reached stress of ~ 12 kPa at ~ 75% of compressive strain13. We note that the mechanical properties of aerogels are linearly related to the density of the samples38, and the modulus for the GA of the present study agrees well with the analysis of reference37. Thus, the present HAs possess better mechanical performance as compared to reported results for other heterostructures13 since they have similar density or slightly higher, and in our case they reach much higher compressive stresses without failure.In a previous study, similar HAs with a smaller density of ~ 3.6 mg/cm39. The 90/10 hybrid exhibits almost half of this value of ~ 23.3 S/m, and with further increment of the amount of the hBN the conductivities do not vary a lot within the experimental error  and humidity of important artefacts in storage facilities  which is one of the main objectives of the present work.Both GAs and BNAs are highly efficient gas and oil absorbers45. Prior to exposing the samples to the gas/humid environment, care was taken to dry the samples by heating to 200 °C, followed by immediate measurements of their initial weight under dry conditions. The samples were then placed in a desiccator and exposed to saturated gas controlled environment, while their mass weight gain due to absorption was monitored by regular gravimetric measurements until the maximum mass increment was reached. More details can be found in the experimental section. From Fig. We tested the efficiency of the proposed hybrids and the GA for absorption of formaldehyde, hydrochloric acid and acetic acid, which are among the most commonly examined gases, as well the water vapour (humidity) absorption. Formaldehyde, in particular, is considered as a model polar VOC pollutant46. Formaldehyde is physiosorbed on graphene48, and this absorption is weak because of its small binding energy, large binding distance and small charge transfer from formaldehyde to the graphene sheets48. On the other hand, hBN (sponge like) exhibits superb formaldehyde absorption performance due to its high specific surface area and its abundant surface hydroxyls and amines46. Furthermore, the HAs are more hydrophilic compared to the rGO as deduced form the humidity absorption measurements discussed below, which also contribute to the high performance toward gaseous formaldehyde46. Additionally, chemisorption takes place on the hBN layers and contributes to high formaldehyde absorption via Cannizzaro-type disproportionation reactions, during which formaldehyde is converted into less toxic formic acid and methanol46. Another factor that can enhance the formaldehyde absorption is the surface properties of hBN. Hydrogen bonding between formaldehyde and hydroxyl or amine groups is very crucial in the absorption of formaldehyde50, while the formaldehyde molecules and hBN layers show both planar configuration, resulting in lower adsorption resistance46. Finally, formaldehyde has π-bonding between C and O atoms, while hBN also shows large 2D delocalized π-bonded structure. Consequently, π−π bonding interaction can occur between hBN and formaldehyde and this strong interaction enhances the absorption of the latter46.The high absorption of formaldehyde of the HAs can be mainly ascribed to the polarity of the molecules of formaldehyde. It is considered that materials with high specific surface area and a hydrophilic surface can be effective adsorbents for formaldehydeb = 0.29 eV51. When the formaldehyde molecules are adsorbed onto the neat rGO sheets, formaldehyde shows the preference to be located perpendicular to the sheet with H atoms close to the sheet, as shown in Fig. 52. Thus, graphene then becomes a n-type semiconductor, the valence electrons are increased and charge transfer from the electron donor molecules, formaldehyde, to the graphene sheets takes place51.As already mentioned, formaldehyde is known to be weakly physiosorbed on reduced graphene oxide sheets as a consequence of its small binding energy to graphene which is equal to E53. Formaldehyde exhibits larger adsorption energy and net charge transfer when is chemisorbed on doped graphene in comparison to a corresponding undoped graphene sheet. Specifically, for a boron-doped graphene sheet, the adsorption energy (Eads) and charge transfer (Q) are equal to − 0.543 eV and 0.239 e respectively, while the corresponding values for pristine graphene are − 0.137 eV and 0.094 eV, respectively53. This high adsorption energy is a strong indication that chemical bonds are created between the dopants  and O atom of formaldehyde. The reason behind this behaviour is the hybridisation between the dopants  and C atoms, around the two dopant atoms. Especially for boron, an overlap between B-2p and C-2p orbitals, with the energy ranging from − 3.810 to − 2.236 eV is observed53, which proves the appearance of a strong hybridization between B and C atoms around the doping atom. This strong orbital interaction between the p orbitals of B, N, and the C atoms also alters the magnetic properties of such systems53.As the amount of hexagonal boron nitride is gradually increased in the hetero-structured aerogel, the adsorption of formaldehyde increases (from 90/10% wt. to 50/50% wt.). This can be explained due to the strong chemisorption between the molecules of (adsorbed) formaldehyde and the ‘doped’ with hBN, graphene. It has been shown that doping graphene with boron (B) and nitrogen (N) atoms enhances the interaction between the graphene and formaldehyde significantly54. The related mechanism is shown in Fig. For the interaction between the boron nitride platelets and the formaldehyde, Cannizzaro-type disproportionation reaction of the latter has been reported to be dominant56 as can be deduced by the same approximately adsorption rates of all the hybrid aerogels that were examined in HCl, and neat rGO inside formaldehyde. It has been found that especially for a single chlorine atom, the bonding is ionic through the transfer of charge from graphene to chlorine adatom and creates a small local distortion in the underneath planar graphene55. The transfer of a single chlorine adatom on the surface of graphene is achieved almost without barrier. But, the anchoring of a graphene surface with Cl adatoms resulting in several conformations cannot be maintained because of the strong Cl-Cl interaction which in turn facilitates the desorption through the creation of Cl2 molecules.Regarding the adsorption of hydrochloric acid onto the examined pure rGO and hybrid aerogels, a weaker interaction between the HCl molecules and the surface of the prepared materials can be observed, as shown in Fig. 63. For comparison they are listed in the supporting information  was measured to be ~ 97% by the addition of a humidity sensor inside the chamber. Following the same procedure with the gas absorption measurements, the samples were firstly dried at 200° C and then being weighed periodically until they achieved a maximum absorption. As shown in Fig. As already mentioned, we cannot fabricate pure hBN aerogels with this approach, thus we cannot have a direct comparison for this case. The absorption results show that the two materials have different efficiencies depending on the specific vapour. The absorption efficiency is not compromised by mixing of the 2D materials, thus, in order to make as efficient absorbers as possible for a wide range of vapour concentrations, we need to use more than one material. Given the large availability of 2D materials with diverse properties, there is much room for the fabrication of novel highly efficient absorbers beyond the state-of-the-art. Moreover, these hybrids can be exploited in other applications for which electrical and thermal conductivities are required.46. Furthermore, the addition of hBN provides superior thermal conductivity to the HAs12, which make them promising materials for applications at elevated temperatures, further expanding their potential use. The HAs can be used as more efficient VOC absorbers for absorption of multiple compounds, in contrast to the standalone materials which are not efficient for all cases. All the above give the HAs a high degree of multi-functionality which enables their use in a plethora of applications, and, as demonstrated in the main text, the proposed aerogels can be used for protection of artefacts such as paintings in storage facilities in which a high concentration of humidity and VOCs is encountered.In summary, we presented a facile fabrication route for 2D hybrid aerogels comprising of rGO mixed with hBN platelets. The fabrication method is cost effective and scalable compared to high energy demanding methods for the fabrication of pure hBN aerogels, and can be used for mixing other 2D materials with rGO. The resulted HAs are mechanically robust with mechanical properties similar to those of pure GA. The HAs are electrically conductive, despite a decrease that occurs compared to the pure rGO aerogel, which can be useful for applications for which electrical conductivity is required. The most striking result is the very effective absorption capacity of the HAs of formaldehyde and humidity, which is 7–8 times higher compared to the pure GA and at least one order of magnitude higher than a pure hBN aerogelSupplementary Information.


A small number of studies suggested that air pollution was associated with idiopathic pulmonary fibrosis (IPF) exacerbation, incidence and mortality. However, no studies to date were conducted in regions where air pollution is substantial. We aimed to investigate whether there are associations between acute increases in air pollution and hospitalization of patients with a confirmed primary diagnosis of IPF in Beijing.10, PM2.5, NO2, Ozone, SO2 were obtained from 35 municipal monitoring stations for the same period. The association between daily IPF hospitalization and average concentration of each pollutant was analyzed with a generalized additive model estimating Poisson distribution.Daily count of IPF hospitalizations  was obtained from an administrative database for 2013–2017 while daily city-wide average concentrations of PM2.5 concentration during 2013–2017 was 76.7 μg/m3. The relative risk (RR) of IPF hospitalization per interquartile range (IQR) higher (72 μg/m3) in PM2.5 was 1.049 (95% CI 1.024–1.074) and 1.031 (95% CI 1.007–1.056) for lag0 and moving averages 0–1 days respectively. No significant associations were observed for other lags. Statistically significant positive associations were also observed at lag0 with SO2, Ozone and NO2 (in men only). Positive associations were seen at moving averages 0–30 days for PM10 , NO2 , and SO2 (RR per 15 μg/m3: 1.060 (95% CI 1.025–1.097), but not with PM2.5 or Ozone.Daily 24-h mean PMDespite improvement in air quality since the implementation of clean air policy in 2013, acute exposure to higher levels of air pollution is significantly associated with IPF hospitalization in Beijing. Air quality policy should be continuously enforced to protect vulnerable IPF populations as well as the general public.The online version contains supplementary material available at 10.1186/s12931-022-01998-8. Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung diseases (ILD), characterized by inflammation and fibrosis of the pulmonary parenchyma . The exa3) were found to be associated with acute exacerbation of IPF six weeks after exposure in 436 and 192 patients in South Korea [2), Particulate Matter with a diameter less than or equal to 10 μm (PM10) or 2.5 μm (PM2.5) were high in Santiago, Chile [2.5 and nitric oxide in the previous 30 days were significantly associated with IPF acute exacerbation [2 and/or PM exposure was associated with IPF incidence and mortality. To date, no studies have been conducted in a region where ambient air pollution is substantial.Unlike major respiratory conditions (e.g. chronic obstructive pulmonary disease (COPD), bronchitis, asthma), for which evidence of harmful effects from ambient air pollution is well documented –8, evideth Korea  and Franerbation . Two stuerbation , or a faerbation , of forcerbation , 15. Whierbation  and Souterbation  reportedAir quality in Beijing has been progressively improving due to the implementation of the Clean Air Action Plan (CAAP) since 2013 , althoug3 is reported based on hourly data that are available for at least 20 h in every 24 h. For O3, a daily maximum 8-h moving mean concentration is reported based on hourly data that are available for at least 6 h in every 8 h.Since 2013, major air pollutants have been routinely measured at 35 monitoring stations across Beijing, following the new Chinese national standard (GB 3095-2012). These monitoring stations were set up at locations that best represent different sources, for example, sources from road vehicles, urban anthropogenic activities, rural background and wider regional transport or background sources , and O3 were obtained from Jan 18th, 2013 to Dec 31st, 2017 (1809 days) by averaging daily mean readings from all 35 stations. Of the 1809 days, five days with missing data on all air pollutants were excluded. In addition, for O3, daily mean concentration was missing for another 34 days. As a result, the analyses of PM10, PM2.5, NO2 and SO2 were based on the 1804-day dataset whilst the analysis of O3 were based on a 1770-day dataset. Daily mean temperature (°C) and relative humidity (%) were provided by the Beijing Meteorological Service website.Daily city-wide mean concentrations of PM2.5, as a general air quality indicator, was not routinely monitored in Beijing before 2013. In order to examine whether there is difference on the association between PM2.5 and IPF hospitalization before and after the CAAP policy, we further obtained daily mean concentration of PM2.5 data during Apr 1st, 2008 and Dec 31st, 2012 (1508 days) from a single monitor operated by the US Embassy in Beijing. It was previously reported that within a radius of 40 km, this monitor covers 79.2% of the total population, 97.8% tertiary hospital and 79.3% secondary hospitals in Beijing that are eligible to admit IPF cases [2.5 data from this single monitor have been widely used in previous studies [2.5 monitor, we correlated the daily mean concentrations of this monitor with a nearby 1.5 km-apart government monitoring station using data from 2013. Overall, observations from the two monitors showed a high correlation (r = 0.93).PMPF cases . The PM2 studies , 20. To Daily counts of IPF hospitalization for the periods 2008–2012 and 2013–2017 were obtained from a database compiled by the Beijing Public Health Information Center. In Beijing, every government or private hospital at secondary or tertiary level is eligible to provide specialised care and required to submit the front page of each electronic hospital discharge record to the database . DetaileWe defined same-day exposure as lag0 (e.g. the admission date) and examined a priori single-day exposure up to five days (single-day lag0 to lag4) and exposure of moving averages 0–1, 0–2, 0–3, and 0–4 before admission date.While our primary analysis aim was to determine the acute effects of air pollution on IPF hospitalization, we additionally investigated the moving averages 0–30 period to account for potential subacute effects of air pollution on development of worsening symptoms of IPF. The exact exposure time window during which IPF patients develop an episode of worsening symptoms remains debated, although by convention the onset should be within one month prior to diagnosis . ExposurE(Yt) represents the number of IPF cases on day t; ‘C’ is the city-averaged concentration of the pollutant and i is the day lag; β represents log-relative risk (RR) of IPF hospitalisation associated with a unit increase in the pollutant mean concentration; ps indicates penalised spline function to filter out long-term trends and seasonal patterns in daily IPF hospitalisations. temp and RH are the daily mean temperature (°C) and relative humidity (%) respectively at lag0; public holiday and day of week were included as categorical variables. Degrees of freedom (df) for calendar time, temperature and relative humidity were selected based on the parameters used in previous studies [The associations between daily IPF hospitalization and average concentration of each pollutant were analyzed with a generalized additive model (GAM) estimating Poisson distribution: studies –24.Each association was investigated in two-pollutant models if Spearman correlation ratios between these pollutants were less than 0.7. Subgroup analyses were conducted by age (18–64 years vs. ≥ 65 years), sex, season (warm vs. cool), asthma (yes vs. no) and COPD (yes vs. no). We conducted the sub-group analyses at lag0 only because for most studied pollutants, the association was found to be much stronger at lag0 in the main model. The Z-test was used to compare the two estimates derived from each sub-group.The smoothing function of the generalized additive model was used to graphically analyse the exposure–response relationships between the log-RR of IPF hospitalization and air pollutant concentrations at lag0.We did several sensitivity analyses by altering the generalized additive model: (1) to exclude calendar time, as long-term trends and seasonal patterns might also be partly related to pollutant concentrations; (2) to replace calendar time with an interaction term of exposure-by-season; (3) to increase the degrees of freedom of temperature and humidity to six; and (4) to model moving averages 0–4 of temperature and humidity instead of the current day (lag0). The latter two sensitivity analyses were to adjust potential non-linear and lagged confounding effects of weather conditions.All statistical analyses were conducted in R (version 3.0.2) using packages MGCV, DPLYR, and TTR. Relative risk (RR) of hospitalisation for IPF per interquartile range (IQR) increase for each air pollutant were calculated and presented.2.5 concentration during 2008–2012 and 2013–2017 was 88.9 and 76.7 μg/m3 respectively , except the high correlation between PM10 and PM2.5 (r = 0.93), PM10 and NO2 (r = 0.73), PM2.5 and NO2 (r = 0.78)  higher was 1.049 (95% CI 1.024–1.074) at lag0, 1.031 (95% CI 1.007–1.056) at moving averages 0–1 and 1.021 (95% CI 0.998–1.044) at moving averages 0–2. Expressed per 10 μg/m3 higher of PM2.5, the RRs are 1.007 (95% CI 1.003–1.010), 1.004 (95% CI 1.001–1.008) and 1.003 (95% CI 0.999–1.006) respectively. Results of PM10 were similar to those of PM2.5 except that for the moving averages 0–30, where there was a positive association with PM10 , compared to a null association with PM2.5 .Acute exposure to higher PM3) higher in PM2.5 was 1.062 (95% CI 1.025–1.101) .During 2008–2012, the RR of hospitalization for IPF at lag0 per interquartile range (IQR) (83 μg/m3) higher of NO2 on both lag0 and moving averages 0–30 . A significant positive association was observed for SO2 at lag0 only (RR: 1.023 (95% CI 1.002–1.045) per IQR (15 μg/m3) higher). Positive effect estimates of SO2 appeared to be in an increasing trend. For example, the RR at moving averages 0–1 and 0–30 was 1.019 (95% CI 0.996–1.043) and 1.060 (95% CI 1.025–1.097) respectively. A significant positive association was seen at lag0 for O3  higher). Similar associations were observed at least until lag3. Significant positive associations were seen for moving averages 0–1 up to 0–4 ; however, the association at moving averages 0–30 was positive but not statistically significant . The associations with O3 were statistically significant during cool season but not in warm season . While in women, per IQR higher exposure to O3 at lag0 was significantly associated with IPF hospitalization . There were no significant effect modifications by age, season, COPD or asthma with each pollutant, although there is a tendency that patients aged ≥ 65 years had a higher hospitalization risk with higher exposure to each pollutant except NO2. For IPF patients with COPD, hospitalization risk  was significantly higher as per IQR higher O3 exposure, as compared to patients without COPD .Stronger positive associations with all pollutants except OOur findings suggest that acute exposure to higher levels of air pollutants, both particulates and gases, was significantly associated with IPF hospitalization in Beijing during 2013–2017. The magnitude of the associated risk is comparable to what was previously observed in Beijing for COPD exacerbation requiring hospitalization .To date, only four studies reported associations between short-term air pollution exposure and acute exacerbation or hospitalization of IPF , 9–11, w2.5 exposure and IPF hospitalization is an important addition to current knowledge. Previously, the Korean study did not have PM2.5 data [2.5 and acute exacerbation of IPF among 192 patients [2.5 exposure in the previous four days was a significant risk factor of IPF hospitalization [2.5 was much higher in Beijing (77 μg/m3 2013–2017) than in Santiago (29 μg/m3 2001–2012), the risk estimate in our study was relatively smaller. This may reflect differences in statistical approaches used , PM2.5 toxicity and population characteristics.Our finding of an association between acute PMlization , which i2.5, as compared to more recent exposure (i.e. past 30 days), was relatively more important in leading to IPF hospitalization. This is in contrast to a Japanese study of 152 patients in which a significant positive association between IPF acute exacerbation and prior 30-day average PM2.5 exposure was found [10 exposure and IPF hospitalization risk. This finding highlighted the potential of coarse PM in triggering symptoms among IPF patients via direct deposition in the respiratory tract over a sub-acute period [10 mainly come from dust whilst for PM2.5, traffic is the largest source with coal combustion and biomass burning contributing in winter months [Our study has suggested that more acute exposure (i.e. past three days) to PMas found . We did e period . In Beijr months , 26. We r months , which er months . Both cor months . Collect2.5 observed in 2013–2017, the associations observed in 2008–2012 were relatively stronger and the lag time to hospitalization was longer (5 vs. 2 days). It should be noted that PM2.5 data from 2008 to 2012 were only based on a single monitor. Although this is not a direct assessment of health benefits resulting from the Clean Air Action Plan, our findings seem to echo previous reports that improvement in air quality has indeed improved several morbidity and mortality outcomes in the Chinese population [We found that, as compared to the associations with PMpulation , 29, 30.3 up to preceding five days was significantly associated with IPF hospitalization. Further stratifying the associations by season, only in cool season can the statistically significant positive associations be observed. This is somehow unexpected as previous studies in Beijing or the northern part of China found that short-term effects of O3 on COPD exacerbation [3 concentrations in summer months and reported a significant positive association with acute exacerbation of IPF [3. As ours is the only study to date that reported seasonal variations of O3 associations with IPF hospitalization, these patterns remain to be determined in future studies. An alternative explanation is that O3 exposure in cool season may represent a proxy of other more important factors, such as viral infection, which is an known trigger in worsening IPF that may require hospitalization [3 is known to have the capability to exacerbate chronic lung conditions including asthma and COPD. In addition, O3 can cause breathing difficulty by bronchoconstriction, thereby increasing the risk of hospitalization among individuals with existing respiratory diseases including IPF [3 can reach and accumulate at the lower lungs because of its low water solubility, leading to inflammation and impaired small airways function, and potential hospitalization risk [This study found that acute exposure to Oerbation  and dailerbation  were morn of IPF  whilst Sn of IPF . The stun of IPF  and Japan of IPF  did not lization . Being ading IPF . Animal ion risk , 34.2 exposure [2 concentrations by 70% was recorded in Beijing from 2013 to 2017 [2 concentration. Associations did not appear to be significantly affected by further adjustment of PM2.5. These results indicated that continued investment on renewable and clean energy, with a steady reduction of traditional fossil energy consumption, still remain pivotal to SO2 abatement in order to mitigate the harmful impacts on respiratory diseases. As with O3, patients with chronic respiratory diseases may be sensitive to the effects of SO2, which has the capacity to induce oxidative stress, airway inflammation and breathing difficulty [Previous studies either found no associations between acute exacerbation of IPF and SOexposure , or thatexposure . Despite to 2017 , we stilfficulty .2 exposure and IPF hospitalization in the overall population. Interestingly, we found the same effect size for both moving averages 0–30 and lag0. Only in the men-only sample, this positive association became statistically significant. This finding is partly in line with the Johannson study of 436 (80% of them were men) South Korean patients [2 was significantly associated with IPF exacerbation. It should be noted that, association with the most acute exposure period (i.e. the week before manifested IPF exacerbation) was weaker and not statistically significant in the Johannson study. Similarly, the Japanese study of 152 patients (70% of them were men) reported significant positive associations between prior 30-day average NO2 and IPF acute exacerbation. In contrast, the French study did not find any association with NO2 [2 in the previous four days and IPF hospitalization in all populations, with the association being stronger among women [2 has been commonly studied as an indicator of traffic emission and is usually highly correlated with PM2.5, therefore it remains difficult to study its independent effects. Nonetheless, some have argued that NO2, via the airway inflammation pathway, could have direct and adverse impacts on respiratory health [We observed a marginally positive association between concurrent-day NOpatients , in whicwith NO2 . The timng women . NO2 has3 on IPF hospitalization was more pronounced in women, in line with studies which generally found women had a higher respiratory hospitalization risk from O3 exposure, particularly during the cold season [2 effects, we only found significant associations in men. The sex-specific  and gender-specific  differences of air pollution effects on respiratory health outcomes still largely remain inconsistent across studies [We observed that the risk of Od season . And for studies , and futTo our best knowledge, this is by far the first and the largest time-series study that was conducted in a city with high levels of ambient air pollution, using a relatively large number of IPF hospitalizations over a 5-year period from a representative database. The study has limitations. First, it is an ecological study by design, and hence the modelled risk estimates should not be interpreted as predictive of individual hospitalisation probability. Given the time-series study design, we were unable to adjust for important individual-level factors of IPF such as smoking and socioeconomic status. However, the proportion of these risk factors are unlikely to change substantially in the same population which we were investigating over a short period of time. Notably, time-varying factors such as seasonal viral or bacterial infection will likely have a more important role to confound these relationships, but we did not have these data for further investigation. Second, the use of daily, outdoor, city-wide average air pollutant concentrations inevitably will have introduced bias to health estimates because we cannot take into account place of residence and time-activity patterns  from the study population. Due to privacy reasons, we were only provided area-level (urban district or township) residential address for each patient for this secondary analysis, therefore we cannot model air pollution exposure at individual residence. However, this time-series analysis is an important first step to inform our next immediate work to study the impact of modelled air pollution at residence on health outcomes in a cohort of IPF patients should consent of accessing address data was granted. In addition, personal monitoring of air pollution exposure among IPF patients will provide even more novel insights into the exposure patterns and the associated health risks. Third, as with the Chilean study , our out2.5 by one-third (from 87 μg/m3 in 2013 to 58 μg/m3 in 2017) in the first phase. Although the annual mean PM2.5 in Beijing decreased to around 40 μg/m3 by end of 2021, it is still eight times higher than the recently updated WHO target value of 5 μg/m3, and therefore remains a significant health threat as demonstrated in this study. The concentrations for nitrogen dioxide and ozone, both of which are known to be harmful for respiratory health [The implementation of Clean Air Action Plan in Beijing successfully reduced the annual mean concentration of PMy health  and the In conclusion, this study provides evidence that acute exposure to higher levels of air pollution is associated with IPF hospitalization in Beijing. Local air quality policy should be stringently enforced, and carefully monitored for the progress to protect vulnerable populations, the general public and the planet.Additional file 1.Figure S1. Air quality monitoring stations across Beijing. Table S1. Spearman correlation between air pollutants during 2013-2017. Table S2. Associations between PM2.5 and PM10 (per IQR increase) and IPF hospitalisation in Beijing at different lags during 2013-2017. Table S3. Associations between PM2.5 (per IQR increase of 83 μg/m3) and IPF hospitalisation in Beijing at different lags during 2008-2012. Figure S2. Comparisons of associations between PM2.5 and IPF hospitalization for periods 2008-2012 and 2013-2017. Table S4. Associations between gaseous pollutants (per IQR increase) and IPF hospitalisation in Beijing at different lags during 2013-2017. Table S5. Associations between ozone (per IQR increase) and IPF hospitalisation in Beijing at different lags during 2013-2017: by season. Table S6. Results of the sensitivity analyses. Table S7 Results of two-pollutant models. Figure S3. Exposure-response curves between air pollution exposure and IPF hospitalization at lag0.