The Iberian porpoise inhabits the Atlantic coast of Portugal and Spain. The population is relatively small and there is a high number of individuals accidentally captured in fisheries. Using airplane surveys, we estimated that there were only 2254 porpoises overall between 2011 and 2015 in the coast of Portugal. The highest annual number of porpoises was recorded in 2013 . However, in the following year, our study revealed that the population had been reduced approximately by half . The northern area of Portugal presented the most suitable habitat for the Iberian harbour porpoise, where coastal fisheries represent a particularly important socio-economic activity. Measures to decrease fishing effort are urgently needed as well as detailed information on seasonal Iberian harbour porpoises’ use of space.2, CV = 21.99%) in the Portuguese coast. The highest annual porpoise estimates were registered in 2013 , followed by a sharp decrease in 2014 . The porpoise density and abundance estimated in 2015 remained lower than the 2013 estimates. A potential distribution analysis of the Iberian porpoise population was performed using ensembles of small models (ESMs) with MaxEnt and showed that the overall habitat suitability is particularly high in the Portuguese northern area. The analysis also suggested a different pattern in porpoise potential distribution across the study period. These results emphasize the importance of further porpoise population assessments to fully understand the spatial and temporal porpoise habitat use in the Iberian Peninsula as well as the urgent need for on-site threat mitigation measures.The Iberian porpoise population is small and under potentially unsustainable removal by fisheries bycatch. Recently, a marine Site of Community Importance (SCI) was legally approved in Portugal, but no measures ensued to promote porpoise conservation. Information about porpoise abundance and distribution is fundamental to guide any future conservation measures. Annual aerial surveys conducted between 2011 and 2015 show a low overall porpoise abundance and density (2254 individuals; 0.090 ind/km Phocoena phocoena meridionalis) [A sharp decline in genetic diversity detected over the past 25 years indicates that the harbour porpoise population in the western Iberian Peninsula may be small and isolated . Porpoisionalis) . The harionalis) , and a hionalis) ,5. Howevionalis) .Efforts to address the need for conservation measures applied to the harbour porpoise population in Portugal were initiated in 2010, including annual porpoise population surveys and trials of mitigation measures to reduce bycatch in fisheries ,7. TheseThe porpoise population in Portugal is, in fact, known to be particularly susceptible to interactions with coastal fishing gears . The difIn Portuguese coastal waters, we conducted a standardized aerial survey protocol replicated annually over a 5-year period in order to collect harbour porpoise sightings data. Aerial surveys are considered a standardized and cost-efficient census methodology providing robust estimates , constitThe aims of this study were to understand how harbour porpoises were distributed in Portugal within the study period, how abundance and densities evolved over time, and also to identify the most suitable areas for porpoises in the western Iberian Peninsula. Our findings on abundance and density estimates in Portugal are also discussed considering results from other surveys on Iberian waters (SCANS II and III).2, including a 23,728 km2 continental shelf, which is generally narrow although wider profiles occur associated to the northern coast of the country. The study area  was defined by a 20-nautical-mile (nm) buffer along the Portuguese coastline , Centre (9154.15 km2), Alentejo (3424.86 km2), and Algarve (5771.52 km2) see [The Portuguese exclusive economic zone (EEZ) covers 327,667 kmkm2) see ). In thekm2) see ,20.This study was conducted in the framework of a broad-scale marine megafauna survey to obtain annual density and abundance estimates for several cetacean and seabird species. Annual aerial surveys were conducted in September between 2011 and 2015 except for 2013, when the survey was conducted in early October. High-wing airplanes equipped with two bubble windows  were used to survey over a predesigned, systematic set of parallel 20-nm-long transect lines, which were obtained using DISTANCE  to ensurFlights were performed at an average speed of 100 knots (185 km/h), at an altitude of 500 ft (150.4 m). Surveys were conducted in weather conditions safe for flying operations (no fog or rain) with visibilities > 3 km and under Beaufort (windforce) scale ≤ 3, which are considered suitable for porpoise sightings ,24. SurvSighting data were registered in customized forms, including GPS position, declination angle , species identification, group size, presence of calves, behavior, swimming direction relative to the transect, and detection cue. For each sighting, the distance from the transect line to the animal or group of animals was calculated using the declination angle and the airplane’s altitude ,23.Conventional Distance Sampling (CDS)  was usedTo analyze the data, we tested combinations of the most recommended models for detection functions  . The AkaWe used ecological niche models (ENMs), which are statistical and machine-learning approaches to relate species distribution data (observations) and environmental predictor variables to describe, understand, and predict the distribution of the species, e.g., .4+) considering its importance for phytoplankton growth and marine trophic webs, e.g., [Several eco-geographical variables (EGVs) are known as potentially relevant habitat drivers for cetaceans. According to literature, we built the ESM using information on bathymetry, distance to coast ,27,28, ss, e.g., . All stas, e.g., ,34,35.raster package for R [2) using the inverse distance weighting method, available in the R gstat package [The slope and distance to coast variables were computed from bathymetry using the built-in tools provided by the ge for R . The dyn package ,39.The correlation between EGVs was assessed  using thWe adopted an ensemble approach of ecological niche models to reduce the uncertainty levels of models’ prediction and assessment of harbour porpoise habitat suitability in the present study . We furtThe modelling procedure was conducted using R version 3.6.0  and the The predictive power of the model was evaluated using the Continuous Boyce Index (CBI) . The CBIFrom 2011 to 2015, a total of 195 transects and a total distance of 8635 km were surveyed by airplane. Overall, 56 sightings were registered corresponding to 83 harbour porpoises , Table 2The total number of sightings was used in DISTANCE to estimate the detection function since truncation did not improve the detection function quality, despite the lower detection probability for distances over 200 m from the centre line.We tested combinations of the most recommended models and due to lower AIC value (614.17), the uniform key with cosine adjustments was the best model combination using data from all sampled years, when comparing to models using the half normal key model with cosine adjustments (AIC = 614.73), half-normal key with hermite polynomial adjustments (AIC = 614.73) and the hazard-rate key with simple polynomial adjustments (AIC = 614.84). The histogram presenting the probability of detection function shows a general decreasing pattern with increasing distance from the transect line, and the resulting estimate of the effective strip width (ESW) was 159.90 m (95% CI: 143.66–177.98 m) .2 (2) were registered in 2011, whereas the highest harbour porpoise estimated annual abundance and density  were registered in 2013 followed by a sharp decrease in 2014, with only 1653 estimated individuals and a 0.066 ind/km2 density (CV = 43.27%). The overall expected group size was 1.39 individuals (CV = 7.80%). In all analysed data frames, the expected group size value was chosen over the observed value (to account for possible group size bias due to increasing distance from the transect line).Between 2011 and 2015, the overall estimated abundance (using g(0) = 0.364) was 2254 individuals (CV = 21.99%) with a density of 0.090 ind/km2 . The lown = 27), as well as the highest density estimates . On the other hand, only four sightings were registered in the smaller Alentejo sector (p = 0.475), the median group size was higher in the Algarve sector  when compared to the other sectors.Considering the different sectors, the highest number of harbour porpoise sightings were registered in the North sector   althoughConsidering the variables’ relative contribution to explaining the annual porpoise occurrence probability, the mean chlorophyll concentration (Chl-a) was the most important variable in 2011, 2013, and 2014, whereas bathymetry and SST were the most important variables in 2012 and in 2015, respectively .−3 . However, when considering AA, AB, and AC blocks in SCANS III (corresponding to the harbour porpoise ICES assessment unit) the much larger area leads to a drastically lower density value (0.04 ind/km2) confirming the importance of the western Iberian coast to the Iberian porpoise population. This is in agreement with the relatively large number of porpoise strandings recorded over the last 20 years in the western Iberian coast, particularly in the Portuguese northern coast, which concentrates 60% of the total Portuguese and Galician harbour porpoise registered strandings [In SCANS III (2016) , the porrandings .2), where an abundance of 2357 porpoises was estimated along with a very low density (0.017 ind/km2)  and 2013 . These estimates were also higher than those obtained for the western Iberian coast in the SCANS III survey (2016)  [In the present study, the highest annual harbour porpoise abundance and density estimates in Portuguese waters occurred in 2012 . Duringin July, . In factin July, , the denuly, [2) ,58 than uly, [2) ). In facThe expected harbour porpoise group size in the present study  is in liEven though the Iberian porpoise population was thought to be isolated from other porpoises ,68, ther2, CV = 42.43%) and Centre sectors  , the highest estimated porpoise density was registered in the North (0.140 ind/km 39.75%) . The SCIIn the study area, the models predicted the most suitable conditions for harbour porpoise occurrence were found predominantly in coastal and shallow waters, as already described in other studies considering different populations of porpoise, e.g., ,70,71. C−3) followed by a plateau, and a new steady, less pronounced increase in porpoise occurrence probability at higher Chl-a concentrations (>2 mg m−3), similar to the other years. One of the highest harbour porpoise abundance estimates was obtained in 2012 when the highest habitat suitability was detected in a very narrow portion of the central and northern Portuguese coast and in the southwestern coast (south of Sines). Oscillations of the Iberian upwelling system may contribute to porpoise annual  abundance and density variations. It is possible that upwelling phenomena become more irregular in duration and strength towards the end of summer [However, in 2012 the occurrence probability variation with increasing Chl-a concentrations presents a different pattern when compared to the remaining study years: an initial sharp increase at relatively low Chl-a concentrations  [In addition, it is concerning that in 2013  a low habitat suitability was estimated in the Alentejo and the Algarve sectors. As mentioned earlier, high Chl-a concentrations and lower SST values in the Centre and North sectors contributed to the concentration of the potential porpoise distribution in these coastal areas. The fact that the 2013 survey was carried out in early October, whereas in the remaining years surveys were carried out in September, may account for some of the variation. However, the highest annual abundance estimate (in 2013) was followed by the highest annual number of stranded porpoises in Portugal , which i labrax) ,83,84,85The habitat suitability maps for the harbour porpoise in the study area  emphasize the importance of coastal areas between Nazaré  and the western coast of Galicia (Spain). Even though an MPA dedicated to the protection of porpoises was recently designated in the central coast of Portugal (SCI Maceda—Praia da Viera), there are no other protected areas with representative marine areas in northern Portugal or western Galicia. However, the definition of a critical area for porpoises was proposed in 2018 in western Galicia , and porResults indicate that a transnational marine protected area could be important for the conservation of the Iberian harbour porpoise . Other iThe seasonal and annual variability of the Iberian upwelling system emphasizes the importance of seasonal porpoise surveys in the future, to fully understand the spatial and temporal porpoise habitat use in the Iberian Peninsula. Within areas with overall higher habitat suitability, porpoises may use different portions of the available habitat according to varying environmental conditions and resources. Seasonal changes in the distribution of harbour porpoises have been suggested in Europe ,90,91 asConsidering the harbour porpoises’ need for a constant energy intake ,95, it iThe overall HSI map (for the period between 2011 and 2015) suggests a higher habitat suitability in central-northern Portugal , corroboAccurate abundance and density estimates depend on several factors affecting field surveys . In this study, the bias levels can be considered constant since the platform, observers, and field protocols were the same in all studies . FurtherA further limitation in this study was the yearly small sample size used for the potential distribution analysis. To decrease the predictive uncertainty, the assessment of harbour porpoise habitat suitability was performed using ESMs , which s2, CV = 21.99%) and one year later for the western Iberian coast  [2, CV = 9.91% for a design-based analysis) [−2, CV = 28.5%) [The porpoise densities estimated in the present study in Portugal between 2011 and 2015   currentlnalysis) . LikewisThe annual fluctuations in harbour porpoise abundances in Portugal revealed an abrupt decrease in 2014. Whether this abundance decrease in Portugal was due to mortality or to displacement to other areas (nearshore–offshore movements are unlikely but migration to other latitudes outside the study area is plausible) remains unclear. Larger-scale coordinated and periodic surveys covering at least the entire Iberian population are needed to better understand the annual abundance fluctuations detected in the present study.This study emphasizes the importance of transboundary conservation efforts involving Spain and Portugal, including further porpoise population assessments and the need for on-site threat mitigation measures supported by legal frameworks involving the development of human activities . Despite the efforts to legally approve an SCI dedicated to the protection of harbour porpoises in Portugal under the Habitats Directive framework, no further measures were approved to halt the porpoise population decrease.


Using the density functional theory, we calculate electronic states of various nanoribbons and nanodiscs formed from selected two-dimensional materials, such as graphene, silicene, and hexagonal boron nitride. The main objective of the analysis is a search for zero-energy states in such systems, which is an important issue as their presence indicates certain topological properties associated with chirality. The analysis is also supported by calculating transport properties. The two-dimensional 2D) materials, such as graphene, TMDCs, and other van der Waals crystals, have turned out to be very promising materials for applications in nanoelectronics and photonics D materia,4,5,6. TSignificant attention is also focused on graphene nanoribbons, in which a wide variety of band-gaps can be observed—from metallic to semiconducting ones ,12,13,14Even though most of the research on two-dimensional structures has been carried out on graphene, it is not the only 2D material. Following graphene, many other two-dimensional graphene-like materials have been synthesized, such as, for instance, silicene, hexagonal boron nitride (h-BN), transition metal dichalcogenides (TMDs), oxides, and carbides ,36,37,38This work focuses on nanodiscs and finite-length nanoribbons of graphene, silicene, and h-BN and particularly on their electronic properties studied by the density functional theory (DFT). It is worth noting that a comprehensive analytical tight-binding model of nanodiscs has been studied previously by Ezawa ,48,49,50To support the above conclusions, we also consider transport properties of nanodisc–lead devices, where the electrodes are made of zigzag graphene, silicene, and h-BN ribbons, passivated with hydrogen atoms. The central region has been selected as a zigzag trigonal nanodisc as this is the only form of the studied nanodiscs that exhibits the zero-energy states. The remaining part of this article is as follows. In this paper, we restrict our considerations to three stable 2D materials: graphene, silicene, and h-BN. As already mentioned above, graphene is composed of carbon atoms with a honeycomb structure of hexagons. In the simulation codes, a zero-dimensional nanodisc can be made either from a finite-length nanoribbon or from individual hexagons. This also applies to silicene and h-BN. To maintain stability, the edges of all structures have been passivated with hydrogen atoms.In turn, for the transport analysis, the device is made from three parts, including the right and left electrodes as well as the central scattering region. Electrodes in such a case are in the form of long (semi-infinite) nanoribbons of silicene, graphene, and h-BN. These two leads are connected to the central part formed by the zigzag trigonal nanodiscs of various sizes and shapes.All calculations performed in this work have been carried out based on the density functional theory (DFT)  within tack grid  for tranE through the central region from the left to the right electrodes, V is the applied voltage.Calculations of the transport properties are based on the DFT approach, coupled with the non-equilibrium Green’s function (NEGF) technique ,60. BaseIn this section, we investigate the electronic properties of finite-length zigzag nanoribbons of graphene, silicene, and h-BN, and especially the zero-energy states. Such zero-energy states are important because they remain zero energy as long as the chiral symmetry is preserved. For constructing finite-length nanoribbons, we make a primitive hexagon (benzene shaped), which is a unit cell of the considered 2D materials. Then, to generate a nanoribbon we repeat it along the width (W) and along the length (L). A finite-length nanoribbon can be considered as a parallelogrammic nanodisc, when its length and width are equal. For stability of the considered structures, the edges have been passivated with hydrogen atoms. To obtain a clear view, the optimized structures of the graphene, silicene, and h-BN finite-length nanoribbons are shown in L is faster. Hence, the metallic behavior of these structures depends on their length and width, which is consistent with the fact that infinite-length nanoribbons have a flat band of degenerate zero-energy states [We use the total density of states (TDOS) and the energy spectrum diagram to check the presence/absence of the zero-energy states. Some of these diagrams are displayed in y states ,19. The L and width W, see We have also investigated the zigzag h-BN nanoribbons of finite length, and checked the behavior of the gap with the length m standing for Hydrogen (H), Carbon (C), Silicon (Si), Boron (B), or Nitrogen (N).To search further for zero-energy states, we study the electronic properties of the nanodiscs of various shapes and sizes, and for the selected 2D materials—graphene, silicene, and h-BN. Each nanodisc is constructed by connecting a certain number of hexagons. Due to a large variety of nanodiscs in terms of size and shape, we investigate only a few selected nanodiscs which are shown in First, we calculate the electronic properties of armchair trigonal (AT), zigzag hexagonal (ZH), and armchair hexagonal (AH) nanodiscs. C), Silicon (B), Nitrogen (N), and Hydrogen (H) atoms.Another type of nanodisc we study is the zigzag trigonal nanodisc. As already mentioned above, they are constructed by connecting several hexagons. The shape of these nanodiscs is shown in From the results obtained for various types and shapes of nanodiscs, it is evident that the zero-energy states emerge rather rarely. Among different nanodiscs, the zigzag trigonal ones with N To gain further insight into the peculiar electronic properties of zigzag trigonal nanodiscs, we determine their transport properties. To do this, we consider a two-probe molecular junction consisting of two semi-infinite nanoribbons of graphene or silicene as electrodes, which are connected to a zigzag trigonal nanodisc as the central region, as shown schematically in Current–voltage, In order to gain an intuitive representation of quantum transport in the devices under consideration, we plot in We have used density functional theory to study electronic properties of finite nanoribbons and of various nanodiscs based on 2D materials such as graphene, silicene, and hexagonal boron nitride. The main objective of this analysis was a search for zero-energy states. Such states play an important role as their presence is connected with certain topological aspects of a given structure. In addition, such states also determine metallic behavior of the nanosystem. The zero-energy states exist rather rarely, and we have found them, e.g., in trigonal nanodiscs of graphene and silicene with zigzag edges. In turn, there are no zero-energy states in boron nitride nanodiscs and nanoribbons. For this material, all nanodiscs are in the insulator state, with a relatively large energy gap at the Fermi level.The conclusions based on the density functional theory have also been confirmed by calculating transport properties (


Doping is a great strategy for tuning the characteristics of graphene-based nanomaterials. Phosphorous has a higher electronegativity as compared to carbon, whereas boron can induce p-type conductivity in graphene. This review provides insight into the different synthesis routes of phosphorous- and boron-doped graphene along with their applications in supercapacitors, lithium- ions batteries, and cells such as solar and fuel cells. The two major approaches for the synthesis, viz. direct and post-treatment methods, are discussed in detail. The former synthetic strategies include ball milling and chemical vapor discharge approaches, whereas self-assembly, thermal annealing, arc-discharge, wet chemical, and electrochemical erosion are representative post-treatment methods. The latter techniques keep the original graphene structure via more surface doping than substitutional doping. As a result, it is possible to preserve the features of the graphene while offering a straightforward handling technique that is more stable and controllable than direct techniques. This review also explains the latest progress in the prospective uses of graphene doped with phosphorous and boron for electronic devices, i.e., fuel and solar cells, supercapacitors, and batteries. Their novel energy-related applications will continue to be a promising area of study. In the last few decades, rapid industrialisation has resulted in a high demand for energy, which is coupled with the depletion of natural resources . The sciThe rapid progress of research on doped graphene analogues can be seen in the high number of publications   and the s-orbital, out of the three p-orbitals, are used to produce covalent bonds with nearby carbon atoms, whilst the pz orbital is employed to produce a filled π bonding molecular orbital and a vacant π* anti-bonding molecular orbital ,492 hybrThe doping of graphene with heteroatoms offers redox active sites, which enhance the capacity of the probes and electrodes. Previously, a review article covering the detailed discussion on environmental application of phosphorous- and boron-doped graphene nanosheets was published . In addiP-GNS can be synthesised either by direct or post-treatment methods. In direct methods, a carbon source such as benzene, toluene, alginate, and glucose, etc., is reacted with a phosphorous source, viz. phosphorous trichloride, triphenylphosphine, phosphoric acid, or phosphorous pentaoxide, to yield P-GNS. In the latter methods, previously synthesised GO is reacted with a phosphorous source such as tri-n-octylphosphine, tetradecylphosphonic, tri-n-butylphosphine acid, phosphoric acid, triphenylphosphine, polyphosphoric acid, or triphenylphosphine, to produce P-GNS. The synthesis methods, sources, and the applications of P-GNS are summarized in 3) and benzene (C6H6) in the temperature range of 800–1050 °C in a chamber was used to synthesise P-GNS (Direct pyrolysis of phosphorous trichloride (PClse P-GNS  74]. Th. Th3) an4 molecules and substitutional doping within the graphitic matrix can cause phosphorous atoms to interact with the graphitic lattice below the material’s surface. Measurements using an X-ray photoelectron spectroscopy (XPS) technique showed that phosphorous was bonded to carbon with two bonding configurations, P–C or P–P. However, the P–O bonds were also observed near the material’s surface. At a low phosphorous content, phosphorous existed in two different bonding configurations where the P–O bonds were observed at high phosphorus contents, and P–C species were difficult to detect because their signals overlapped.Both free, stable P−1 argon flow rate. The BET surface areas of the P-GNS and the non-phosphorous material were similar.Liu et al.  synthesiP-GNS was synthesised by the pyrolysis of phosphoric acid as the phosphorous-containing source and alginate as the carbon-containing source at 900 °C under inert atmosphere . Graphen2O5) was used as the phosphorous precursor and glucose was used as the carbon source. The phosphorous source displayed a temperature-dependent transformation as shown in the following reaction  wasD/IG, was 1.25, which was greater than the undoped graphene (0.92). The G band is related to the C–C vibrational mode, while the D band, the defect activated band, is related to sp2 hybridized carbon nanomaterials. The ID/IG ratio gives indication about the defect densities. The amount of phosphorous in P-GNS was 1.78 at.%. The insertion of phosphorous induced structural disorders into the graphitic lattice. Due to phosphorous’ excellent electron-donating qualities, this finally improved the electron delocalization. As a result, the conductivity and charge transfer were improved.The amount of phosphorous varied from 1.0 to 6.0 g for 2.0 g of glucose. With an increase in phosphorous content, the mesoporosity was observed to rise. The Raman spectra revealed that the defect ratio of the D to G band, i.e., I2. The two characteristic Raman bands of reduced GO were observed at 1350 and 1590 cm−1, respectively. The D band displayed a red shift in P-GNS and there was a decrease in intensity of ID/IG. The XPS spectra of P-GNS displayed peaks at 134.4 eV and 133.5 eV due to P–O and P–C bonding, respectively [The thermal decomposition method involves chemical decomposition of a substance in the presence of heat. The reaction is endothermic in nature as heat is required to break the covalent bonds. P-GNS can be prepared by this approach using phosphoric acid, triphenylphosphine, tri-n-octylphosphine, tetradecylphosphonic, and tri-n-butylphosphine acid as doping agents. Yuan et al. used phosphoric acid to dope reduced GO. During annealing, the oxy groups were removed with the release of CO and COectively . VariousSong and coworkers studied the formation of P-GNS using the thermal decomposition method of three different phosphorous-containing surfactants  at two different temperatures, 800 and 900 °C. The mixed surfactant systems led to more efficient doping as compared to a single surfactant due to an increase in d-spacing , which resulted in more penetration of the phosphorous atoms into this spacing .Non-volatile and thermally stable 1-butyl-3-methylimidazolium hexafluorophosphate was used by Li et al. for in situ phosphorous doping of graphene nanosheets. The amount of phosphorous in P-GNS was 1.16 at.%. During the annealing process, he P-GNS .2 under argon atmosphere. The fraction of graphitic and elemental phosphorous in P-GNS prepared in the absence of H2 was higher than the same synthesised in the presence of H2. The sample was purified and any remaining high-oxidation state phosphorous species in P-GNS was eliminated by the reductive conditions formed by H2 at 1000 °C, as evidenced by the atomic percentage of P being 79% vs. 69% of the entire signal. The XPS studies showed different peaks at 129.6 eV, 131.0 eV, and 132.5 eV, attributed to elemental phosphorous, graphitic phosphorous, and oxidized graphitic phosphorous, respectively [MacIntosh et al. synthesised P-GNS from GO using triphenylphosphine as a phosphorous source at 1000 °C with or without the presence of Hectively .3PO4 as an electrolyte and phosphorous source. Anhydrous H3PO4 phosphoric acid facilitated the exfoliation of the graphite layers. Upon dilution, H3PO4 dissociated into H+ and PO43− ions, which passed through the graphite layers and cleaved to form a P-GNS. The HR-TEM micrographs revealed wrinkled and folded graphene sheets. The XPS analysis of P-GNS showed 0.68 at.% phosphorus, confirming the P-doping in GNS. Moreover, the electrochemical activity of P-GNS was enhanced as compared to GNS [The electrochemical erosion method is the most effective way to create doped GNS in the presence of direct current and graphitic electrodes. Thirmual et al. prepared P-GNS using Hd to GNS .Different boron precursors such as triisopropyl borate, triethylborane, phenylboronic acid, diborane, boron powder, boron oxide, benzene-1, 4-diboronic acid, boric acid, and orthoboric acid can be used for the synthesis of B-GNS. Different synthesis methods along with the various sources used and the applications are summarized in 3)3, acted as a boron-containing source that decomposed at a high temperature and reacted with the atoms of carbon to make B–C bonding configurations as follows:In the CVD methodology, the growth substrate is reacted with volatile compounds leading to the formation of the desired materials under inert conditions . High-qu3 to sp2 conversion of the C–C bond. Cattelan et al. also synthesised B-GNS using diborane, boron-containing source and methane, and carbon-containing precursor, using polycrystalline copper foil as a growth substrate [2BO and CBO2 was also considered. Three- to five-layered graphene was synthesised using this method at 950 °C directly on copper substrates in the presence of boron powder as the boron source and ethanol as the carbon precursor with a boron content of 0.5 at.% [2 V−1 s−1 carrier mobility at room temperature [2/Ar with a 4.3 at.% of B [3) bonding configuration where carbon atoms were replaced by boron atoms was common, but a boron silane (BC4) configuration occurred due to excess edge sites and defects [The DFT calculations showed that the incorporated elemental form of boron accelerated the spubstrate . There w0.5 at.% . B-GNS h0.5 at.% . The XPS0.5 at.% . The Ramperature . Boric at.% of B . Similar defects .The CVD method has an advantage that large area B-GNS are allowed to be synthesised easily . However2O3 as the boron source [4) and boron tribromide (BBr3) in the presence of potassium resulted in the generation of B-GNS at 150–210 °C in 10 min. The amount of boron was about 2.56 at.% as determined by XPS analysis [Self-assembly is a bottom-up approach where the components of an unorganised system assemble themselves to form a larger functional unit by non-covalent interactions. Selva and coworkers were able to dope reduced GO up to 10 and 20 at.% boron using Bn source . The atoanalysis . This me2H6), and H2. Vapours of B2H6 were produced by the introduction of boron triflouride-diethyl etherate to sodium borohydride in the presence of tetraglyme. The B2H6 vapours were carried to the arc chamber by first passing the H2 at 200 Torr and then He (500 Torr) through the B2H6 generator. In the second approach, boron-packed graphite electrodes were used to conduct the arc discharge for the synthesis of B-GNS in the presence of H2 (200 Torr) and He (500 Torr). The XPS analysis showed that B-GNS synthesised using the second approach contained an increased amount of boron (3.1 at.%) as compared to the first approach (1.2 at.%) [An electrical breakdown of an inert gas causes an arc-discharge, which results in a prolonged electrical discharge. Panchakarla used this method in two different ways to synthesise B-GNS. In the first approach, B-GNS were synthesised employing the arc-discharge of graphite electrodes in the flow of helium (He), diborane (B.2 at.%) . Palnitk.2 at.%) . The pre2O3) was ultrasonically mixed with an aqueous solution of GO; and in the second step, thermal annealing of the mixture was carried out at four different temperatures  for simultaneous reduction and doping. The schematic representation is shown in 3 and BC2O, respectively. At 1000 °C, the peak at 190.8 eV became more predominant because of the reduction of oxygeneous moieties and the formation of more B–C bonds. High temperature favoured the formation of the B–C bonds rather than the B–O bonds. The maximum boron concentration in BT-rGO was found to be (6.04 ± 1.44) at.% at 1000 °C [Thermal annealing is a process of altering the surface morphology of materials and the key factor determining the bonding configuration is temperature. Yeom et al. synthesised thermally reduced boron-doped graphene oxide (BT-rGO) in a two-step reaction. Firstly, a boron precursor (B 1000 °C .3 and Ar (1:4 v/v) with a 250 mL min−1 of total flow rate for 2 h. The XPS peaks were obtained corresponding to BC3 and BC2O nanodomains  and is useful for growing single crystals from a solution in an autoclave at a high temperature and pressure. Thirumal et al. used a two-step thermal approach to synthesise B-GNS. Firstly, GO was thermally reduced at 500 °C (T-GNS), and in the second step, T-GNS was treated with boric acid in a Teflon- lined autoclave to produce boron-doped graphene (HB-GNS) .3BO3) as the boron source [2O3). The boron oxide then diffused into the lattice of graphene and the carbon atoms were substituted by boron as follows [B-GNS was also obtained via a one-step hydrothermal method using boric acid  showed two bands. The D band peak position at 1351 cmd of GOF . This meFew reports are available in which the vacuum activation method is used for the synthesis of boron-doped graphene nanoribbons. Xing et al. used boric acid as a boron-containing precursor to synthesise boron-doped graphene nanoribbons. Graphene maintained its decreased micrometer-sized structure after vacuum reduction and ultrasonic processing, but after doping with boron, the large-scaled graphene sheets were cut into nanoribbons. The substitutional boron doping caused a macro-residual stress, which promoted the growth of nanoribbons. The size of the graphene sheets was successfully reduced with boron doping and the conductivity of B-GNS was improved .P-GNS has been studied for its applications in electronic devices ,82, enerFuel cells are used to convert the energy from a chemical nature to an electrical nature. Hydrogen gas is fed into the anodic compartment where it is oxidised and the oxygen gas is fed into the cathodic compartment where it is reduced. The ORR is the rate-determining step that occurs in the cathodic compartment . ORR can3OH) in electrolyte inhibits the ORR at the platinum surface. This can be avoided by metal-free electrocatalyst such as P-GNS. Phosphorous atoms increase the absorption and cleavage of the oxygen– oxygen bond due to the charge polarization of the heteroatom and carbon bond. Qiao and coworkers reported that dual-doped graphene (PN-GNS) synthesised by pyrolysis of GO (as the carbon source) and diammonium hydrogen phosphate (as the nitrogen and phosphorous source) acted as a better electrocatalyst as compared to single-doped and undoped graphene [The poisons such as carbon monoxide (CO) and methanol (CHgraphene . The syngraphene .0.8Sr0.2MnO3). The introduction of perovskite to undoped graphene increased the number of electrons (n) moved from anode to cathode electrode 2.7 to 3.6 at −0.5 V, but it did not alter the current density. This problem was overcome by fabricating perovskite with dual-doped graphene. Here the n value increased to 3.8 at −0.5 V. This may be due to acceleration or conductivity effects provided by perovskite. The kinetic analysis showed that the direct four-electron pathway was favoured [The ORR activity of dual-doped graphene can be further improved by their fabrication with inexpensive perovskite such as  showed excellent electrocatalytic activity, which was five to six times higher than P-GNS and two times higher than NS-GNS . A similShewanella oneidensis bacteria, displaying a comparable catalytic current density to Pt/C [Nitrogen-, iron-, sulphur-, and phosphorous-doped graphene was synthesised using the direct pyrolysis of  to Pt/C . The pre to Pt/C . The enh to Pt/C . The BPNLithium-ion batteries are important energy-producing and storage devices. These are rechargeable batteries, which contain lithium solution as an electrolyte. The importance of lithium-ion batteries in energy-related devices nowadays can be understood from the Nobel Prize given in 2019 to three scientists, Stanley Whittingham, John Goodenough, and Akira Yoshino, for their innovation in the synthesis of lithium-ion batteries. The use of these lightweight, rechargeable, and powerful lithium-ion batteries from electronic gadgets to electric vehicles have revolutionized our lives. The negative electrode of a conventional lithium-ion cell is composed of carbon-based materials, while the positive electrode is a metal oxide. During charging, ions move from anode to cathode and the reverse happens during discharging. Due to its low affinity for lithium atoms and the tendency of deposited lithium atoms to cluster on the graphene surface, pure graphene is not a good choice for lithium storage . Moreove−1), with nearly no loss across 80 cycles, indicating that P-GNS-based electrodes possess a good longevity [−1 at a current density of 1000 mA g−1. Due to low abundance and uneven global distribution of lithium ions, the increasing demand of Li-ion batteries can hardly be meet.Zhang’s group used P-GNS in lithium-ion batteries as an anode material for the first time. They also compared the results with undoped graphene and found that P-GNS acted as a superb electrode because of various topological defects introduced on its surface during the doping process. This led to a randomized carbon lattice that improved the lithium insertion characteristics. P-GNS has a considerably larger reversible discharge and charge capacity than undoped graphene  (474 mA h g−1 after 50 cycles at 50 mA g−1 and 160 mA h g−1 after 600 cycles at 2000 mA g−1). This might occur as a result of the dopants’ high inter-layer spacing, which aided the insertion and extraction of potassium ions [P-GNS is also a viable option for anodes in sodium-ion batteries . Na-ion ium ions .Supercapacitors have high capacitance values as compared to conventional capacitors because they link the gap between rechargeable batteries and electrolytic capacitors. They are also known as gold caps, ultracapacitors, or super caps. Supercapacitors come in a variety of forms, including hybrid capacitors, electrochemical pseudocapacitors, and electrostatic double-layer capacitors. The first type of supercapacitors use carbon materials for electrode preparation, and charge separation is achieved using the Helmholtz double layer at the junction of the electrolyte and the surface of a conductive electrode. In electrochemical pseudocapacitors, conducting polymers and metal oxide electrodes are used and charge separation is achieved by Faradaic electron charge transfer with electrosorption, intercalation, and redox reactions. In the third type, hybrid capacitors are a combination of both electrodes; one that stores the charge faradaically and the other stores the charge electrostatically.Due to graphene’s enormous surface area and large electric double-layer capacitance, it has recently been employed as an electrode in supercapacitors . However−1, a high specific capacitance of 367 Fg−1, and a high energy density of 59 Wh kg−1. After many hundreds of cycles, there was no discernible loss in any particular capacitance. Thirumal et al. [−1 at a current density of 0.5 Ag−1. Thus, the different approaches affect the capacitance values because different defects are created by the different methods. DFT relates the enhanced specific capacitance of P-GNS with structural changes in the lattice. DFT calculations were used by Song et al. [Graphene doped with phosphorous exhibited improved capacitive performance in aqueous electrolyte due to higher pseudocapacitance and a strong conducting network in the graphene structure. A supercapacitor was created by Karthika et al. , utilisil et al.  also syng et al.  to ident−1 at a current density of 1 Ag−1 [−1 at 1 Ag−1), which was six times higher than bare polyaniline. Moreover, this value further increased with an increase in current density from 1 to 15 Ag−1 [Polyaniline–graphene-based electrodes exhibited high specific capacitance of 480 Fgf 1 Ag−1 . This va 15 Ag−1 .−1 at 0.05 Ag−1 current density was present in PN-GNS. P-GNS is a superior supercapacitor electrode than a broad potential window of 1.6 V in an aqueous electrolyte because it contains functional groups that include phosphorus [Because of the synergistic effects of the heteroatom dopants, co-doping of heteroatoms has been seen as a potential way to improve the energy storage performance of graphene-based materials. Excellent specific capacitance of 183 Fgosphorus .The applications of B-GNS are discussed in different subsections, viz. solar cells, sensors, supercapacitors, lithium-ion batteries, fuel cells, and photocatalysts. The properties of the materials are briefly discussed in next subsections.The substituted boron atoms in the graphene lattice acted as active sites for adsorption of oxygen and speeding up oxygen–oxygen bond breaking. Molina-Garcia et al.  observed3 and graphitic N were the main active sites among various boron doping or/and nitrogen configurations. Mazanek et al. [Wu et al.  carried k et al.  also synk et al. .−1) and a low onset potential (−0.10 V), BNP-GNS demonstrated excellent electrocatalytic activity [With a high current density (55 A cmactivity . Due to activity .2), and transparent conducting layer (fluorine tin oxide) [2-based solar cell with an open current voltage of 0.53 V, and a short current density of 18.8 mA cm−2 was developed by Li et al. [The solar cell is an electrical device that changes sunlight or artificial light into electrical energy through the photovoltaic effect and thus it is also known as the photovoltaic cell. The absorption of light energy, which produces excitons or electron–hole pairs, is one of the three fundamental characteristics needed for a solar cell to function. The separation of charge carriers of different types is the second step, and the independent extraction of those carriers to an external circuit is the third step. Dye-sensitized, organic, quantum dot, perovskite, and perovskite solar cells are examples of common solar cells. The four layers of a solar cell are the interface layer , hole transport layer -9,9′,-spiro bi fluorene), electron transport layer (TiOn oxide) . The pown oxide) . A B-GNSi et al.  under oni et al. ,131. The2-adorned B-GNS for use as a lithium-ion battery anode material. In comparison to bare SnO2 and B-GNS, they discovered that the synthesised hybrid had the largest reversible capacity of 744 mAh g−1 at a current density of 100 mAh g−1. An improved lithium interaction resulted from the SnO2, a spacer within the GNS, increasing the likelihood of lithium intercalation and alloying against re-stacking of the 2D planes. Due to the wrinkled graphene network and homogenous dispersion of tiny SnO2 nanoparticles (NPs), a rise in reversible capacity was seen with increasing boron content in B-GNS [Due to their low memory loss, high energy density, and low self-discharge rate, rechargeable lithium-ion batteries are extensively employed in portable electronic devices . Using ain B-GNS .−1 at 50 mA g−1). This anode showed increased cycle stability and reversible capacity of 540 mAh g−1 at 100 mAh g−1 after 100 consecutive cycles. The presence of defect sites and heteroatoms in the presence of boron and Ag NPs was attributed to these outstanding electrochemical performances. Tian et al. [−1 at 0.1 C after 100 cycles. The excellent high rate of performance was attributed to the B-strong rGO’s electrical conductivity. The composite cathode’s electric conductivity was enhanced and the shuttle effect was delayed by boron doping on rGO. Due to the co-dopants’ synergistic effects, BN-GNS produced by the hydrothermal process performed better than single-doped graphene. For the objective of preserving active material during the cycle and enhancing the carbon’s wettability in the organic electrolyte, borax and nitrogen dopants had significant binding opportunities with polysulfide species [Silver (Ag) NPs embedded on B-rGO served as the anode material in a nanocomposite that was synthesised by Bindumandhavan et al. . Due to n et al.  have als species . The nex species .−1 and low migration barrier of 0.07 eV. This may be due to the substrate being doped with boron, which causes it to become electron-deficient and causes a sizable charge transfer from potassium to the substrate. Due to the inhibition of dendritic development and prevention of potassium atom clustering, there is good cycling stability [Potassium-ion batteries are gaining popularity as lithium-ion battery substitutes due to the abundant availability of potassium in the Earth’s crust. B-GNS has the potential to be used as an anode material for potassium-ion batteries due to its high specific capacity of 546 mAh gtability ,137.−1, which was three times higher than reduced GO (135 Fg−1). A supercapacitor’s specific capacitance typically depends on the electrode’s BET surface area and electrical conductivity, both of which decrease as the annealing temperature rises. On the other hand, boron-doped GO lowered the electrical conductivity and BET surface area increased as the annealing temperature rose from 300 to 1000 °C. At a higher temperature (1000 °C), the doping of boron heteroatoms may create defect-like small pores in the graphene nanosheet’s plane that prevents the growth of graphitic structure [Supercapacitors based on doped graphene electrodes showed higher interfacial capacitance as compared to undoped ones. Some researchers reported that the presence of dopant on the graphitic lattice might lead to electrochemical reduction–oxidation reactions on the surface, which would ultimately enhance the capacitance of the material. The specific capacitance of boron-doped reduced GO was 448 Fgtructure .2SO4 at various current densities (1 Ag−1 to 4 Ag−1). The curves of charge–discharge were triangular in shape  measurements on thermally reduced graphene and B-GNS in 0.5 M Hin shape a, and CVin shape b, which ectively c,d, whicNumerous publications also examined the effects of co-doping graphene with two or more heteroatoms. Chen et al. produced BN-GNS with atoms ranging from 0.6% to 2.1% (B) and 1.74 to 2.56% (N). In order to get a satisfactory performance in electrochemical energy storage, dopants were simultaneously introduced, creating a synergistic effect between boron and nitrogen . The finHeteroatom doping is one of the best techniques for altering the properties of graphene. Depending on the type of heteroatom dopant such as boron, nitrogen, phosphorous, sulphur, and fluorine, and doping configurations, heteroatom-doped graphene nanomaterials can be used for a spectrum of applications.In this review, we have discussed direct and post-treatment methods for the synthesis of P-GNS and B-GNS. As compared to B-GNS, research on P-GNS is still in its infancy and the comparative evaluation of heteroatom doping on the structural, textural, and morphological properties is still unexplained. Various characterisation tools, viz. XPS, TEM, SEM, Raman coupled with DFT calculations, have been used to study the structural properties of doped graphene-based nanomaterials. The starting dopant material, precursors, temperature, reaction time, and other factors all affect the characteristics of the obtained materials. However, due to the heterogeneity of the doped graphene, conflicting results are reported and the current understanding of the characteristics of heteroatom-doped graphene is still insufficient. The innovative uses of doped graphene materials for energy conversion, energy storage, and gas storage have been addressed. Because of their fast electron transport and three-dimensional porous structure, materials based on doped graphene perform better in energy-related devices. Because of the additional possibilities offered by heteroatom doping, graphene research will continue to flourish. Despite the positive advancements made in the field of doped graphene-based materials, there are still numerous obstacles that need to be overcome, viz. the limited number of publications demonstrating their applications towards the environmental field and biological toxicity. These issues need to be critically considered to extend their practical applications and for their large-scale applications.


Scientific Reports 10.1038/s41598-023-29374-6, published online 10 February 2023Correction to: The original version of this Article contained errors.The Article contained an error in Affiliation 6, which was incorrectly given as ‘Accelerator Division 6, High Energy Accelerator Research Organization (KEK), 1‑1 Oho, Tsukuba, Ibaraki 305‑0801, Japan’. The correct affiliation is listed below:Innovation Center for Applied Superconducting Accelerators, High Energy Accelerator Research Organization (KEK), 1‑1 Oho, Tsukuba, Ibaraki 305‑0801, JapanAdditionally, the Article contained an error in Results and discussion section, under ‘Selection of the sealing metal’ subheading,“In our previous study, synchrotron X-ray photoelectron spectroscopy (XPS) revealed that there was residual photocathode material on Si and Mo substrates even after the thermal cleaning, indicating that there was strong bonding/alloying between the photocathode and the substrates.”now reads:“In our previous study, synchrotron radiation X-ray photoelectron spectroscopy (SR-XPS) revealed that there was residual photocathode material on Si and Mo substrates even after the thermal cleaning, indicating that there was strong bonding/alloying between the photocathode and the substrates.”The subheading ‘Photoemission measurement’,now reads:“Spectral response photoemission measurements.”Under ‘Lifetime under continuous illumination’ subheading,“These results suggest other cause(s) as the origin of leakage.”now reads:“These results suggest other cause(s) as the origin of degradation.”30 and there is room for improvement toward the theoretical value of ~ 50%.”“The electron transmission efficiency through our current bilayer graphene is ~ 5%now reads:30 and there is room for improvement toward the theoretical value of ~ 50% for monolayer.”“The electron transmission efficiency through our current bilayer graphene is ~ 5%Finally, in the Methods, under the subheading ‘Sandwiching bialkali antimonide photocathodes between graphene and nickel thin films’,43 on Cu substrates and transferred onto TEM mesh grids using an established polymer-supported method that involves distilled water exposure44. Bilayer graphene, instead of the monolayer, was used to minimize mechanical voids generated during the transfer process.”“Graphene consisting of mainly monolayer regions with some multiple layer regions was synthesized via chemical vapor deposition (CVD)now reads:43 on Cu substrates were purchased from Graphenea and transferred onto TEM mesh grids using an established polymer-supported method that involves distilled water exposure44. Bilayer graphene, instead of the monolayer, was used to minimize mechanical voids generated during the transfer process. Polymer support was removed using acetone.”“Graphene consisting of mainly monolayer regions with some multiple layer regions was synthesized via chemical vapor deposition (CVD)The original Article has been corrected.


Individuals with IBD have a reduced quality of life and while treatment has improved, a cure remains elusive. Interleukin-4 differentiated macrophages (M(IL4)s) from healthy donors and IBD patients in remission promote epithelial wound repair and reduce the severity of colitis in a mouse model: findings that support the autologous transfer of M(IL4)s to treat IBD. However, issues remain if this novel therapy is to advance to clinical evaluation: a much greater understanding of the possible heterogeneity within the human M(IL4) population, the biology of any sub-groups therein and the biology of any M(IL4) subtypes is needed.To determine if cryopreservation, sex, and disease status in Crohn's disease (CD) impact the phenotype and function of M(IL4)5) were activated with IL-4 . Fresh and cryopreserved M(0) and M(IL4) were stained using a panel of 18 metal-conjugated antibodies. Data were acquired on a Helios CyTOFII mass cytometer. FCS files were imported into Cytobank for manual gating (viable CD45+CD3-CD19- singlet cell events) and exported for meta-clustering in R with the CATALYST package using the FlowSOM function with 10 metaclusters.Blood mononuclear cells were collected from healthy donors, and individuals with active CD or in remission (n=6/group), and differentiated to macrophages with GMP-grade recombinant human M-CSF . Macrophages s from CD patients in remission showing increased CD206 mRNA, CYTOF analysis revealed that the macrophages were more similar to those from individuals with active disease than those from healthy controlsFlowSOM analysis on M(IL4) from healthy donors indicated clear differences between M(0) and M(IL4), with 8 metaclusters >1.5% of M(IL4)s: the most abundant metaclusters express high and intermediate CD206, PDL1, CD11b, CD33, CD64, HLA-DR and low CD14 levels. There were no significant differences in these M(IL4)s metaclusters between males and females, or fresh vs. cryopreserved cells using this characterization strategy. M(IL4) from patients with active CD, were markedly different with the absence of three high-intermediate CD206in vitro are revealed as a heterogeneous population, and subsets characterized by increased high CD206 expression are generally absent in active Crohn’s disease. Intriguing while prior experiments with M(IL4) from CD patients in remission reduced the severity of colitis in rag1-/- mice, the characterization of these cells via 18 protein markers indicates they are more like M(IL4)s from patients with active disease compared to healthy controls. While presenting autologous M(IL4) transfer as a novel approach for IBD, a much fuller understanding of the phenotype and function of M(IL4)s (and sub-populations therein) is required before this would become a therapeutic optionHere human macrophages activated with IL4 CAGNone Declared


Autologous fillet flaps are a common reconstructive option for large defects after forequarter amputation (FQA) due to advanced local malignancy or trauma. The inclusion of osseous structures into these has several advantages. This article therefore systematically reviews reconstructive options after FQA, using osteomusculocutaneous fillet flaps, with emphasis on personalized surgical technique and outcome. Additionally, we report on a case with an alternative surgical technique, which included targeted muscle reinnervation (TMR) of the flap. Our literature search was conducted in the PubMed and Cochrane databases. Studies that were identified were thoroughly scrutinized with regard to relevance, resulting in the inclusion of four studies (10 cases). FQA was predominantly a consequence of local malignancy. For vascular supply, the brachial artery was predominantly anastomosed to the subclavian artery and the brachial or cephalic vein to the subclavian or external jugular vein. Furthermore, we report on a case of a large osteosarcoma of the humerus. Extended FQA required the use of the forearm for defect coverage and shoulder contour reconstruction. Moreover, we performed TMR. Follow-up showed a satisfactory result and no phantom limb pain. In case of the need for free flap reconstruction after FQA, this review demonstrates the safety and advantage of osteomusculocutaneous fillet flaps. If the inclusion of the elbow joint into the flap is not possible, we recommend the use of the forearm, as described. Additionally, we advocate for the additional implementation of TMR, as it can be performed quickly and is likely to reduce phantom limb and neuroma pain. The multimodal treatment of primary malignant bone or soft tissue tumors involves multiagent chemotherapy, radiotherapy, and wide surgical resection. Since the combination and enhancement of these regimes, long-term survival rates have improved significantly over the last decades and the operative treatment advanced from direct amputation to limb-sparing surgery . HoweverWith regard to the upper extremity, interscapulothoracic amputation (ISTA) or forequarter amputation (FQA) is the most radical ablative procedure . It invoRecent developments in prosthetic medicine have created devices that offer multi-functional joints with fine motor capabilities, as well as improved comfort and aesthetics . With thThe aim of this article was to systematically review previous approaches for chest wall stabilization and shoulder contour reconstruction after FQA with osteomusculocutaneous free fillet flaps. Moreover, we report on a case with an alternative surgical technique that incorporates the forearm, wrist, and metacarpus of the amputated limb into the flap in combination with TMR. The simultaneous utilization of TMR provides the first results on feasibility and improved neuropathic pain management after FQA and osseous “spare-parts” reconstruction.The identification of studies for this review was based on the Preferred Reporting Systems for Systematic Reviews and Meta-Analysis (PRISMA) statement . The MeSFirst, the titles and abstracts of the citations were individually scrutinized to determine which were relevant to the review. Subsequently, studies were excluded if they were not available in English or German, or if they described the usage of cutaneous and musculocutaneous (soft-tissue) fillet flaps or other reconstructive procedures (non-fillet flaps) after FQA. This resulted in the identification of six articles that describe the usage of osteomusculocutaneous fillet flaps for reconstruction following FQA. Two of these were excluded from the study as they did not provide enough details on the surgical technique used, as well as outcome measurements ,15. Fourn = 6). All of the patients survived the initial surgery.Ten cases of shoulder contour reconstruction and thoracic wall stabilization with osteomusculocutaneous free fillet flaps after FQA were described in the four publications that were identified . In 8 oun = 8). Other options were the suprascapular artery (n = 1) and the internal thoracic artery (n = 1). In 5 out of 10 cases, two venous anastomoses were completed. In the majority of cases, the brachial or cephalic vein of the flap was connected to the subclavian or the external jugular vein (n = 7). Three cases required revision surgery due to an infected hematoma (n = 1), partial skin necrosis (n = 2), and/or arterial thrombosis (n = 1). Another case required tumor re-excision after the confirmation of a R1 tumor margin. Three out of a total of six sarcoma patients developed pulmonary metastases within the first 18 months after surgery, and two of these patients died within the observation period. Another patient died 13 years after the initial operation from a local recurrence of the sarcoma. Both patients with traumatic FQA survived the follow-up period.Considering the vascular supply of the flap, the subclavian artery was predominantly anastomosed to the brachial artery , is a recognized technique in reconstructive and traumatic surgery ,27,28,29Instead of utilizing the amputated limb, local or free flap reconstructive options may be used for defect coverage after FQA. Indeed, several reports exist, which demonstrate the successful use of these techniques, such as the fasciocutaneous deltoid, the tensor fascia latae (TFL), or the TFL + rectus femoris flap ,39,40. SDespite the potential physiological and psychological benefits for the patient, very few cases of osteomusculocutaneous free fillet flaps for chest wall and shoulder reconstruction have been described in previous publications. Our systematic literature search identified four articles that give detailed information on this technique in a total of ten cases  2,16,1717,18. HiIn contrast, in their subsequently published articles, Osanai and colleagues as well as Koulaxouzidis et al. described techniques that connect the distal humerus to the clavicle or the sternum (in cases where a complete resection of the clavicle was necessary) and created a lateral prominence that resembles the natural silhouette of the shoulder ,37,44,45The results illustrate that the functional and cosmetic outcomes are highly dependent on the location and extent of the tumor or trauma. Local tumor progression of our patient required the resection of the complete clavicle, scapula, and the first three ribs. The upper arm had to be excluded from the flap to accomplish tumor free margins, permitting the previously published surgical approach that incorporates the elbow joint into the flap ,18.Thus, our surgical options were limited to the utilization of the forearm and the hand, as the osteomusculocutaneous free flap for the reconstruction of the thoracic wall and shoulder. Therefore, we decided to use a new surgical approach—by connecting the radius to the sternum, we were able to utilize the flexed wrist instead of the elbow joint to imitate the natural shoulder contour . Short-tCommon complications following extremity amputation are the occurrence of phantom limb pain and the development of neuromas . The preIn the majority of reports, including our own case, tumor infiltration of the shoulder girdle or chest wall was the indication for FQA. Using the “spare-parts” of an extremity that was impaired by local cancerous progression asks the question of whether this procedure is a safe oncological approach. In this context, the fillet flap technique uses the identical principle of the resection–replantation technique reported by Windhager et al. . The autHowever, in cases where FQA may be prevented or primary wound closure is possible, the overall prognosis of this special patient group must be taken into account, in particular when considering osteomusculocutaneous fillet flap reconstruction after FQA due to sarcoma. Even if primary tumor resection is successful, the disease-free five year survival of sarcoma patients requiring FQA is below 30% . While STherefore, we advocate that the indication for FQA has to be individually considered and carefully evaluated with each patient after case discussion in a specialized interdisciplinary tumor board . However, if this process concludes that FQA is the best treatment option, radical tumor resections and subsequent osteomusculocutaneous fillet flap reconstruction, including TMR , should be the first choice of surgical treatment.In case of FQA and the need for free flap reconstruction, we consider the osteomusculocutaneous free fillet flap as the first choice. It enables the reconstruction of the chest wall integrity, provides support for a prosthesis socket, and improves the appearance of the shoulder contour. When using this technique, the remaining anatomical structures of the thorax, the vascular supply, and the distal resection margin of the amputated upper extremity are crucial components that have to be considered when the overall design of the flap is determined. If the inclusion of the elbow joint into the flap is not possible due to local tumor expansion or trauma, we recommend the use of the forearm and hand, as described. In general, we advocate for the additional implementation of TMR, as it can be performed quickly and is likely to reduce the occurrence of phantom limb and neuroma pain. However, the reviewed case series, as well as our own experience, emphasize that patients require careful evaluation of the benefit of FQA, as well as an individual solution for reconstructive surgery if the procedure is deemed to be the best possible option.


The ideal treatment for sensory hearing loss is to regenerate inner ear hair cells (HCs) through stem cell therapy, thereby restoring the function and structure of the cochlea. Previous studies have found that Lgr5+ supporting cells (SCs) in the inner ear can regenerate HCs, thus being considered inner ear progenitor cells. In addition to traditional biochemical factors, physical factors such as electrical conductivity also play a crucial role in the regulation of stem cell proliferation and differentiation. In this study, the graphene substrates were used to culture Lgr5+ progenitor cells and investigated their regulatory effects on cells. It was demonstrated that the graphene substrates displayed great cytocompatibility for Lgr5+ progenitors and promoted their sphere-forming ability. Moreover, more Myosin7a+ cells were found on the graphene substrates compared with tissue culture polystyrene (TCPS). These results suggest that graphene is an efficient interface that can promote the differentiation of Lgr5+ progenitors into HCs, which is great significance for its future application in combination with Lgr5+ cells to regenerate HCs in the inner ear. Inner ear sensory hair cells (HCs) mainly function for transduction of mechanical stimuli into electrical signals and are mechanoreceptors for sound recognition . Aging, The most ideal treatment for sensory hearing loss is to regenerate inner ear HCs to restore the structure and function of the cochlea . The behHerein, in this work, we fabricated graphene substrates and studied their regulatory effects on the proliferation and differentiation. Graphene has been reported to significantly promote neuronal differentiation of neural stem cells (NSCs). Several studies have reported their potential for applications in the biomedical field, including drug delivery , photothLgr5-EGFP-IRES-creERT2 mice (stock no. 008875) were purchased from The Jackson Laboratory. All animal experiments were performed in accordance with protocols that were approved by the Animal Care and Use Committee of Southeast University (Approved No. 20200402025) and the National Institute of Health’s Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the number of animals used and to prevent their suffering.For genotyping of transgenic mice, the tail tips were first collected, and genomic DNA was obtained by adding 180 uL 50 mM NaOH and incubating at 98°C for 1 h, followed by adding 20 uL 1 M Tris-HCl (pH 7.0). The tube was then vortexed vigorously for 1 min for complete tissue dispersion. The primers used for genotyping are as follows; wild-type (R) ATA CCC CAT CCC TTT TGA GC; Lgr5: (F) CTG CTC TCT GCT CCC AGT CT; mutant (R) GAA CTT CAG GGT CAG CTT GC.The graphene substrates were purchased from Nanjing MKNANO Tech. Co., Ltd. Specifically, the graphene was prepared by chemical vapor deposition (CVD) and then transferred to the surface of coverslips to obtain a graphene substrate. For cell culture, the graphene substrates were immersed in 75% alcohol for 1 h, then washed three times with sterilized water and irradiated under ultraviolet light overnight.The surface of graphene substrates was observed by Scanning Electron Microscope (SEM) . The graphene substrates were then characterized by a Raman microscopy (Renishaw inVia) and an X-ray diffractometer (XRD) .The cochleae of Lgr5-EGFP-creERT2 mice  were dissected out and collected in a tube. Subsequently, the collected cochleae were digested by trypsin  at 37°C for 8 min, followed by adding equal volume of soybean trypsin inhibitor (Worthington Biochem) to terminate the digestion. Cochleae tissue were dissociated into single cell suspensions by blunt tips (Eppendorf) and then filtered with a 40 μm cell strainer (BD Biosciences). Finally, the obtained single cells were sorted by a BD FACS Aria III (BD Biosciences) through GFP channel. Finally, the sorted cells were cultured on graphene substrates and tissue culture polystyrene (TCPS), respectively.The cells sorted by FAC were cultured in DMEM/F12 medium supplemented with N2 , B27 , EGF , bFGF , and IGF-1 , heparin sulfate  (full medium), and ampicillin . For sphere-forming assay, the sorted cells were seeded on TCPS or graphene substrates with 200 cells per well for 5 days. Subsequently, we measured the number and diameter of the formed spheres to evaluate their proliferation capacity. For differentiation assay, the sorted single cells and formed spheres were differentiated separately. The cells or spheres were cultured in a 4-well dish for 10 days, and immunofluorescence staining was then applied to analyze the differentiation of Lgr5+ cells. As described in previous reports, cell aggregation with more than 5 cells were considered a sphere or colony.After culture, the cells grown on different substrates were fixed with 4% paraformaldehyde for 1 h at room temperature and then washed with PBS containing 0.1% Triton X-100 (PBST). The cells were then blocked with PBS containing 1% BSA for 1 h at room temperature. Afterwards, the primary antibody anti-Myosin7a (Proteus Bioscience) was diluted and incubated with these cells at 4°C overnight. After that, the cells were washed with PBST and then incubated with secondary antibody along with 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) for 1 h at room temperature. Finally, the cells cultured on different substrates were washed and then covered with coverslips in fluorescence mounting medium (DAKO). The cells were observed and captured with a laser scanning confocal microscope .p < 0.05 was considered statistically significant. At least three individual experiments were conducted for all experiments.All data were analyzed with GraphPad Prism6 software and presented as mean ± SD. Two-tailed, unpaired Student’s t-tests were used to determine statistical significance when comparing two groups, and a value of Graphene substrates used in our work were fabricated by a CVD method and then transferred to the surface of coverslips. The morphology of the graphene substrates was observed from the SEM image . Figure To evaluate the cytocompatibility of graphene substrates, we isolated Lgr5+ cells from Lgr5-EGFP- CreERT2 mice by FAC sorting and cultured the sorted cells on graphene substrates and TCPS for different times. The flow cytometry plots displayed that about 5.8% of the whole cochlear cell population were Lgr5+ progenitors . After cThe capacity of self-renew is an important characteristic of stem cells and progenitor cells. Therefore, we cultured the sorted cells on graphene substrates and TCPS for 5 days to form spheres, respectively, to determine their proliferation capacity. To investigate the HC regeneration capability of the formed spheres on different substrates, we performed differentiation assay for 10 days after 5 days of sphere-forming assay, as shown in To further explore the HC regeneration capability, we cultured the sorted Lgr5+ cells on laminin-coated graphene or TCPS substrates for 10 days of differentiation . The celin vitro (HCs in the mammalian cochlea mainly function for transduction of mechanical stimuli into electrical signals, thus play an important role in sound recognition. Irreversible damage or loss of HCs due to aging, ototoxic drugs, trauma, inflammation and other stress can lead to permanent hearing loss. In recent years, great progress has been made in HC regeneration, many studies have successfully induced embryonic stem cells and pluripotent stem cells to differentiate into hair cell-like cells in vitro . Recentlin vitro .Recently, Smith-Cortinez et al. reported the long-term presence of Lgr5+ SCs in the adult mouse cochlea . These iin vitro regulation of graphene on inner ear progenitors, especially their proliferation and differentiation.Graphene substrates have been shown to have great cytocompatibility and electrical conductivity, and have been extensively studied in the biomedical field. Various studies have suggested that graphene substrates could support cell culture and regulate the proliferation and differentiation of different types of stem cells . The regin vitro. However, there was no statistical difference in the diameter of the formed spheres. The results indicate that graphene can promote the sphere-forming ability of Lgr5+ progenitors. The results of differentiation assay suggested that Lgr5+ progenitors could differentiate into Myosin7a+ cells, and the number of Myosin7a+ cells on graphene was larger than TCPS, indicating that our prepared graphene substrates could promote the generation of HCs from Lgr5+ progenitors. Recent studies have found that the regeneration of HCs from inner ear progenitors were regulated by several genes, including Pou4f3, Atoh1, Cdh23, Jag2, Skp2 (The sphere-forming assay suggested that Lgr5+ progenitors cultured on graphene substrates generated more spheres than those cultured on TCPS g2, Skp2 . We specIn summary, we prepared graphene substrates by depositing graphene onto coverslips. We found that the graphene substrates promoted the sphere-forming and HC regeneration capabilities of cochlea Lgr5+ progenitors. The results suggest that graphene is an efficient interface that can promote the differentiation of Lgr5+ progenitor cells into HCs, which is essential for its future application in combination with Lgr5+ cells to regenerate HCs in the inner ear. In future work, we will continue to explore better graphene-based scaffolds to advance the application of graphene in stem cell therapy. In addition, we plan to further explore the specific mechanism by which graphene substrates regulate cell proliferation and differentiation. Understanding the specific mechanism of the interaction between graphene and inner ear Lgr5+ progenitors may provide more information for promoting HC regeneration through tissue engineering approaches.


The neuronal cell adhesion and recognition molecule L1 does not only ‘keep cells together’ by way of homophilic and heterophilic interactions, but can also promote cell motility when cleaved into fragments by several proteases. It has largely been thought that such fragments are signs of degradation. Now, it is clear that proteolysis contributes to the pronounced functional diversity of L1, which we have reviewed in this work. L1 fragments generated at the plasma membrane are released into the extracellular space, whereas other membrane-bound fragments are internalised and enter the nucleus, thus conveying extracellular signals to the cell interior. Post-translational modifications on L1 determine the sequence of cleavage by proteases and the subcellular localisation of the generated fragments. Inside the neuronal cells, L1 fragments interact with various binding partners to facilitate morphogenic events, as well as regenerative processes. The stimulation of L1 proteolysis via injection of L1 peptides or proteases active on L1 or L1 mimetics is a promising tool for therapy of injured nervous systems. The collective findings gathered over the years not only shed light on the great functional diversity of L1 and its fragments, but also provide novel mechanistic insights into the adhesion molecule proteolysis that is active in the developing and diseased nervous system. Neural cell adhesion molecules, also called cell recognition molecules, belong to an integral membrane protein superfamily with characteristic adhesive and signalling properties . In partL1 has been described as a cell recognition molecule , which fThe protein backbone of L1 consists of a short and highly conserved cytoplasmic domain, a transmembrane part, and an extracellular region formed by six immunoglobulin (Ig)-like and five fibronectin-type III (FNIII)-like domains , as showInitially, L1 was found in the nervous system, and has been thoroughly studied. However, the molecule has been also detected in different types of cancer . In patiSeveral proteases are involved in the process of the ectodomain shedding of L1 B; these X [X is involved in the processing of L1 by proteases, and myelin basic protein (MBP) was identified as a serine protease for L1, which interacts with L1 in a LewisX-dependent manner [Shiverer mice, which are deficient in MBP, show a progressive disorder characterised by tremors and seizures, leading to early death [shiverer mice) or the mutagenesis of the proteolytically active or cleavage sites, as well as by the application of serine protease inhibitors. The MBP-mediated generation of L1-70 promotes neurite outgrowth and the survival of neurons, as shown in vitro. Interestingly, in dissociated cerebellar neurons from wild-type and MBP-deficient shiverer mice, and when cultured in a medium supplemented with the MBP antibody or L1 holding the MBP cleavage site, the formation of neurites and neuronal survival is hampered [X-based interaction between L1 and MBP in the nervous system [L1 carries the carbohydrate LewisX , which iX . LewisX t manner ,68. MBP t manner ,71,72,73ly death ,74. Surply death . After tly death ,68. MBP hampered ,68. The s system ,68.shiverer embryos in utero prevented the manifestation of all the developmental spinal cord abnormalities mentioned above. However, these parameters become abnormal after the in utero injection of proteolytically inactive MBP. These findings suggest that the serine protease MBP acts on L1 to facilitate important morphogenic events during the early stages of nervous system development [Further studies on the relevance of the proteolytic activity of MBP on L1 in vivo, in the developing spinal cord, have identified the proteolytically active site in MBP . A serinelopment .In addition to its essential role in the formation of the nervous system, L1 also stimulates recovery processes in animal models of acute and chronic neurodegenerative entities . Does th858RKHSKR863) and the appearance of an 80 kDa fragment (L1-80), and stimulate the migration and axonal outgrowth of dissociated cortical and cerebellar neurons [reeler) mice invade the marginal zone, unlike the cells of the wild-type mice. It is therefore worth mentioning that the developing L1-deficient cerebral cortex displays morphological abnormalities in layer formation, partially overlapping with those seen in the cerebral cortices of the reeler mice. However, in utero electroporetic administration of L1-80 into the cortices of reeler embryos normalises neuronal migration [In the search for other early proteases/binding partners that target L1, the extracellular matrix protein Reelin has been identified as interacting with cell adhesion molecule L1 . Reelin  neurons . Remarka neurons . On the  neurons , since tigration . These figration . Thus, tIn this respect, it is important to mention that another member of the CAM family, the neural cell adhesion molecule NCAM, is prone to proteolysis in a similar fashion to L1. NCAM is crucial not only for the proper development of the nervous system, but also for maintaining the high cognitive functions of the adult brain . Simila1 activates the cleavage of L1 by a serine protease at the plasmalemma. This yields a sumoylated transmembrane L1 part of approximately 70 kDa  by cathepsin E . L1-30 e1172, or the cathepsin E cleavage site at E1167, eradicates the formation of L1-30, whereas alteration of the nuclear localisation signal at K1147 averts the nuclear internalisation of the fragment, but not its generation. Additionally, L1-30 production can be blocked by pepstatin, an aspartyl protease inhibitor, which also inhibits the L1-induced migration of cerebellar neurons and Schwann cells in dorsal root ganglia, thus impairing axonal myelination [Modification of the sumoylation site at Klination . Howeverlination ,112. Mutlination . These oWhen serine proteases and cathepsin E cleave L1 at the plasma membrane, another membrane-bound fragment of approximately 55 kDa (L1-55) is generated : see FigInterestingly, the post-translational modification of L1 may determine which fragments can be proteolytically generated ,110. In 1136LILL) in the transmembrane domain and one FXXLF motif (F1046HILF) in the fifth FNIII-like sequence of L1. L1136LILL is also present in the co-regulators (co-activators and co-repressors) of nuclear receptors, which are DNA-binding transcription factors essential for the development, differentiation, and metabolism of the eukaryotic cells [The nuclear presence of L1 fragments implies possible interactions with other molecules. In the search for motifs in L1 that are known to mediate possible interactions between L1 and nuclear molecules, Kraus et al.  identifiic cells ,126,127.ic cells ,131,132.ic cells . AlteratRecently, a new potential binding partner of the intracellular L1 domain has been identified (included into the previously mentioned fragment L1-55) . L1-55 bAll these observations raise the question of whether the cleavage and nuclear translocation of fragments can be seen also for other L1 family members. Notably, NCAM is proteolytically cleaved by matrix metalloproteases at the plasma membrane ,148. WheAnother provocative question is whether the third FNIII-like domain of L1, which is a target of many proteases, can be used as a potential therapeutic stimulator of L1-specific functions. To answer this question, Schulz et al.  used a 2Kataria et al.  identifiExperimental evidence gathered in recent years sheds light on the great functional diversity of L1 and its fragments that emerge in the process of proteolysis. L1 not only mediates adhesion between cells, but can also promote cell motility when cleaved into fragments by several proteases. Now, it is clear that proteolysis is not a sign of degradation; rather, it contributes to the functional heterogeneity of L1, together with distinct post-translational modifications of the cleaved fragments. Carbohydrates attached to the protein backbone and co-entering the cell nucleus contribute to specific functions of the carrier molecule/fragment. Moreover, carbohydrates can affect sumoylation and the intracellular fate of proteolytic fragments, and shape morphogenic events that are required not only for proper development but also for the regeneration of the nervous system. Taken together, these data indicate that targeting the proteolysis of cell adhesion molecules is a promising tool for therapy of the acute or chronically injured nervous system.


Sarcoidosis is an enigma diagnosed by ruling out other etiologies of granulomatous inflammation. The multisystem manifestations of sarcoidosis and the clinical polymorphism pose a diagnostic challenge to all physicians. The skin is the most commonly affected organ after the lungs in sarcoidosis. Dermatological manifestations can appear before, during, or after systemic involvement, and the type of skin lesion can have prognostic significance. Also, a biopsy of skin lesions is less invasive and more accessible to perform than a biopsy of visceral organs. Thus, in certain ways, cutaneous manifestations can aid in the diagnosis and prognosis of systemic disease. This article has focused on the frequently encountered skin lesions of sarcoidosis along with their prevalence, clinical features, and management. Sarcoidosis is a multisystemic disease that affects people from all over the world. It is characterized by the presence of non-caseating granulomas in the involved organs. Granulomas can be found in any organ, but the lungs are the most common organs involved with bilateral hilar lymphadenopathy .Jonathan Hutchinson described the first case of sarcoidosis in 1875 when it was more of a dermatological curiosity. However, as science progressed and more research was conducted, the disease gradually evolved into a multisystemic one ,3. GlobaSarcoidosis has a variety of clinical symptoms, but virtually all patients experience respiratory tract involvement at some point. The most common symptoms are dry cough, dyspnea, and chest discomfort, particularly in patients with severe endobronchial or parenchymal involvement . The nexThe underlying mechanism of sarcoidosis is believed to be a link between genetic susceptibility and environmental or infectious factors. Additional research is needed to determine the exact cause of sarcoidosis, how granulomas form, and the various skin lesions that sarcoidosis can cause such as erythema nodosum and LP, maculopapular, nodular, and annular lesions. Skin sarcoidosis affects roughly 25% of people with systemic illness and may also arise in isolation . A varieCS is known as the great imitator because of its wide range of morphologies . It is cCutaneous lesions can aid in diagnosing sarcoidosis and are easily accessible tissues for biopsy . It is cCommon dermatological manifestations of sarcoidosis will be discussed in the subsequent text.Papular and plaque sarcoidosisThe most frequently seen variants of CS are papules and plaques. As per a study by Rim Ishak et al. in 2015 on 76 patients from the American University of Beirut Medical Center diagnosed with CS between 1992 and 2010, 37 patients had plaques (49%) and 22 patients had papules (29%) . The finMaculopapules are red-brown to purple, less than 1 cm in diameter, and very weakly infiltrated with some epidermal alteration. They are less commonly skin-colored, yellow-brown, or hypopigmented. The papules have a characteristic translucent yellow-brown tint in the background of erythema. The distinctive apple jelly color of the granulomatous skin lesion is seen on diascopy ,26. An uThey're widely diffused and found predominantly on the face and neck, especially on the eyelids, around the orbits, and in the nasolabial folds, as well as the occipital area of the neck . Recent Papules, notably on the extensor surfaces of arms, face, scalp, back, and buttocks, can progress into plaques greater than 5 mm ,31. ThesSubcutaneous sarcoidosisSubcutaneous sarcoidosis is the least common among the specific lesions of the CS. Its incidence is high in the fourth decade and most common in women than men. Multiple, firm, asymptomatic to slightly painful, mobile, round to oval, skin-colored nodules frequently occur in a bilateral and asymmetric pattern on the extremities . Ahmed eSubcutaneous sarcoidosis typically manifests at the start of the disease, and it usually indicates sarcoidosis with non-severe systemic involvement and is not linked to chronic fibrotic illness. A clinicopathological study by J Marcoval et al. in 2005 revealed that in 85 of 480 patients with systemic sarcoidosis, granulomatous cutaneous involvement was found. Subcutaneous sarcoidosis was diagnosed in 10 of the 85 cases, and in all these 10 cases, subcutaneous nodules appeared at the beginning stage of the disease. None experienced chronic or severe sarcoidosis consequences such as pulmonary fibrosis and bone cysts . DiffereThe need for and the type of treatment depends on the severity of the systemic condition. Systemic corticosteroid therapy is the basis of treatment for patients with significant systemic involvement or disfiguring skin lesions. The therapeutic response of skin lesions to oral corticosteroids was observed in all patients who received corticosteroids as their primary treatment in a series conducted by Ahmed and his colleagues as mentioned above. The daily dosage ranged from 20 to 40 mg, and responses were frequently evident four to eight weeks after treatment began . In rareScar sarcoidosisLesions of CS can also appear in pre-existing scars . A scar Clinically, the lesions present as papules, plaques, nodules, and Ill-defined erythemas. Plaque formation was seen in the scars of eight patients in a study by T Atci and his colleagues . When noExamining the scars of individuals with suspected or confirmed sarcoidosis is significant since a biopsy of these scars can be easily performed, confirming the diagnosis and preventing more invasive examinations . KeloidsLupus pernioLP is the most distinctive cutaneous lesion of sarcoidosis. The exact mechanism of development of LP in cases of sarcoidosis is unknown. It is more commonly seen in women with long-standing sarcoidosis, as evident in the subsequent studies discussed below ,26,45. ALP can be a vigorous disease that obstructs the upper respiratory tract internally and externally, necessitating aggressive therapy . It is aErythema nodosumIt is the most common non-specific cutaneous lesion of sarcoidosis as no granulomas are found on histological examination. Approximately 10-22% of all erythema nodosum cases are caused by sarcoidosis . Its mosIt is an acute marker of sarcoidosis and is believed to be triggered by the undergoing inflammatory process. Inflammation of the subcutaneous fat gives rise to tender, warm subcutaneous nodules that range in color from erythematous to violaceous to brown. It is most commonly observed on the shins . There aTriad of erythema nodosum, bilateral hilar lymphadenopathy on X-ray, and joint symptoms such as arthritis of the ankles, wrists, and elbows make up Lofgren's syndrome, which is highly specific for sarcoidosis . Though Diagnosis and managementTo establish the diagnosis of CS, a biopsy and histopathological examination is required, along with the morphological presentation. Sarcoidosis should be well-considered in the differential diagnosis of various skin lesions . It mustTreatment options are primarily based on circumstantial evidence. Observation without therapy is recommended, as most lesions are asymptomatic and often resolve spontaneously. However, disfiguring and extensive skin lesions associated with severe systemic illness require treatment . TreatmeSmall papules and plaques are often treated effectively with monthly intralesional triamcinolone injections. Treatment with a topical corticosteroid and a hydrocolloid occlusive dressing on a weekly basis can also be useful . ClinicaLimitationsThis review has some limitations. It doesn't include uncommon dermatological manifestations of sarcoidosis like ichthyosiform sarcoidosis, scalp sarcoidosis, atrophic and ulcerative sarcoidosis, mucosal and nail sarcoidosis, and a few of the studies mentioned here are case studies and reports with a very small sample population.Sarcoidosis is a multisystem idiopathic disease that forms noncaseating epithelioid cell tubercles in affected tissues or organs. Understanding the wide range of sarcoidosis clinical manifestations can help avoid diagnostic delays. Skin is the first and most common extrapulmonary manifestation of sarcoidosis. The most common cutaneous manifestations are macules, papules, plaques, subcutaneous nodules, LP, scar sarcoidosis, and erythema nodosum. Maculopapules, subcutaneous nodules, and erythema nodosum are typically associated with acute sarcoidosis. They indicate a favorable prognosis, whereas plaque-type lesions and LP are more commonly associated with advanced stages and necessitate treatment. Regardless of the extent of cutaneous involvement, patients with CS must be closely monitored. Sarcoidosis-related skin eruptions are exceedingly diverse and can resemble a variety of skin illnesses. It's tough to classify CS because many kinds appear to be mixed, and there is no consistently effective treatment. More future studies are required on the diagnosis and management aspects to improve the care of patients with CS.