Rolling treatments have been identified as a promising fabrication and deformation processing technique for graphene/metal composites with high performance. However, it is still a challenge to choose appropriate rolling parameters to achieve high strength, ductility and electrical conductivity of the composite simultaneously. In this study, graphene/Cu composites were prepared with an in situ growth method and rolling treatment. The effects of rolling deformation and temperature on the microstructural evolution of graphene and Cu grains, interface bonding between graphene and the matrix, mechanical and electrical properties were systemically investigated. The cold-rolled composite with 85% deformation displayed a maximum ultimate strength of 548 MPa, a high elongation of 8.8% and a good electrical conductivity of 86.2% IACS. This is attributed to oriented graphene arrangement and matrix grain refinement. Our research provides a comprehensive understanding for the rolling behavior of graphene/Cu composites, and can promote the development of graphene-based composites with high performance. Graphene, a two-dimensional nanomaterial consisting of single-layered carbon atoms, has aroused the interest of many researchers because of its unique properties, including its ultrahigh carrier mobility , superioThe common problems that researchers face come into three aspects: (1) graphene easily aggregates in the metal matrix due to its huge surface energy and poor wettability to metals, which leads to overall performance degradation ,13; (2) The rolling process is one of the most common plastic deformation methods used for metal matrix composites in the industry, and it has also been used recently in graphene/metal composites to improve their strength and toughness ,19,20,21Although several successful examples using rolling deformation were found to improve composite properties, the fragmentation of graphene and the production of numerous residual stresses are still inevitable during the rolling process, which may lead to performance degradation. Therefore, a comprehensive investigation on the influence of rolling parameters on the microstructure evolution and properties of the composite is necessary. However, the previous research studies mainly focused on studying the effectiveness of hot rolling treatments on the enhancement of graphene/metal composite performance, the composite microstructure during cold rolling processes and the interface interactions between graphene and metal matrixes were not investigated deeply enough.In this study, we use an ideal graphene/Cu composite fabricated with an in situ growth method from our previous study as a research model , in whicCu powder was supplied by Ningbo Guangbo Nano Material Co., Ltd., with a purity of 99.9% and a particle size of about 300 nm. Graphene was synthesized using an in situ growth method from oleic acid ).The preparation method of the graphene/Cu composite is described in ref.  and showThe rolling process was as follows: The as-sintered composite was annealed at a rolling temperature for 30 min. In order to compact the composite, the reduction of the first rolling pass was controlled to 40%. Since then, the rolling reduction was 5% during each rolling pass until reaching the final deformation. Then, the sample was annealed for 5 min at the rolling temperature before the next pass. The effects of the rolling temperature and reduction in the microstructure and properties of the composites were investigated. The rolling temperatures were set as 25 °C, 300 °C, 400 °C and 500 °C for comparison according to the recrystallization temperature of copper (269 °C). The rolling deformations of 30%, 55%, 70% and 85% were performed at 25 °C.The morphologies of the composites were observed via scanning electron microscopy  and transmission electron microscopy . The mass fraction of graphene in the composite was 0.120 wt.%, as measured with a CS-901B carbon sulfur analyzer . X-ray photoelectron spectra were obtained with a PHI 5700 ESCA System . A 5569R universal testing machine  was used to test the tensile properties of the graphene/copper composites. The tensile samples were cut along the rolling direction and had dog-bone shapes with a thickness of 1 mm and a width of 2 mm. In the tensile test, the displacement rate was 0.5 mm/min, and the gauge length was 15 mm. A 2512 current conductivity meter  was used for the electrical conductivity test.RDd) and (NDd) were measured. As shown in RDd and NDd are 0.68 mm and 0.63 mm, respectively. As the rolling reduction increases from 30% to 55%, the RDd increases from 0.96 mm to 1.47 mm, while NDd decreases from 0.50 mm to 0.28 mm, respectively. When the rolling reduction is more than 55%, both RDd and NDd undergo little change.In order to achieve a better understanding of the role of graphene during the rolling process, TEM observations of the cold-rolled pure copper and composites with 85% rolling reduction were carried out . Figure In order to investigate the change rule of the microstructure and distribution of the graphene in the composite during the rolling process, XPS analysis and TEM observation were performed.1s, O1s, CuLMM, Cu2p3/2 and Cu2p1/2 can be observed in the survey spectrum , C-O-C (531.6 eV) and C=O bonding (532.8 eV) [The Obonding 5.8 eV [3232.8 eV) .According to the XPS results, the mechanism of the microstructural evolution of graphene with various rolling temperatures could be induced. The multi-pass rolling process makes the graphene fragment thin, and plenty of fresh graphene surfaces are generated. However, in situ grown graphene nanosheets have few oxygen-containing groups, and low-temperature rolling cannot provide a sufficient driving force to the formation of chemical bonding between graphene and Cu, but instead accumulate a lot of residual stress. By contrast, the hot-rolling process can not only prompt the conversion from C=O bonding to Cu-O-C bonding by thermal activation, but can also coordinate the deformation of graphene and relieve the fracture of Cu-O-C bonding by softening the matrix. It is reported that the Cu-O-C bonding contributes to improvement in the bonding strength between the graphene and copper matrix , which mThe representative TEM images of the composites with different rolling temperatures are shown in SEM observation was performed on the fracture surface of the cold-rolled graphene/Cu composites with different rolling ratios, as shown in The tensile properties of the as-rolled composites at different rolling temperatures are shown in k is the Hall–Petch slope and d is the grain size. According to the above TEM results, the rolling temperature has a remarkable influence on the grain size of the Cu matrix, and obvious grain refinement can be achieved by the cold rolling treatment. Secondly, the rolling temperature also affects grain boundary strengthening in the composite. Graphene nanosheets are distributed at the grain boundary in the cold-rolled composite, but turn to become inside the grain in the hot-rolled composite. However, the image force is produced only when the graphene is distributed at the grain boundary, which can hinder the dislocation from slipping to the grain boundary and result in grain strengthening [The impacts of the rolling temperature on the mechanical properties of the graphene/Cu composites can be attributed to grain refinement strengthening, grain boundary strengthening and work hardening. Firstly, the grain refinement strengthening mechanism can be expressed by the following:gthening . Furthergthening . The graThe electrical conductivities of the composite under different rolling parameters were tested, and the results are shown in In addition, the conductivity of the composite slightly improved from 82.2% IACS to 86.2% IACS when the rolling temperature was increased from 25 °C to 500 °C. On the one hand, the original fine grain microstructure became coarser with increasing rolling temperature according previous TEM observations, so the number of grain boundaries decreases, which reduces the scattering of free electrons. On the other hand, based on the XPS results, graphene as a conductive functional medium in the composite has fewer defects at higher rolling temperatures, which is also an important positive factor on the improvements in conductivity.It is worth mentioning that the cold-rolling treatment in this research with large deformations exceeding 80% surprisingly contributes to improve the mechanical and electrical properties of graphene/copper composites. However, significant performance degradation occurs in the cold-rolled composite fabricated with ball milling, with similar deformation ; the harIn this study, the evolution of the microstructure and properties of graphene/Cu composites under different rolling temperatures and rolling deformation were systematically investigated. A hot rolling treatment can reduce the defects of graphene and improve the interface bonding between graphene and a copper matrix, but deteriorate the strength of the composites due to the fragmentation of graphene that is swallowed by copper grains. For cold rolling, the mechanical and electrical properties of the composites both increase continuously with increasing rolling deformation. The cold-rolled composite with 85% deformation achieved a maximum ultimate strength of 548 MPa, a high elongation of 8.8% and a good electrical conductivity of 86.2% IACS. Our research provides a comprehensive understanding for the rolling behavior of graphene/Cu composites, and can promote the development of graphene-based composites with high performance.


Sarcoidosis and hypersensitivity pneumonitis (HP) are two distinct clinical entities that share granulomatous inflammation, although each of them has specific clinical, radiologic and pathologic profiles. Coexistence of the two diseases have been described, suggesting, at least in some cases, a common biologic background. Penicillium spp suggestive of HP, while the positivity of serum angiotensin converting enzyme (ACE) favored sarcoidosis. Case 2: a 42-year old non-smoker woman with occasional finding of enlarged mediastinal lymph nodes had a history of domestic exposure to molds and positive serum precipitins to Aspergillus spp suggestive of HP.We describe two patients showing the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis. Case 1: a 51-year old never smoker man had a history of occupational exposure, episodes of acute exacerbations and positive serum precipitins toIn both cases high resolution computed tomography (HRCT) together with broncoscopy findings allowed to maintain both the diagnoses: HRCT showed both enlarged hilar/mediastinal limph nodes and intersitial lung involvement typical of HP; bronchoalveolar lavage presented marked lymphocytosis and granulomatous nodal lesions were observed at transbronchial needle aspiration.Sarcoidosis and HP share some clinical findings and the differential diagnosis may be difficult. Our cases suggest that a common trait may be responsible for the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis in the same patient. Sarcoidosis and hypersensitivity pneumonitis (HP) are two distinct clinical entities that share granulomatous inflammation, although each of them has specific clinical, radiologic and pathologic profiles.Sarcoidosis is a systemic disease of unknown etiology , althougIn pulmonary sarcoidosis histology typically reveals well-formed non caseating epithelioid granulomas with perilymphatic distribution and bronchoalveolar lavage (BAL) shows a lymphocytosis  sustained by Th1 CD4 + T-lymphocytes). In a small proportion of cases the predominant cells are CD8 + with a Tc1 cytokine profile. High resolution computed tomography (HRCT) usually shows a micro-nodular peri-lymphatic pattern and bilateral hilar and mediastinal adenopathies. Diagnosis relies upon a compatible clinical picture, histologic demonstration of non-caseating granulomas, and exclusion of other granulomatous diseases [HP is characterized by a marked mononuclear infiltration of pulmonary interstitium, more evident in the peribronchiolar/centrilobular compartment; loose granulomatous structures or isolated giant cells can be seen. The distinctive feature of BAL is a marked lymphocytosis, often > 80%, with a variable CD4+/CD8 + ratio. In non-fibrotic HP exposed individuals develop a flu-like illness 4–6 h after exposure, resolving spontaneously or with corticosteroids. In fibrotic forms the clinical presentation is more insidious and non-specific (mainly dyspnea on effort and cough). In the non-fibrotic form HRCT may be characterized by ill-defined centrilobular ground-glass nodules; in fibrotic HP signs of fibrosis are present, sometimes mimicking a UIP pattern. Recently, international guidelines have been published, using a systematic approach to the diagnosis of HP [We report two cases with concomitant clinical, radiological and pathological features of sarcoidosis and HP, suggesting a common biologic background, at least in some cases.Penicillium spp. A new bronchoscopy with transbronchial needle aspiration (TBNA) of mediastinal lymph nodes disclosed a non-necrotizing granulomatous pattern with numerous aggregates of epithelioid histiocytes  were normal: Forced Vital Capacity (FVC) 4.11 L , Forced Expiratory Volume in the 1st second (FEV1) 3.17 L (86%), FEV1/FVC 77%, and Total Lung Capacity (TLC) 5.70 L (81%) with moderate reduction of Diffusing Capacity for Carbon monoxide (DLCO single breath 42%). Arterial Blood gases at rest were in the normal range. Six minute walking test (6MWD) revealed a normal distance walked (660 m) and a severe desaturation with nadir oxygen saturation of 80%. Chest x-ray and high resolution computed tomography (HRCT) were remarkable for partially calcified hilar and mediastinal lymph nodes and a diffuse infiltrative lung disease with areas of ground glass density admixed to lobular-shaped zones of hypo-attenuation, ill defined centrilobular nodules and signs of fibrosis , FEV1 3.85 L (104%), FEV1/FVC 83%, TLC 6.87 L (95%), DLCO 42%; DLCO/VA 49%.Aspergillus spp antigens.A 42-year old non-smoker woman was occasionally found as having mediastinal lymph node enlargement on chest CT; pulmonary abnormalities were not found. She reported hypertension and prior left facial nerve palsy. Lymphocytosis was found at BAL (39% lymphocytes with CD4/CD8 ratio 3.5). Malignant cells and infectious agents were absent. Mediastinal sarcoidosis was diagnosed and no therapy was prescribed. Eighteen months later the patient developed progressive exertional dyspnea and a restrictive ventilatory defect with severe DLCO impairment were documented at PFTs: FVC 1.69 L (44%), FEV1 1.45 L (45%), FEV1/FVC 86%, TLC 3.19 L (55%), DLCO 33%. Prednisone was started  and a slight functional improvement was obtained . Three years later, because of worsening dyspnea she attended the outpatient clinic of our hospital. At chest CT ill-defined areas of ground glass attenuation were observed as well as multiple enlarged hilar and mediastinal lymph nodes. A worsening of the known restrictive ventilatory disorder became obvious on PFTs . BAL lymphocytes were 61% with a CD4/CD8 ratio 3.75. TBNA of subcarinal lymph nodes disclosed numerous small lymphocytes and microgranulomatous aggregates of epithelioid histiocytes. TBLB included fragments of lung parenchyma with a mononuclear septal infiltrate, alveolar foamy macrophages and a multinucleated giant cell. A careful review of medical history revealed a previously unreported domestic exposure to molds. Serum precipitins displayed reactivity to After multidisciplinary discussion the case was labelled as simultaneous occurrence of HP and mediastinal sarcoidosis. Prednisone daily dose was raised to 12.5 mg per day; a clinical and functional improvement  was obtained.We added in Table Konig and colleagues revised a series of 46 cases of sarcoidosis: 14 of them had a history of significant exposure and inhalation challenge favoured a diagnosis of HP [Sarcoidosis and HP share some clinical findings and the differential diagnosis may be difficult, especially in patients without a history of professional or environmental exposure. In 1981 is of HP .Penicillium spp and Aspergillus spp, respectively). On the other hand, although the pathogenesis of sarcoidosis has been relatively elucidated, the trigger remains elusive. Infectious organisms  or environmental exposures are possibly involved in some cases but a definitive evidence is lacking [In our cases the association between sarcoidosis and HP is supported by clinical, laboratory, imaging and pathological findings. In particular, both had voluminous bilateral hilar and mediastinal lymph nodes and non necrotizing granulomatous aggregates of epithelioid cells: these findings are typical of sarcoidosis. History, lung imaging and laboratory tests are all consistent with HP. The list of antigens potentially causing HP in predisposed individuals is broad and continuously growing . In both lacking .In HP, epithelioid histiocytes predominate only focally, usually around the airways, resulting in a subtle granulomatous appearance. Well-formed (sarcoid-like) granulomas are rare. Isolated multinucleated giant cells are common and, in a minority of cases, represent a striking feature. In contrast, discrete well-formed non-necrotising granulomas are the histological hallmark of sarcoidosis. Granulomas comprise a compact circumscribed cluster of epithelioid and multinucleated histiocytes with minimal or no central necrosis. They are often associated with a peripheral infiltrate of lymphocytes and a distinctive pattern of lamellar fibrosis .Finally, both sarcoidosis  and HP  have bee


To the Editor,Chronic Spontaneous Urticaria (CSU) is caused by the activation of skin mast cells (MCs) by various signals including IgG and IgE autoantibodies in autoimmune (type IIb) and autoallergic CSU, respectively.Upon IgE‐mediated activation, MCs release the soluble isoform of the high affinity IgE receptor (sFcɛRI), which results in increased serum levels.p < 0.0001; Figure Patients with CSU had significantly higher sFcεRI serum levels (median ± IQR: 1.9 ± 62.9 ng/mL) than HCs  and significantly correlated with sFcεRI levels, albeit weakly . Chronic Spontaneous Urticaria patients with normal and elevated IgE (>40 IU/mL) versus low IgE (<40 IU/mL) had significantly higher sFcεRI levels  or chronic inducible urticaria  from Novartis, Menarini, Uriach, FAES, Pfizer. MSD and has received a research Grant from GSK and Novartis. AGA or recently was a speaker and/or advisor for and/or has received research funding from Almirall, Amgen, AstraZeneca, Avene, Celldex, Escient Pharmaceuticals, Genentech, GSK, Instituto Carlos III‐ FEDER, Leo Pharma, Menarini, Novartis, Sanofi–Regeneron, Thermo Fisher Scientific, Uriach Pharma/Neucor. CEHG has done consultancy work recently for Celltrion and Sanofi. TJ or recently was a speaker and/or advisor for and/or has received research funding from ALK‐Abello, Allergy Therapeutics/Bencard, Novartis and Thermo‐Fisher Scientific. GNK or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Chiesi, GSK, Menarinin, Novartis, Pfizer, Sanofi, Vianex. UR is or recently was a speaker and/or advisor for Almirall, Abbvie, Janssen, Sanofi, Novartis and UCB. PS is or recently was a speaker and/or advisor for and/or has received research funding from AbbVie, Allergika, Almirall‐Hermal, Amgen, Beiersdorf, Biocryst, BMS, Boehringer‐Ingelheim, Celgene, CSL‐Behring, Eli‐Lilly, Galderma, Hexal, Janssen, Klinge, Klosterfrau, LEO‐Pharma, LETI‐Pharma, L´Oreal, Novartis, Octapharma, Pfizer, Pflüger, Pharming, Regeneron, Shire, Takeda, Regeneron, Sanofi‐Genzyme and UCB Pharma. TK, Tamar Kinaciyan is or recently was a speaker and/or advisor for and/or has received research funding from ALK, Sanofi/Regeneron, Novartis, CSL Behring, Biocryst, Takeda and KalVista. MMakris is or recently was a speaker and/or advisor for and/or has received research funding from Astra Zeneca, Chiesi, GSK, Novartis, Pfizer, Sanofi, Menarini, Elpen, Vianex. PSG or recently was a speaker and/or advisor for and/or has received research funding from AbbVie, Aimmune, ALK‐Abello, Amgen, AstraZeneca, Bencard, Biomed, Bühlmann Diagnostics, Galderma, GlaxoSmithKline, Jansen, LEO, Lilly, L`Oréal, Menarini, Novartis, Pfizer, Pierre Fabre, Roche Pharma, Sanofi Regerenon, Stallergenes and Thermo Fisher. GS is also a medical advisor and/or has received payment for lectures from Novartis, CSL Behring, Pfizer, Abvie, Astra‐Zeneca, Nuvo Pharmaceuticals, and the Allergy Asthma and Immunology Society of Ontario. MMaurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB, and Uriach. SA or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, Biocryst, CSL Behring, Sanofi, Takeda, ThermoFisher, Moxie and Novartis.Deutsche Forschungsgemeinschaft, Grant/Award Number: RA‐1026/3‐2Supporting Information S1Click here for additional data file.


Posaconazole is a potent broad spectrum mould-active triazole that is increasingly used in children for treatment of aspergillosis, mucormycosis, and endemic mycoses. Although posaconazole has a favorable safety profile in pediatric patients, we recently observed an excess mineralocorticoid syndrome characterized by hypertension and hypokalemia within three weeks of treatment initiation in two patients. Both showed endocrinological evidence of posaconazole inhibition of 11-β-hydroxylase. As this condition is seldom reported in children, we conducted a systematic review of the literature for reports of this condition in pediatric cases.https://pubmed.ncbi.nlm.nih.gov/ and https://scholar.google.com/) was performed using key phrases of pediatrics (< 18 years) plus posaconazole plus hypertension, hypokalemia, mineralocorticoid excess, or 11-β-hydroxylase. Variables included age, sex, underlying condition, indication for posaconazole, blood pressure > 95th% for age and height, time from exposure to posaconazole to onset of hypertension, hypokalemia (≤3mEq/L), plasma aldosterone, serum 11- deoxycorticosterone, and serum 11-deoxycortisol.A systematic review of the literature . Four of 5 patients were male. Patients were treated for mucormycosis, histoplasmosis or ABPA. All patients developed hypertension within three weeks of starting posaconazole. Hypokalemia occurred in 4 out of 5 cases. Consistent with posaconazole inhibition of 11-β-hydroxylase, patients with available data had elevated serum 11- deoxycorticosterone, and/or elevated serum 11-deoxycortisol, and/or decreased or undetectable plasma aldosterone. All patients were managed with antihypertensive therapy.Children who develop hypertension and hypokalemia within 3 weeks of receiving posaconazole should be evaluated further for an excess mineralocorticoid syndrome and 11-β-hydroxylase inhibition. Management may consist of discontinuation of posaconazole and/or initiation of antihypertensive therapy.Jong Chung, MD, Cardinal Health: Advisor/Consultant|Dispersol Technologies: Advisor/Consultant|Forma Therapeutics: Advisor/Consultant|Global Blood Therapeutics: Advisor/Consultant|Jazz Pharmaceuticals: Advisor/Consultant Thomas J. Walsh, MD PhD, Abbott: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Karyopharm: Advisor/Consultant|Lediant: Advisor/Consultant|Lediant: Grant/Research Support|Merck: Grant/Research Support|Omeros: Advisor/Consultant|Omeros: Grant/Research Support|Partner Therapeutics: Advisor/Consultant|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Statera: Advisor/Consultant|T2 Biosystems: Advisor/Consultant|T2 Biosystems: Grant/Research Support


This results in an equilibrium interlayer distance of 3.5 Å and a binding energy per carbon atom of 37 meV, confirming the presence of weak van der Waals interaction between the graphene and the phosphorene layers. The electronic properties of the heterostructure are evaluated under different values of interlayer distance, strain and applied vertical electric field. We demonstrate that G/P heterostructures form an n-type Schottky contact, which can be transformed into p-type under external perturbations. These findings, together with the possibility to control the gaps and barrier heights, suggest that G/P heterostructures are promising for novel applications in electronics and may open a new avenue for the realization of innovative optoelectronic devices.We present a comprehensive study of the structural and electronic properties of a graphene/phosphorene (G/P) heterostructure in the framework of density functional theory, including van der Waals interaction in the exchange–correlation functional. While the G(4 × 1)/P(3 × 1) superlattice usually used in the literature is subject to a strain as high as about 7%, the in-plane strain could be drastically reduced to under 1% in the G(4 × 13)/P(3 × 12) heterostructure investigated here. Adapting the lattice constants of the rectangular lattices, the equilibrium configuration in the  Graphite crystals are a possible source to exfoliate single atomic layers of carbon atoms, namely graphene (G) ,2. Great2h ,6.Phosphorene shows several unique properties: it possesses a peculiar band structure whose dispersion is nearly linear along the armchair directions but parabolic in the perpendicular directions ,7. DepenPhosphorene or, more generally, few-layer BP, possesses not only anisotropic but also very high carrier mobilities ,27, with2/Vs ,28, whic2/Vs . In fact2/Vs . Moreove2/Vs  that is 2/Vs , allowinperature ,9. Phospperature ,33. In s–P alloy . As an a–P alloy . The app–P alloy ,37,38. F–P alloy , or it c–P alloy ,41.p-type Schottky contact at the G/P interface, which could be transformed into an n-type Schottky contact varying, for example, the interlayer distance [However, phosphorene presents different limitations concerning its application in electronic devices, since it is unstable under environmental conditions . To overdistance , the impdistance  or the adistance . The infdistance .In this work, we investigate the structural and electronic properties of crystalline G/P heterostructures as a function of the interlayer distance and of an applied vertical electric field. We use a large coincidence lattice to avoid artificial in-plane strains due to too small cells used in the modeling shown by most theoretical studies. The main method is the density functional theory (DFT) including vdW interaction in the exchange–correlation (XC) functional. The atomic geometries of the resulting heterostructures are compared with those of the isolated 2D crystals. The accompanying electronic structures are tuned with the G/P layer distance and an external electric field. In particular, the Schottky barrier heights for electrons and holes, as well as their modification, are investigated.aabaabWe carry out the first-principles simulations within the DFT implemented in the Quantum Espresso suite ,47. The oretical ,38,50,51 4.62 Å) .abx and y directions is required to obtain a minimal mismatch fy, and it will significantly influence the structural and electronic properties of the G/P heterostructure. This is illustrated in x and y directions. Significant changes may occur when increasing or decreasing the lattice constants by about 7%. A correspondingly large effect is expected for the band structure and the gap opening in phosphorene and, to a minor extent, for the Fermi velocities of the Dirac bands. Given the presence of an excessively large mismatch along the y direction and a huge resulting strain in the G/P heterostructure, we resorted to considering a larger coincidence lattice [x and y directions. The lattice constants are now babThe construction of a reasonable coincidence lattice between graphene and phosphorene asks for a representation of graphene using a nonprimitive rectangular unit cell with lattice constants  lattice  using a z-direction is set to avoid spurious interactions between neighboring slabs. The 2D Brillouin zone (BZ) is sampled with a k-point mesh.At this stage, to apply the plane-wave expansion implemented in the Quantum Espresso suite, the heterostructures are periodically repeated in normal direction. Therefore, a vacuum space of 15 Å in the To obtain the equilibrium configuration, we apply a three-step procedure: (1) due to the much stronger stiffness of the graphene lattice as compared with BP see , we impod δy see a,c; and d  or holes (p-type) as distances of the CBM, W for a material. Comparing the work function n-type Schottky contact somewhat in contrast to the G(4 × 1)/P(3 × 1) strained heterostructures found in the literature [p-type Schottky contact. These results for graphene are opposite to conventional metals, which should give rise to n-type contacts [Utilizing the bilayer heterostructure, with the band structure given in terature ,44. More=0.64 eV  indicaticontacts .d.A vertical tensile or compressive strain on the heterostructure leads to an increase or decrease in the interlayer distance d, the P-derived gap is only weakly decreased. The graphene-derived Dirac cones survive with a small gap of about 10 meV around the Dirac point. However, in d on the position of the Dirac point is visible.In n-type doping of graphene, while for distances greater than 3.5 Å, there is a p-type doping of graphene.In fact, the Dirac cone moves below or above the Fermi level of the heterostructure and, in particular, when the interlayer distance is less than 3.5 Å, there is an d has consequences for the Schottky barriers. From the graph shown in p-type Schottky contact to an n-type Schottky contact. The sum of the two barrier values d rises, similar to the interband energy at The variation in the band edges and the Dirac point with the interlayer distance al study .F in the normal direction, i.e., perpendicular to the heterostructure.The interaction between graphene and phosphorene in their heterostructure, but especially the resulting charge transfer, can be remarkably tuned by an external electric field F. For negative values of an applied electric field, we observe a gate-field-induced p-type doping of graphene. For positive values, instead, we obtain an n-type doping of graphene. Applying a positive electric field greater than 0.05 V/Å, the Schottky barrier n-type Schottky contact to a p-type Schottky contact, as shown in In p-type to an n-type Schottky contact from interlayer distances smaller to larger than 3.4 Å. Such a conductivity transition also occurs under the action of an external electric field for positive strengths bigger than 0.05 V/Å. In the equilibrium case (d = 3.5 Å and electric field strength F = 0), the less-strained heterostructure exhibits a Schottky barrier of opposite type compared with that of the significantly more strained systems studied in the literature. Summarizing, we demonstrated the possibility for the preparation of almost strain-free graphene/phosphorene contacts, which are fundamental for the design of novel elastic and anisotropic devices based on vdW heterostructures containing graphene as electrode and phosphorene as the material with the conducting channel. The range of values of the proposed G/P Schottky barriers compare well with those made up of gold and silicon. The advantages of using G/P for new devices are low cost, high flexibility and small size.By means of density functional theory, we investigated the structural and electronic properties of graphene/phosphorene heterostructures under strain and an external vertical field. We focused especially on the resulting Schottky barrier between the two 2D crystals. To overcome the significantly large lateral strain of previous studies, caused by the employ of small unit cells, we investigated graphene (4 × 13)/phosphorene(3 × 12) coincidence lattices with very large supercells containing 352 atoms. We demonstrated that the electronic properties of graphene and phosphorene remain preserved upon their contact with an interaction within a typical vdW distance. We have also shown that varying the interlayer distance around the equilibrium values and the external electric field, it is possible to tune the positions of the band extrema in the electronic band structure of phosphorene relative to the Fermi level. Moreover, the Dirac cones of graphene surviving from the contact formation can be moved upward or downward by means of playing with the external perturbation. As a consequence, the upper band extrema will be filled with electrons, or holes will appear in the lower one. This behavior allows to control the Schottky barrier height of this metal–semiconductor bilayer system, enabling a switch in the conduction type of the Schottky contact. In fact, it changes from a


We examine the performance of a finite-time, endoreversible Otto heat engine with a working medium of monolayer or multilayered graphene subjected to an external magnetic field. As the energy spectrum of multilayer graphene under an external magnetic field depends strongly on the number of layers, so too does its thermodynamic behavior. We show that this leads to a simple relationship between the engine efficiency and the number of layers of graphene in the working medium. Furthermore, we find that the efficiency at maximum power for bilayer and trilayer working mediums can exceed that of a classical endoreversible Otto cycle. Conversely, a working medium of monolayer graphene displays identical efficiency at maximum power to a classical working medium. These results demonstrate that layered graphene can be a useful material for the construction of efficient thermal machines for diverse quantum device applications. There is rapidly growing interest in the development of quantum technologies, devices that take advantage of the unique properties of quantum systems to enhance their performance. This, in turn, has led to an increased focus on the field of quantum thermodynamics ,2,3,4. WWhen considering possible systems to use as the working medium of a quantum heat engine, graphene stands out as an intriguing candidate.Graphene’s optical, electronic, and mechanical properties have been extensively studied in recent years ,14,15,16When graphene layers are stacked to form a multilayer system, the behavior of the system can vary depending on the stacking order. For example, the relativistic character of the charge carriers is only preserved for some layer numbers and stacking arrangements, leading to a unique energy spectrum when in the presence of a perpendicular magnetic field .As the Efficiency, defined as the net work per cycle divided by the heat absorbed into the working medium from the hot thermal reservoir,Endoreversible thermodynamics [efficiency at maximum power (EMP), which corresponds to maximizing the power output with respect to the external control parameter and then determining the efficiency at that maximum power output. Endoreversible cycles have also been studied in the context of quantum heat engines. We draw particular attention to Ref. [To maximize engine efficiency, the strokes of the cycle must be carried out quasistatically. However, truly quasistatic strokes require an infinite cycle duration, thus leading to vanishing power output. Practically useful metrics of heat engine performance must, therefore, account for cycles implemented in finite time. dynamics ,35,36 pr to Ref. , where i to Ref. , the EMPThe heat engine performance analysis carried out in Ref.  assumes In In multilayer graphene structures, the graphene sheets are placed on top of each other in different stacking configurations and are connected through weak van der Waals forces. The stacking configurations are determined by the orientation of the two triangular sublattices that make up the primary honeycomb lattice of a single sheet. For two stacked sheets, three possible orientations, A, B, and C, are possible, each corresponding to displacing one of the sublattice atoms along the edge of the honeycomb with respect to the neighboring sheet . Subject in ref. . In our  in ref. . Signifin [B is the magnitude of the magnetic field, e is the electron charge, ℏ is Planck’s constant, and K and In monolayer graphene, the application of a perpendicular magnetic field results in unevenly spaced Landau levels with an energy spectrum proportional to the root of the level quantum number n ,(3)En=±For a bilayer system, the most stable coupling corresponds to Bernal or AB stacking. This consists of displacing the A sublattice atoms of the upper layer so that they lie on top of the B sublattice atoms of the lower layer. Contrary to the monolayer case, the bilayer system has a quadratic dispersion relation, which gives rise to an interesting phenomenon. While the Dirac equation still models the dynamics of the low energy states, the quadratic dispersion relation indicates that the described charge carriers have mass. In this case, under a perpendicular external magnetic field, the Landau level spectrum for the bilayer graphene presents a linear dependence with the magnetic field, as shown in En=±ℏωcnEn,NNote that the energy spectra in Equations –5) incl incl5) iTo accurately determine the partition function, we need to carefully consider the degeneracy of the energy levels, especially for the zero-energy state. The compact form of counting these degenerate states in the partition function is given by,n, then the energy spectrum can be approximated asThe partition function for the energy spectrum given in Equation  does notn, we can approximate the partition function sum as an integral of the form,For large Noting that,The equilibrium thermodynamic properties of the multilayer graphene system can be determined from the partition function as follows,T in the high temperature regime. From In S)–magnetic field (B) diagram. The first stroke (B) plays the role of an inverse volume, increasing during the compression stroke ,,19), 2727, and  we arrivHere we have defined  strokes . ExaminiEquation  that thiquations  and 23)κ≡B1/B2 aThe efficiency and power are plotted as a function of the compression ratio, Due to the inherent trade-off between efficiency and power mentioned above, efficiency alone does not provide the most practically useful metric of engine performance. Instead, this role is played by the efficiency at maximum power. In this case, the EMP is found by maximizing the power output with respect to the compression ratio, ficiency ,46,(32)The CA efficiency is especially notable as, like the Carnot efficiency, it depends only on the temperatures of the reservoirs and not only the characteristics of the working medium. However, unlike the Carnot efficiency, the CA efficiency does not provide an upper bound on the efficiency at maximum power, and can be exceeded under certain circumstances.Due to the complicated expression for power in Equation , we maxiFor the bilayer and trilayer systems, however, we see that the EMP exceeds the CA efficiency. The EMP is largest for the bilayer system, decreasing slightly in the trilayer case. This trend continues, with the EMP of larger layer numbers converging back towards the CA efficiency. However, it is important to note that if we increase the number of graphene layers significantly beyond the trilayer case, the assumptions made in determining the closed form of the partition function begin to break down.It has been previously shown for both classical and quantum working mediums that, within the regime of linear response, EMP is bounded by the CA efficiency ,50,51,52To probe the behavior of the EMP for a multilayer graphene working medium in and around the linear response regime, we define From these results, we see that two conditions must be met for the EMP to exceed CA. First, the difference in bath temperatures must be sufficiently far from the equilibrium limit of  in ref.  for harmFor any arbitrary choice of parameters, it is not guaranteed that the Otto cycle will function as an engine. In general, there are four possible types of thermal machines, corresponding to all possible combinations of directions of heat and work flow consistent with the first and second laws of thermodynamics. An engine corresponds to positive work output, along with heat flow from the hot bath into the working medium, and from the working medium into the cold bath. A refrigerator corresponds to negative work output, along with heat flow from the cold bath into the working medium and from the working medium into the hot bath. A heater corresponds to negative work output, along with heat flow from the working medium into both baths. Finally, an accelerator corresponds to negative work output along with heat flow from the hot bath into the working medium and from the working medium into the cold bath.By examining the signs of Equations , 15), , , and 2020 acrossIn Experimental implementation of the multilayer graphene engine requires precise control of the number of layers as well as a tunable magnetic field of sufficient strength to induce Landau quantization. Fine control over multilayer structures has been demonstrated by folding monolayer graphene nanoribbons  and precGraphene is also a prominent Dirac material, a class of systems whose electronic structure gives rise to charge carriers that behave as relativistic fermions. In particular, the energy spectrum of monolayer graphene can be mapped to that of the relativistic Dirac oscillator . We noteWe have examined the performance of an endoreversible Otto cycle with a working medium of a multilayer graphene system. We have found that all examined performance metrics, including the efficiency, power, EMP, and parameter regions under which the cycle functions as an engine or refrigerator all depend significantly on the number of layers. Most notably, we have found that the EMP for bilayer and trilayer graphene working mediums exceeds the Curzon–Ahlborn efficiency. Conversely, we have demonstrated that the EMP of a monolayer graphene working medium is identical to the CA efficiency. We have also found two conditions necessary for the graphene EMP to exceed the CA efficiency, namely the cycle must be sufficiently far from the equilibrium limit and must be operating in the low temperature regime corresponding to


Many methodologically diverse computational methods have been applied to the growing challenge of predicting and interpreting the effects of protein variants. As many pathogenic mutations have a perturbing effect on protein stability or intermolecular interactions, one highly interpretable approach is to use protein structural information to model the physical impacts of variants and predict their likely effects on protein stability and interactions. Previous efforts have assessed the accuracy of stability predictors in reproducing thermodynamically accurate values and evaluated their ability to distinguish between known pathogenic and benign mutations. Here, we take an alternate approach, and explore how well stability predictor scores correlate with functional impacts derived from deep mutational scanning (DMS) experiments. In this work, we compare the predictions of 9 protein stability‐based tools against mutant protein fitness values from 49 independent DMS datasets, covering 170,940 unique single amino acid variants. We find that FoldX and Rosetta show the strongest correlations with DMS‐based functional scores, similar to their previous top performance in distinguishing between pathogenic and benign variants. For both methods, performance is considerably improved when considering intermolecular interactions from protein complex structures, when available. Furthermore, using these two predictors, we derive a “Foldetta” consensus score, which improves upon the performance of both, and manages to match dedicated variant effect predictors in reflecting variant functional impacts. Finally, we also highlight that predicted stability effects show consistently higher correlations with certain DMS experimental phenotypes, particularly those based upon protein abundance, and, in certain cases, can significantly outcompete sequence‐based variant effect prediction methodologies for predicting functional scores from DMS experiments. Rosetta complex ΔΔG values also appear to correlate well (0.61) with dataset UBI4(b), based on a FACS assay that relates well to stability. The next best correlating datasets for other genes had Spearman's rho values of up to 0.53, across both ΔΔG and |ΔΔG|.However, other works have shown individual correlations between stability predictions and DMS functional scores can reach up to 0.57 for targets like NUDT15 , TPMT, CYPC9(a), UBI4(b)). While growth assay datasets from some specific targets, like bla or P53, also show good agreement, they are uncharacteristic and more likely represent good protein‐specific performance unrelated to the underlying assay type. Abundance‐based approaches could be said to directly relate to the stability of target proteins, thus being better tailored to detecting loss of protein function. VAMP‐seq has been specifically developed for this purpose and shown to correlate well with experimental thermodynamic and predicted stability measures  and PSD95 (PDB ID: 6QJL) did not contain the binding partners relevant for the specific DMS assays, or were monomeric, explaining the inability of stability predictors to reflect intermolecular interactions. More suitable complex structures were not currently available in the PDB. However, both GAL4 and BRCA1(a) DMS datasets show increased correlation with stability values, when using complex structures. The GAL4 structure (PDB ID: 3COQ) contains a transcription factor dimer that is bound to a DNA duplex, allowing us to evaluate variant effects both on dimerization and DNA recognition. The BRCA1(a) dataset was derived from an assay interrogating BRCA1‐BARD1 heterodimer interactions, which are represented in the structural data (PDB IDs: 7JZV and 1JM7).We investigated the coverage of mapped and other available structures for the binding DMS proteins , to see what factors might underly the low correlations. We found that structures for HRAS stabilizing than they actually are, resulting in a stronger correlation with the functional scores from DMS assays. Given that non‐loss‐of‐function disease variants tend to be structurally milder, we would expect them to be poorly predicted by conventional stability predictors, since their damaging effects are unlikely to be due to destabilization  do not seem to demonstrate the same capabilities. This demonstrates that the noise in current computational stability predictors could be alleviated by combining multiple well‐performing tools, perhaps with a specific emphasis on methodologies based on empirical potentials that approximate physics terms, as both FoldX and Rosetta fall into this category. Overall, the performance of Foldetta suggests stability predictors have applicability in disease variant identification, and further ensembling approaches combining currently available predictors may lead to yet even better results, especially if ensembles are trained and the individual tools are weighted.In this study we also demonstrated the utility of using complex structures of biological units, as monomer structures may not be sufficient for assessing the full functional impact of a variant, for instance due to molecular mechanisms involving intermolecular interactions, as shown previously  was run based on the protocol laid out in Park et al.  or Selenium (https://github.com/baijum/selenium-python) packages. Some predictions for certain datasets or variants could not be completed due to software or webserver errors.FoldX 5.0 was run using default parameters as previously described , they need to be divided by a scaling factor of 2.94 (previously established in Park et al.  to bringFor DMS datasets present in our recent benchmarking studies, we used the previously calculated VEP values (Livesey & Marsh, To compare the agreement between GAL4 DMS scores and FoldX stability predictions for variants, both score sets were rank normalized to the range of 0–1. As they showed better correlation, absolute stability values were chosen for the comparison, and any variants that were indicated to increase the functional outcome of the DMS assay were removed to focus on the loss‐of‐function aspect of the predictions. Normalized stability values were subtracted from the normalized DMS scores, where a positive delta for a variant indicates FoldX is underpredicting its functional effect, in relation to DMS data, while a negative delta means FoldX overestimates the functional impact of a variant. A value close to zero indicates agreement between FoldX and the DMS assay on the relative severity of a variant. To visualize prediction accuracy on a structure, median delta values were derived from all variants with a DMS score at a given position.4.3Full‐pairwise Spearman's correlations for complete observations were calculated using the R “psych” Revelle,  and “corFor the predictor correlation ranking against DMS functional values, a scoring scheme involving pairwise comparisons of each predictor against every other predictor for every DMS dataset was derived. For a given DMS dataset and two predictors, only the common subset of variants, for which both prediction and assay values were available, was used to calculate Spearman's rho values. The correlation values were rounded to two digits after the decimal point and were compared only if neither predictor was completely missing data for a given DMS dataset. After a successful comparison, the predictor with a larger correlation value was rewarded a point, or each predictor was granted half a point in the case of a draw after rounding. In the end, each predictor's score was divided by the total number of successful comparisons it was involved in to normalize the scores. This normalization also gives a chance for predictors with a few missing DMS datasets not to fall behind in the scoring scheme due to undersampling issues. Error bars were derived using the “binom.confint” function from the “binom” package (Dorai‐Raj, The authors declare no conflicts of interest.Data S1: Supporting informationClick here for additional data file.


Adipose-derived stem cells (ADSC) therapy shows promise as an effective treatment for dystrophinopathy. Fibro-/adipogenic progenitors (FAPs) play an essential role in the myogenesis of muscle satellite cells and contribute to muscle fibrosis and adipocyte infiltration. The interleukin 4 (IL-4) pathway acts as a switch that regulates the functions of FAPs. The interaction between FAPs and engrafted cells remains unclear. In this study, we used a co-culture system to investigate possible crosstalk between the FAPs of dystrophic mice and ADSC overexpressing IL4 (IL4-ADSC) and control ADSC. Systemic transplantation of IL4-ADSC and control ADSC in dystrophic mice was conducted for 16 weeks, after which motor function and molecular improvements were evaluated. Overexpression of IL4 in ADSC significantly promoted myogenesis in vitro, increasing the expression of Pax7, Myogenin, and MyHC. Co-culture indicated that although myoblasts derived from control ADSC promoted adipogenic and fibrogenic differentiation of FAPs, FAPs did not significantly affect myogenesis of ADSC-derived myoblasts. However, overexpression of IL4 in ADSC inhibited their myotube-dependent promotion of FAPs differentiation on the one hand and promoted FAPs to enhance myogenesis on the other. Dystrophic mice administered with IL4-ADSC-derived myoblasts displayed significantly better motor ability, more engrafted cells showing dystrophin expression, and less muscle fibrosis, intramuscular adipocytes, and macrophage infiltration than mice administered control-ADSC-derived myoblasts. In conclusion, IL4 activation enhanced the therapeutic potential of ADSC transplantation in dystrophic mice, possibly by improving the myogenesis of IL4-ADSC and altering the crosstalk between engrafted stem cells and resident FAPs. DMD gene leading to defective dystrophin cause DMD. Progressive pathological changes in muscles due to fibrosis and fatty infiltration are hallmarks of advanced DMD . Oil Red O staining revealed that FAPs (Co-cult with VEH-ADSC) form more lipid-laden adipocytes compared to mono-cultured FAPs and FAPs (Co-cult with IL4-ADSC)  were dramatically increased compared to those in mono-cultured IL4-ADSC Fig. A and C. We speculated that FAPs may secrete cytokines that promote the myogenesis of IL4-ADSC-derived myoblasts. Therefore, we investigated the mRNA expression levels of several common myogenesis-promoting factors  and IL4 in co-cultured FAPs and mono-cultured FAPs  significantly improved terminal myogenesis caused by IL4-ADSC-derived myoblasts; (ii) the obviously enhanced effect of IL4-ADSC-derived myoblast transplantation on muscle fibrosis via activation of the IL4 pathway in FAPs, compared to that of VEH-ADSC-derived myoblasts; (iii) significantly less infiltration of muscle by mdx + IL4-ADSC compared to that of mdx + VEH-ADSC, due to IL4 activation inhibiting the adipogenic differentiation of FAPs promoted by ADSC-derived-myoblasts. For the first time, we report that overexpression of IL4 effectively improves the effect of ADSC therapy on muscle fat infiltration in mdx mice, thereby providing a new concept in ADSC therapy that may help enhance muscle fat infiltration in mdx mice.We found that IL4 expression in the TA of 6-month-old mdx mice was increased compared to that of C57/BL6 mice, which was consistent with previous reports indicating that the regenerative stage of mdx mouse limb muscles was possibly associated with infiltration by T cells or eosinophils , 37. EleThis study was affected by certain limitations. Firstly, we simply focused on the relationship between engrafted cells and FAPs, and failed to investigate the benefits conferred by the in vivo study to other mechanisms. Further research should focus on elucidating more complicated interactions that may exist between other cell types. Furthermore, the improved post-transplantation therapeutic effects exerted by IL4-ADSC on mdx mice cannot be said to have benefited from the altered crosstalk between engrafted IL4-ADSC and FAPs or from the improved myogenic impact of IL4-ADSC themselves, although the in vitro co-culture study of IL4-ADSC and FAPs does offer some evidence. Besides, many studies show the detrimental effects of promoting the activity and generation of this cytokine, as it is an immunosuppressor of several cell activities. In this regard, IL4 has been shown to worsen the outcome of important diseases, such as cancer, virus, and parasitic diseases , 41. ThuTo the best of our knowledge, this is the first study to determine the extra benefits conferred by a combination therapy involving IL4 administration and cell therapy on the positive effects exerted by muscle micro-environment cells on the regenerative therapy of DMD. In conclusion, IL4 overexpression improves the therapeutic potential of ADSC transplantation in mdx mice, possibly by altering crosstalk between engrafted stem cells and resident FAPs and improving the myogenesis efficacy of IL4-ADSC.