One of the urgent problems of materials science is the search for the optimal combination of graphene modifications and carbon nanotubes (CNTs) for the formation of layered hybrid material with specified physical properties. High electrical conductivity and stability are one of the main optimality criteria for a graphene/CNT hybrid structure. This paper presents results of a theoretical and computational study of the peculiarities of the atomic structure and the regularities of current flow in hybrid films based on single-walled carbon nanotubes (SWCNTs) with a diameter of 1.2 nm and bilayer zigzag graphene nanoribbons, where the layers are shifted relative to the other. It is found that the maximum stresses on atoms of hybrid film do not exceed ~0.46 GPa for all considered topological models. It is shown that the electrical conductivity anisotropy takes place in graphene/SWCNT hybrid films at a graphene nanoribbon width of 4 hexagons. In the direction along the extended edge of the graphene nanoribbon, the electrical resistance of graphene/SWCNT hybrid film reaches ~125 kOhm; in the direction along the nanotube axis, the electrical resistance is about 16 kOhm. The prospects for the use of graphene/SWCNT hybrid films in electronics are predicted based on the obtained results. In the last decade, the possibility of combining graphene and CNTs has attracted much attention from the research community in order to obtain new multifunctional hybrid materials with promising properties due to the synergistic effect caused by the interaction of nanostructures of various dimensions—1D nanotubes and 2D graphene ,7,8,9,102/Si substrate has been presented by Liu et al. [5), fast response time (~100 μs), and ultra-wideband sensitivity in the range of electromagnetic radiation from visible to near-infrared. Liu et al. have also developed the flexible photodetector utilizing van der Waals bonded graphene-SWNT hybrid films as the light-harvesting layer. This device on a flexible polyethylene terephthalate substrate demonstrated a high photoresponsivity of ~51 A/W and a fast response time of ~40 ms over the visible wavelength range [2 molecules. It was found that the H2 response in SWCNT/graphene nanohybrid improved by 50% as graphene provides more efficient charge transfer [−1, outstanding power capability of ~390 mA∙g−1, and cyclability over 1000 operating cycles with maximum Coulombic efficiency [−1 in an ionic liquid at room temperature. In addition, an increase in the specific capacity of electrodes by 29% after 1000 operating cycles were recorded, which indicates their excellent cyclicity [Graphene/SWCNT hybrid structures with horizontally oriented nanotubes find their application as a material for creating the element base of various nanodevices. In particular, highly sensitive photodetectors have been developed on the basis of atomically thin graphene/SWCNT hybrid films. A photodetector based on van der Waals graphene/SWCNT heterostructures located on a SiOu et al. . The proth range . An all-th range . A hybritransfer . Layeredficiency . Composiyclicity .Along with the development of various devices based on graphene/SWCNT hybrid structures, fundamental studies of the regularities of physical processes in these structures are also being carried out. The mechanisms of thermal and electrical conductivity in graphene/SWCNT hybrid structures are studied using computer simulation methods. Using the method of nonequilibrium molecular dynamics, it was found that the thermal boundary conductivity in hybrid structures based on horizontally oriented SWCNTs and graphene nanoribbons increases linearly with increasing temperature due to the significant role of inelastic phonon scattering. It was shown that as the strength of the interphase interaction increases, the thermal boundary conductivity monotonically increases due to the emerging enhanced phonon coupling between SWCNTs and graphene . Based oThe aim of this paper is to study the peculiarities of the atomic structure and the regularities of current flow in hybrid films formed by bilayer zigzag graphene nanoribbons and a SWCNT  layer using theoretical and computational methods. The choice of SWCNTs  and zigzag graphene nanoribbons is due to the following reasons. Chiral SWCNTs  with a diameter of 1.2 nm are among the most frequently synthesized single-walled nanotubes ,33,34. IThe atomic structure of graphene/SWCNT hybrid films was calculated using the self-consistent charge density-functional tight-binding (SCC-DFTB) method . This meIn order to quantitatively evaluate the stability of graphene/SWCNT hybrid films to internal deformations, the distribution of local stresses of the atomic network was calculated. The stress on each atom was calculated as the ratio of the force acting on the atom to the surface area of the atom, taking into account its immediate environment. The force was defined as the derivative of the energy of the atom with respect to its coordinates x, y, z. The energy of each atom was calculated by the SCC-DFTB method in the DFTB+ software package version 20.2 ,43.T(E) and static electrical conductivity G. The function T(E) is determined by the expression:FE is the Fermi energy of the material of the contacts, TF is the thermal broadening function; e is the electron charge, h is the Planck’s constant, e2/h is the quantum of conduction .The electrical conductivity was calculated within Landauer–Buttiker formalism . This foT(E) were carried out for supercells of graphene/SWCNT hybrid films consisting of 250–300 atoms. In view of the large dimension of the considered electronic system, the original method for the accelerated calculation of the transmission function T(E) was applied using the original Mizar program [T(E) for a small number of k-points of the first Brillouin zone and then interpolating it for any k-point of the first Brillouin zone and recovering the full transmission function T(E).In this study, the calculations of the transmission function  program . This meTo analyze the electronic distribution in the studied graphene/SWCNT hybrid films, the Mulliken Population Analysis (MPA) was carried out . AccordixL = 1.72 nm and yL = 1.12 nm, respectively.To construct atomistic models of graphene/SWCNT hybrid films, we used SWCNTs  with a diameter of 1.2 nm and bilayer zigzag graphene nanoribbons. One of the graphene layers was shifted relative to the other in the direction of the Y-axis . Wherein bilayer graphene was located above the SWCNT surface at a distance of 0.34 nm. In total, three topological models of the graphene/SWCNT hybrid films were considered. These models differed in the width of the graphene nanoribbon in each layer. With an increase in the width of the nanoribbon, the displacement of the graphene layers relative to each other in the direction of the Y-axis  changed. In the first version (model V1) of the initial graphene/SWCNT film, the width of the graphene nanoribbon was 2 hexagons (~0.5 nm), the displacement of the layers along the Y-axis was 0.48 nm. In the second version (model V2), the width of the graphene nanoribbon was 3 hexagons (0.71 nm), the displacement of the layers was 0.27 nm. In the third version (model V3), the width of the graphene nanoribbon was 4 hexagons (0.92 nm), the displacement of the layers was 0.06 nm. The distance between graphene layers along the Z-axis (perpendicular to the nanotube axis) was 0.34 nm for all considered topological models of graphene/SWCNT hybrid films. xL, yL with the optimization of the atomic network geometry of the supercell constructed for these xL, yL. The lengths of the translation vectors of the supercells after optimization are shown in xr and yr, respectively). xr/yr) of nanotubes in graphene/SWCNT hybrid structure. According to these data, the degree of deformation was 1.2 for all three topological models. The atomic structure of the initial graphene nanoribbons was also deformed as a result of the interaction of nanoribbons with each other and with the nanotube. Moreover, depending on the width of the graphene nanoribbon, different orientations of the graphene layers with respect to the nanotube were observed. As can be seen from The initial atomic structures of the supercells were optimized to find their equilibrium configuration, i.e., configurations characterized by the minimum energy. The atomic structure of the supercells was optimized by the SCC-DFTB method. In the course of optimization, a relaxation scanning of the energy surface of the hybrid film was carried out. This scanning implied a step-by-step change in the lengths of the translation vectors As noted in fH, which was determined by the following formula:filmE is the energy of the hybrid film, grE is the energy of graphene layers, tubeE is the nanotube  energy, N is the number of atoms in the supercell. The structure of the hybrid film was configured in such a way that its total energy in absolute value was less than for its individual components. The ΔfH values are given in Another confirmation of the energy stability of the constructed supercells was the result of calculating the formation enthalpy ΔFE. The values of FE for each topological model of the hybrid film are given in gapE opens (see The next stage of the study was to identify the features of the electronic structure of the studied graphene/SWCNT hybrid films. The distributions of the density of electronic states (DOS) were calculated for each of the constructed supercells. Our task was to determine how the DOS profile of graphene/SWCNT hybrid films was formed by evaluating the contribution of individual graphene nanoribbons and nanotube . pens see  as in the versus 0.157e for model V1), which led to an increase in the intensity of the DOS peak at the Fermi level for individual graphene nanoribbons in this case , which characterized the probability of the passage of electrons through the given structure. The resulting plots of the function T(E) are shown in T(E) profile near the Fermi level determines the value of electrical conductivity G. The T(E) plots for the direction of current transfer along the Y axis are marked in green, and along the X axis in red. The values of the T(E) in the plots are given in quanta of conductance e2/h. To explain the obtained dependencies, the T(E) plots of its constituent graphene and nanotube (in a square frame) are presented for each topological model of graphene/SWCNT hybrid film. The presented plots demonstrate that either graphene (current transfer in the direction of the X-axis) or a nanotube  (current transfer in the direction of the Y-axis) makes a decisive contribution to the formation of the T(E) profile. The T(E) profile contours of graphene/SWCNT hybrid film near the Fermi level largely repeat the DOS profile contours in this energy range. This allows us to use the conclusions about the influence of the electron charge density redistribution between the atoms of the nanotube and graphene layers, made in the analysis of the DOS, to explain the differences between the T(E) profiles of the models V1 and V2 and the T(E) profile of the model V3. In order to quantify the ability of graphene/SWCNT hybrid films to conduct current, we calculated the electrical resistances in the directions of current transfer along the X and Y axes . The resistance was calculated as the reciprocal of the electrical conductivity G, which was determined by Formula (2). The calculated resistance values are presented in yR was less than xR. This can be explained by the fact that the value of T(E) in the direction of the Y-axis is equal to “2” over a large energy interval, but in the direction of the X-axis, the T(E) reaches the value “3” at the Fermi level and then decreases to unity in almost the entire considered energy range. On the contrary, in the case of the topological model V3, the resistance values in different directions of current transfer differ by a factor of tens, i.e., the phenomenon of electrical conductivity anisotropy takes place. In the direction of the X-axis, the resistance reaches ~ 125 kΩ. This is explained by the fact that the function T(E) takes values less than unity over the entire energy range near the Fermi level. In the direction of the Y-axis, the resistance was about 16 kΩ, which was three times higher than the resistance values for models V1 and V2 since the T(E) at the Fermi level takes almost zero value in this case  profiles for the topological models V1, V2, and V3, we calculated the maps of the transmission function T, on which the wave number k was plotted. This wave number corresponds to the direction in which the partition of the reciprocal space was carried out. The calculated maps T are shown in For a visual interpretation of the yk), the function T(E) for the models V1 and V2 takes maximum values (of the order of 3), either at the Fermi level (model V1) or in the immediate vicinity of it (model V2). This result was in good agreement with the features of the profiles of the function T(E) in the vicinity of the Fermi level shown in xk), the function T(E) takes on the value “2” at almost all points of reciprocal space with the exception of individual “islands” explaining small deviations of the function T(E) from the value “2” near the Fermi level observed in T(E) in the direction of the X-axis for the model V3 was zero throughout the reciprocal space, except for a small number of edge points located far from the Fermi level. As can be seen from T(E) at the Fermi level and in its vicinity was close to zero and gradually increased with distance from it. In the direction of the Y-axis, the map T was more rarefied since the function T(E) has a large number of conduction channels in this direction of current transfer. This explains the anisotropy of the conducting properties observed for this topological model of graphene/SWCNT hybrid film.These maps clearly show that in the case of the current transfer in the direction of the X-axis (partition by In this work, the theoretical and computational study of layered films formed by bilayer graphene and a layer of chiral SWCNTs was carried out. The results of this study made it possible to determine new topological models of graphene/SWCNT hybrid structures, characterized by high energy stability, and to reveal the regularities of the topological control of their electrically conductive properties. For the first time, at the level of computer simulation, we considered the atomic configurations of graphene/SWCNT hybrid films, in which the mutual arrangement of the graphene layers and the SWCNT layer led to the formation of structural regions with increased density, which corresponds to the data of modern experiments on the synthesis of graphene/CNT films . Based o


In the 2016 experiment by Crossno et al. the electronic contribution to the thermal conductivity of graphene was found to violate the well-known Wiedemann–Franz (WF) law for metals. At liquid nitrogen temperatures, the thermal to electrical conductivity ratio of charge-neutral samples was more than 10 times higher than predicted by the WF law, which was attributed to interactions between particles leading to collective behavior described by hydrodynamics. Here, we show, by adapting the handbook derivation of the WF law to the case of massless Dirac fermions, that significantly enhanced thermal conductivity should appear also in few- or even sub-kelvin temperatures, where the role of interactions can be neglected. The comparison with numerical results obtained within the Landauer–Büttiker formalism for rectangular and disk-shaped (Corbino) devices in ballistic graphene is also provided. Soon after the advent of graphene, it became clear that this two-dimensional form of carbon shows exceptional thermal conductivity, reaching the room temperature value of 00 W/m/K , being o00 W/m/K . Althoug00 W/m/K ,4 allowity point . One canty point , but dirThe Wiedemann–Franz (WF) law states that the ratio of perature (1)κelσ=For metals, Equation  with L≈LL≈L0  holds true of L0  with a fIn graphene, the situation is far more complex, partly because o et al.  show thaHigh values of the Lorentz number  can be understood within a hydrodynamic transport theory for graphene ,15,16, wIn this paper, we show how to adapt the handbook derivation of the WF law  in ordertangular ,20,21 antangular ,23 samplThe remainder of the paper is organized as follows. In C) derived within kinetic theory of gases [v is a typical particle velocity, and ℓ is the mean-free path (travelled between collisions with boundaries or other particles). C in Equation , as follows from Equation  vanishes in the Equation  and the Equation  for d=2, for d=3 , but the for d=3 ,27 even  for d=3 .C in Equation =d2nEquation , we obtaNow, taking Equation , obtainiIt is now sufficient to divide Equations  and 17)17) side-d. More careful analysis also shows that the parabolic dispersion of Equation  value of σ0  may therTo understand the above conjecture, we refer to the approximate dispersion relation for charge carriers in graphene, showing up so-called Dirac cones,The value of the Fermi velocity Charge carriers in graphene are characterized by an additional (next to spin) quantum number, the so-called valley index. This leads to an additional twofold degeneracy of energy levels, which needs to taken into account when calculating the density of states,Subsequently, the carrier concentration at F index for symbols denoting the Fermi energy and the Fermi wavevector to emphasize that they can be tuned (together with the concentration) by electrostatic gates, while the Fermi velocity In the above, we intentionally omit the ocity vF  is a matDespite the unusual dispersion relation, given by Equation , the relEquation  leads tomC=ℏ22π∂AEquation  for freen  , replaciC  corresponds to y μ>0 is gigiven byL=κσ0T=FL=κeiven by3Ln=gsgvh∫Before calculating For instance, the linear transmission-energy dependence =9ζ gap may enhance the Lorentz number. Instead of Equation , we putFor Equation  can be aThis time, the result given in Equation  can be sm.An apparent feature of Equation  is that nductors . SimilarEquation  for Δ≫kBA different behavior appears near the band boundary, i.e., for grals Ln  matters.Closed-form expressions for Asymptotic forms of Substituting the above into Equation , we obtam  and evanescent waves Tons, see ),53)knknW and lj is the half-odd integer angular momentum quantum number, with a corresponding transmission probabilityk is same as in Equation T(ε)Equation , and≈g0ΩXThe exact transmission-energy functions Equation  for the T) from the Wiedemann–Franz regime, with a flat Close to the charge-neutrality point, i.e., for Equation   or to the bottom of the conduction band (the unipolar case), proves that the bipolar band structure is also important  as expected for a model transmission energy dependence, L the sample length.Finally, the Lorentz numbers, for different dopings and temperatures, are elaborated numerically from exact solutions available for the rectangular sample and the Corbino (edge-free) disk in graphene, both connected to heavily-doped graphene leads. The results show that Our results complement earlier theoretical study on the topic  by inclu


Thanks to the unique properties of graphite oxides and graphene oxide (GO), this material has become one of the most promising materials that are widely studied. Graphene oxide is not only a precursor for the synthesis of thermally or chemically reduced graphene: researchers revealed a huge amount of unique optical, electronic, and chemical properties of graphene oxide for many different applications. In this review, we focus on the structure and characterization of GO, graphene derivatives prepared from GO and GO applications. We describe GO utilization in environmental applications, medical and biological applications, freestanding membranes, and various composite systems. The fun1F1]n show small flakes of fluorographene which consist of multiple wrinkled sheets. Whereas micrographs of CRG do not show such wrinkled structure of multiple sheets, the last micrographs of TRG show small flakes of multiple-sheet structure which are highly wrinkled. According to EDS 1]n. The synthesis of such material consists of two consecutive oxidation steps of graphite. After the first oxidation by the Tour method, GO is obtained and further used as a starting material for the second oxidation. The second oxidation runs according to the Tour method as well n [Fluorographene is fluorinated graphene with stoichiometry [C1F1]n ,87. As w1F1]n . The pre1F1]n . For the1F1]n . Isoprop1F1]n , ethanol1F1]n , acetoni1F1]n , and chl1F1]n  can be m1F1]n . The pro1F1]n .In order to provide typical analytical results of GO, a sample of GO was prepared by modified Tour’s method  and analTransmission electron microscopy (TEM), energy-dispersive spectroscopy (EDS), and scanning electron microscopy (SEM) were used to study the surface of GO. The first micrographs in The composition of the sample can be determined via X-ray fluorescence (XRF). The composition of GO depends on the level of oxidation of the sample. Generally, graphene oxide is composed of carbon, oxygen, and hydrogen, but there are very often other impurities from the starting materials, such as sulfur, chlorine, nitrogen, manganese, and potassium . ManganeThe composition of TO-GO can be also investigated by elemental analysis (EA) . The res−1 and 1600 cm−1, respectively, are usually registered. The first local maximum is called the D band and shows a quasitetrahedral coordination with sp3 carbon hybridization . The other local maximum is called the G band and detects a planar arrangement with sp2 hybridization (regular graphene lattice). The D/G ratio, calculated from the intensity of peaks, shows the level of oxidation of the sample and should be around 1.00 [Raman spectroscopy is a powerful tool for the determination of defect rate. Using Raman spectroscopy, two local maxima around 1350 cmund 1.00 .X-ray diffraction is used to determine the interlayer distance between GO layers. Whereas pure graphite has (002) reflection at 26.3° that corresponds to the interlayer distance of 3.342 Å , the  to determine the composition of the sample surface and more interestingly to determine the ratio of individual functional groups. Two local maxima are usually detected around ~284.4 eV for the C1s peak and around ~532.4 eV for the O1s peak. Maxima for N1s, S2s, and S2p peaks might also be found, showing the contamination of the sample by sulfur and nitrogen. The composition is very variable and depends on the level of oxidation of the sample . The dec2O, CO, and CO2.With simultaneous thermal analysis in an inert atmosphere, the temperature of exfoliation is investigated. The literature claims that the temperature of the exfoliation of graphene oxide is around 200 °C . The obtAtomic force microscopy (AFM) can be employed in order to study the thickness of the GO sample, therefore investigating the number of layers. It is known from the literature that a monolayered sample of GO has a thickness of 0.8–1.2 nm ,110. She2, CO, NO2, and NH3. Thanks to the oxygen groups decorating the basal planes and the edges, GO is capable of covalent or noncovalent interactions with various molecules. GO can be employed in catalysis for converting polluting gases during industrial processing. The elimination of such harmful gases can be performed by capturing and storing gases, catalyst reactions of gas conversion, or direct utilization [One of the biggest threats to the environment is air pollution caused by the industrial release of harmful gases such as COlization . Apart f2 [2 permeation performance [2 were developed, enhancing the diffusivity selectivity, solubility selectivity, and reactive selectivity [2S [2 [x [The functional groups of few-layered GO composites exhibit unique adsorption behavior towards CO2 ,115,116.formance . Multi-pectivity ,121,122.ectivity ,126,127.ectivity ,129, forectivity , H2S [13vity [2S ,132,133,y [2S [2 ,135,136,2S [2 [x ,138 can 2 conversion [2 reduction and solar energy harvesting.Thanks to the unique electronic properties, GO-based composites exhibit superior photocatalyst abilities for COnversion ,140. Hsunversion  reported−1 at 293 K [2+ ions is very low, even with oxygen groups on GO acting as active sites [GO exhibits high adsorption ability towards Cd(II), Co(II), Au(III), Pd(II), Ga(III), and Pt(IV) ,143,144.at 293 K . On the ve sites . With thve sites ,154,155.ve sites ,158,159.ve sites  reportedThe first possible application in this field is GO-based biosensors. GO-based biosensors rely on their preferred interaction with single-strand DNA (ssDNA) rather than double-strand DNA (dsDNA). This effect is caused by the effective hiding of nucleo-bases in dsDNA in a helical structure, which prevents GO from direct interaction with nucleo-bases ,162,163.Another interesting application is gene delivery, which is a promising way to treat genetic disorders, including cancer. The therapy uses gene vectors protecting DNA from nuclease degradation. GO sheets have been covered by polyethyleneimine (PEI) as a surface modifier for gene delivery into the cells. The delivery runs through complexation by electrostatic interaction and covalent conjugation for the loading of plasmid DNA (pDNA) ,164.Small-molecule drug delivery seems to be another promising medical application of GO. Small molecules of drugs can be attached to a GO surface using pH-sensitive linkers. A complex of doxorubicin and GO (DOX-GO) shows a release of DOX from GO dependent on pH due to higher solubility of DOX at low pH . MoreoveGO membranes may be used as ionic and molecular sieves or for selective gas transport. GO membranes were first introduced to the world by Nair et al. . It was As a reaction to Nair’s paper, Sun et al.  demonstr3N4 ceramic matrix was enriched by multilayered graphene or graphene oxide to study the influence of the addition on mechanical, tribological, and electrical properties. The addition of multilayered graphene caused higher hardness, modulus, and bending strength in comparison to graphene oxide addition. However, the addition of graphene oxide and multilayered graphene resulted in lower mechanical properties but better electrical and tribological properties [Graphene and graphene oxide are very promising materials for the reinforcement and general enhancement of mechanical properties of high-temperature materials. Some researchers studied the effects of graphene oxide on high-temperature materials such as metal alloys and ceramics. The mechanical resistance can be significantly improved by only 1 vol.% of GO. High energy ball milling was used to disperse graphene oxide powder in an aluminum (AlMg5) alloy matrix. Hot pressing was used to densify the obtained material . More froperties .Ordinary Portland cement (OPC) is one of the most used materials in the field of civil engineering thanks to the thirst for urbanization. The concrete is produced by mixing aggregates, binder (OPC), and water for hydration. Concrete has its advantages, such as unique compressive strength, as well as disadvantages, including poor crack formation resistance or low tensile strength . Researc2 during manufacturing [2 during the carbonation is magnesium oxychloride cement  [Magnesium oxychloride cements (MOCs) are promising alternatives to Portland cement. Let us note that OPC production is connected to high emissions of COacturing . An alte cement) . In orde cement) . Even th cement) .2 and toxic gases such as ammonia, acetone, formaldehyde, H2S, SO2, and NOx. There is also a possibility to convert CO2 by photocatalytic reaction using GO-based composites. Organic dyes and inorganic heavy metal ions in water represent another worldwide environmental issue that can be solved by using GO. There are also medical applications such as gene delivery, which is a very promising way of treating genetic disorders; drug delivery for targeting cancer; and GO-based biosensors. GO-based membranes can be employed as molecular and ionic sieves or for selective gas transport. In high-temperature materials, GO works mainly as an additive used for reinforcement and general enhancement of mechanical properties. Employing GO into building materials such as ordinary Portland cement or magnesium oxychloride can enhance their flexural and compressive strength as well as MOC’s poor water resistance.In this article, the history, synthesis, properties, and application of graphene oxide were reviewed. There are many GO derivatives, including graphene acid, fluorographene, and graphene oxide reduced by thermal or chemical reduction (TRG or CRG). Graphene oxide as well as its derivatives have plenty of various applications. Thanks to the oxygen functional groups on the edges and basal plane, GO can be used as a solution for environmental problems such as excess of CO


As such, visually‐grounded questions have long been of interest to theoretical linguists and cognitive scientists. Moreover, they have inspired the first attempts to computationally model natural language understanding, where pioneering systems were faced with the highly challenging task—still unsolved—of jointly dealing with syntax, semantics and inference whilst understanding a visual context. Boosted by impressive advancements in machine learning, the task of answering visually‐grounded questions has experienced a renewed interest in recent years, to the point of becoming a research sub‐field at the intersection of computational linguistics and computer vision. In this paper, we review current approaches to the problem which encompass the development of datasets, models and frameworks. We conduct our investigation from the perspective of the theoretical linguists; we extract from pioneering computational linguistic work a list of desiderata that we use to review current computational achievements. We acknowledge that impressive progress has been made to reconcile the engineering with the theoretical view. At the same time, we claim that further research is needed to get to a unified approach which jointly encompasses all the underlying linguistic problems. We conclude the paper by sharing our own desiderata for the future.Answering a question that is  From Quine  could identify a zebra on first acquaintance armed with this symbolic representation alone ’ , interpret negation (‘but is not as wide’) and resolve the anaphora (‘that supports it’).The importance of combining these two main challenges—modelling of symbolic grounding and communication exchanges—was acknowledged by one of the first computational systems about natural language understanding, which focused on visually‐grounded dialogues. Winograd  introducdesiderata, that we use to review recent achievements in a specific subtask tackled by Winograd’s system, namely answering visually grounded questions.From Winograd’s sample dialogue, we extract a list of main linguistic phenomena  and skills (reasoning and pragmatic‐based interpretation) that we believe a multimodal system should be able to model. We will refer to this list as our Thanks to efforts within computational linguistics and computer vision, Visual Question Answering (VQA) has become a widely studied task, and important progress has been made on the development of computational multimodal models. VQA has been treated both as a downstream task and as a pre‐training task to effectively encode multimodal input and trasfer it to other multimodal tasks. In this paper, we will discuss both uses of it. By reviewing how current models handle each of our desiderata, we will highlight where further research is needed to turn VQA from an in‐lab exercise to a real‐life application, and point to what we think is feasible to achieve in the short and medium term.2In the last years, there has been a steep increase of interest in the task of answering visually grounded questions. This revival was motivated by the development of models to assist visually impaired people  which encodes the contexts in which it occurs , each handled by a dedicated module. Whilst NMN  of our list of desiderata extracted from Winograd’s dialogue sample. By so doing, we also emphasize what we believe deserves further attention from the language and vision community.3desiderata we extracted from Winograd’s dialogue sample.As we mentioned above, Winograd looked at the challenges for a visually grounded interactive system solely from the perspective of the language modality (the images were assigned pre‐compiled symbolic representations). On the other hand, most of the work carried out recently on VQA has been driven by the computer vision community. We are now in the fortunate position to promote a joint view on how the long‐standing theoretical questions about grounded language understanding are addressed by computational models. Hence, in what follows, we review where the current visually‐grounded research stands with respect to the 3.1Is there anything which is bigger than every pyramid but is not as wide as the thing thatsupportsit?’. As seen in Section Winograd called for a system that is able to infer from the visual scene the answer to a question of the type: ‘visual reasoning; Andreas et al., non‐relational questions, which require reasoning about the attributes of one particular object instance, to relational questions , and to perform a higher‐level reasoning step over this perceptual knowledge. If one views language from a denotational semantic perspective, it becomes clear that the move from non‐relational to relational skills is also crucial to master language phenomena of increasing complexity, for which yet another step is necessary, namely to deal with questions involving relations between sets of objects. For instance, to properly represent quantifiers a model has to identify the sets of relevant objects; similarly, gradable adjectives require a comparison of the set of entities against which they are interpreted; negation of, for example, a noun points to the alternative sets of the negated noun (the set of other candidate objects), etc. Answering to questions involving these expressions is therefore a higher‐level problem as compared to first‐level relations and non‐relational questions described above.As we have mentioned above, several diagnostic datasets have been released with the aim to assess model abilities to reason over a question grounded in a visual context , in an image, the object to which the expression refers  and gradable adjectives . These expressions can be vague, that is, their interpretation can depend on the context in which they are used. For example, the applicability of words like most or big in a certain context depends on the properties of the set of objects that are relevant for their interpretation. Moreover, their interpretation can be borderline and therefore differ across human speakers.‘at least two or more than half. In contrast, quantifiers such as few or most—whose intepretation largely depends on the  context in which they are uttered—are absent. A strand of work has focused on quantifiers combining formal semantics and cognitive science to propose models to perform grounded quantification in a human‐like manner  image  has been undertaken by the QA community early on. It was shown to be an interesting case‐study in between QA, information retrieval and dialogue systems: users are given the chance to refine their query/question based on the linguistic answer they received (Webb & Webber, Multimodal models have been evaluated also on visual dialogue tasks, in which the agent has to answer a FUQ by grounding it on the dialogue history and on the image the question is about. The most popular dataset, VisDial (Das, Kottur, Gupta, et al., When opening the box of interaction, the next challenge that pops up immediately is question generation. Task‐oriented visual games (de Vries et al., Most multimodal conversational models exploit the encoder‐decoder architecture (Sutskever et al., 4.2The VQA task has been further extended to QA about videos. The largest‐scale Video‐QA dataset currently available is TVQA (Lei et al., 5Reviewing the literature on VQA is, by itself, a stimulating activity since progress is tangible and fast. We hope that this paper will contribute to promote further work and collaboration between experts in the language and vision community, which we have shown to be crucial for the development of fully fledged multimodal models. We agree with the call for more research on contextual language learning promoted by Bisk et al. , and for


After irradiation with UV light, both amides underwent trans to cis isomerization, yielding 40% and 22% of the cis isomer of L1 and L2 amides, respectively. Quantum yields of this process were determined as 6.19% and 2.79% for L1 and L2, respectively. The reverse reaction  could be achieved after thermal or visible light activation. The analysis of the theoretically determined equilibrium structure of the transition-state connecting cis and trans isomers on the reaction path indicated that the trans-cis interconversion is pursued via the flipping of the substituent, rather than its rotation around the N=N bond. The kinetics of thermal back-reaction and the effect of the presence of the selected ions on the half-life of the cis form were also investigated and discussed. In the case of L1, the presence of fluoride ions sped the thermal relaxation up, whereas the half-life time of cis-L2 was extended in the presence of tested ions.Azobenzene derivatives are one of the most important molecular switches for biological and material science applications. Although these systems represent a well-known group of compounds, there remains a need to identify the factors influencing their photochemical properties in order to design azobenzene-based technologies in a rational way. In this contribution, we describe the synthesis and characterization of two novel amides (L1 and L2) containing photoresponsive azobenzene units. The photochemical properties of the obtained compounds were investigated in DMSO by UV-Vis spectrophotometry, as well as  The development of so-called smart materials, whose functions can be activated or inhibited on demand via external stimuli, is of growing interest for material science and biomedical applications . The pretrans (E) isomer and the bent metastable cis (Z) form −): 451.0 for compound C26H19N4O4, calculated 451.5.Azobenzene-4,4′-dicarboxylic acid dichloride  was gradually added to a round-bottom flask containing a magnetic stirred solution of 2-amino-4-nitrophenol  in anhydrous dichloromethane (10 mL) and 4-dimethylaminopyridine  used as a HCl scavenger. Subsequently, the reaction mixture was stirred under a reflux condenser for 12 h (temperature ~40 °C). The obtained precipitate was filtered off under reduced pressure and crystalized from a fresh portion of dichloromethane.L2: orange solid, 155 mg (58%), mp. 322–325 °C; TLC: Rf = 0.50 ; 1H NMR ): 6.99 , 7.14 , 8.01–8.25 , 8.77 , 9.92 , 11.66 , and 13.30 ; 13C NMR ): 107.4, 115.9, 119.9, 122.5, 123.3, 123.3, 126.4, 129.6, 131.2, 133.8, 137.0, 139.5, 139.6, 154.1, 154.6, 156.5, 165.2, and 167.1; IR (KBr pellet) cm−1: 3442, 3096, 1736, 1686, 1637, 1602, 1527, 1421, 1341, 1262, 1185, 870, 783, and 698; HRMS ESI(−), ([M − H]−): 541.1 for compound C26H19N6O8 calculated 541.4.The equilibrium structures and energies of the L1 and L2 compounds in DMSO were determined by employing the Density Functional Theory (DFT) with the hybrid exchange–correlation functional CAM-B3LYP (the long-range-corrected version of B3LYP using the Coulomb-attenuating method ) togethe−5 M) and 1H NMR spectroscopy (c ~ 10−3 M). The reverse isomerization was led in darkness at 333.15 K or using a solar light simulator.UV irradiation experiments were carried out in a quartz cuvette (l = 1 cm) in DMSO. The progress of the photoisomerization was monitored by UV-Vis spectrophotometry  to study their interactions with metal cations and tetra-n-butylammonium (TBA) salts , hydrogen sulfate, thiocyanate, perchlorate, p-toluenesulfonate, benzoate BzO−, acetate AcO−, and dihydrogen phosphate) in order to test the interactions with anions. The stock solutions of ligands (~10−4 M) and metal perchlorates or TBA salts (~10−2 M) were prepared by weighing the respective quantities and dissolving them in DMSO in volumetric flasks. Titrations were carried out in a quartz cuvette with path length of 1 cm with a starting volume of the ligand solution equal to 2.3 mL. To suppress the deprotonation process, titrations were also carried out in the presence of acetic acid . On the basis of the experimental data, the stability constant values were determined using BindFit v.05 software [Complexation studies were performed via the UV-Vis titration of the ligands solution in DMSO with the respective metal perchlorates  and tetra-n-butylammonium fluoride (0.004 mmol) in a 15 mL of acetone: dichloromethane mixture . Subsequently, the mixture was stirred until complete dissolution. After solvent evaporation under reduced pressure, the FTIR spectra of the obtained samples were recorded. For the 1H NMR experiments, the samples were dissolved in 0.7 mL of DMSO-6d before analysis.Complexes for FTIR and trans (E) and cis (Z). According to the calculations performed at the CAM-B3LYP/6-311++G theory level, the most stable structures of L1 and L2 in DMSO solvent , see trans L1 conformers (L1E) and four trans L2 conformers (L2E) with relative energies within 6 kJ/mol , to likely be at room temperatures. As far as the cis isomers are concerned, the most stable cis L1 structure was predicted to be 53 kJ/mol higher in energy than the lowest energy trans L1, while the relative energy of the most stable cis L2 structure was calculated to be 52 kJ/mol (with respect to the lowest energy trans L2). In addition, we found other cis L1 (L1Z) and cis L2 (L2Z) conformers, whose formation from their corresponding, most stable cis structures might be considered likely, as their relative energies are larger by only 1–6 kJ/mol  [trans L1 (1.812), cis L1 (1.946–1.948), trans L2 (1.812–1.815), and cis L2 (1.946–1.951) seem to confirm that the N=N bond order approaches 2 in all considered L1 and L2 systems. In particular, the WBI values indicate that the double-bond character is more profound in the cis isomers, which is consistent with the slightly shorter (by 0.005 Å) N=N separations predicted for those species.In all studied es (WBI)  calculattrans to cis isomerization of azo compounds [trans to cis isomerization of L1.The photochemical behavior of amides was studied by spectroscopic and theoretical methods. In the UV-Vis spectra of the compound solutions in DMSO, the changes upon UV light irradiation (λ = 365 nm) were observed . After 2ompounds . The detompounds ,47) is m0→Si excitation energies with their corresponding oscillator strengths, see In order to support the analysis of the UV-Vis spectra of L1 and L2 solutions in DMSO, we calculated . The observed upfield shifts of OH, NH, and aromatic signals for the cis-enriched mixture of L1 and L2 indicated a characteristic effect of the magnetic shielding of the overlapping phenyl rings of the concaved cis form [On the basis of cis form . The moscis-enriched mixture upon UV-irradiation is consistent with the theoretically predicted energy profiles corresponding to the trans→cis isomerization of L1 and L2 depicted in trans and cis minimum energy structures are separated by the kinetic barriers whose heights (in the trans→cis direction) were evaluated to be 155.7 and 150.5 kJ/mol for L1 and L2, respectively. Clearly, surmounting such significant kinetic barriers would not be possible at room temperature without providing sufficient activation energy (as the rate constants of ca. 10−15–10−14 s−1 are predicted for these processes at T = 298.15 K).The obtainment of the cis to trans isomerization of L1) was possible upon the sample heating at 333.15 K in darkness, whereas the analogous back-isomerization of L2 nitro derivative was achieved after the sample irradiation with visible light. The cis to trans thermal transition of L1 followed the first-order kinetic model , which indicates a larger stability of this form in comparison to the unsubstituted azobenzene . In ordo 2 days .cis-enriched mixture of L2, with visible light, a hyperchromic effect in the region of π→π* band was observed, suggesting cis to trans isomerization. The reverse process , as it was mentioned before, required a longer time (6 min) to achieve the photostationary state.After 4 min of the irradiation of the trans-L2. The 1H NMR spectra of the trans-L2, cis-enriched mixture obtained after irradiation with UV light and solution heated at 333.15 K (previously irradiated with UV light) are shown in cis isomer  of L2, was shifted to lower ppm values (Δδ = −0.17 ppm) at higher temperature, whereas the proton signal related to the second ring (○) was slightly shifted downfield (Δδ = 0.03 ppm), in comparison to the spectrum registered at 298.15 K. The observed shielding effect is likely a consequence of intramolecular CO∙∙∙OH hydrogen bonds breaking, induced by thermal energy provided to the system. Such an interpretation is also supported by the analysis of the UV-Vis spectrum of L2 solution, in which the significant hyperchromic effect observed during the sample heating is associated with heteroatoms, such as oxygen and nitrogen (the region of n→π* transition band).Heating the previously UV-irradiated solution of L2 in darkness caused the increase of the band at ca. 450 nm that corresponds to n→π* transition a. Slight−5 s−1 and the half-life time of the cis isomer estimated as 5.4 h at 298.15 K (15 min at 333.15 K)  . The kinivatives ,51.cis→trans isomerization required overcoming a much smaller, yet substantial, kinetic barrier of 103.0 and 98.4 kJ/mol for L1 and L2, respectively. Since the corresponding Gibbs activation energies (ΔG‡) at T = 298.15 K predicted theoretically  agree relatively well with those obtained experimentally (see −5 s−1 for L1 and 2.0 × 10−4 s−1 for L2) calculated for these reverse isomerization processes using the above mentioned ΔG‡ values seem reliable. In addition, we would like to point out that in both L1 and L2, cases the equilibrium structure of the transition state  and the analysis of the imaginary vibration  indicates that the trans↔cis interconversion is pursued by the flipping of the X substituent, rather than its rotation about the N=N bond, see the transition state structures (labeled TS) depicted in Theoretical calculations showed that ally see , the ratDue to the presence of NH and OH groups serving as the moieties enabling the formation of hydrogen bonds, L1 and L2 compounds may interact with ions. In fact, such potential host-guest interactions may have an influence on the thermal relaxation of azo compounds ,52. Amon1H NMR and FTIR spectra (1H NMR of free amide L1 at 9.47 ppm was broadened and shifted downfield (Δδ ~ 0.33 ppm) in the presence of fluoride anions, thus suggesting the involvement of hydroxyl moieties in the fluoride ion binding (via the formation of H-bonds). The signal of NH protons was slightly shifted to higher ppm values (Δδ = 0.04 ppm), which can be connected with host-guest interactions. In the FTIR spectra of L1 recorded in the presence of fluoride ions, the band at ca. 3400 cm−1 ascribed to the stretching vibrations of the OH and NH groups was broadened and shifted to higher wavenumbers (by 68 cm−1) in comparison to the spectrum of free amide. The amide I band (seen in the L1 spectrum at 1629 cm−1) was split in the complex spectrum and shifted to higher wavenumbers. The shape and intensity of the bands corresponding to the C-O stretching vibrations at 1280–1200 cm−1 were changed in the presence of the anion. The observed changes may be a consequence of the heteroatoms involvement in the interactions with fluoride ions.Among the anions tested, the species exhibiting 1:1 stoichiometry are formed by L2 and fluoride, acetate, or copper(II) ions, whereas 1:2 (S:A) stoichiometry is more probable when L2 interacts with benzoate or dihydrogen phosphate anions. Among the last mentioned, the nitro derivative interacts more strongly with the Y-shaped carboxylic anions. As strongly basic anions in DMSO may cause the deprotonation of amide based ligands, the interactions of L1 and L2 compounds with ions were tested in the presence of the excess of acetic acid, which was used to suppress potential deprotonation ,54. Spec spectra . Namely,1HMR spectrum of the UV-irradiated solution of L1, the shifts of signals ascribed to the protons of the cis form in the presence of fluoride anions were seen , suggesting the involvement of the cis form in the interactions with the anion. On the basis of spectrophotometric titration, it was determined that under measurement conditions, the species of 1:2 stoichiometry (S:A) were formed , with respect to the latter. Recalling that the relative energy of cis L1 (in the absence of F−), with respect to trans L1, was predicted to be substantially larger (53 kJ/mol) than the relative energy of cis L1 (in the presence of F−), with respect to trans L1/F− (3 kJ/mol); one may conclude that the attachment of F− renders the cis and trans isomers of L1 nearly isoenergetic.In the ere seen . The chae formed a. This r−∙∙∙HF complex consists of the negatively charged L2 and HF molecules connected via the hydrogen bond). This finding seems to be supported by the analysis of the FTIR spectrum registered for L2 in the presence of fluoride ions . The stoichiometry of the formed species with fluoride and copper(II) ions has changed at increased temperature, which suggests a different mode of amide-ion interactions  ions stabilized the cis isomer obtained after thermal activation.The presence of tested ions influenced the rate of the thermal olutions . After t1H NMR spectra and theoretical calculations, it was concluded that in DMSO, the most stable form of L1 is a symmetric trans isomer, whereas for nitro derivative L2, the most probable structure corresponds to a trans form, with the peripheral rings rotated by 180 degrees, with respect to each other. The UV-irradiation of both azo-bearing compounds induced trans to cis isomerization. The photoisomerization process of L1 resulted in a higher conversion to the corresponding cis isomer than in the case of L2 (40% vs. 22%). The quantum yield of the trans to cis isomerization of L2 was over two times lower than for L1. The comparison of the half-life times of the respective cis-amides showed the higher stability of cis-L1 than cis-L2 and unsubstituted azobenzene. The return to a pure trans form of L1 was possible after heating the sample in darkness, whereas, in the case of L2, this thermal activation also caused the breaking of intramolecular hydrogen bonds. The rate of thermal back-isomerization could be altered by the presence of ions. Fluoride ions interacting with L1 via hydrogen bridges caused faster cis to trans relaxation. In the case of L2, the presence of tested ions decreased the cis to trans isomerization rate, probably due to the increased affinity of the L2 form obtained after thermal activation towards ions. The results of the theoretical calculations performed for the L1 and L2 species revealed not only the equilibrium structures of their most stable isomers, but also those corresponding to the low energy isomeric forms (together with their relative energies). The analysis of the intrinsic reaction path connecting the trans and cis isomers of both the L1 and L2 systems resulted in the recognizing that the trans-cis interconversion process is pursued by the flipping of a substituent, rather than its rotation about the N=N bond.The new amide derivatives of azobenzene-1,4-dicarboxylic acid were obtained in good (L1) and moderate (L2) yields using a facile synthetic protocol. On the basis of the


TOLLIP polymorphism has been implicated in the development and prognosis of idiopathic pulmonary fibrosis (IPF), mainly in whites. However, ethnic differences in the characteristics of other interstitial pneumonia (non-IPF) subtypes are unclear. We evaluated the association between the rs3750920 genotype and the clinical characteristics of Japanese patients with fibrosing interstitial lung diseases (ILD). We genotyped 102 patients with fibrosing ILD (75 IPF and 27 non-IPF patients) and analyzed the interaction between the rs3750920 genotype distribution and their clinical characteristics. The overall frequencies of the C/C, C/T, and T/T genotypes were 69%, 25%, and 6%, respectively. The proportion of minor T allele carriers was larger in IPF patients than in non-IPF patients . In addition, survival at 3 years was significantly better for carriers than for non-carriers of the T allele. There was no significant association between genotype distribution and change in pulmonary function after introduction of antifibrotic agents. The frequency of the minor T allele of rs3750920 was low in Japanese patients with fibrosing ILD, particularly in non-IPF patients. Carriers of the minor T allele had better survival than non-carriers. Presence of the T allele might thus be an indicator of better outcomes for fibrosing ILD. IPF is distinct from non-IPF ILD; however, IPF and non-IPF ILD share some morphological features and pathological mechanisms2. Findings suggesting a common fibrotic pathogenesis in pulmonary fibrosis have led to recent clinical trials of antifibrotic agents that target not only IPF but also other types of fibrosing ILD4, and to the coining of the term progressive-fibrosing interstitial lung diseases (PF-ILD)5.Idiopathic pulmonary fibrosis (IPF) is a lung disorder characterized by fibrosis of the lung interstitium. Although IPF is the most common and most severe subtype of chronic fibrosing interstitial pneumoniaTERT, TERC, PANR, and RTEL1 had a higher risk of pulmonary fibrosis development and progression and worse outcomes for a variety ILD types6. In addition, shortened leukocyte telomere length was related to poor outcomes for IPF and HP9. In addition to these findings regarding telomere length and telomere-maintenance genes, a genome-wide association study (GWAS) found that single nucleotide polymorphisms (SNPs) in MUC5B and TOLLIP might be associated with IPF susceptibility and clinical outcome11. Interestingly, the rs3750290 genotype—a functional SNP within TOLLIP—interacted with IPF outcome in post hoc analysis of the PANTHER trial: a randomized clinical trial of prednisone, azathioprine, and N-acetylcysteine (NAC) for IPF13. In that study, the T/T genotype of rs3750920 was associated with significantly better survival after NAC therapy, as compared with placebo, while patients with the C/C genotype had worse survival after NAC treatment13. Thus, there may be drug–gene interaction, and genotype-stratified use of antifibrotic agents should be considered in IPF treatment. However, the association of rs3750920 polymorphism with other types of fibrosing ILD was not analyzed. In addition, the current guidelines for IPF1 recommend nintedanib and pirfenidone as the main treatment for fibrosis; NAC treatment is not the current standard. Thus, associations with other antifibrotic agents should be analyzed. Moreover, ethnic differences may exist; however, the present genomic data for IPF have mostly been collected from white populations, and it is unclear if these data are applicable to non-white populations, including Asian populations.Among host factors for ILD, genomic factors have been implicated as risk factors for developing pulmonary fibrosis and were reported to be associated with clinical outcomes. Patients with telomere-related rare variants in TOLLIP rs3750290 SNPs with the clinical characteristics of Japanese patients with fibrosing ILD.This study examined associations of 5. Acute exacerbation of fibrosing ILD was diagnosed by using criteria reported by the international working group on acute exacerbation of IPF14. The data were locked at the end of 2020. The institutional review board of Toho University Graduate School of Medicine approved this study (A18043), and the research was performed in accordance with relevant guidelines/regulation. All patients provided written informed consent.We recruited and collected blood samples from 102 patients who were treated for fibrosing ILD at our institution during the period from 2018 through 2020. The following patient characteristics were extracted from medical records: age, sex, smoking history, laboratory data, pulmonary function test results, gender-age-physiology score, development of acute exacerbation, treatment for fibrosing ILD, and outcome. IPF and other fibrosing ILD were diagnosed by using the guidelines of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association and the statement of the ATS/ERSPeripheral whole-blood samples were obtained from patients and stored at − 80 °C. Genomic DNA was extracted with a High Pure PCR Template Preparation Kit , in accordance with the manufacturer’s instructions. The genotype of rs3750290 was determined by real-time PCR using a TaqMan SNP Genotyping Assay . Real-time PCR was conducted with an Applied Biosystems QuantStudio 3D Real-time PCR system .2 test and Fisher exact test. We used the Kaplan–Meier method to analyze outcomes. The log-rank test was used to compare two groups. Cox proportional hazards analysis was used to identify independent predictors of survival. All P values are two-sided, and a P value of less than 0.05 was considered to indicate statistical significance. Statistical analysis was done by using SPSS version 27  and PRISM version 8 .Continuous variables were analyzed with the unpaired t-test when comparing two groups and with one-way ANOVA when comparing more than two groups, as appropriate. Categorical variables were compared with the χThe baseline characteristics of the 102 patients with fibrosing ILD are shown in Table The genotype distribution of rs3750920 in relation to fibrosing ILD subtype is shown in Table Table Kaplan–Meier curves were used to analyze outcome in relation to genotype. Figure Next, we directly compared outcomes for fibrosing ILD in carriers and non-carriers of the T allele of rs3750920. As shown in Fig. Finally, we analyzed the pulmonary function of patients who received antifibrotic agents, including inhaled NAC, during the observation period. Change in FVC during the interval from the start of an antifibrotic agent to 1 year later was compared. We were only able to analyze 22 patients treated with nintedanib Fig. A, 14 patTOLLIP and the clinical characteristics of Japanese patients with fibrosing ILD. The frequencies of the C/C, C/T, and T/T genotypes were 69%, 25%, and 6%, respectively, in the total sample and 63%, 30%, and 7% in IPF patients. The present findings and the respective genotype distribution of 22%, 50%, and 28% for patients in the PANTHER trial13 suggest that Japanese are less likely than whites to be carriers of the rs3750920 minor T allele. Similarly, the genotype distribution of SNPs in MUC5B (rs35705950) were different in Japanese IPF and NSIP patients than in a German cohort15. The rs35705950 minor T allele was present in 3.4% of IPF patients and 1.7% of NSIP patients in Japanese cohorts, as compared with 33.1% and 27.4%, respectively, in German cohorts. Thus, the minor T allele might be less frequent in MUC5B (rs35705950) and TOLLIP (rs3750920) SNPs in Japanese. SNP data provided by the National Center for Biotechnology Information showed a rs3750920 T allele frequency of 43% in Europeans and 32% in east Asians16. A Japanese genetic database (TOGO VAR) indicated that 23% of Japanese had the minor T allele17. The lower frequency of the minor T allele in Japanese subjects compared to European subjects might explain why the proportion of T allele carrier is lower in our IPF patients than in IPF patients in the PANTHER cohort. However, the frequency of the T allele was higher in our patients, especially IPF patients (37%), than in subjects of Japanese database. These findings suggest that there may be an association between IPF development and rs3750920 polymorphism, as indicated by previous GWAS11.We observed an association between the rs3750290 genotype in 18. Although we could not assess genetic distribution in relation to ANA seropositivity in our patients, this tendency was not observed in our patients with CTD-ILD, NSIP, and UCIP.The proportion of T allele carriers was significantly higher in IPF patients than in non-IPF patients in our study. To our knowledge, this is the first report to compare genotype distribution between IPF and other fibrosing ILD subtypes. Oldham et al. reported that the TT genotype of rs3750920 was more frequent in antinuclear antibody (ANA)–positive (ANA titer ≥ 1:320) patients with IPF and interstitial pneumonia with autoimmune features than in those who were ANA-negative13. In contrast, a recent study of 62 white patients with IPF reported no association of survival with rs3750920 genotype19. The present patients with the T allele had significantly better 3-year survival than did those without the T allele, regardless of treatment. This difference remained even when we limited the analysis to IPF patients. However, since the prevalence of the minor T allele was low, especially in non-IPF patients (only 3 patients had C/T and 1 patient had T/T), it was difficult to conduct survival analysis of non-IPF patients. Moreover, because we could not validate the association of the minor T allele of rs3750920 with better outcomes for fibrosing ILD in multivariate analysis, we cannot conclude that rs3750920 genotype is associated with the outcome for fibrosing ILD. We also analyzed the association between decline in FVC and treatment with the antifibrotic agents pirfenidone, nintedanib, and NAC, for each genotype. NAC has been used as inhaled form in Japan21. Although we found no significant interaction between rs3750920 genotype and antifibrotic treatment in our small sample, it is intriguing that FVC improved after inhaled NAC therapy in all 3 patients with the T allele  play a pivotal role in the innate immune system and inflammatory response22. Activation of TLRs by exogenous pathogen–associated molecular patterns triggers inflammatory signaling pathways, which results in suppression of infection. In addition, TLRs recognize host-derived endogenous ligands such as pathogen-associated molecular patterns and are involved in regulating non-infectious tissue injury23. TLR2 and TLR4 are localized on the surface of cells such as alveolar macrophages and lung epithelial cells in the lungs and are crucial in regulating inflammatory response and fibrosis24. TOLLIP encodes toll-interacting protein (TOLLIP), which is a negative regulator of TLRs, including TLR2 and TLR425. TOLLIP is an intracellular adaptor molecule that can bind to IL-1R–associated kinases (IRAK-1) and inhibit activation of nuclear factor kappa B (NFκB), which results in resolution of the inflammatory response caused by the TLRs/ligand signal pathway26. rs3750920 is a functional synonymous variant coding SNPs in TOLLIP exon 3; it was marginally associated with IPF susceptibility in 2 GWAS studies11. TOLLIP mRNA levels were significantly higher in persons with the T/T rs3750920 genotype than in those with the C/C and C/T genotypes in human samples25. Thus, increased TOLLIP expression by the minor allele might be associated with pathogenesis, responsiveness to treatment, and/or ILD prognosis. However, the complexity of immune homeostasis complicates our understanding of pathogenesis. TLR2 signaling was reported to promote pulmonary fibrosis in a model of bleomycin-induced pulmonary fibrosis28. Inhibition of TLR4 exacerbated bleomycin-induced pulmonary fibrosis29, while another study reported that TLR4 enhanced fibroblast activity, thereby promoting wound healing and fibrosis30. In addition, TOLLIP inhibited TLR4 downstream and suppressed inflammation under acute inflammatory conditions. In contrast, in low-grade, chronic inflammation, TOLLIP translocated to mitochondria and facilitated chronic inflammation26. The link between SNPs and the pathogenesis of pulmonary fibrosis should be further investigated.The biological mechanisms underlying the interaction of This study has several limitations. First, it was conducted at a single center and the sample size was small. In addition, we noted no significant difference in overall survival, perhaps because the observational period was short (108 ± 104 months). A nationwide Japanese analysis of genomic factors in idiopathic interstitial pneumonia is ongoing (NEJ036A: UMIN000032117) and might validate our findings. Second, we could not directly compare the genetic distribution of rs3750920 in our patients and healthy Japanese subjects. However, international and Japanese SNP databases provided useful information for analysis of the association of genetic distribution and disease.The present findings indicate that few Japanese with fibrosing ILD, especially those without IPF, are carriers of the rs3750920 minor T allele. Survival might be better for carriers than for non-carriers of the T allele. However, genotype was not associated with change in pulmonary function after treatment with any antifibrotic drug. To our knowledge, this is the first study to investigate associations of clinical characteristics, including outcome for fibrosing ILD, with rs3750920 genotype in a non-white population. Despite the limitations of this study, our results should provide insights regarding IPF and fibrosing ILD treatment. A nationwide Japanese genomic study is ongoing and might validate the present findings.


Chemical vapor deposition (CVD) is regarded as the most promising technique for the mass production of graphene. CVD synthesis under vacuum is the most employed process, because the slower kinetics give better control on the graphene quality, but the requirement for high-vacuum equipment heavily affects the overall energy cost. In this work, we explore the possibility of using electroformed Cu substrate as a catalyst for atmospheric-pressure graphene growth. Electrochemical processes can produce high purity, freestanding metallic films, avoiding the surface defects that characterize the rolled foils. It was found that the growth mode of graphene on the electroformed catalyst was related to the surface morphology, which, in turn, was affected by the preliminary treatment of the substrate material. Suitable conditions for growing single layer graphene were identified. Since its first synthesis, graphene has been a hot topic for many research groups , because2/CH4 gas mixture can be diluted with an inert gas such as argon; two different growth modes have been identified in these atmospheres [Alternatively, the Hospheres . The firAlong with these limitations, synthesis performed at atmospheric pressure has the advantage of excluding high vacuum equipment and reducing largely the production costs, which heavily affect CVD graphene mass production and pose a high barrier to its technological breakthrough . The aimThe quality of the prepared materials was assessed by different characterization techniques: X-Ray fluorescence (XRF), X-Ray diffraction (XRD), and atomic force microscopy (AFM) were used to evaluate substrate purity, crystalline orientation and surface roughness. After electroforming, Cu foils underwent annealing  in hydrov/v phosphoric acid, 25% v/v ethanol, 5% v/v 2-propanol, and 0.1 M urea [2 current density for 30 s. Both substrate annealing and graphene chemical vapor deposition were performed in a tubular furnace using a quartz vial; both treatments were carried out at 1000 °C and atmospheric pressure. In the annealing treatment, pure hydrogen was supplied to the vial at the flow rate of 5 NL/h for two hours, while the CVD atmosphere was a H2-CH4 gas mixture, with CH4 content of 3 vol%. Further experimental details are reported elsewhere [4/H2 flow for 2, 4, 6 and 8 min, while the annealed and the annealed-polished substrates were subjected to process times ranging from 2 to 20 min.Electroformed substrates were prepared by using a stainless-steel mandrel as the cathode and a Cu plate as the sacrificial anode. The cell was set up in the standard two electrodes configuration; the electrolyte used was the Cuproplus bath for Cu plating, supplied by Tecnochimica; plating parameters were used according to the product datasheet. Resulting free-standing Cu foils were 2 cm × 2 cm in size, with a thickness of 50 µm and a good surface finishing. The setup for preparing the Cu foils is illustrated in 1 M urea ; the prolsewhere . To inve2 and a vertical resolution of 0.1 nm. XRD patterns were acquired by means of a Philips PW1830 spectrometer, on a surface area of 2 cm2. Scanning electron microscopy (SEM) analysis was performed using a ZEISS EVO 50 EP instrument equipped with a field-emission gun, under the accelerating potential of 5 kV. Raman spectra were acquired by means of a Horiba LabRam HR800 spectrometer equipped with an argon ion laser operating at 514 nm (2.41 eV). The scattered radiation was collected through a 50 × objective keeping the beam power below 1 mW to avoid sample heating and graphene damage. The intensity correction system (ICS) was always kept active, and a diffraction grating with 600 lines/mm was used; acquisition time was always 45 s.Purity of the obtained samples was assessed by a Fischerscope X-ray Xan instrument, while surface morphology of Cu foils was investigated by using a NT-DMT SOLVER PRO atomic force microscope, with a scanning area of 100 µmGraphene catalytic growth on Cu is generally considered as a surface deposition process, with a typical adsorption-aggregation mechanism . From thSurface morphology of the as-plated foil is characterized by several protrusions roughly globular in shape; somewhere, elongated terraces are also observed a.In the annealing treatment, surface and volume diffusion can produce atomic redistribution, causing the observed reduction in surface roughness. Actually, the annealed surface looks highly smooth, with rare protrusions probably deriving from original large globules flattened only partially during the annealing treatment b.The electropolished surface appears more heterogeneous and consists of terraces and depressions with different sizes delimited by shallow steps c. Electr−1; it is the only first-order Raman process in graphene and is associated to the degenerate E2g phonon at the Γ point of the Brillouin zone. At 1350 cm−1 the D band is usually found, where “D” stands for “defect”: in fact, D Raman peak is originated by a second order process that involves a phonon at the Brillouin zone corner (A1g) and a defected state, treated as a 0 frequency quasi-particle to preserve the formalism [−1, the 2D band is observed; the 2D peak is, indeed, a second-order process where two phonons with opposite wave vectors were involved; hence, the momentum conservation is satisfied without the need of a defect state [G/I2D) is accepted to be lower than 1, and 2D Raman line shape has a FWHM of 24 cm−1 and is fitted by a single component Lorentzian function [−1), which is usually fitted by a single Lorentzian function, as in the case of single layer graphene (SLG). This is due to the decoupling of the layers comprising the turbostratic FLG, each of which retains a high percentage of the SLG transport properties [2D/IG intensity ratio.Raman spectrum of graphene layers features several bands, three of which are of uttermost importance when it comes to describing the main properties of the system of interest. The G band is located, in pristine samples, at 1582 cmormalism ,23,24. Fct state . The 2D function . The speoperties . In the operties : positioRaman spectra on untreated Cu foils showed a luminescence band , typical2D/IG = 0.6) and can be fitted with a single Lorentzian curve, its large FWHM linewidth (58 cm−1) suggests that the film consists of FLG, for the reasons explained above.Intensity of the 2D band progressively increased with increasing deposition time, and the D band was always present, probably related to the small dimension of the graphene domains. The graphene sample with 8 min of deposition time displayed a Raman spectrum d with loSEM observations  revealedSome isolated flakes exhibit hexagonal shape, which is favored by the etching action of hydrogen (97 vol% in the CVD atmosphere) at the edge sites . The ave2/CH4 atmosphere, continuous monolayer graphene was found  compared to pristine and annealed foils, since shorter treatments  led to Raman spectra similar to that in −1, slightly shifted towards higher wavenumbers with respect to pristine graphene. In addition, the position of the 2D peak shifted likewise. On the other side, the D-peak position seems to be consistent in all the reported spectra, remaining within the instrument spectral resolution. Full width at half maximum for the 2D peak is typical of multilayer materials as regards the as-plated and annealed-polished catalysts (>50 cm−1), while it was almost half of that value for the SLG grown on the annealed Cu substrate, in good agreement with the literature. Intensity ratios are always lower than 1 in the case of ID/IG, symptomatic of a good degree of order but small grain size, while the I2D/IG ratio varied depending on the number of layers present (see Results).All the Raman spectra presented show the main peaks typical of graphene. As can be seen from 2D/IG ratio. The growth route is characterized by the formation of several islands with incomplete substrate coverage  crystalline orientation and its surface became highly smooth, thus, promoting monolayer graphene growth. In fact, the 2D band FWHM is close to the value measured on Si/SiOgraphite . Moreoveonolayer . The ID/The existence of monolayer graphene on annealed Cu could be related to its strong crystalline orientation and the high growth rate of graphene on Cu (111) planes ,36. Howe2-CH4 gas mixtures [4 partial pressure of 1 Pa, single layer graphene with rare multilayer domains was produced; the number of these domains increased at higher CH4 concentrations. If results coming from low-pressure CVD experiments [4 partial pressures ranging from 1 Pa to 63 Pa. Hence, the high CH4 partial pressure (3 kPa) used in this work was expected to produce massive multilayer graphene [The formation of FLG regions on the annealed substrate b may be mixtures . Under aeriments ,9,14,33 graphene . On the 2-CH4 atmospheres [It can be noted that a consequence of using high partial pressures of methane is the reduction in the process time, which decreases from 30–60 min for pressures lower than 63 Pa ,14,33 doospheres .Electropolishing altered the smoothness of the original annealed surface, creating a number of defects that were regarded as preferential sites for nucleation and growth of multilayer graphene. As a result, the growth mode on the annealed-polished surface was similar to that observed on the as-plated Cu substrate, although the reaction time needed to reach a good surface coverage was longer (20 min compared to 6 min), probably because of the lower concentration of surface defects a,c.2D/IG ratio; FWHM was quite large; in conclusion, data support the hypothesis of having 4 to 5 graphene layers on top of annealed-polished electroformed Cu substrate.On the other hand, longer deposition time produced the most ordered of all three films, with good surface coverage and larger domains. The 2D band was less shifted but also less intense, as can be seen from the IAs reported at the beginning of the Discussion section, all the G-band positions in In this paper, we reported the study of graphene/FLG nucleation and growth on fully self-developed Cu substrates made by electroforming process. A complete morphological characterization of the substrates was presented, along with related graphene film Raman analysis. Moreover, electroformed Cu foils were treated to change surface conditions, and modifications in deposited film quality were highlighted. In particular, a conventional annealing treatment produced a highly smooth surface, where single layer graphene was grown. According to the existing literature, massive multilayer graphene would be expected to form in place of single layer graphene, under the investigated growth conditions. Conversely, Cu substrates with uneven surface generated graphene films consisted of few-layer/multilayer islands. Future developments will focus on testing the proposed AP-CVD process on different electroformed substrates, to further explore the electroplating potentialities in graphene synthesis. In addition, the CVD process itself can be improved to yield a desired number of graphene monolayers, mainly by optimizing the methane content in the growth atmosphere.


The strategy affords easy access to a broad scope of 2-substituted and 1,2-disubstituted pyrenes. The C1-substituent can be easily transformed into carboxylic acid, iodide, alkynyl, aryl or alkyl functionalities. This approach gives access to arylated pyrene ammonium salts, which outperformed their non-arylated parent compound during aqueous Liquid Phase Exfoliation (LPE) of graphite and compare favourably to state-of-the-art sodium pyrene-1-sulfonate PS1. This allowed the production of concentrated and stable suspensions of graphene flakes in water.A new and diverse family of pyrene derivatives was synthesised  via C–H arylation of pyrene-1-carboxylic acid.Novel pyrene surfactants for aqueous graphene exfoliation were prepared  On this regard, LPE offers a straightforward approach to obtain graphene dispersions directly from graphite.2 LPE is based on exposing directly the material to a solvent with a surface tension that favours an increase in the total area of graphite crystallites.2 Typically solvents used are NMP and DMF. However, LPE in water is also possible by using an exfoliating agent.3 This also allows to non-covalently functionalise the graphene flakes in situ, by tuning their surface chemistry depending on the exfoliating agent used.2During the last few years graphene has emerged as a revolutionary material attracting much attention due to its unique properties and multiple applications.3 In this context, pyrene derivatives have arisen as a privileged scaffold due to its strong affinity for graphene.4 For instance, several types of pyrene derivatives  would offer a flexible platform to that end. The palladium-catalysed C–H ortho-arylation of aryl carboxylic acids offers an oxygen and moisture-compatible way to derivatise these common feedstocks while choosing the fate of the acid moiety, which can be preserved or removed during the arylation reaction by judicious choice of reagents and conditions.15–17 Thus, the use of a silver-salt additive can lead to decarboxylated products,16 whilst replacing it with a tetramethylammonium salt, the ortho-arylated carboxylic acids are obtained.17Although reports on pyrene-functionalised graphene flakes are very abundant, examples of cationic pyrene-derived surfactants used to obtain suspensions of positively charged graphene flakes are scarce and require further investigation.ivatives .11 Notab1) and 3,5-iodoxylene (2a). After screening of the reaction parameters,18 both the 2-arylated pyrenecarboxylic acid 3a and the corresponding decarboxylated 2-arylpyrene 5a could be obtained in good yields (3a and 5a). Arylated carboxylic acids 3 were obtained in very good yields regardless of the substituents in iodoarenes 2. Both electron-withdrawing and electron-donating functionalities were broadly tolerated; haloarenes were also obtained in good yields (entries 3g–j) and the use of trifluoromethylated aryl iodides led to excellent yields (entries 3k and 3m). Ester-substituted products, which are amenable for further derivatisation, were also obtained in good yields (entries 3o and 3p). On the other hand, products of decarboxylative C–H arylation 5 were obtained in moderate to good yields in most cases and only in two particular cases the decarboxylative coupling proved inefficient (entries 5k and 5n). Nonetheless, the desired products could still be obtained in good yields by decarboxylation of the corresponding carboxylic acid.19 Importantly, this decarboxylative coupling can be a useful one-step alternative to access 2-arylpyrenes. Finally, using a modified protocol of our recent iododecarboxylation of carboxylic acids,20 arylated pyrene acids 3 could be further derivatised into the corresponding iodoarenes 4,18 which grant access to a whole new family of unexplored pyrene derivatives (vide infra). In this case yields ranged from moderate to good, although as expected, the best yields were obtained among the most electron-rich substrates (4a–e). To our delight, some substrates bearing electron withdrawing groups and halogen substituents also gave very satisfactory results . In general, products 3–5 were obtained in good yields and reactions could be scaled up with ease .The feasibility of the proposed approach was first assessed using pyrene-1-carboxylic acid .18PS1 is one of the most commonly used negatively charged organic surfactants for aqueous graphene exfoliation and has found application in different graphene-based technologies.2Pyrene cations logue 11 .18 CompoPS1, see  under th10a–d and non-arylated pyrene cation 11. As expected, the more concentrated suspensions, prepared with electron-poor compounds 10b and 10d, were darker than the rest.Aqueous suspensions of exfoliated graphene were diluted (×10) for visual inspection. The pictures in 10 is that steric clashes result in the benzylic ammonium group to be oriented perpendicular to the plane of the pyrene ring, locking the molecule in a favourable conformation  for analysis of lateral size. an 30 mV , confirmIn conclusion, we have developed a versatile strategy for the synthesis of 2-arylated pyrenes, including 1,2-disubstituted derivatives with several functionalities easily introduced in position 1, such as carboxylic acid, iodide, alkynyl, aryl and alkyl . This approach also offers a one-step alternative to the synthesis of 2-aryl pyrenes and opens new possibilities for the design and synthesis of unprecedented functional pyrene-based materials, previously unexplored due to its synthetic inaccessibility. Importantly, the cationic arylated pyrene ammonium salts accessible by this method can be used to obtain stable aqueous graphene suspensions by liquid phase exfoliation of graphite, composed mostly of single- and few-layer graphene flakes, and of concentrations comparable to those achieved with state-of-the-art anionic pyrene exfoliators.The authors declare no conflict of interest.SC-011-C9SC05101E-s001


Introduction: Interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders characterized by the pathogenetic involvement of interstitium. Therefore, an elucidation of the etiology and pathogenesis as well as the identification of diagnostic and prognostic biomarkers of such diseases is more compelling than ever. It is of note that there is increasing evidence of the involvement of extracellular vesicles (EVs) in the pathogenesis of lung diseases including lung cancer, chronic obstructive pulmonary disease and pulmonary fibrosis. It has been speculated that EVs play a pivotal role as mediators of intercellular communication, as well as the highlighting of the role of EVs as co-operators in the development of lung diseases such as IPF. Methods: The present study aimed to carry out a systematic exploratory search of the literature (through the scoping review approach) to identify and systematize the main results of the pathogenetic role of EVs in pulmonary fibrosis models and biological fluids from ILD patients, including plasma, bronchoalveolar lavage (BAL) and sputum. Conclusion: Fibroblast-to-mesenchymal differentiation, collagen and extracellular matrix deposition are key mechanisms in the development and progression of IPF. EV-coupled miRNA are important modulators of biological processes in terms of intercellular communication as shown in pulmonary fibrosis models as well as biofluids. The helpfulness of EVs as diagnostic and theranostic markers is worth further investigation. The evolving potential of EVs to translate effective EV-based therapies into clinical practice is of growing interest, due to the urgent need for novel therapeutic strategies for IPF patients. Interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders characterized by the pathogenic involvement of the interstitium . Many ILIn recent years, it has also been reported that patients with non-IPF ILDs, such as non-specific interstitial pneumonia , fibrotiThere is increasing evidence of the involvement of extracellular vesicles (EVs) in the pathogenesis of lung diseases, including lung cancer, chronic obstructive pulmonary disease and pulmonary fibrosis. It has been speculated that EVs play a pivotal role as mediators of cell–cell communication, as well as having a co-operator role in the development of lung diseases such as IPF . ‘ExtracStandardized recovery of EVs from an EV-containing matrix is still challenging and many questions remain about the effects of specific pre-analytical variables on different classes of EVs. This may be due to the fact that mammals have more than 30 types of biofluids. To these we can add lavages of various compartments, which are not true biofluids.Extracellular vesicles are secreted by a wide variety of cells under physiological and pathological conditions and have been described as important mediators of intercellular communication in different pathologies. They carry a wide variety of bioactive molecules such as DNA, RNA, lipids and proteins, which enable them to regulate host cell activity and behaviour by activating different signalling pathways . MechaniThe aim of the present study was to conduct a systematic exploratory search of the literature (by a scoping review approach) to obtain a systematic picture of what we know about the pathogenetic role of EVs in pulmonary fibrosis models and biological fluids from ILD patients, including plasma, bronchoalveolar lavage (BAL) and sputum.We used the scoping review protocol  and descThe inclusion criteria were peer-reviewed, empirical or perspective papers  with: (a) relevance to the study topic, i.e., involvement of EVs in pulmonary fibrosis studied in different biological fluids from ILD patients, as well as in in vitro and in vivo models; (b) language: English; (c) type of journal: preference for journals relating to pneumology with full text or abstract; d) type of study: review, case report, case series, original article or letter to the editor. Studies were excluded if: (a) they were not relevant to the topic of study; (b) they were written in languages other than English; (c) they did not adequately report their objectives and conclusions; (d) the full text of abstracts located was not (yet) available.A systematic search of the literature was conducted in the PubMed online database. The term we entered in our Boolean search syntax was: extracellular vesicles or exosomes AND . As already mentioned, the search was limited to the English language and papers available in full text form. We did not search the grey literature . Two independent reviewers  screened the abstracts and titles, and ascertained the availability of the full-texts. If the papers met the eligibility criteria they were considered. Any disagreement of the reviewers was resolved by consensus or by the leading reviewer (M.d.). Using a coding structure devised by members of the research team, one author (M.d.) extracted formal data items  and a random 5% were checked by another (L.B.). Regarding the content of the literature included, three independent reviewers  extracted text quotations on: (1) analysis of EVs in lung fibrotic models and their involvement in the pathogenesis of pulmonary fibrosis, or (2) detection of EVs in sputum, BAL and serum from ILD patients. These independent extractions were later paired for qualitative data synthesis, which was also supplemented with brief summaries of each paper made independently by the two reviewers. The extractions and summaries of all reviewers were then combined. The literature search yielded all articles concerning “extracellular vesicles”, an umbrella term that covers all vesicle types, including “exosomes” and “microvesicles”  generated by inward budding of the cell membrane (endocytosis), subsequent shaping of multivesicular bodies and release by exocytosis. During the release into the extracellular space, the peripheral membrane of these multivesicular bodies fuses and the exosomes incorporate various membrane proteins, including tetraspanins . These surface proteins are recognized as markers of exosomes. Of the 16 studies selected, three included the possible involvement of EVs in pulmonary fibrosis models, three speculated that EVs could be a potential new target for clinical treatment of lung diseases, four analysed BAL EVs in the pathogenesis of ILDs, two concerned the role of EVs from sputum as potential biomarkers of IPF and three suggested a possible role of EVs as mediators and disseminators of inflammation in ILD patients. The results of SANRA are reported in The formation of fibroblastic foci, excessive deposition of extracellular matrix proteins cellular senescence and senescence-associated secretory phenotype factors are key factors that directly cause IPF; however, the underlying mechanisms are still unclear ,2,13. BeHuman lung fibroblasts (HLF) are the most abundant cells in the lung interstitium. These mesenchymal cells produce the extracellular matrix that gives the lung its structural integrity and has a critical role in wound healing. HLFs also perform an innate immune function as sentinel cells and may play an active role in moderating the response to harmful stimuli.Lacy and colleagues reported that activation of HLF by IL1-β inhibited TGF-β-induced myofibroblast differentiation and that EVs containing prostaglandins have antifibrotic effects on activated and naïve HLFs . Guiot eA functional role of bone-marrow-derived mesenchymal stem cell (BMSC)-secreted EVs has been implicated in HLF, yet their action in the treatment of IPF is not fully understood. Wan et al. investigated BMSC-derived EVs expressing miR-29b-3p in HLF in the treatment of IPF, reporting a low expression of miR-29b-3p and an overexpression of frizzled 6, α-SMA and collagen I . They spAnother event that incites fibrosis is the increased deposition of collagen in the interstitium. This increases its tensile strength, in line with the nature of fibrotic lung disease . Xu et al. showed elevated COL1A1 and fibronectin gene expression in experimental silicosis mice, with and without exosomes derived from human umbilical cord mesenchymal stem cells . The autBronchoalveolar lavage is a useful biological fluid for studying inflammatory cell infiltrates and presumably also for isolating EVs to detect biomarkers of ILD ,33,34,35There is emerging evidence that BAL EVs play an essential role in the pathogenesis of various ILDs, including IPF . Martin-The pathogenesis of IPF is very complex, and involves several epithelial and mesenchymal cell populations, including fibrocytes that are mesenchymal progenitor cells derived from CD14+ peripheral cells, thought to be involved in the normal wound-healing response . AlthougIn parallel to the contribution of EVs to fibrotic mechanisms, BAL EVs generated by sarcoidosis patients are reported to display pro-inflammatory effects ,43,44,45Qazi et al. reported higher levels of exosomes in BAL from sarcoidosis patients than in BAL from healthy controls, and also higher concentrations of CD54 and MHC molecules . The autIn support of a direct effect on monocytes, the same group of researchers recently reported that EVs from BAL samples of sarcoidosis patients induced dose-dependent elevation of IL1-β in monocytes, confirmed also in PBMCs and enriched monocytes. Other literature reported the interesting role of the mononuclear phagocyte (MNP) system in lung disorders, including sarcoidosis, where tissue infiltration by MNPs is a hallmark . It has been speculated that exosomes are mediators and disseminators of inflammation, opening the way for further investigations of the link between CCL2 and exosomal leukotrienes in sarcoidosis . To confMicroRNA transcriptional regulators are further markers that may have a pro-inflammatory role in pulmonary sarcoidosis. Kishore and colleagues investigated the expression of miRNA packaged in EVs during cell communication in BAL from sarcoidosis patients. Interestingly, they found an increased expression of miR-146a, miR-150 and cellular miR-21 in chest X-ray stage II of sarcoidosis and an inverse correlation with lung function parameters, and speculated on whether a typical extracellular miRNA profile might characterize distinct sarcoidosis clinical phenotypes .A few studies analysed EVs from plasma samples, and most validated an exosome-associated biomarker in the blood of patients that may provide novel, less invasive tools for diagnosis . Guiot eTo our knowledge, only one paper investigates the expression of exosomal surface markers in serum from IPF patients . The autFurther studies are needed to obtain data on communication signatures/exosomal profiles in serum from IPF patients. Such data could offer new insights into IPF pathogenesis and could enable the survival of IPF patients to be predicted more reliably. Induced sputum has been proposed as a useful, non-invasive method for the assessment of airway diseases, including ILDs ,50. GuioFibroblast-to-mesenchymal differentiation, the deposition of collagen and extracellular matrix and cellular senescence  are key