FE) of monolayer graphene, and the maximum difference in transmission up to 0.92 is achieved. Moreover, we also discuss the influence of the asymmetry degree to further investigate the modulation effect of graphene on the quasi-BIC mode.In this paper, we combine the dielectric metasurface with monolayer graphene to realize a high quality(Q)-factor quasi-BIC-based optical modulator, and the corresponding modulation performances are investigated by using the finite-difference time-domain (FDTD) method, which can be well fitting by the Fano formula based on the temporal couple-mode theory. The results demonstrate that bound states in the continuum (BIC) will turn into the quasi-BIC with high Q-factor by breaking the symmetry of every unit of the metasurface. Meanwhile, the amplitude and bandwidth of transmission based on the quasi-BIC mode can be efficiently adjusted by changing the Fermi energy ( Generally speaking, metamaterials can couple to the incident electromagnetic fields due to their periodic subwavelength structural elements and exhibit properties that do not exist in nature. Thus, they have attracted wide attention and produced pioneering electromagnetic and photonic phenomena in the past two decades ,2,3,4,5.BICs are states that keep localized even if they exist together with a continuum of radiating waves in the same spectrum that can take energy away. As quite general wave phenomena, since BICs were first theorized in quantum mechanics , they haFE, by employing bias voltage [In 2018, Y. Xu et al.  and Y. K voltage ,32,33. A voltage ,35, abso voltage ,37,38,39 voltage ,40, and  voltage ,42. Mean voltage ,44. BaseFE of monolayer graphene, and the maximum difference in transmission up to 0.92 is realized. Moreover, we also discuss the influence of the asymmetry degree to further investigate the modulation effect of graphene on quasi-BIC mode.In this article, we combine the monolayer graphene with dielectric metasurface to achieve a high Q-factor quasi-BIC-based optical modulator. By using the 3D finite-difference time-domain (FDTD) method, we have ascertained the resonance wavelength of BIC of the dielectric metasurface, and studied the effect of structural asymmetry on BIC. By breaking the symmetry of every unit of the metasurface, BIC will turn into the high Q-factor quasi-BIC. Meanwhile, the amplitude and bandwidth of transmission based on the quasi-BIC resonance can be flexibly adjusted by changing the h1 = 200 nm and h2 = 500 nm, respectively. The periods of square split-rings in the x and y directions are both x = PyP = 1300 nm. Meanwhile, the lengths of different parts in an unit of arrays of square split-rings are x3= x4 = 100 nm and y = 800 nm, respectively. The refractive indexes of silica and silicon are set as 1.44 and 3.45, respectively. The asymmetry parameter α is defined as α = |x1−x2|/2. Simultaneously, the optical conductivity of graphene is associated with the Fermi energy FE and carrier mobility μ according to the random phase approximation. In the local limit, it is expressed as [T is set as 300 K, the carrier mobility is c is the speed of light in vacuum. Although this work focuses on numerical simulation research, the proposed structure can be relatively convenient to manufacture experimentally compared with the other optical modulators. The dielectric metasurface based on silica substrate is easy for integration under the current CMOS technology, and monolayer graphene grown by chemical vapor deposition can be transferred over the silicon-based metasurface using standard transfer techniques [|E0| is set to 1. Moreover, it is worth noting that the proposed absorber also demonstrates polarization-insensitivity due to its center symmetric feature. The non-uniform mesh is performed, and the minimum mesh size inside monolayer graphene is set as 0.01 nm and gradually enlarges outside the graphene layer for economizing storage space and decreasing computing time.As shown in chniques . The comα = 0, the bandwidth of resonance is disappearing, and the Q-factor is theoretically infinite. Then, when α = 50, a high Q-factor (4719) narrow dip with an asymmetric line shape at 1415.68 nm, that is a quasi-BIC mode appears in the transmission spectrum, which can be well fitting by the Fano formula based on the temporal couple-mode theory [t and r are the transmission and reflection coefficients with t2 + r2 = 1. Moreover, the wavelength of the quasi-BIC mode is decreased and red-shifted with the increase of α, as shown in α, which leads to the decrease of Q-factor of the quasi-BIC mode with the increase of α, as shown in Firstly, we consider the transmission characteristics of the proposed metasurface shown in Q-factor 19 narrowFE of graphene layer when α = 75. As shown in FE = 0.8 eV is introduced, the transmission dip is slightly red-shifted. Meanwhile, the dip becomes flat and broadens with the decrease of FE, which means the Q-factor is also clearly decreased. Thus, the proposed hybrid graphene/silicon/silica metasurface can be used as the efficient optical modulator by changing the FE of graphene, which can be dynamically manipulated by employing bias voltage.To manifest the performance of this optical modulator based on the quasi-BIC, we compare the transmission spectra of the dielectric metasurface without and with different FE according to Equation (1), which is shown in FE is decreased from 0.8 eV to 0.5 eV. However, the imaginary conductivity of graphene is positive when FE = 0.8 eV, which leads to the metallic behavior of graphene; the imaginary conductivity of graphene becomes negative when FE = 0.5 eV, which causes graphene to behave like a lossy dielectric [FE is decreased from 0.8 eV to 0.5 eV, the real conductivity of graphene grows fast at the resonance wavelength, which means the increase of absorption of graphene [ħ is the reduced Planck constant ε0 and siε are the permittivity of free space and silicon, respectively, gV is applied bias voltage, e is the electron charge, and h1 is the thickness of square split-rings. Thus, the Fermi energy of graphene is increased with bias voltage, and there is a trade-off between the value of bias voltage and the extinction ratio of the proposed modulator. However, the bias voltage required to increase the Fermi energy of graphene to 0.5 eV to 0.8 eV is about 17.393 V, and this power consumption is not large in practical applications. Thus, the proposed modulator can still play an important role in practical applications. Significantly, the real conductivity of graphene increases with the amount of EF of graphene in the THz band, which represents the opposite trend for the near-infrared regime. Significantly, the real conductivity of graphene increases with the amount of FE of graphene in the THz band, which represents the opposite trend for the near-infrared regime. For this reason, some researchers designed and investigated the graphene-based modulator by setting the high conductivity of graphene in the THz band [To explain this phenomenon, we calculate the wavelength dependent conductivity of graphene with different electric . Moreovegraphene . Since tgraphene , the redgraphene  EF≈ℏVF(πTHz band ,53.α = 75 for FE = 0.8 eV, 0.5 eV, and 0.1 eV, respectively, and calculate the absolute value of the transmission difference T1 can reach 58.2% at the resonance wavelength of 1421.31 nm. Thus, an effective and adjustable amplitude modulator can be realized in the near-infrared regime, which can provide potential applications in biosensor and communication.Then, in order to better investigate the tunability of the proposed modulator, we study the transmission of the structure when α to further look into the modulation effect of graphene on the quasi-BIC mode, as shown in α = 0, that is, there is no perturbation in the structure, the graphene with FE = 0.5 eV has a slight effect on the transmission spectrum. While the α is not equal to 0, that is, in the case of the perturbation, the quasi-BIC mode is excited in the structure, and the same graphene has a huge influence on the transmission spectrum. Furthermore, the max difference of transmission is changed to 0.92 at the wavelength of 1417 nm when α = 75. Even if α = 50, the max difference of transmission is 0.87 at the wavelength of 1416 nm, which means that a small α can achieve good modulation performance for our structure. This also shows its advantage in practical application.Next, we will consider the influence of asymmetry parameter FE of monolayer graphene, and the maximum difference in transmission up to 0.92 is realized. Moreover, we also discuss the influence of the asymmetry degree to further investigate the modulation effect of graphene on the quasi-BIC mode. Thus, we believe our results have potential applications in optical modulators, bio-chemical sensors, and optical filters.To conclude, a high Q-factor quasi-BIC-based optical modulator is proposed in the near-infrared regime, and the corresponding modulation performances are investigated by using the FDTD method, which can be well fitting by the Fano formula based on the temporal couple-mode theory. The results demonstrate that BIC will turn into the quasi-BIC with high Q-factor by breaking the symmetry of every unit of the metasurface. Meanwhile, the amplitude and bandwidth of transmission based on the quasi-BIC mode can be flexibly adjusted by changing the


Humidity sensors are important in industrial fields and human activities. Metal−organic frameworks (MOFs) and their derivatives are a class of promising humidity−sensing materials with the characteristics of a large specific surface area, high porosity, modifiable frameworks, and high stability. The drawbacks of MOFs, such as poor film formation, low electrical conductivity, and limited hydrophilicity, have been gradually overcome with the development of material science. Currently, it is moving towards a critical development stage of MOF−based humidity sensors from usability to ease of use, of which great challenges remain unsolved. In order to better understand the related challenges and point out the direction for the future development of MOF−based humidity sensors, we reviewed the development of such sensors based on related published work, focusing on six primary types , and others) and analyzed the sensing mechanism, material design, and sensing performance involved, and presented our thoughts on the possible future research directions. Humidity sensors play an important role in human health ,2,3,4, eIn recent years, MOF−based humidity sensors have received more and more attention . The maiThe structural characteristics of MOFs make them suitable for humidity sensing. Firstly, MOFs own a large specific surface area and high porosity ,51. The The working process of humidity sensors includes the adsorption of water molecules, signal conversion, signal transmission, and signal output, in which the adsorption of water molecules and the signal conversion and transmission process occurs in the sensing materials . When thA humidity atmosphere−providing system and a signal−receiving system are equally important for researching humidity sensors. Humidity atmospheres can be provided by saturated salt solutions , but thedryZ represents the impedance value of sensors in a dry atmosphere and wetZ represents the impedance value of sensors in a wet atmosphere. The sensitivity is defined as the ratio of the response and water concentration (response/water concentration). However, in some reported work, there is no strict distinction between response and sensitivity. The working range is defined as the humidity range within which humidity sensors can work normally (without affecting the accuracy and stability). Different working ranges correspond to different application scenarios Cl, and the sensing films were prepared on the electrodes in situ with click reaction .As well as in situ film formation on electrodes, mixing MOFs as fillers in polymers is also a good method to form high−quality sensing films. Ru et al.  reported2O3 with different morphologies and researched the humidity−sensing properties (2O3 with different morphologies showed different porosities (2O3−based humidity sensor with the largest specific surface area exhibited the highest response (1568) in 11–95% RH with a small hysteresis (0.59% RH) and a fast response (<2 s)  c–e.C represents the capacitance of the humidity sensors, S and d are the area and distance between the parallel plates, respectively, and k is the electrostatic force constant (9.0 × 109 N·m2/C2).Capacitive−type humidity sensors are another attractive class of sensors , where tWhen water molecules are adsorbed on the sensing materials, the dielectric permittivity of the materials becomes larger, resulting in the increased capacitance of the sensors. The most important factor is the water adsorption ability, and the testing frequency also influences the capacitance . Thanks 2O to 2.3 vol% H2O, the capacitance of the Fe−BTC sensor showed an increase of 4.4 pF. Liu et al. n . The capacitance of the sensor increased for more than five orders of magnitude when the humidity was higher than 40% RH, and showed no response to the temperature.Achmann et al.  reportedu et al.  preparedo et al.  reported3(BTC)2 film through the method of homogeneous nucleation. The hydrophilic linker and copper metallic oxygen clusters make Cu3(BTC)2 highly hydrophilic. The capacitance of the Cu3(BTC)2−based sensor increased from 130.6 pF to 253.6 pF with a hysteresis of <1% RH and a sensitivity of ~1.499 pF/% RH in the humidity range of 11.3–84.3% RH. Sapsanis’s group .4H2O, Ln = Eu, Tb). The pores of the Ln−MOFs were occupied by water molecules, and the fluorescence was quenched when the water molecules were removed and recovered after hydration. Mohapatra et al. ·nH2O) containing cyano groups. The introduced cyano group and carboxylic acid group can form hydrogen bonds with water molecules. The linear detection range of the Eu−MOF−based sensor was 0–100% RH with excellent recycle ability (at least 7000 s). Wang et al. ·7(DMF)}n. The reaction between the DPNDI group and water molecules affected the electronic transfer in the MOF, resulting in solvatochromism  of MOFs during photoluminescence. The introduction of color−changing functional groups, encapsulation of guests, and introduction of multiple emission centers in MOFs may be beneficial to the ratiometric detection of water. Drache et al.  reportedchromism a. The Coependent b–d.3CN·MeOH·1.5H2O⊂Cu2(L)2I2). Since the structural parameters of the MOF changed under the action of humidity, different guests (H2O or DMF) were encapsulated. The MOF−based sensor showed different degrees of color changes under humid atmospheres (33–57% RH) and the color was time−dependent. Yin et al. ·0.75H2O·1.75DMA  composites) by in situ polymerization. The porous nanostructure of the ZnCo2O4 and the swelling effect of PPy provide more water adsorption sites. The sensitivity of the QCM sensor was 58.4 Hz/% RH in the humidity range of 0–95% RH, with a small hysteresis (3.9% RH) and a fast response (8 s). Zhang et al. [2 QCM humidity sensors with three morphologies. Among them, the sensor with a hollow spherical morphology (the highest specific surface area) possessed the best sensing characteristics including high sensitivity (33.8 Hz/% RH), fast response (5 s), and good stability (>30 days). What is more, Chen et al. [2/chitosan (CS) nanostructure. The particle size of the SnO2 NPs was ~20 nm, which is beneficial to generate a large specific surface area. Therefore, the MOF−SnO2/CS−based QCM sensor exhibited a high sensitivity (~43.14 Hz/% RH) to humidity change (0–97% RH).MOF derivatives were also utilized in QCM−type humidity sensors. Zhang et al.  preparedg et al.  preparedn et al.  preparedMOF−based electrically transduced humidity sensors, fluorescent−type humidity sensors, and QCM−type humidity sensors are able to detect humidity in most application scenarios. In addition, the MOF−based humidity sensors used in some special conditions still need to be researched . There are several types of MOF−based humidity sensors that can be used in special scenarios .Optical fiber has the advantages of anti−electromagnetic interference and corrosion resistance, and has been widely used in the detection field ,155,156.2  in the humidity range of 20–90% RH, with a resolution of 0.1% RH, a sensitivity of 0.119 nm/% RH, and an ultrafast response speed (0.1 s)  d. Chen e3O4. The changes in the electrical conductivity and dielectric properties of the sensor after adsorbing water can be detected by the microwave resonator. The sensor showed a sensitivity of 3.40 MHz/% RH in a wide humidity change (5–99% RH) with a fast response (<5 s).Microwave sensors are highly compatible with other circuit modules and are sensitive to environmental changes or the electromagnetic property changes of surrounding materials , making Surface acoustic wave (SAW) sensors are also used in humidity sensing . When thFor a qualitative indication of water molecules, Ullman et al.  fabricatAs summarized above, with the development of material science, the humidity−sensing performance indexes of MOF−based humidity sensors have been greatly improved. Different types of humidity sensors own different technical characteristics, while different applications have different requirements. In order to find the most suitable type of humidity sensor to meet the actual requirements, it is reasonable to compare the sensing performance indexes of the different types of MOF−based humidity sensors .Among all types of MOF−based humidity sensors, impedance−type humidity sensors possess smaller hysteresis, better linearity, and a shorter response time, but the structure of this type of sensor restricts their application in detecting water molecules in liquid media. Capacitive−type humidity sensors can detect low concentrations of water molecules, but with worse linearity, and resistive−type humidity sensors have the characteristic that can work under direct current with a fast recovery time. Fluorescent−type humidity sensors are widely used in the detection of water molecules in solvents, but the poor circulation, linearity, and long response time limit their wider application. QCM−type humidity sensors can be used for low humidity detection, although their poor selectivity, the difficulties in miniaturizing and integrating them, and their high cost limit their application scenarios. Fiber−optic−type humidity sensors can achieve high resolution humidity detection with high stability, but the special materials, high cost, and low sensitivity limit their application.In summary, the research on humidity sensors based on MOFs has made promising progress in recent years. The impedance−type, capacitive−type, resistive−type, fluorescence−type, QCM−type, and other types of humidity sensors based on MOFs have been successfully prepared. There are some common and unique features among the different types of MOFs−based humidity sensors.(1)Strong hydrophilicity. When the detection takes place in a low humidity range, strong hydrophilicity can help the sensor to operate effectively, and when the detection is in full humidity range, strong hydrophilicity can make the sensor more sensitive.(2)High porosity. The adsorption and diffusion of water molecules and the transmission of electron signals all require channels, and the selectivity of sensors can also be improved by the design of the channels.(3)Adjustable structure. One of the most attractive features of MOFs among humidity−sensing materials is the adjustable structure, which allows researchers to prepare MOFs for different requirements .(4)Good stability. For practical and user−friendly humidity sensors, reliability and recyclability are necessary. The structural stability of MOFs is the premise of stable sensors.Similarities:(1)Connection. For electrically transduced humidity sensors, a good connection is needed. The adsorption, diffusion, signal conversion, conduction, and device fabrication of water molecules all put forward a higher connection in sensing films.(2)Conductivity. For electrically transduced humidity sensors and SAW sensors, the changes in conductivity caused by the adsorbed water molecules can be converted into readable signals.(3)Luminescence. For fluorescent MOF−based humidity sensors, the luminescent property was influenced by metal centers and ligands. Specifically, metal centers influence the intensities, the position of emission peaks, and the emission colors, and ligands also show influence in charge transfer or host−guest interaction.(4)Optical properties. For MOF−based fiber−optic humidity sensors, the change of refractive index is very important, which requires the optical performance of MOFs.Differences:In addition, there are still many worthwhile directions to be pursued for researchers in material design and device development.(1)How to combine characterization, data, and simulation calculations to reveal the in−depth sensing mechanism of MOF−based humidity sensors and understand the structure−performance relationship.(2)How to screen existing MOFs or predict potential MOFs as sensitive materials for humidity sensors based on their structural or fundamental properties.(3)How to develop humidity−sensitive MOFs with better performance in extreme environments .(4)How to further improve the selectivity of MOF−based humidity sensors.These challenges are ubiquitous and need to be addressed urgently in MOF−based humidity sensors. The in−depth research of these issues will provide new understanding and strategies for the development of MOF−based humidity sensors.


Circulating soluble programmed death ligand 1 (sPD-L1) can negatively regulate T-cell function and serve as a prognostic or predictive marker in a variety of cancers. However, rare studies have evaluated the potential roles of sPD-L1, and no study has estimated its predictive value for the efficacy of immune treatment in colorectal cancer (CRC).Plasma samples from 192 CRC patients were used to estimate correlations between clinicopathological features and sPD-L1, secreted PD-L1 (secPD-L1) and exosomal PD-L1 (exoPD-L1). Baseline and posttreatment sPD-L1 levels were also investigated in 55 patients with metastatic CRC (mCRC) treated with chemotherapy ± targeted therapy and 40 patients with proficient mismatch repair (pMMR) mCRC treated with combination immunotherapy. Both sPD-L1 and secPD-L1 were quantified by enzyme-linked immunosorbent assay, while exoPD-L1 was analyzed using flow cytometry.secPD-L1 was the major component and positively correlated with sPD-L1 in CRC, while exoPD-L1 was almost undetectable. Higher levels of sPD-L1 were detected in patients with distant metastasis, especially those with distant lymph node metastasis and tissue combined positive score (CPS) instead of tumor proportion score (TPS). Chemotherapy or targeted therapy did not significantly impact sPD-L1 concentration. Progressive disease on combination immunotherapy was associated with an increase in sPD-L1 level, whereas no significant change was observed in patients with durable clinical benefit.sPD-L1 mainly consisted of secPD-L1, and its level was higher in patients with distant metastasis, especially distant lymph node metastasis and positive CPS. sPD-L1 is a potential dynamic marker to identify rapid progression on combination immunotherapy and avoid ineffective treatment for pMMR CRC.The online version contains supplementary material available at 10.1186/s12967-023-03879-0. Growing evidence suggests that blocking the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway offers promising efficacy and prolonged survival in multiple types of tumors. While PD-1/PD-L1 monotherapy has revolutionized the treatment of deficient mismatch repair (dMMR) colorectal cancer (CRC) , its comPD-L1 can be expressed on the membranous surface of multiple cells, including tumor cells, immune cells and other cells in the tumor microenvironment (TME) . PD-L1 iRecently, soluble forms of PD-L1 (sPD-L1), which include exosomal PD-L1 (exo-PD-L1) and secreted splice variants (secPD-L1), have been identified in the peripheral blood and proven to inhibit the functions of T cells, meditate tumor evasion, and promote tumor progression . sPD-L1 Limited studies have evaluated the role of sPD-L1 in CRC. Recently, three alternative splicing isoforms of secPD-L1 have been identified and their functions were assessed in a preclinical model of CRC . In contIn this study, we aimed to analyze the association between sPD-L1 and clinicopathological features, including tissue PD-L1 IHC staining. We further explored the dynamic changes during systemic therapy and their predictive value for combination immunotherapy in CRC.The study enrolled a total of 232 patients Fig.  admittedPeripheral blood samples were collected into EDTA tubes and isolated cell-free plasma samples were stored at – 80 ℃.The response was assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 . Durableg for 20 min at 4 ℃, 2000 × g for 15 min at 4 ℃ and then 12,000 × g for 30 min at 4 ℃. The collected supernatant was ultracentrifuged at 200,000 × g for 2 h at 4 ℃ . The supernatant was collected as secPD-L1. The pellet was washed with 1 mL of PBS and followed by a second ultracentrifugation at 200,000 × g for 2 h at 4 ℃. The supernatant was discarded and the exosomes were resuspended in 100 µL of PBS.Thawed plasma samples (1 mL) were differentially centrifuged at 360 × The size and concentration of exosomes were detected by nanoparticle tracking analysis (NTA) using a NanoSight NS300 instrument . The morphology of exosomes was examined using transmission electron microscopy. The isolated exosomes were placed on a copper grid and negatively stained with uranyl acetate. Images were acquired using a JEM-1400 (JEOL) at 80 kV voltage.Exosome lysates were obtained by adding radioimmunoprecipitation assay (RIPA) buffer with protease inhibitors and the protein concentration was determined by BCA protein assay kit (Thermo Scientific). Approximately 20 μg of total exosome protein was electrophoresed on a 10% sodium dodecyl sulfate–polyacrylamide gel and electrotransferred onto a PVDF membrane (Millipore). The membrane was blocked with 5% milk for 2 h, incubated overnight at 4 ℃ with antibodies specific for PD-L1 , TSG-101  and CD63 , and the incubated with a horseradish peroxidase-conjugated secondary antibody. The blots on the membrane were developed with ECL detection reagents (Pierce) and captured using Chemidoc MP (Bio-Rad).sPD-L1 and secPD-L1 concentrations were measured using an enzyme-linked immunosorbent assay  in accordance with the manufacturer’s instructions. The detection range was from 7.81 pg/mL to 500 pg/mL and measurements below the detection limit were recorded as “7.81 pg/mL”.The staining method used for flow cytometry of exosomes coupled to beads was modified based on the methods described by Morales–Kastresana  and TheoFormalin-fixed paraffin-embedded (FFPE) tissue containing histologically confirmed colorectal cancer was retrieved and subjected to immunohistochemistry (IHC) staining with an anti-human PD-L1 monoclonal antibody  to assess PD-L1 expression. Tumor proportion score (TPS)  ≥ 1% and combined positive score (CPS)  ≥ 10 were considered “positive” in our study.Categorical variables were compared by the chi-square test or Fisher’s exact test. Continuous variables were compared using the Mann–Whitney test, the Kruskal–Wallis test or the Wilcoxon matched-pairs test. Survival data were estimated by the Kaplan–Meier method and tested the difference was tested by the log-rank test. Correlations were determined by the Spearman coefficient. Cutoff values for continuous variables were determined based on the Receiving Operating Curve (ROC) method. A two-tailed p value  < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS statistical software  and GraphPad Prism 9 software.We first isolated secPD-L1 and exoPD-L1 Fig. a from 30To assess the levels of different forms of plasma sPD-L1 in CRC, we first enrolled 68 patients with stage I–III CRC. The levels of sPD-L1 and secPD-L1 were measured by ELISA. The secPD-L1 concentration significantly correlated with the sPD-L1 concentration, while no correlation was found between the levels of exoPD-L1 and sPD-L1 Fig. c. CorrelTo evaluate the role of sPD-L1 in metastatic pMMR CRC, we enrolled 124 patients and investigated the correlation between sPD-L1 concentration and clinical features mainly metastatic sites Table a. Among Among 124 patients with mCRC, 55 patients received first-line treatment at our hospital with response assessment available. Patients were treated with FOLFOXIRI + bevacizumab (n = 28), mFOLFOX6 + bevacizumab (n = 14), mFOLFOX6 + cetuximab (n = 7), FOLFIRI + bevacizumab (n = 2) and mFOLFOX6 (n = 4). No significant dynamic changes were observed after systemic therapies . The baseline clinical characteristics are displayed in Additional file In this study, we evaluated correlations between soluble forms of PD-L1 and clinicopathological features and assessed the dynamic changes after systemic treatment. To date, limited studies have assessed different soluble forms of PD-L1 in cancer, and controversial results have been reported. exoPD-L1 is more abundant than secPD-L1 in the plasma of melanoma patients . A similsPD-L1 did not correlate with any clinicopathological features in our study, while a previous study revealed that only lymphatic invasion was negatively associated with sPD-L1 in stage I–III CRC patients . InteresJAMA Oncology revealed that tissue CPS, instead of TPS, is the strongest predictor of immunotherapy response in advanced gastroesophageal adenocarcinoma [Several studies have estimated the correlation between tissue PD-L1 expression and sPD-L1 concentration and obtained controversial results. sPD-L1 levels have been revealed to not correlate with tumor PD-L1 expression in lung cancer , 39, braarcinoma . Interesarcinoma . A previarcinoma . Thus, P+ T cells and dendritic cells discriminated non-responders to checkpoint blockades while exoPD-L1 secreted from B cells and monocytes had no obvious significance in that regard [The dynamic changes of sPD-L1 after drug exposure have rarely been estimated. Increased sPD-L1 levels were observed after radiotherapy , 41, 56 t regard . Even dit regard . TherefoThere are also some limitations in our study: First, previous studies have suggested that soluble PD-L1 has the potential to function as an early marker to predict the response to immunotherapy. However, we did not collect dynamic samples at cycle 2 or 3 to fully estimate the predictive role of sPD-L1. Second, limited samples were included in our analysis to estimate the composition of different forms of soluble PD-L1 and the dynamic changes after systemic therapy and immunotherapy. Only seven non-responders to chemotherapy ± targeted therapy were included, complicating the analysis of the discrimination for different responses. Third, the isolation method used in our study was ultracentrifugation, which may have accounted for the loss of PD-L1 on exosomes. Despite the aforementioned limitations, our study provided some detailed descriptions of the correlations between sPD-L1 and clinicopathological features. Our study for the first time revealed a positive correlation of sPD-L1 with distant lymph node metastasis and tissue CPS. Moreover, we identified a dynamic biomarker to predict the efficacy of combination immunotherapy in pMMR mCRCs for the first time. As a dynamic marker, sPD-L1 overcomes the limitations (failing to identify pseudoprogression and delayed response) of traditional radiological assessment in immunotherapy. sPD-L1 may help to identify rapid progression on combination immunotherapy to avoid ineffective treatment, but studies of larger cohorts are warranted to further determine whether an early increase in sPD-L1 level at C2 may identify non-responders.Additional file 1.Figure S1. Pretreatment of sPD-L1 level and genomic alterations from 54 patients with metastatic colorectal cancer. The plot is modified from an open-source template (https://github.com/ptgrogan/excel-oncoplot). Table S1. Correlations between different forms of soluble PD-L1 and clinicopathological features in patients with stage I-III pMMR colorectal cancer. Table S2. Baseline clinical characteristics of patients with proficient mismatch repair (pMMR) colorectal cancer treated by regorafenib combined PD-1 inhibitor.


Azadirachta indica (A. Juss), also known as the neem tree, has been used for millennia as a traditional remedy for a multitude of human ailments. Also recognized around the world as a broad-spectrum pesticide and fertilizer, neem has applications in agriculture and beyond. Currently, the extensive antimicrobial activities of A. indica are being explored through research in the fields of dentistry, food safety, bacteriology, mycology, virology, and parasitology. Herein, some of the most recent studies that demonstrate the potential of neem as a previously untapped source of novel therapeutics are summarized as they relate to the aforementioned research topics. Additionally, the capacity of neem extracts and compounds to act against drug-resistant and biofilm-forming organisms, both of which represent large groups of pathogens for which there are limited treatment options, are highlighted. Updated information on the phytochemistry and safety of neem-derived products are discussed as well. Although there is a growing body of exciting evidence that supports the use of A. indica as an antimicrobial, additional studies are clearly needed to determine the specific mechanisms of action, clinical efficacy, and in vivo safety of neem as a treatment for human pathogens of interest. Moreover, the various ongoing studies and the diverse properties of neem discussed herein may serve as a guide for the discovery of new antimicrobials that may exist in other herbal panaceas across the globe. The need to expand the available pharmaceutical repertoire is underlined by several recent reports, including the 2019 Antibiotic Resistance Threat Report by the Centers for Disease Control and Prevention; this document states that in the United States alone, more than 2.8 million antibiotic-resistant infections and more than 35,000 related deaths occur each year . These fin vitro synergistic activity with existing antibiotics when used against two multidrug-resistant enteric bacterial species , commonly known as the neem tree, is a tropical evergreen tree that is native to the Indian subcontinent  have been used as house-hold remedies for human illnesses. Moreover, millions of people globally use neem twigs as a source of chewing sticks for dental hygiene  . In recein vitro activities of these compounds and others isolated from neem seed oil have been reviewed and range from anti-inflammatory and antiulcer to spermicidal and anti-psoriasis , many of which have been found to be bioactive and to have diverse utility on their own. Out of the more than 300 unique compounds have been identified within the neem tree, some of the more abundant phytochemicals  have already been defined as potential drugs with a wide range of biological activities . The comsoriasis . Two recin vitro methods such as broth dilution, disc or agar diffusion, and agar overlay assays are commonly used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of each treatment. A few in vivo models have been implemented to more accurately reflect human infection and disease testing; these models include intraperitoneal or intravenous injection, or oral or gastric administration of neem oil-related drugs in mice, rats, guinea pigs, and rabbits. These published animal studies indicate that the acute toxicity level of neem greatly depends on the plant component and solvent used to make the extract, as well as on the treatment route and species used in the model; for a comprehensive review on this topic, see  model is a reliable method to assess the acute in vivo toxicity of medicinal plants, in which ethanolic extracts of neem leaves and seeds had higher levels of toxicity than aqueous extracts of the same materials. Although the available in vivo data will need to be further developed before neem oil extracts and phytochemicals are applied in a clinical setting, the United States Environmental Protection Agency has stated that cold-pressed neem oil should have “no unreasonable adverse effects to the US population and the environment”  and C. albicans in vitro or ex vivo , Acacia tree , Cinnamomum verum (cinnamon), Salvadora persica (miswak), Syzygium aromaticum (clove), Zingiber officinale (ginger), Allium sativum (garlic) and Curcuma longa (tumeric) extracts against some species of bacteria and cultured dental caries  appear to be more susceptible to extracts from other plants in some studies  the ability of neem oil to prevent the growth of the grape product-spoiling species Aspergillus carbonarius and to inhibit the production of mycotoxin by strains of this fungus  . The ressubtilis . Furthers fungus , 2) the nd maize , 3) the  storage , 4) the  72–100% , and 5)  in vivo . These dA. indica has been shown to be effective against many important human pathogens. Overall, a large number of studies have been published in the last decade on this topic, especially as they relate to the ever-growing number of antibiotic-resistant organisms. In this vein, several bacterial species that cause wound infections are found on the long list of antibiotic resistant threats, including S. aureus and P. aeruginosa  produce extracts that have moderate to significant levels of antimicrobial activity against several pathogens: S. aureus, E. coli, E. faecalis, P. aeruginosa, Salmonella typhi, Streptococcus agalactiae, Shigella boydii, B. subtilis, Klebsiella pneumoniae, and Candida tropicalis, as listed in A. indica-based components often show superiority to other plants; a few exceptions include aqueous garlic extract and ethanolic green tea extract that were each shown to work better than neem extracts to kill Bacillus anthracis or S. aureus and E. coli, respectively  components , are notably recalcitrant to outside stressors, including those from the immune system and from therapeutics . Dependim agents . Additiom agents .S. aureus, E. faecalis, and P. aeruginosa  biofilm adherence at 62.5 and 125 μg/ml, respectively  and minimum biofilm eradication concentrations (MBEC) for this extract were 100 and 300 μg/ml, respectively, against S. aureus and 300 and 500 μg/ml, respectively, against V. cholerae  annually . Althougfections , have bepatients . FurtherRT alone . To addrA. indica. For example, the glycolipid sulfonoquinovosyldiacylglyceride (SQDG) that has been isolated from neem leaves was shown to have potent antiviral activity against HSV-1 and -2; the half maximal effective concentrations (EC50) were 9.1 and 8.5 μg/ml, respectively. The same study also found that HSV-infected, SQDG-treated macrophages produced significantly less proinflammatory cytokines than untreated controls  most commonly cause oral and genital infections, with an estimated half a billion people living with HSV type 2 and nearly four billion people with HSV type 1 in any given year . Becausecontrols . It has  viruses . Concurr viruses . Additioin vitro . The prein vitro assays with promising candidates revealed that kaempferol 3-O-β-rutinoside and epicatechin were able to inhibit DENV-2 infectivity by 77.7% and 66.2%, respectively, without significant cell toxicity  protein of influenza. Though requiring further testing, this may indicate the ability to act as a universal drug against the flu virus  should be further explored in clinical trials for their antimalarial capacity.Although the area of research regarding ach year . While tach year . Studies strains . These pd so far . Despitenfection . The ges of pups . Additiol trials . Another malaria . Providiin vitro and in vivo  the application of individual neem phytochemicals and derivatives thereof as antimicrobial agents alone or used in combination with existing treatments, 2) additional pre-clinical and clinical studies to determine the toxicity and effective in vivo dosing of specific phytochemicals as compared to parent neem extracts, and 3) the inclusion of hundreds of available medicinal plant products, extracts, and phytochemicals in screens for potential inhibitors of emerging and resistant infectious diseases. It is important to note that to gain maximal utility from these areas of research, close attention should be paid to the types of extracts (including both the particular part of the plant and the solvent) that have already been tested against which organisms. Some level of standardization should be considered so that comparisons can be made and patterns can be recognized across multiple studies. This may become easier when the antimicrobial activities of more individual phytochemicals are determined. En masse, A. indica represents a novel source of antimicrobials that may be used to combat drug resistance and emerging threats to human health. Furthermore, the research that has been done on the neem tree can be used as a guide to encourage the investigation of other traditionally used natural products for their utility as modern pharmaceuticals.In order to develop realistic


The rising prevalence of gestational diabetes mellitus (GDM) calls for the use of innovative methods to inform and empower these pregnant women. An information chatbot, Dina, was developed for women with GDM and is Norway’s first health chatbot, integrated into the national digital health platform.The aim of this study is to investigate what kind of information users seek in a health chatbot providing support on GDM. Furthermore, we sought to explore when and how the chatbot is used by time of day and the number of questions in each dialogue and to categorize the questions the chatbot was unable to answer . The overall goal is to explore quantitative user data in the chatbot’s log, thereby contributing to further development of the chatbot.An observational study was designed. We used quantitative anonymous data  from the chatbot’s log and platform during an 8-week period in 2018 and a 12-week period in 2019 and 2020. Dialogues between the user and the chatbot were the unit of analysis. Questions from the users were categorized by theme. The time of day the dialogue occurred and the number of questions in each dialogue were registered, and questions resulting in a fallback message were identified. Results are presented using descriptive statistics.P=.013). The chatbot was able to answer 88.51% (2512/2838) of all posed questions. The mean number of dialogues per week was 36 in the first period and 26.83 in the second period.We identified 610 dialogues with a total of 2838 questions during the 20 weeks of data collection. Questions regarding blood glucose, GDM, diet, and physical activity represented 58.81% (1669/2838) of all questions. In total, 58.0% (354/610) of dialogues occurred during daytime (8 AM to 3:59 PM), Monday through Friday. Most dialogues were short, containing 1-3 questions , and there was a decrease in dialogues containing 4-6 questions in the second period (Frequently asked questions seem to mirror the cornerstones of GDM treatment and may indicate that the chatbot is used to quickly access information already provided for them by the health care service but providing a low-threshold way to access that information. Our results underline the need to actively promote and integrate the chatbot into antenatal care as well as the importance of continuous content improvement in order to provide relevant information. Gestational diabetes mellitus (GDM) is defined as glucose intolerance that arises and is discovered during the second or third trimester of pregnancy . GloballUse of information and communications technology has the potential to improve public health by increasing efficiency, lowering costs, and improving quality of care . DiffereHealth technology solutions such as chatbots are rarely implemented in health care after the initial pilot study phase . Previou Further specific aims are to explore how many questions each dialogue contains and the time of day the chatbot is used. We subcategorized questions that led to a fallback message from the chatbot to obtain a deeper understanding of which type of questions the chatbot was unable to answer. This knowledge may provide insight into the use of health chatbots and potentially establish more general theoretical knowledge on this type of chatbot.Our study aim is to provide a basis for improvement and further development of Dina the chatbot by exploring log data on what type of information the users’ seek, with the research question being as follows: What type of information do users seek in a health chatbot providing support on GDM?In 2016, a pilot study for the project revealed an incoherent follow-up and lack of personally adapted information provided to women with GDM. Contrary to current practice when promoting health technology solutions , Dina thQuestions from users to the chatbot were categorized see , and allWe identified the time of day that dialogues took place and the number of questions in each dialogue.The time of day the dialogue took place was grouped into day (8 AM-3:59 PM), afternoon (4 PM-11:59 PM), and night (midnight-7:59AM), while the number of questions in each dialogue was categorized into 1-3, 4-6, 7-9, and ≥10 questions. We registered the frequency of questions the chatbot was unable to answer that resulted in a fallback message from the chatbot . Questions resulting in a fallback message were subcategorized and counted numerically see  to explot tests were used for comparisons of means. Results are presented visually in charts [The unit of analysis was the individual dialogue. Dialogues were manually registered and thoroughly read by the first author (MHS). In dialogues, users could either type their questions in free text or click theme buttons. Dialogues could therefore consist of free-text questions, theme button questions, or a mix of the 2. All dialogues are displayed the same way in the chatbots log, making it impossible to distinguish between the predefined questions and free-text questions. Therefore, it was not possible to determine if a user chose to spell “blood sugar” in free text or if they pressed the theme button “blood sugar.” Both free-text questions and predefined questions were counted as a whole, but questions that led to fallback would naturally be free-text questions, as the chatbot offers answers to the questions that are predefined. Differentiation between free-text and theme button questions will be considered in the future development of the chatbot. Variables were coded as nominal or interval. We used descriptive statistics: frequencies, proportions, and percentages. For continuous variables, we have reported mean as the central tendency with SD. Normal distribution was tested by Q-Q plot. Chi-square tests were performed to explore associations between variables, and independent n charts . IBM SPSThis study was conducted as a collaboration between Haukeland University Hospital, Western Norway University of Applied Sciences, and Bergen municipality. The chatbot’s platform and technological design have been validated in a risk and vulnerability analysis by the technical department at Haukeland University Hospital, and users’ data are protected according to the General Data Protection Regulation . Data arA total of 610 dialogues containing 2838 questions were registered during data collection. In the first period, 288 dialogues were registered, containing 1329 questions, while in the in the second period, 322 dialogues were registered, containing 1509 questions.Questions by category and period are presented in P<.001). The remaining categories involving screening for GDM , birth and postpartum period, treatment (medications), general information concerning the pregnancy, informational videos, and questions on social health benefits represented 17.58% (499/2838) of questions.Questions on blood glucose, diet, the GDM diagnosis, and physical activity accounted for 58.81% (1669/2838) of all questions, with little variation by period. The most frequent single category was questions on blood glucose levels, accounting for 24.07% (683/2838) of all questions. Questions on maneuvering and orienting in the chatbot (information about the chatbot) decreased from 18.28% (243/1329) in the first period, to 6.69% (101/1509) in the second period  and 26.8 (SD 24.34) for the first and second period, respectively. The dialogues by day of the week and time of day for the 2 periods combined are presented in In total, 90.7% (553/610) of all dialogues took place Monday through Friday, and 58% (354/610) took place during the daytime (8 AM-3:59 PM). The dialogues registered during the afternoon accounted for 28.2% (172/610) of dialogues Monday through Friday. There was little registered activity during weekends.The number of questions in each dialogue ranged from 1 to 38, with a mean value of 4.65 for the 20 weeks of registration. Short dialogues (1-3 questions) were most frequent, both in the first  and second period . Long dialogues of >7 questions were stable across the 2 periods.There was a decrease in number of dialogues containing 4-6 questions from the first period  to the second period  of all questions asked by users. P=.002), while the fallback questions the chatbot did not understand decreased from 32.1% (50/156) to 18.2% . Fallback questions about pregnancy in general and nonsensical questions showed small variations between the 2 periods.Fallback questions on GDM increased from 26.3% (41/156) to 42.4% (72/170) from the first to the second period (Nearly 60% (1669/2838) of all questions from users were on blood glucose, diet, GDM, and physical activity, and the chatbot was able to answer 88.51% (2512/2838) of all posed questions. The chatbot was most frequently used during the daytime, Monday through Friday, and most dialogues were short, containing 1-3 questions. However, the mean number of dialogues per week was 36 in the first period and 26.83 in the second period.Few prior studies have evaluated health chatbots based on log reviews . InksterDespite some unanswered questions, we found that exploring user behavior in the chatbot will provide useful information for planning and organizing future antenatal care. A previous study on a comparable supportive chatbot developed for patients with breast cancer explored user behavior by asking a weekly question and by observing the retention rate among users . As all As there is currently a lack of a standardized methods for evaluating health chatbots, a comparison of chatbots performances may be challenging ,28. In gDespite the fact that Dina the chatbot was integrated into the Norwegian digital health platform and made available for all pregnant Norwegian women between the 2 periods of registration, we found that the weekly mean number of dialogues was 36 in the first period and 26.83 in the second period. Although this change was not significant, it could be explained by a possible insufficient promotion of the chatbot among both pregnant women and health care personnel . PreviouAs the chatbot currently does not provide users with the opportunity to express if they are satisfied with the answer, we used the percentage of questions that the chatbot was unable to answer  as a measure of how well it operates. Our findings showed that a fallback message was given in 11.49% (326/2838) of all questions asked to Dina the chatbot. The goal is to keep the percentage of fallback as low as possible in order to meet user satisfaction . In a prThere are several challenges when it comes to integrating this type of new technology into the established health care . StudiesThe strengths of this study are its use of the chatbot log data from 2 different periods during the course of continuous development and maintenance of the chatbot . UtilizaOur findings indicate that users seek information on topics relevant to them at the time, such as blood glucose, diet, and physical activity, and that the most frequently asked questions mirror the cornerstones of GDM treatment. This may indicate that the chatbot is used to quickly access information already provided to users by the health care service, but the chatbot offers a low-threshold way to access that information.Furthermore, results indicate that Dina version 2.0 guides the user in a more efficient way. However, the low mean number of dialogues per week in the second period (26.83) suggests further efforts should be put into promoting and integrating the chatbot into Norwegian antenatal care. We view our findings as potentially relevant to future development of informational and supportive health chatbots. The authors finds a low-threshold design is an advantage, as this will provide easy access to information the user is also provided through other channels in the health service to further support self-efficacy. As our society quickly becomes more digital, there is a call for the health care service to keep up with the rapid development . We see The majority of posed questions pertained to blood glucose, diet, the GDM diagnosis, and physical activity, and the chatbot was able to answer about 9 out of 10 of all questions from the users. The most frequent use was during the daytime, Monday through Friday, and the majority of dialogues were short, containing 1-3 questions. However, the mean number of dialogues per week was 36 in the first period and 26.83 in the second period.


Residence at moderately high altitude and its relationship with WHO Group 1 pulmonary arterial hypertension symptom severity and clinical characteristics: the Pulmonary Hypertension Association Registry.Shoaib Fakhri, Kelly Hannon, Kelly Moulden, Ryan Peterson, Peter Hountras, Todd Bull, James Maloney, Teresa De Marco, Dunbar Ivy, Thenappan Thenappan, Jeffrey S. Sager, John J. Ryan, Sula Mazimba, Russel Hirsch, Murali Chakinala, Oksana Shlobin, Matthew Lammi, Dianne Zwicke, Jeffrey Robinson, Raymond L. Benza, James Klinger, Daniel Grinnan, Stephen Mathai and David Badesch; on behalf of the PHAR Investigators.https://doi.org/10.1177/2045894020964342.Pulmonary Circulation, 10 (4), 2020. DOI: An error was reported to us by the PHAR registry in coding that has impacted data interpretation on one of our quality of life metrics, the SF‐12.The coding error failed to reverse code responses for four of the twelve SF‐12 questions. All twelve questions are used (in different proportions) to calculate both the mental and physical SF‐12 scores. The reverse coding error impacts both the physical and mental SF‐12 scores, although in different proportions.Participant responses to questions are coded on a scale of one to five, where one is the worst outcome, and five is the best outcome. The four questions below should have been reverse coded to follow the same scale.Participant answers are preserved and accurate; however, the coding of the data for certain questions was written in error. We have rerun our analysis.The results are qualitatively the same as in our published paper . The p‐value is lower but still insignificant.Since multiple imputation is used for missing data, the slight change in the SF‐12 score impacts imputed values for other covariates, which then causes very slight changes to all the other numbers in the report. Again, no qualitative differences.A PHAR data update was released post‐publication. Analysis was re‐run on the updated data, results/conclusions did not substantively change.We apologize for the error.


The present paper investigates droplet and aerosol emission from the human respiratory function by numerical and experimental methods, which is analyzed at the worst-case scenario, a violent sneeze without a face covering. The research findings develop the understanding of airborne disease transmission relevant to COVID-19, its recent variants, and other airborne pathogens. A human sneeze is studied using a multiphase Computational Fluid Dynamics (CFD) model using detached eddy simulation coupled to the emission of droplets that break up, evaporate, and disperse. The model provides one of the first experimental benchmarks of CFD predictions of a human sneeze event. The experiments optically capture aerosols and droplets and are processed to provide spatiotemporal data to validate the CFD model. Under the context of large random uncertainty, the studies indicate the reasonable correlation of CFD prediction with experimental measurements using velocity profiles and exposure levels, indicating that the model captures the salient details relevant to pathogen dispersion. Second, the CFD model was extended to study the effect of relative humidity with respect to the Wells curve, providing additional insight into the complexities of evaporation and sedimentation characteristics in the context of turbulent and elevated humidity conditions associated with the sneeze. The CFD results indicated correlation with the Wells curve with additional insight into features, leading to non-conservative aspects associated with increased suspension time. These factors are found to be associated with the combination of evaporation and fluid-structure-induced suspension. This effect is studied for various ambient air humidity levels and peaks for lower humidity levels, indicating that the Wells curve may need a buffer in dry climates. Specifically, we find that the increased risk in dry climates may be up to 50% higher than would be predicted using the underlying assumptions in Wells’ model. I.The ongoing COVID-19 pandemic has driven a need for research focus associated with the dispersion of respiratory droplets in daily life situations. This continues to be an issue due to the increasing number of vaccine breakthrough cases along with the occurrence of emerging virus variants of COVID-19. It is generally regarded that airborne transmission paths are associated with droplets and aerosols formed from sneezes, coughs, speech, and breathing.µm.µm, with limited improvement by using the toilet lid.The recent literature has analyzed a variety of theoretical and real-life situations to assess the virus transmission potential from a fluid-dynamic standpointPrevious investigations from the authors of this paper have further characterized the classroom setting with numerical methods.The present work is focused on the airborne droplet and aerosol emission paths while analyzing the worst-case event of the human respiratory function, a violent sneeze event without any face covering in use. This paper starts with the discussion of the difference between droplets and aerosols and what it means to transmission. This paper then discusses the experimental and numerical studies used in the effort. In Sec. IV, the simulated results are compared and validated with respect to measured velocities and exposure. Finally, the validated CFD model is used to simulate differing conditions of relative air humidity. Quantifying the effect of this ambient parameter could be key to further the understanding and control of airborne transmitted viruses, such as COVID-19.II.µm. The modern literature has measured and reported significantly higher numbers for the total expelled number, travel distance, and expulsion velocity of aerosols during a violent sneeze.d2-relations for the evaporation time (τEvap) and the settling time (τSed) for droplets are defined, respectively, as follows:d ≤ 50 µm) defines small droplets, a fraction that would certainly evaporate prior to complete sedimentation to the ground from a base level (y = 2 m). In contrast, the green-shaded area (d ≥ 100 µm) indicates the large droplet fraction. The latter would certainly fall completely with minor contribution of drying due to their small surface-to-volume ratio. The yellow-shaded area (50 ≤ d ≤ 100 µm) is affected similarly by both processes and could complete either falling or evaporation first depending on the ambient conditions. The cut-off size reported in Fig. 2(a) in Ref. µm. µm are shown to fall due to the low evaporation resistance of fully dry air. In humid conditions (90% relative humidity), the cut-off size was found at 60 µm. Fully saturated, moist air would theoretically not allow droplets of any size to evaporate; hence, a further reduction of that threshold could occur in real systems. Low temperatures and high relative humidity were shown to reduce the cut-off size, allowing more droplets to settle to the ground prior to complete drying.Fundamental historic studies by Wells,DtdD∼D02,τSed=y0gDµm occurs in conjunction with the medium–high relative humidity of practical systems. Larger droplets would reach the ground, whereas droplets below the size of 80 µm would fully evaporate prior to complete settling. Additionally, elevated relative air humidity could inhibit the droplet evaporation rates. Three-dimensional diffusive and dispersive effects, as well as any wind or venting-induced flow movement, could redirect the smaller droplets along the ±z directions and distract them from their ideal ballistic trajectory, which may lead to measured inconsistencies when sampling is done along the x and y coordinates. Both aerosols and smaller droplets could also be affected by a certain amount of thermal buoyancy, allowing the aerosols to stay suspended in air for minutes before sedimentation.Further decomposition of the system physics is provided in In summary, the resulting system behavior shows a strong sensitivity to the size of the droplet or aerosol. A smaller droplet diameter would reduce drag forces and sedimentation rates while enhancing three-dimensional diffusive and dispersive effects and other movement dictated by ambient system conditions. Additionally, smaller droplets evaporate faster due to their smaller volume and greater surface-to-volume ratio. A combination of the effects mentioned above explains the complexity of tracking the transmission hazard in systems with high aerosol percentage. Therefore, the present study is defined as a numerical and experimental investigation of the worst-case scenario of human droplet and aerosol emission, a violent sneeze without any face covering in use. The focus is set on the effect of relative humidity since this effect was reported to be among the key influencers on the real-life system. A state-of-the-art commercial CFD tool, Star-CCM+,III.A.et al.2 at a frame rate of 125 fps. The camera was aimed at an opaque, blacked-out curtain to serve as the background, while the test person sneezed perpendicular to the lens axis. All sneezes were recorded under minimal ambient light pollution and in a dust-free environment to minimize ambient particulate noise. The temperature of the room was maintained at 20 °C with 28% ambient relative humidity. The processing was done with ImageJThe experimental setup used for the study is based on the work of Reyes The x, y data from the imagery were processed in PIVlabB.2O phase change), as described in previous work.CFD simulation was developed to extract additional insight into the character and drivers of droplet/aerosol transport. The effort is utilizing a commercial CFD code, Star-CCM+, with an Eulerian–Lagrangian multiphase model. The physical scenario is modeled as an Eulerian multicomponent gas phase that couples to liquid Lagrangian saliva droplets , + values are used in the prism layers . The equations couple to an incompressible state equation, n, the mass fraction, Yn in Eq. 2), oxygen (O2), carbon dioxide (CO2), and water vapor (H2O). The ambient conditions for N2, O2, and CO2 were defined at mass fractions of 0.7, 0.2, and 0.05, respectively, whereas the remaining H2O mass fraction varied with time due to the phase change in liquid droplets. The coupling to the liquid phase occurs through the energy and mass fraction source terms from evaporation, given as Se,evap and SY,evap in Eqs. B is the Spalding transfer number and g* is the mass transfer conductance. Index i represents each component of the mixture of components, and ϵi is the fractional mass transfer rate.In the aforementioned equations, The model includes aerodynamic drag,2 and a height of 4 m. The computational mesh is indicated in λ) ranges from The geometry modeled in the computational domain is indicated in µm and a standard deviation of 0.01 µm. The volume flow rate for the Lagrangian fraction peaks at 4 l/s based on the inlet velocity spike profile with a maximum value 50 m/s. Initial temperature and pressure conditions of the modeled surrounding are set to standard conditions (T = 23 °C and p = 101 and 325 Pa). The thermal gradients were induced by defining a room temperature and inlet/wall/ground temperature of 23 °C, a body temperature of 29 °C, a buccal surface and breath temperature of 37 °C, and a face temperature of 33 °C to approximate human body temperatures. In order to understand the accuracy of the results, a mesh sensitivity study of the present model was carried out to study this from the perspective of velocity and dispersion. This study expands on the model of our previous work.The air inlet shown in IV.Section A.1.2.Global values were obtained via an experimental case where airborne droplets from the subject are tracked against a contrast-enhanced, isolated background  analyze the influence of relative air humidity (RH) based on the validated CFD model. Section 1.et al.TAB , vs the initial droplet diameter. The plot clearly signifies a sedimentation curve; however, the indefinite time associated with evaporated droplets leads to run time. Hence, it is proposed to evaluate the Wells curve as performed in TSed [Eq. Based on the validated CFD model, a reconstruction of the Wells curve is investigated in this section. The results from the base case from the experiment benchmark with a RH of 28% are depicted in TSed Eq. . For thiTSed Eq. . Note thμm) appears worse for lower relative humidity [see The overall study of the droplets with respect to the Wells curve is further investigated with respect to a varied relative humidity in dity see  and beha2.et al.In order to assess the impact of evaporation on transmission risk, the suspended contents of the material that is non-evaporative are evaluated. For the model, it was assumedV.et al.et al.,µm (10% RH) to 100 µm (50% RH) and reduced further to 70 µm (90% RH). Finally, the amount of dehydrated solids was shown to reduce significantly with increasing humidity and reach a minimum level at and above 50% RH with no further reduction potential. Therefore, the findings support a 33% reduction of the airborne transmission risk in wet climates, or vice versa, the risk of contracting airborne infection is increased by almost 50% in desert and winter climates or in dry indoor environments.This paper has numerically and experimentally investigated the key fluid-dynamic characteristics, which are known to be in high correlation with airborne disease transmission of infectious viral particulate, such as COVID-19. A violent sneeze without a face covering or other physical protection in use was studied to detail the worst-case of respiratory emission potential. The high counts of emitted droplets and aerosols make a sneeze the worst-case of the human respiratory function. The numerical model uses detached eddy simulation and the Lagrangian–Eulerian multiphase model coupling with the Taylor analogy breakup method. The CFD model was found to be relatively insensitive to further grid refinement while providing reasonable correlation with our corresponding experimental data. The data were taken using an optical imagery method and processed to validate spatiotemporal exposure maps, vertical velocity profiles, and emission propagation profiles. The model was further validated against recent literature data from the study by Vuorinen


Nanoparticles in drug delivery have been widely studied and have become a potential technique for cancer treatment. Doxorubicin (DOX) and carbon graphene are candidates as a drug and a nanocarrier, respectively, and they can be modified or decorated by other molecular functions to obtain more controllable and stable systems. A number of researchers focus on investigating the energy, atomic distance, bond length, system formation and their properties using density function theory and molecular dynamic simulation. In this study, we propose metaheuristic optimization algorithms, NSGA-II and U-NSGA-III, to find the interaction energy between DOXH molecules and pristine graphene in three systems: (i) interacting between two DOXHs, (ii) one DOXH interacting with graphene and (iii) two DOXHs interacting with graphene. The result shows that the position of the carbon ring plane of DOXH is noticeably a key factor of stability. In the first system, there are three possible, stable configurations where their carbon ring planes are oppositely parallel, overlapping and perpendicular. In the second system, the most stable configuration is the parallel form between the DOXH carbon ring plane and graphene, and the spacing distance from the closest atom on the DOXH to the graphene is 2.57 Å. In the last system, two stable configurations are formed, where carbon ring planes from the two DOXHs lie either in the opposite direction or in the same direction and are parallel to the graphene sheet. All numerical results show good agreement with other studies. Drug delivery and its encapsulation efficiency are major concerns for medical research. Many conventional medical treatments have a low proficiency and may have adverse side effects; targeted drug delivery offers an alternative to effectively defeat such diseases. There are many approaches to the technology of drug delivery, including the encapsulation of drugs using nanotubes ,2,3 and A frequently adopted anti-cancer drug is Doxorubicin (DOX), which tends to show a significant improvement in cancer treatment. One derivative of DOX is a doxorubicin nitrate, (DOXH)NOthan DOX . Howeverthan DOX ,12. The than DOX ,14,15.In terms of the delivery process, the binding between DOX and graphene has been widely studied, and we refer the reader to a comprehensive review by Sanchez et al.  for the Artificial intelligence (AI) has also been utilized in the area of nanotechnology to obtain an optimal structure or a stable system. Specifically, metaheuristic algorithms can be applied directly if the objective function and the constraints are defined. For example, using genetic algorithm, Cuckoo search, Symbiotic organism search and Firefly algorithm tunes hyperparameters for the multi-layer perceptron artificial neural network and models nanovector in the system of drug delivery ,23. Non-Here, we focus on facilitating the stability of the system by investigating the interaction and activity between DOXHs and a flat graphene sheet using a mathematical model and heuristic algorithm techniques. The Lennard-Jones potential function is utilized to determine the non-bonded interaction energy between two materials. This energy function has been successfully used to determine the interaction between DOXs and bio-molecules, including liposome and peptide nanotubes ,29. The The methodology, including molecular description, mathematical derivation for the interaction energy between two non-bonded molecules and the use of NSGA-II and U-NSGA-III, is given in n and III-m, respectively, where The stabilities of the three systems, which are (i) the interaction energy between two DOXH molecules, (ii) the interaction energy between a DOXH and a flat graphene sheet and (iii) the interaction energy between two DOXHs and a flat graphene sheet, are investigated. The Lennard-Jones potential function is exploited to measure the energy of the system. In each system, NSGA-II and U-NSGA-III algorithms are utilized to determine the stability, and 30 experiments fixing seeds from 1 to 15 in each system are reported. NSGA-II and U-NSGA-III algorithms are employed from the open-source multi-objective optimization framework in Python . Then thThe atomic structure of DOXH is depicted in Furthermore, in each DOXH molecule, we create a point and three vectors, as shown in In terms of a graphene sheet, we assume a perfect flat hexagonal lattice located on the We can use either the Lennard-Jones potential or Buckingham potential to describe the non-bonded interaction between graphene and drugs. The polynomial function of the Lennard-Jones potential is an appropriate option because our goal is to identify the analytical expression for the interaction. Additionally, because the electronic structure of a molecule is outside the scope, the density functional theory method can be disregarded.A and B are attractive and repulsive Lennard-Jones constants, respectively. Further, The 6-12 Lennard-Jones function for two non-bonded atoms can be written ase et al. .Moreover, the mixing rule is utilized in the system of two atomic species, which are i and j located a distance For two separated (non-bonded) molecular structures, the interaction energy can be evaluated using either a discrete atom–atom formulation or by a continuous approach. Thus, the non-bonded interaction energy may be obtained as a summation of the interaction energy between each atom pair, namelyi in the molecule that is modeled as discrete. The energy is obtained by summing all atoms in the drug that are represented discretely.In the interest of modeling irregularly shaped molecules, such as drugs, an alternative hybrid discrete-continuous approximation can also be used, which is given byFor conveniencem in the case of hybrid discrete-continuous approximation, we defineP located at P to the plane is First, we consider the interaction energy between a point On using the substitution and changing the limit of integration , and the coordinate points of 69 atoms are stored so as to investigate the obtained numerical results. Moreover, the solutions from each generation of experiments are accumulated by saving the history module in order to plot the learning curve and to see how the solution converges to a stable point.The noticeable numerical results from the three systems are related to the carbon ring plane on the DOXH molecule. Therefore, instead of reporting all positions of 69 atoms, we emphasize the related parameters between two carbon ring planes of the DOXH molecules and the carbon ring plane of the DOXH with the flat graphene sheet.For the system of two DOXH molecules, we measure the distance between their center of masses denoted by The numerical values presented in From the experimental statistics calculated from 50 experiments (25 of NSGA-II and 25 of U-NSGA-III), the resulting percentage of Type A1, A2 and A3 are z-axis and the carbon ring plane of the other molecule to be on the z-direction and rotating the other DOXH on the z-axis. The results are shown in x-axis) and the offset angles (upper x-axis) of the three configurations are zero, which confirms the optimum position between two DOXHs.In the tuning process, we choose seeds II-5, III-2 and III-3 to represent Types A1, A2 and A3 configurations, respectively. The system is initiated by making the center of mass of one DOXH be on the To guarantee a local minimum, three dimensional energy profiles of the three stable configurations are plotted. We observe that there are a number of stable local minima, but the numerical values reported here are at the global minimum in the neighborhood, as shown in E (eV). The numerical results are presented in For the case of the interaction energy between a DOXH molecule and a flat graphene sheet, we report the perpendicular distance from the DOXH center of mass to the graphene sheet z-direction and rotating it on both the x- and y-axes from the default setting where the DOXH center of mass is on the z-axis, and the graphene sheet is set to be on the As depicted in E (eV). From We report the closest distance between the center of masses of two DOXHs Both types give similar energy values in the range of z-axis. Then, two procedures are applied to observe the energy behavior of the adjustment, which moves the second DOXH in the x-direction and rotates the first DOXH on the z-axis. The two stable configurations of Type B1 and Type B2 are evidently stable and reach the local minima, as shown in From 50 experiments, the probability of Type B1 occurring is ions see . FurtherA number of theoretical studies have been carried out to investigate the attachment of DOX or DOXH to graphene or to graphene oxide. Most of the works have undertaken molecular dynamic simulation. Here, we propose the use of a heuristic algorithm to determine the stable configuration for the interaction between the DOXH molecule and the flat graphene sheet.Tone et al.  studied Mirhosseini et al.  studied According to the work by Song et al. , they stSince there is no definite definition of the separation distance between DOX and graphene, we define The results given in For seed III-8, representing Type B2, we achieve the distance between the Hchniques ,20,35.In terms of the energy, the total energy of the two systems of a DOXH interacting with a graphene sheet is The main discrepancy in our work from others is the use of DOXH instead of using DOX. This causes only a minor difference in the drug structure and the atomic positions; however, our findings are in good agreement and have proximate values in both distance and energy. Therefore, using a metaheuristic algorithm, we used NSGA-II and U-NSGA-III, is another approach to obtaining a stable configuration of nanoparticles. The concept of these algorithms is quite different from well-known methods, such as density function theory and molecular dynamic simulation. The density function theory investigates the electronic structure of a group of molecules to form a stable configuration, and molecular dynamic simulation measures the energy of molecules by simulating the movements of atoms and molecules using the valet algorithm. Here NSGA-II and U-NSGA-III aim to optimize and get the best solution by adapting over generations.We have studied three systems: (i) the interaction energy between two DOXH molecules, (ii) the interaction energy between a DOXH and a flat graphene sheet and (iii) the interaction energy between two DOXHs and a flat graphene. Each system consists of 30 experiments using NSGA-II and U-NSGA-III algorithms to find the most stable structure. All systems show that the stable configurations have remarkable relationship with the inclined angle and the rotated angle between two carbon ring planes of DOXHs and the graphene sheet.System (i) shows three possible, stable configurations where their carbon ring planes of two DOXHs are oppositely parallel, overlapping or perpendicular. The perpendicular configuration gives the lowest energy, of, on average, around All experiments on system (ii) result in the same outcome, where the most stable configuration is the parallel form of the DOXH carbon ring plane and the graphene with Our findings are based on an elementary mathematical derivation, and the use of heuristic algorithms are comparable with previous studies where they employ expensive computational calculations. Therefore, this theoretical study can be thought of as a first step in designing a DOXH interaction with graphene in the drug delivery system, which can reduce the time of calculation.


Remote epitaxy is a promising approach for synthesizing exfoliatable crystalline membranes and enabling epitaxy of materials with large lattice mismatch. However, the atomic scale mechanisms for remote epitaxy remain unclear. Here we experimentally demonstrate that GaSb films grow on graphene-terminated GaSb (001) via a seeded lateral epitaxy mechanism, in which pinhole defects in the graphene serve as selective nucleation sites, followed by lateral epitaxy and coalescence into a continuous film. Remote interactions are not necessary in order to explain the growth. Importantly, the small size of the pinholes permits exfoliation of continuous, free-standing GaSb membranes. Due to the chemical similarity between GaSb and other III-V materials, we anticipate this mechanism to apply more generally to other materials. By combining molecular beam epitaxy with in-situ electron diffraction and photoemission, plus ex-situ atomic force microscopy and Raman spectroscopy, we track the graphene defect generation and GaSb growth evolution a few monolayers at a time. Our results show that the controlled introduction of nanoscale openings in graphene provides an alternative route towards tuning the growth and properties of 3D epitaxial films and membranes on 2D material masks. Remote epitaxy represents a promising method for the synthesis of thin films on lattice-mismatched substrates, but its atomic-scale mechanisms are still unclear. Here, the authors demonstrate the growth of exfoliatable GaSb films on graphene-terminated GaSb (001) via seeded lateral epitaxy, showing that pinhole defects in graphene serve as selective nucleation sites. For example, the weak van der Waals interaction between the film and graphene creates new strain relaxation pathways for highly mismatched growth3 and enables exfoliation of free-standing crystalline membranes for flexible devices4 and tuning properties via strain in novel geometries5. Since the first demonstrations for compound semiconductors6, epitaxy and exfoliation from graphene have been demonstrated for a variety of other materials including transition metal oxides7, simple metals8, halide perovskites3, and intermetallic compounds5. These films are typically thought to grow via a remote epitaxy mechanism6, in which epitaxial registry between film and substrate is achieved via remote interactions that permeate through graphene.Remote epitaxy of three-dimensional materials on graphene-terminated surfaces8. However, the magnitude of the potential fluctuations is only Δϕ = 0–40 meV, which is smaller than the kBT ~ 70 meV thermal energy at typical growth temperatures 500 ∘C. Experimentally, the ability to grow and exfoliate crystalline films from graphene is often cited as evidence for growth via these remote (screened) interactions7. In practice, however, it remains an outstanding challenge to fabricate defect-free graphene or perfect graphene/substrate interfaces, especially because graphene cannot be grown directly on arbitrary substrates. Additional layer transfer steps are often required. The effects of native and transfer-induced defects in graphene, which are difficult to control12, are generally overlooked in the remote epitaxy mechanism. Microscopic measurements during growth are required to understand the atomic-scale mechanisms for growth under realistic conditions.The atomic scale mechanisms of remote epitaxy, however, remain unclear. Model calculations suggest that for perfect graphene/substrate interfaces, the substrate lattice potential permeates through graphene and may be sufficient to template epitaxial growth13, we find that pinholes are created by native oxide desorption from the substrate. GaSb nucleates directly from the underlying GaSb substrate in the pinholes, followed by lateral overgrowth and coalescence of a continuous film. The resulting films have similar structural quality as previous reports8 and can be exfoliated to produce free-standing membranes. Since GaSb shares similar bonding character, constituent vapor pressures, surface diffusion coefficients, and growth conditions as other III-V materials, we anticipate that the seeded lateral epitaxy mechanism may explain the growth of other materials on transferred graphene. We experimentally track the evolution of GaSb films grown on graphene/GaSb(001) by combining molecular beam epitaxy (MBE) synthesis with in-situ electron diffraction and photoemission spectroscopy (XPS), plus ex-situ atomic force microscopy (AFM) and scanning electron microscopy (SEM).Here we experimentally demonstrate that pinhole-seeded lateral epitaxy explains the growth of atomically smooth, exfoliatable GaSb films on a graphene-terminated GaSb (001) substrate. Using the same graphene transfer procedures as previous reports2 to seed growth18. It improves upon conventional ELO in two key ways. First, due to the weak Van der Waals interactions and small pinholes (10–300 nm diameter), graphene masks permit the etch-free exfoliation of large scale single-crystalline GaSb membranes for applications in flexible electronics. Second, the atomic thinness of graphene is an attractive feature compared to conventional ELO masks, for applications where an electronically transparent interface is desired, e.g. a tunnel junction20. Seeded lateral epitaxy also carries an advantage over purely remote epitaxy: whereas remote epitaxy is only expected to apply for substrates with polar bonding6, seeded lateral epitaxy can produce epitaxial films on nonpolar substrates15. Remote epitaxy also requires clean graphene/substrate interfaces, free from interfacial oxides or other contaminants1. Our experiments demonstrate that the introduction of defects provides powerful knob for controlling epitaxial growth of covalent 3D materials on 2D materials surfaces, similar to recent work on growth of 2D materials on patterned 2D masks22.This growth mode is conceptually similar to selective area epitaxy and epitaxial lateral overgrowth (ELO), that employ openings in a dielectric mask such as SiO13 (Methods). HCl25 and HCl+H2O2 solutions27 are also commonly used to etch native oxides from GaSb. The other half of the sample has an exposed GaSb surface for direct epitaxy.We first demonstrate the epitaxy and exfoliation of single crystalline GaSb films on a graphene-terminated GaSb 001) substrate. Figure  substrat∘C in an Sb2/Sb1 flux to desorb the native oxides from the substrate. On the bare GaSb side, the native oxide removal is confirmed by the appearance of bright semi-streaky spots in the RHEED pattern. The graphene-terminated side looks qualitatively similar, although the pattern is not as bright and there is diffuse intensity around the specular reflection. We attribute these differences in part to scattering through monolayer graphene that is randomly oriented in-plane.Immediately prior to growth we follow the standard procedure of annealing at 520 c(2 × 6) reconstruction of GaSb (001) [Fig. ω = 0, we observe a second peak shifted by ω = −15 arc seconds. The full width at half maxima (fwhm) of these two peaks are 10.44 and 12.59 arc seconds, respectively, compared to a width of 6.74 arc seconds for a homoepitaxial film. In addition, photoluminescence measurements reveal similar materials quality between films grown on graphene/GaSb (001) and a bare GaSb substrate . Figure We now show that GaSb films grow on graphene-terminated GaSb (001) via a lateral epitaxy, seeded at pinhole defects. We first examine the creation of pinhole defects in graphene, which form due to native oxide desorption from the substrate immediately prior to GaSb film growth.1. However, such clean interfaces can be difficult to fabricate in practice, especially for III-V semiconductor substrates like GaSb since III-Vs are typically terminated with an amorphous ~3 nm thick native oxide28. This oxide must be removed before film growth in order to reveal the underlying crystalline template for an epitaxial film. Although we adopt an HCl etching procedure to remove the substrate native oxides prior to forming the graphene/substrate interface (Methods), some residual oxides may remain.Figure p < 5 × 10−10 Torr). After a 350 °C ultrahigh vacuum anneal to clean surface adsorbates, we observe a significant O 1s intensity at binding energy of 531 eV. In addition, we observe a satellite to the Sb 3d3/2 core level at binding energy of 540 eV, indicative of Sb-oxides.Our in-situ photoemission spectroscopy measurements reveal that some interfacial oxides remain after the etch procedure. Figure 2/Sb1 flux, no oxide components are detected in the Sb 3d or Ga 3p core levels, suggesting that the GaSb-oxides have fully desorbed. We also observe a finite O 1s core level intensity that decreases as a result of the 515 °C anneal, and decreases further after the 540 °C anneal. At this point the chemical state of the remaining oxygen above 515 °C is unclear, since no oxide components are detected in the Ga 3p, Sb 3d, or C 1s core levels, suggesting that neither the GaSb substrate nor the graphene itself is oxidized  samples removes most of the oxides, despite the presence of the graphene overlayer. After annealing at 515 °C with an Sb∘C appears qualitatively smooth with no tears or holes observed in the SEM images  are well known to etch graphene29, particularly at edges and at extended defects like grain boundaries. In the present case, we expect that the larger strains around these protrusions may enhance the oxygen etch rate at these locations, compared to smoother regions of the graphene. Similar enhanced oxygen etching of graphene on other substrates has been attributed to roughness and impurities in the underlying substrate30.The pinholes appear to be localized at the bumps that were observed after annealing to 350 ∘C, the areal density and diameter of the pinholes increases as observed in the AFM images  13. Therefore, it appears that native oxides trapped at graphene/III-V interfaces are common to both wet (aqueous) and dry (in air)31 transfer procedures, due to the reactivity of III-V surfaces32. Further improvements in interfacial cleanliness may require in-vacuum or glovebox transfer procedures33.An important question is whether the presence of oxides and creation of pinholes upon annealing are unique to our wet graphene transfer process, or if the creation of pinholes is more general. Note that we use the same HCl etching procedure that has been used previously for transferred graphene on III-Vs35 or intercalation under the graphene37, as has been observed in other systems.These pinholes serve as nucleation sites for direct epitaxial growth. Figure After 2 ML of GaSb growth, nearly all of the holes have nucleated GaSb islands, which we further quantify in Supplemental Fig. ∘C, which is below the native oxide desorption temperature. We find that the resulting GaSb film grown at 350 ∘C is polycrystalline  sample for which we do not remove the interfacial oxides. For this sample, we anneal to 350 D and G modes on both the exfoliated membrane side and on the substrate side, indicating that exfoliation tears the graphene . These pinholes are created by native oxide desorption from the substrate. The resulting GaSb films have similar characteristics and structural quality as previous reports of remote epitaxyλ is long compared to the average spacing L between pinhole defects (λ >> L). Previous experiments on confinement heteroepitaxy demonstrate that the effective surface diffusion length for group-III metal adatoms on graphene is of order 10 microns, since metal adatoms preferentially nucleate at graphene defects over length scales of order 10 microns37. Our preliminary experiments on lithographically defined graphene stripes reveal a similar picture . Therefore, adatoms can sample enough of the surface to nucleate at pinhole defects, rather than on the inert graphene. Remote epitaxy would require a larger separation between defects, L > λ.Seeded lateral epitaxy occurs in the graphene/GaSb system because (1) graphene is chemically inert and (2) the surface diffusion length ∘C is less than unity. Similar behavior has been observed for selective area epitaxy of III-V films on patterned dielectric masks, such as SiO2 and SiNx14.The long effective surface diffusion length arises from a combination of long surface diffusion and a high adatom desorption rate Fig. a, since ϕ ~ 15 meV6, which is smaller than the thermal energy kBT ~ 70 meV at growth temperature 500∘C. An estimate of the free carrier screening from graphene also suggests this potential should be weak. For a free electron gas with density 1019 − 1020 cm−3, the same density as graphene (graphite)38, the Thomas-Fermi screening length is approximately 1/k0 ~ 2 Å. This is less than the film/substrate layer spacing of ~5 Å1, suggesting that the screened potential above the graphene is exponentially weak. In contrast, the potential modulation at a graphene pinhole is expected to be much larger, Δϕ ~ 1 eV, since this involves adatoms making chemical bonds to the graphene or to the underlying substrate. The pinholes provide the low energy sites for nucleation and growth. Epitaxial registry is obtained because the pinholes are locations of direct epitaxy to the substrate. Given these factors that favor seeded lateral epitaxy when there is a finite density of graphene defects (L << λ), our results suggest that previous demonstrations of remote epitaxy can alternatively be explained by a seeded lateral epitaxy mechanism.The relative size of potential modulations also explains the preferred nucleation and growth from pinholes Fig. b. On graL << λ), the defects dominate the growth mechanism. Due to the interfacial oxides, we expect that most graphene that is transferred to a foreign substrate will lie in this high defect density regime. Characterization of the graphene quality before the pre-growth anneal  and Supplementary Fig. ∘C) and Supplementary Fig. Our experiments demonstrate that in the presence of a high concentration of graphene defects (L > λ) immediately prior to film growth, i.e. including the pre-growth annealing. Graphene that is directly grown on the substrate of interest, rather than transferred, provides a cleaner starting point for such studies. III-nitride39 and metal films37 on epitaxial graphene/SiC, and III-arsenide films on CVD graphene/Ge  of ultra high purity CH4 at 1050 ∘C on Cu foil, as described in refs. 41. The graphene/Cu foils were then cut and and flattened using clean glass slides to match the dimensions of the semiconductor substrate. Approximately 200 nm of 950 K C2 PMMA  was spin coated on the graphene/Cu foil at 2000 RPM for 2 minutes and left to cure at room temperature for 24 hours. Graphene on the backside of the Cu foil was removed via reactive ion etching using 90 W O2 plasma at a pressure of 100 mTorr for 30 s. The Cu foil was then etched by placing the PMMA/graphene/Cu foil stack on the surface of an etch solution containing 1-part ammonium persulfate  and 3-parts H2O. After 16 hours of etching at room temperature, the floating PMMA/graphene membrane was scooped up with a clean glass slide and sequentially transferred onto five 5-min water baths to rinse any etch residuals.Our graphene synthesis and transfer procedure is a modified polymer-assisted wet transfer of CVD-grown graphene∘C for 15 minutes, then at 150 ∘C for another 15 min. The PMMA was dissolved by submerging the sample in an acetone bath at 80 ∘C for 3 h. This is followed by an IPA rinse and nitrogen drying. The sample is indium bonded onto a molybdenum puck and outgassed at 150 ∘C for 2 h in a loadlock at a pressure p < 5 × 10−7 Torr before introduction to the MBE growth chamber. Finally, the sample is annealed at ~350 ∘C for 1 h in the MBE chamber to desorb organic residuals.GaSb (001) substrates were etched in 38% HCl solution for 5 min followed by a 2-propanol rinse to remove some of the native oxides. We then used the etched GaSb substrate to scoop the PMMA/graphene stack from the final water bath. To remove water at the graphene/substrate interface, the samples were baked in air at 50 GaSb films were grown in a custom molecular beam epitaxy chamber (Mantis Deposition) using an effusion cell for Ga and a thermal cracker cell for Sb (MBE Komponenten). Temperatures were measured using a pyrometer that is calibrated to the native oxide desorption temperature of GaAs. In-situ reflection high energy electron diffraction (RHEED) measurements were performed using a Staib RHEED gun at 15 keV.p < 5 × 10−10 Torr) transfer chamber, such that samples are transferred in vacuum and are not exposed to air. We use a non-monochromated Al Kα x-ray source (1486.6 eV) and an Omicron EA125 hemispherical analyzer with an energy resolution of 1.08 eV. Samples were annealed in the MBE and measured in the XPS at room temperature.X-ray photoemission spectroscopy (XPS) measurements were performed in an XPS chamber that is connected to the MBE via an ultrahigh vacuum (μm2 area. Atomic force microscopy (AFM) measurements were performed using a Bruker Dimension Icon in tapping mode.Field emission scanning electron microscopy (SEM) was performed using a Zeiss GeminiSEM 450. Raman spectroscopy was performed using a 532 nm wavelength laser (Thermo Scientific DXR Raman Microscope). The laser power is kept below 5 mW in order to prevent damage to the graphene. In order to acquire representative raman spectra, 2600 spectra where captured and averaged over a 2500 Kα radiation. Symmetric ω − 2θ measurements (ω is the sample tilt in the scattering plane and 2θ is the Bragg angle) and azimuthal pole figure (ϕ) scans were performed using a 4 bounce Ge 220 monochromator on the incident radiation. Rocking curve measurements were performed using an additional 3 bounce Ge 220 analyzer crystal.X-ray diffraction measurements were performed using a four-circle Malvern Panalytical Empyrean diffractometer, using Cu p < 2 × 10−6 Torr). The film was then exfoliated with two methods. Crystalbond 509 adhesive, with a flow point of 120 ∘C, was gently smeared on glass slide on a hot plate at 150 ∘C. The sample is then placed film-side down on the adhesive and allowed to cool. The membrane can be easily exfoliated by gently dropping the glass slide from a height of approximately one foot onto a clean surface. The force from the drop is enough to release the substrate from the membrane, leaving the membrane adhered on the glass slide. Thermal release tape  was also used to exfoliate by stamping onto the sample, and then carefully peeling the tape away from the substrate.To exfoliate the GaSb epilayer, a 100 nm Ni stressor layer was deposited on the GaSb / graphene / GaSb (001) heterostructure at room temperature using a metal evaporator (Angstrom Engineering Inc.) in high-vacuum (2.Steady-state photoluminescence (PL) measurements were performed at 300 K with a CW Ar-ion pump laser at a wavelength of 514.5 nm, using a 1500 nm (600 gr/mm) grating and a liquid-nitrogen cooled Ge detector. The power density was approximately 6.96 watts/cmSupplementary InformationPeer Review File