In this paper, reduced graphene oxide functionalized with cobalt ferrite nanocomposites (CoFe@rGO) as a novel type of electromagnetic wave (EW) absorbing materials was successfully prepared by a three-step chemical method including hydrothermal synthesis, annealing process and mixing with paraffin. The effect of the sample thickness and the amount of paraffin on the EW absorption properties of the composites was studied, revealing that the absorption peaks shifted toward the low frequency regions with the increasing thickness while other conditions had little or no effect. It is found that the CoFe@rGO enhanced both dielectric losses and magnetic losses and had the best EW absorption properties and the wide wavelength coverage of the hole Ku-Band when adding only 5wt% composites to paraffin. Therefore, CoFe@rGO could be used as an efficient and lightweight EW absorber. Compared with the research into traditional absorbing materials, this figures of merit are typically of the same order of magnitude, but given the lightweight nature of the material and the high level of compatibility with mass production standards, making use of CoFe@rGO as an electromagnetic absorber material shows great potential for real product applications. In recent years, electromagnetic wave (EW) absorbing materials have attracted substantial attention due to the widespread use in military and civil applications, such as electromagnetic protection, anechoic chambers, radiation-proof materials12456789107122O3, γ-Fe2O3 and Fe3O4 have good EW absorption effect within a certain frequency range  due to their high magnetization intensity and magnetic anisotropy1516192022232 hybridization of 3 carbon atoms with σ-bonds on the 2D plane and π-bonds orthogonal to them. Reduced graphene oxide (rGO), a widely-known derivative of graphene obtained from chemical reduction of graphene oxide by thermal, chemical or electrical treatments, possesses good dielectric properties, which can be used to prepare absorbing materials with dielectric loss mechanism121825Metallic nano-oxides are an important type of absorbing materials; therefore, developing magnetic nano-materials with large magnetic loss and high magnetic permeability is a promising approach for absorbing materials2O4 mixed to rGO nanocomposites (CoFe@rGO) were prepared by facile hydrothermal synthesis. It was found that when adding only 5 wt% composites to paraffin, the prepared CoFe@rGO with a thickness of 2.3 mm had the best EW absorption property. Compare with previous studies on the Fe3O4/graphene and CoFe2O4/graphene, this material had much lower amount (only 5%) and much wider bandwidth (7.17 GHz), which is much more suitable as a lightweight broadband electromagnetic wave absorbing coating. Considering its simple synthetic method and controllable ratio in the final composites, this kind of synthesized materials would be highly valuable in commercial use.Based on the above considerations, CoFexFe2-xO3 and CoFe@rGO. xFe2-xO3 particles were short rod-like or rice-like shaped particles, densely packed together and exhibiting localized agglomeration. The rice-like particles were about 400 nm in length with a diameter of about 180 nm. 2O4 particles were unevenly distributed in the graphene substrate, presenting pronounced localized agglomeration. The rice-like particles were about 400 nm in length with a diameter of about 200 nm. 2O4 are well-dispersed on RGO sheets. The high-resolution TEM image of the CoFe2O4 particles exhibits a lattice spacing of 0.295 nm corresponding to the (311) planes.−1 and G-band at 1593 cm−1, and 2D-band at 2670 cm−1. For graphene, the D-band and G-band are the Raman characteristic bands. The D-band was due to the random arrangement of graphite or induced by lattice defects of C atoms. The higher the intensity of the D-band, the more the lattice defects in the crystals. The G-band is due to the stretching vibration of C atoms in the sp2-hybridized plane  while the 2D-band is due to the secondary Raman scattering of regional boundary phonon. The intensity ratio of D-band to G-band, ID/IG, could characterize the degree of crystal disorder. The intensity ratio of D-band to G-band (ID/IG) for graphene oxide was 0.88. The red curve represents the Raman spectrum for the prepared CoFe@rGO. The D-band, G-band and 2D-band of the CoFe@rGO were at 1345 cm−1, 1589 cm−1, and 2704 cm−1; the corresponding intensities were 86.26, 100.49, and 11.14. The ratio of D-band to G-band (ID/IG) was 0.86, slightly lower than that of the graphene oxide. This indicates that CoFe2O4 eliminated defects during the preparation of CoFe@GO nanocomposites, which affected the Raman peaks of graphene. There were weak Raman peaks for CoFe2O4 in the spectrum of CoFe@rGO at 520 cm−1, and 533 cm−1 in the inset of 2O4 in the Raman spectrum.xFe2-xO3. This may be due to the overlap of the diffraction peak of the reduced graphene oxide and that of the ferric oxide, which indicates that during the heating process and annealing process of the facile hydrothermal synthesis, the ordered graphite crystal structure was reduced to some extent, that is, the graphene oxide was reduced into reduced graphene oxide. Moreover, apart from the reduced graphene oxide in the composites, we can detect the presence of CoFe2O4, Fe2O3, and Fe. The diffraction peaks of CoFe2O4 were at 30.08°, 35.24°, and 43.06°, corresponding to the crystal planes (220), (311), and (400). These peaks matched the standard PDF CARDS of CoFe2O42O3 were found at 24.14°, 33.15°, 40.85°, 49.48°, 54.09°, 57.43°, 62.45°, and 63.99°; these peaks corresponded to the crystal plane reflection of the (012), (104), (113), (024), (116), (122), (214), and (300) planes respectively. The diffraction peaks of Fe2O3 matched the standard PDF CARDS2/(H2 + Ar) = 8/100 at 360 °C for 3 h, CoFe2O4 and Fe were generated by reducing the cobalt ferrite. There were also diffraction peaks identifiable with the presence of Fe2O3 in the XRD result, implying that the cobalt ferrite was not fully reduced. The remaining cobalt ferrites existed as CoxFe2-xO3 in the CoFe@rGO.To clarify the microwave absorption properties, the reflection loss (RL) can be calculated according to transmission line theory and using the relative complex permittivity and permeabilityZin) is calculated by:While the normalized input impedance  were measured by the coaxial reflection - transmission network method. The results are presented in The complex permittivity of GF-15 was too high, leading to poor matching with the complex permeability, such that the EW absorption properties had not been improved. For GF-5, its complex permeability was similar to that of GF-15, whereas the complex permittivity was obviously reduced, which is promising to improve the impedance matching characteristics of the composites. Therefore, the EW absorption properties of CoFe@rGO were enhanced.According to the following equations:3O4, the dielectric loss is increased and the magnetic loss is reduced with the inclusion of Co element into ferrite. In the frequency range of 2~14 GHz, with increasing the amount of CoFe@rGO to paraffin, the magnetic loss tangent gradually increased. Compared with samples GF-5 and GF-10, the magnetic loss tangent of sample GF-15 was improved in the range of 2~18 GHz, exhibiting a higher magnetic loss. Therefore, the impedance matching characteristics of the composites could be improved by carefuly controlling the addition of CoFe@rGO to paraffin.and using the eletromagnetic parameters of samples GF-5, GF-10 and GF-15, the dielectric loss tangent and the magnetic loss tangent were calculated. The relationship of the dielectric loss tangent vs. frequency and the magnetic loss tangent vs. frequency were plotted, as shown in 2O4 was 1:1, after annealing in the mixed gas of H2/Ar for 3 h, the prepared CoFe@rGO by adding 5 wt% composites into paraffin had the best EW absorption property.The EW absorption properties of CoFe@Rgo  were tabulated in 2O4 particles. For sure, the contribution of CoFe2O4 to the impedance matching of the composites and the EW absorption cannot be neglected. The microstructure of the composites also greatly promoted the absorption of the incident wave. In addition, other factors such as interface scattering and the polarization were as well beneficial to EW absorption. As a dielectric loss material, rGO was the main absorbent for enhancing the dielectric permittivity. The EW was absorbed by interacting with the electromagnetic field, while its degradation depended on the dielectric relaxation and interface polarization. When the EW entered into the composites, the directional movement of the carriers in the reduced graphene oxide formed a dispersion current, leading to dielectric relaxation and polarization at the interface. Thereby, the electromagnetic energy was consumed by being converted into heat. Meanwhile, the Fe in the composites acted as a dielectric material and could also absorb the EW by the polarization relaxation effect. By adding magnetic CoFe2O4 particles into the rGO dielectric material, the composites were formed. On the one hand, the impedance matching of the composites was improved. The impedance difference between the composites and air was reduced, which was beneficial to letting more EW into the inside of the composites. On the other hand, the composites were magnetized, generating natural resonance etc. The composites had a dual nature of magnetic and dielectric loss, which was conducive to the EW absorption and to broaden the absorption bandwidth. The interface polarization in the composites could facilitate the electromagnetic wave absorption. rGO had the characteristics of large specific surface area, layered structure and so on. When mixing with CoFe2O4 particles, a large number of interfaces were generated, like the interface between CoFe2O4 particles and rGO. The scattering and the polarization at the interface could induce interaction between electromagnetic waves, thereby facilitating the EW absorption by the composites.According to the EW absorption properties of CoFe@rGO with different additive amounts, it is found that the complex permeability of GF-5, GF-10 and GF-15 were almost the same, whereas there were big differences in complex permittivity. GR-5 had the highest complex permittivity and showed the best EW absorption property, indicating that the additive amount of composites to paraffin could influence the dielectric loss significantly shown in . However2O4 contributed primarily to the EW absorption. The good absorbing property of the composites was due to the dielectric loss of CoFe2O4 and the dielectric relaxation and polarization of rGO. This novel and lightweight absorbing material has good prospects for commercial applications.In summary, a novel absorbing material reduced graphene oxide functionalized with cobalt ferrite nanocomposites (CoFe@rGO) was prepared. When the additive amount was 5 wt% to paraffin, the sample showed the best EW absorption property. In this case, when the thickness was 2.3 mm, the reflection rate reached the lowest at 16.63 GHz by −25.66 dB, and the bandwidth corresponding to RL less than −20 dB was 2.03 GHz. When the thickness was 2.7 mm, the bandwidth corresponding to RL less than −10 dB was 7.17 GHz from 10.87 to 18.04 GHz, covering the entire Ku band. The EW absorption mechanisms of CoFe@rGO were studied. The EW absorber was mainly attributed to the dielectric relaxation and polarization of rGO. Besides, the interface scattering and the hysteresis loss of CoFexFe2-xO3 by hydrothermal reaction. Existing literature indicated α-Fe2O3 nano rings could be prepared by hydrothermal reaction by adding FeCl3. In a similar manner, the hydrothermal reaction for preparing CoxFe2-xO3 was undertaken for 12 h at a furnace temperature of 220 °C by controlling the mole fraction of Co and Fe and adjusting the quality of FeCl3•6H2O and CoCl2•6H2O. After the reaction was completed, the reactor was cooled to room temperature in air. The solution was then centrifuged, and the precipitates were dried, giving the brick-red solid powder intermediate CoxFe2-xO3;Preparation of Co2O3/rGO nanocomposites by facile hydrothermal synthesis with the prepared CoxFe2-xO3 and graphene oxide (GO). The literature showed that graphene oxide GO could turn into reduced graphene rGO by hydrothermal reactionxFe2-xO3 (mass ratio of 1:1) were uniformly dispersed in a solution of ethanol and glycerol (ratio of 3:1), followed by placing the mixed solution in the reactor for hydrothermal reaction at a furnace temperature of 180 °C for 12 h. After the reaction was completed, the reactor was cooled to room temperature in air. The solution was then centrifuged, and the precipitates were dried, giving brown CoxFe2-xO3/rGO nanocomposites;  Preparation of CoFexFe2-xO3/rGO nanocomposites from step (ii) were annealed at 360 °C in mixed gas of H2/Ar = 8/92. Finally, CoxFe2-xO3/rGO nanocomposites were reduced into CoFe@rGO. Preparation of CoFe@rGO. The prepared CoCoFe@rGO were prepared by facile hydrothermal synthesis. The preparation process had three steps:The different mixture proportions of the measured samples are illustrated in The samples were characterized by field emission scanning electron microscopy (FESEM) , X-ray diffraction (XRD) (Rigaku DMAX-RB), and Raman spectroscopy . The electromagnetic parameters of the samples were measured by a vector network analyzer system (HP722ES) from 2 to 18 GHz. Reflectivity loss values were calculated by Matlab software according to the complex permittivity and complex permeability. The CoFe@rGO prepared with the above process were mixed with paraffin to make a paste that could be shaped into coaxial samples. The electromagnetic parameters of the samples were tested by vector mesh analyzer to calculate the absorption properties. The sample had an inner diameter of 3.0 mm, an outer diameter of 7.0 mm, and a thickness of 2.0 mm. Three different sets of samples were prepared for comparative experiments, in which, the adding proportion of the composites were 5%, 10%, and 15%, respectively; while the amount of paraffin was 0.5 g for all three samples.How to cite this article: Ding, Y. et al. Reduced Graphene Oxide Functionalized with Cobalt Ferrite Nanocomposites for Enhanced Efficient and Lightweight Electromagnetic Wave Absorption. Sci. Rep. 6, 32381; doi: 10.1038/srep32381 (2016).


The present study aims to enhance the understanding of the tumor microenvironment of lung cancer patients who underwent surgery, by means of analysis of PD-L1 expression in tumor cells and in intratumoral immune cells (IICs). It was found that PD-L1 expression was more frequent in tumor cells than in IICs. Collective analysis by Tissue Microarray Assay (TMA) for PD-L1 expression in tumor cells and IICs did not reproduce the findings for separate individual analysis of tumor tissues. Patients with past history of smoking were more likely to express PD-L1 in tumor cells than those who never smoked. Patients with past history of smoking were less likely to have PD-L1 positive IICs compared to those who had never smoked. The immunohistochemical expression of PD-L1 in tumor cells and IICs did not correlate with survival.Lung cancer is the leading world cause of cancer-related death, in both genders, and smoking is the main etiological factor. The discovery of immune checkpoints corroborates the hypothesis that ligands presented in tumors modulate the mechanisms of carcinogenesis and the immune activity of tumor microenvironment. Among the most studied coregulatory molecules, PD-1 Lung cancer remains the leading cause of cancer death worldwide, for both men and women. Over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18% [In Brazil, according to 2016 estimates of INCA , the incidence rate for tracheal, bronchus, and lung tumors will be 17330 new cases  for men and 10890 cases  for women [Despite major advances in the personalized medicine, non-small-cell lung cancer is still related to poor prognosis.Until recently, non-small-cell lung cancer was considered a nonimmunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunological responses in lung carcinogenesis . The disRecent studies show that tumor cells and antigen presenting cells modify tumor microenvironment through PD-1 receptor activities involving their ligands, PD-L1 and PD-L2 , 6. PD-1 CD274 gene [Programmed cell death 1 ligand 1 (PD-L1) or B7 homolog 1 (B7-H1) is a type I transmembrane protein encoded by the274 gene .The PD-1 function occurs primarily in peripheral tissues, where the T cells can contact their immunosuppressive ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed by tumor cells, stromal cells, or both –15. It hMore than that, PD-L1 expression may also vary according to different tumor microenvironments  and evenOne recent study showed that PD-L1 expression was not associated with gender, histology, differentiation status, or lymph node metastasis. However, PD-L1 expression was increased in stage III NSCLC compared with stage I/II .Other studies showed that PD-L1 expression was significantly associated with smoking –21, gendThe role of PD-L1 expression neither as a prognostic nor as a predictive factor is controversial, being suggested in several studies , 23, 24.Indeed, recently, the KEYNOTE-001 trial of pembrolizumab (a humanized antibody that targets the programmed cell death 1 receptor) for advanced NSCLC showed a significantly favourable survival in patients with that PD-L1 expression greater than 50% in comparison to those with expression lower than 50% .PD-L1 seems to be a mutable biomarker, with variable expression patterns related to heterogeneity in different areas within primary or metastatic lesions.Histopathological material aging or the interval between tissue collection and treatment may also influence PD-L1 expression –30.Positivity criteria for PD-L1 expression  are not standardized yet and that certainly may contribute for all these discrepancies.This study attempts to elucidate PD-L1 expression in lung tumor microenvironment. Possibly it may help to understand different clinical outcomes in lung cancer and establish more effective therapeutic measures.Tumor tissue samples and data were obtained from 177 cases. These patients underwent surgical resection of primary lung cancer between 2003 and 2014 at Barretos Cancer Hospital, Brazil. H&E stained sections were reviewed by a pathologist (CSN) and histological subtyping was assessed using the current World Health Organisation 2015 classification. Staging was undertaken according to the 7th edition AJCC tumor, node, metastasis (TNM) classification. The ethical use of human tissue for research was approved by the Institutional Review Board, and the design of this study followed the principles of the Declaration of Helsinki and also complied with the principles of good clinical practice.Inclusion criteria include patients older than 18 years of both genders, diagnosed with non-small-cell lung cancer , who underwent pneumonectomy, lobectomy, segmentectomy, or nodulectomy with available slides and paraffin blocks for histopathological analysis in the Pathology Department of Barretos Cancer Hospital.Exclusion criteria include inappropriate histopathological material by either poor quality or shortage due to its use in other studies and patients with a current diagnosis of another primary malignancy in any location of the body other than nonmelanoma skin cancer or in situ carcinoma of the cervix.PD-L1 immunohistochemistry membranous expression was assessed in TMA (Tissue Microarray Assay) with 2 cores of 1 mm in diameter of each tumor and also the expression was evaluated in whole tissue section of the same tumors .μ thick and the sections were transferred to positively charged glass slides.TMA blocks were made with MTA I  device , according to manufacturer's specifications. TMA and all the paraffin blocks were sectioned with 4At least one section per paraffin block was stained with hematoxylin-eosin in order to confirm the histology and to certify of tumor tissue availability in the slides by a pathologist and another slide was submitted to PD-L1 immunohistochemistry test.Four micra thick sections (TMA and whole tissue sections) were dewaxed at 80°C for 20 minutes and then were transferred to Ventana BenchMark Ultra Autostainer . Antigen retrieval was performed using Ventana Cell Conditioning solution 1 (pH: 8.5) for 64 minutes at 97°C. Anti-PD-L1 antibody  at titration of 1 : 25 was incubated for 60 minutes at 36°C. The detection of antigen antibody reaction was performed using UltraView DAB Universal Detection kit . Strong membranous trophoblastic staining in the placenta was used as positive control. Tissue expression of PD-L1 was categorized dichotomically into negative (<5% membranous tumor cells expression) or positive (≥5% membranous tumor cells expression)  and alsoData were described on the average, standard deviation, minimum, maximum, and quartiles for quantitative variables and frequency tables for qualitative variables. The agreement between the collective analysis technique or TMA (tissue microarray) and individual analysis was done using the Kappa coefficient to assess the reproducibility.p value than 0.2 in the previous test were selected and subsequently adjusted into a logistics multiple regression model. For modeling, one feature (variable) was removed each time by prioritizing those with higher p value, up to a set of significant variables.The correlation between clinical and demographic characteristics and PD-L1 expression in tumor cells and IICs was determined using the chi-square test (or Fisher's exact test) for the qualitative characteristics. To check the overall association between covariates and PD-L1 marker, those that had lower p value less than 0.2 were selected in simple analysis and adjusted in multiple Cox regression model. Then, modeling was continued as the same description in the logistic regression. To estimate the overall survival curve for PD-L1 expression the Kaplan-Meier method was used.For overall survival, the time between diagnosis and death for any reason (which is the event of interest) or last objective information of individuals who have not died yet was considered. To compare each feature and check the list of features with survival (one at each time), simple Cox regression was used. For joint evaluation between variables, those with For survival analysis only overall survival was considered, because it is a retrospective study and there was no standardization in the follow-up of these patients in the past. In this study we considered the statistical significance of 0.05 and SPSS 21.0 software was used for statistical analysis.In regard to demographic characteristics, as seen in The most common histological type was adenocarcinoma  with II degree of differentiation . Most of tumors had TNM Classification of Malignant Tumours lower than III. Stages I and II were observed in 62 patients (35%) and 53 patients (29.9%), respectively. Lobectomy was performed in 147 cases (83.1%). Adjuvant chemotherapy was performed in 34 cases (19.2%) .PD-L1 was expressed in tumor cells and in IICs. Tumor cells had coarse chromatin, increased nuclei with irregular nuclear membrane, and abundant cytoplasm with ill-defined borders. However, intratumoral immune cells had loose chromatin, smaller fold nuclei without atypia, and variable cytoplasm, sometimes with dendritic expansions .In Figures In p < 0.001) when the immunohistochemical expression of PD-L1 in tumor cells in conventional histological slides  and TMA slides  was evaluated. Similar results were observed with PD-L1 expression in IICs in conventional histological slides  and IICs slides  with Kappa index of 0.328 (p < 0.001).As noted in Once the immunohistochemical expression of PD-L1 was not reproducible between TMA and whole tissue sections, all the analyses (univariate and multivariate) of correlation between PD-L1 expression and covariates  considered PD-L1 expression in whole tissue section.p value = 0.044.As noted in As seen in As seen in p value = 0.022).According to p value = 0.008)  .After logistic regression, smoking was the only variable that remained significant related to PD-L1 expression in antigen presenting cells.p value = 0.029). The chance of positive PD-L1 expression in intratumoral immune cells was also lower for patients with active smoking when compared to patients who had never smoked but without statistical significance   .p value = 0.254. Also, there was no statistically significant difference in the median overall survival when comparing PD-L1 expression in IICs: 49.50 months (95% CI 23.37 to 75.64) for patients with positive PD-L1 expression versus 41.51 months (95% CI 29.99 to 53.04) in patients with negative PD-L1 expression with p value = 0.795 . Considering PD-L1 expression in tumor cells of conventional histological slides , there was a higher median overall survival for patients with tumors that had positive PD-L1 expression; however this difference was not statistically significant: 98.75 months (95% CI 21.26 to 176.24) versus 41.51 months (95% CI 30.05 to 52.98) with According to this study, the frequency of PD-L1 expression in tumor cells was 37.9% of total cases, a little less than a recently published study that showed 53.1% of positivity , althougThis evaluation can occur in different ways: continuous distribution and proportion of PD-L1 positive cells at any intensity , percentThere is no standardized cutoff for positivity. Some studies have used 1%, 5%, 50%, or more to consider positive PD-L1 expression .Therefore, it becomes extremely difficult to establish any relationship between studies as a consequence of no standard positivity criteria for PD-L1 expression, which involves the whole process, from chemical reactions machinery to dilutions of reactants and its reading interpretations. As seen in Another important issue to be discussed is the feasibility of PD-L1 biomarker in order to be measured and analyzed in histopathological slides. Garon et al. noted PD-L1 deterioration in tumor samples cuts more than 6 months before staining . AccordiA recent study showed that tumor microenvironment cells  do not express PD-L1 in a uniform way . Smyth eTumor microenvironment has a wide range of different cell types mainly represented by myeloid-derived suppressor cells, macrophages, dendritic cells, and T lymphocytes beyond tumor cells . There iThis study analysis showed a fair (low) agreement between the two methods of immunohistochemistry , for PD-L1 expression evaluation in lung tumors. The medical literature has pointed to the importance that lung tumor heterogeneity may have regarding PD-L1 expression in small biopsies when compared to surgical specimens.Small isolated samples from a particular tumor region gathered by biopsy or punches for TMA construction, for example, cannot represent PD-L1 expression for the tumor as a whole. This expression cannot be generalized, because of its intrinsic regional variability. Immunohistochemistry assessment of slides covering a tumor in its largest possible area, with the largest represented diameters, seems to provide a more representative description of real PD-L1 expression in lung tumors.In this study, tumors of patients with smoking history were more likely to positively express PD-L1 in tumor cells and they were also more likely to not express this biomarker in IICs. Although the influence of smoking in PD-L1 expression in tumor cells  has alreIt is worth noting that changes in PD-L1 expression can also occur related to previous exposure to chemotherapy, a fact already demonstrated in urothelial carcinomas and lung cancer , 45. TheThere was no statistical significance related to PD-L1 expression and overall survival as previously described. Other studies show apparently not to be a predictive or prognostic value regarding PP-L1 expression , 46, 47.In summary, this study shows that, in a population of patients with non-small-cell lung cancer, the pattern of PD-L1 expression was heterogeneous, represented by two distinct cell types: the tumor cell (higher frequency) and IICs (lowest frequency). Positive PD-L1 expression was observed in 37.9% of tumor cells and in IICs of 24.3% of tumors.p value < 0.001, proving that TMA is not an adequate method to evaluate PD-L1 expression.TMA techniques  and conventional histological slides  showed fair agreement when they evaluated the immunoreactivity of PD-L1 expression in tumor cells (Kappa = 0.307) and in antigen presenting cells (Kappa = 0.328) of patients with non-small-cell lung cancer, Former smokers had a higher PD-L1 expression in tumor cells when compared to those who had never smoked. In contrast, former smokers had a lower PD-L1 expression in IICs when compared to those who had never smoked. There was also no correlation between patterns of PD-L1 expression and survival in this population.


The aim of this study was to explore first‐line nurse managers’ perceptions of the challenges involved in decision‐making concerning older patients who wish to die.A descriptive qualitative design in three communities in Norway between January 2016 and June 2016.Qualitative focus group interviews with eight first‐line nurse managers.One main theme and two themes were identified: Struggling to make the right decision, The challenge of social isolation and loneliness and When life becomes too painful and problematic. The sub‐themes revealed that: Arranging social meeting places where the older patients can talk to other older people is crucial. The participants explained that it was not an easy task to gain an overview of the older patients situation. The right decision could be encouraging the patients to talk about their problems by giving them more time, thereby showing that somebody cares about them. In the literature the term FLNM has been used interchangeably with “head nurse”, “ward sister”, “ward manager, “nursing manager” and “ward leader”  to obtain a range of perceptions  described some of the challenges faced by FLNMs in caring for older patients who wish to die. The 12 communities were contacted by e‐mail in December, 2015. Four communities answered in a positive way but wanted more information about the project, which was sent in February, 2016. Unfortunately, three of the communities declined, thus a new request was sent to two of the other communities on the first e‐mail list. Finally, three communities agreed to participate, thus the focus group comprised eight participants: three first‐line nurse managers from community A, two from community B and three from community C.2.3The study was based on qualitative focus group interviews Morgan, . Focus g2.4This study used a thematic analysis , an anaesthesia nurse (AKB) and as researchers. It can be assumed that their pre‐understanding influenced the interpretation of the themes and sub‐themes Gadamer, . Ideally4.2The role of FLNMs has changed a great deal and future research should focus on the different challenges they encounter in decision‐making. The participants emphasized their everyday work as well as responsibility for their staff (Skytt, Ljunggren, Sjödén, & Carlsson, However, FLNMs in Norway seem to find it difficult to decide whether to prioritise their role of clinician, manager or leader and do not appear to know what to do or who to turn to when they experience challenges in decision‐making in the organization Lageson, . They apALH, Study design; ALH, AKB, data collection; ALH, AKB, AB, ES, data analysis, discussion and preparation.


Pathologic vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury promotes the development of occlusive vascular disease. Therefore, an effective chemical agent to suppress aberrant proliferation and migration of VSMCs can be a potential therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. To find an anti-proliferative chemical agent for VSMCs, we screened an in-house small molecule library, and the selected small molecule was further validated for its anti-proliferative effect on VSMCs using multiple approaches, such as cell proliferation assays, wound healing assays, transwell migration assays, and ex vivo aortic ring assay.Among 43 initially screened small molecule inhibitors of kinases that have no known anti-proliferative effect on VSMCs, a spleen tyrosine kinase (Syk) inhibitor (BAY61-3606) showed significant anti-proliferative effect on VSMCs. Further experiments indicated that BAY61 attenuated the VSMC proliferation in both concentration- and time-dependent manner, and it also significantly suppressed the migration of VSMCs as assessed by both wound healing assays and transwell assays. Additionally, BAY61 suppressed the sprouting of VSMCs from endothelium-removed aortic rings.The present study identified a Syk kinase inhibitor as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its underlying molecular mechanisms, such as its primary target, and to validate its in vivo efficacy as a therapeutic agent for restenosis and atherosclerosis. Normal vascular smooth muscle cells (VSMCs) maintain a minimal proliferation rate and active contractility . HoweverIn the present study, we screened number of small molecule inhibitors of six major kinase subfamilies, to find an alternative therapeutic agent for suppressing VSMC proliferation and migration based on the results of multiple experiments, such as cell proliferation assays, wound healing assays, and transwell migration assays, that assessed the anti-proliferative and migratory effect on in vitro. The effect of the selected small molecule on the sprouting of VSMCs from endothelium-denuded aortic rings was also examined. The results indicated that the selected small molecule, a spleen tyrosine kinase (Syk) inhibitor (BAY61-3606), is an effective agent for suppressing proliferation and migration of VSMCs in vitro and ex vivo and that has therapeutic potential for treating occlusive vascular disease involving aberrant proliferation and migration of VSMCs.For initial screening, through a literature search, 43 small molecules Table , whose eTo examine the concentration-dependent effect of the Syk inhibitor (BAY61), VSMCs were treated with increasing concentrations of BAY61  for 24 h. The cellular proliferation results indicated that BAY61 had a significant anti-proliferative effect at all concentrations tested, although the effect was more profound with concentrations of 5 μM or higher  remained about 50% unclosed Fig. a. FurtheTo further investigate the effect of BAY61 on VSMC proliferation, an ex vivo aortic ring assay was performed. The endothelium-denuded thoracic aortas of rats were cut to prepare aortic rings with thickness of 1 mm. Matrigel-embedded aortic rings were cultured in 10% FBS-supplemented DMEM with either vehicle  or BAY61 (10 μM) for 7 days. VSMC sprouting from the endothelium-denuded aortic rings was inhibited by BAY61 even in the presence of 10% FBS in the culture medium Fig. .Fig. 4BAIn the present study, through a screening of small molecule inhibitors of kinase subfamilies, we identified a Syk inhibitor as a potent anti-proliferative and migratory small molecule for VSMCs. Protein kinases are known to play critical roles in signaling pathways implicated in development, differentiation, death and proliferation of cells . TherefoSyk, along with zeta-chain associated kinase of 70 kDa (Zap-70), is a member of the Syk family of kinases that are activated downstream of Src kinases . Syk is Our data also clearly demonstrated that the Syk inhibitor BAY61 significantly suppressed VSMC proliferation and migration. Previous study had reported that suppression of Syk activation led to subsequent inhibition of extracellular signal-regulated kinas (ERK) 1/2 signaling and p38 mitogen-activated protein kinase signaling . TherefoOur ex vivo aortic ring assay result showed that BAY61 prevented sprouting of VSMCs, and furthermore, suppression of Syk has been suggested to be an effective way to control atherosclerosis via subsequent suppression of endothelin-1 production from endothelial cells . TherefoIn summary, as an effort to identify anti-proliferative agent to control occlusive vascular disease, this paper describes the anti-proliferative and migratory effects of BAY61, a Syk inhibitor, on VSMCs for the first time. The selected Syk inhibitor significantly suppressed VSMC proliferation and migration in vitro and ex vivo. These data suggest that the BAY61 may be a potent therapeutic agent for the treatment of occlusive vascular disease and warrants further studies to evaluate its in vivo efficacy and detailed underlying mechanism.2 flasks at 37 °C in a humidified atmosphere of 95% air and 5% CO2 .All experimental procedures for animal studies were approved by the Committee for the Care and Use of Laboratory Animals, Yonsei University College of Medicine, and were performed in accordance with the Committee’s guidelines and regulations for animal care. Rat aortic VSMCs were isolated and cultured using methods previously published . The thohttp://www.ncbi.nlm.nih.gov/pubmed). For primary screening, VSMCs were seeded in 48-well culture plates using DMEM with 10% FBS and then treated with 10 μM of each candidate compound for 24 h. The anti-proliferative effects of the candidate compounds were determined by a cell proliferation assay.From an in-house small molecule library mainly composed of inhibitors of six major kinase subfamilies, 43 candidate small molecules with no known anti-proliferative effects on VSMCs were selected based on a published literature search using Pubmed  was conducted following protocol previously published , and Abcam (β-actin:ab8227).Aortic ring assay to monitor the outgrowth of VSMCs was conducted following a published protocol with modifications . Brieflyp value of less than 0.05 was considered statistically significant.Quantitative data were expressed as the mean ± SEM (standard error of measurement). For statistical analysis, one-way ANOVA with Bonferroni correction was performed using OriginPro 8 SR4 software  if there were more than three groups. A


This article contains data related to the research article entitled “Atomistic simulation on nanomechanical response of indented graphene/nickel system” . There are five sets of data obtained by molecular dynamics simulations for nanoindentation of five different graphene/nickel systems, which are single nickel system, monolayer graphene on nickel system, double-layer graphene on nickel system, three-layer graphene on nickel system and four-layer graphene on nickel system. The calculated load-displacement of the five different indented systems is also listed. Specifications tableValue of the data•Data presented here provide the nanoindentation mechanical properties of nickel substrate with or without graphene coverage on.•We show the nanoindentation mechanical properties of different number of graphene layers suspended on nickel system.•The enhancement effect of graphene on the contact stiffness and load bearing capacity of graphene/nickel system can be calculated from the data presented here.1The data presented in this article show the displacement and related load of the five different indented graphene/nickel systems , and the22.1In our simulations, models with a graphene sheet suspended on a face-centered cubic (fcc) Ni (111) surface and diamond spherical indenters were established, as shown in 2.2The accuracy of a potential function determines the reliability of Molecular dynamics (MD) simulation. Up to now, there are many types of force fields available, which have been parameterized to describe a variety of systems. The embedded-atoms method (EAM) potential developed by Mishin et al. 2.3An energy minimization process was carried out to avoid overlaps in the positions of the atoms after models completed. The periodic boundary conditions were employed in the transverse directions (XY directions). A Nose/Hoover thermostat was applied to maintain the temperature of 300 k. The equations of motion were integrated using the Verlet algorithm


The complex refractive index of few-layer graphene, n − ik, was extracted from the reflectance contrast to the bare substrate. It was found that each few-layer graphene possesses a unique dispersionless optical index. This feature indicates that the optical conductivity does not simply scale with the number of layers, and that inter-layer electrodynamics are significant at visible energies.We have experimentally studied the dispersion of optical conductivity in few-layer graphene through reflection spectroscopy at visible wavelengths. A laser scanning microscope (LSM) with a supercontinuum laser source measured the frequency dependence of the reflectance of exfoliated graphene flakes, including monolayer, bilayer and trilayer graphene, loaded on a Si/SiO Optical response of graphene has recently emerged as an important subject of research. This interest is partly fueled by the promising prospect of utilizing graphene as a photonic material for device applications12345691015 cm−2).The observation of highly confined and low-loss plasmons at mid-infrared wavelengths121415low-energy approximation breaks down, and the linear band structure and a universal optical conductivity are violated. Presuming that transition from a linear energy dispersion (at IR) to a non-linear one (at UV) occurs smoothly, it is plausible that tangible deviations from the former should begin to appear in the visible regime.On the other hand, the observation of saddle-point excitonsIn this regime, the optical response of thin films may be probed by several methods including near-field microscopy, ellipsometry, and transmission/reflection measurements. The use of near-field probes for interrogating visible graphene plasmons is limited due to the interband transitions and high dissipation under conventional doping levels, as highlighted earlier. Moreover, ellipsometry techniques normally suffer from a low spatial resolution, hindering measurement of small graphene flakes. Therefore, transmission/reflection experiments have constituted the most widely used means to characterize few-layer graphene in the visible spectrum.H and E are the magnetic and electric fields, respectively, ε0 = (n–ik)2 is the permittivity of free space, εc is the complex relative permittivity, σ is the optical conductivity, and ω is the angular frequency of the incident monochromatic optical field. Clearly, if the refractive index, and, consequently, dielectric function εc are independent of frequency, then σ must necessarily be a linear function of ω. Although the precise complex value of the deduced refractive index varies among different experimental determinations, they are closely clustered within a small range: 2.1 < n < 2.7 and 1.0 < k < 1.7.Early optical reflection measurements18192021222324Nonetheless, the best-known transmission measurement was performed on suspended few-layer graphene1728This paper reexamines the optical response of few-layer graphene over the visible range by means of a refined reflectance spectroscopy technique. In particular, we compare the two hypotheses of universal optical conductivity and dispersionless optical index. Note that the latter implies a dispersive optical conductivity varying linearly with frequency.Since the thickness of graphene is several orders of magnitude smaller than an optical wavelength, transmission through graphene essentially samples only the real part of the optical conductivity. The imaginary part, however, manifests in the reflection. The negligible amplitude of the reflection from suspended graphene, thus, renders transmission measurements insensitive to the imaginary part. The same disadvantage persists for reflection measurements where graphene films are directly laid on a substrate. Therein, the reflected power predominantly originates from the reflection at the substrate interface. In order for both the real and imaginary parts of the optical conductivity/index to affect the measured signal, we have coupled the graphene flakes to a Fabry-Pérot resonator. The Fabry-Pérot cavity may be simply realized by deposition of a thin dielectric film on the substrate, whose thickness determines the resonant frequency. Given that the overall reflectance from a Fabry-Pérot structure results from multiple reflections, the effect of the interaction with graphene is magnified. While the phase retardation induced by graphene may be negligible for a single reflection, its accumulation for many reflections, however, yields a measurable effect. This fact has been previously exploited to identify different few-layer graphene flakes2 over-layer. This particular SiO2 thickness provides a third-order Fabry-Pérot absorption resonance corresponding to an antinode at the graphene layer around a (free-space) wavelength of 550 nm. The sample was then annealed in H2 and Ar at a temperature of 500 °C for 3 hours to remove adsorbed contaminants. A graphene flake was exfoliated onto a commercially available Si substrate with a nominally 300 nm-thick SiORegions of mono-layer, bi-layer, and tri-layer graphene were identified by means of Raman spectroscopyμm diameter over the sample using a set of two galvano-mirrors. An X20 Mitutoyo infinity-corrected long working-distance objective lens, with a NA of 0.42, was used to focus the incident light onto and gather the reflected light from the sample. Given the flake dimensions (less than 60 μm on a side) and the working distnace of 2 mm, the deviation of the incidence angle from normal is less than 0.9°. The reflected beam was directed to a Si photodiode which measured the reflected power at each pixel.Reflectance measurements were performed by a laser scanning microscope (LSM)A Fianium SC400 supercontinuum laser was used as the LSM light source whose wavelength was varied from 545 nm to 700 nm by means of an acousto-optic tunable filter with a bandwidth of <2 nm.2 near the graphene flake was determined, after the reflectance measurements, through selectively removing the oxide by hydrofluoric acid etching followed by AFM, which gave a value of 308 nm ± 0.5 nm for the oxide thickness adjacent to the exfoliated graphene flake.The thickness of the oxide layer enters to the data analysis (below) as an input parameter and its accurate determination is essential to the accuracy of the ultimate results. Therefore, despite the fact that ellipsometry and scanning electron microscopy (SEM) were performed on the substrate, the actual thickness of the SiOAs RG, normalized by that of the bare substrate, R0. The measured reflectance for each graphene few-layer followed a Fabry-Pérot lineshape centered around ~600 nm. The contrast to the substrate monotonically increased for thicker graphene few-layers. This is qualitatively anticipated since thicker flakes absorb more and appear darker. Interestingly, the reflectance spectra underwent a slight red shift for thicker flakes. The resonance shift evidently demonstrates the loading effect of graphene on the Fabry-Pérot cavity. This shift is a manifestation of the significance of the imaginary  part of the optical conductivity (index).2 were obtained from ref. In the literature, reflection/transmission analyses on graphene usually involved applying thin-film approximations, which neglect the phase retardation associated with transmission through and reflection from graphene. Here we used a complete Fresnel analysis on the graphene-loaded Fabry-Pérot multilayer cavity. The substrate was modeled as a semi-infinite medium. A 3.3 Å thickness was assumed for each layer of graphene, corresponding to its van der Waals interlayer distance. The refractive indices of Si and SiOThe dielectric functions of graphene were modeled based on: first a universal optical conductivity and, second, a complex constant over the wavelength range of interest. These two forms were incorporated into the Fresnel theory in order to explain the measured data, as shown in The deduced optical refractive indices were, further, used in order to calculate the opacity of suspended few-layer graphene based on the Fresnel theory. The fact that each graphene few-layer possesses a different optical index is also interesting. It has been previously argued that the equal steps in the opacity of few-layer graphene indicate that the electrodynamics of graphene is predominantly determined by its in-plane response. However, the result that each few-layer graphene exhibits a unique optical index suggests that inter-layer electrodynamics significantly affect the optical response of graphene in the visible regime. Moreover, the difference in the imaginary parts imply that optical conductivity does not simply scale with the number of layers.2 substrate by applying the Fresnel theory of reflection/refraction to the air/graphene/SiO2/Si multilayer. We found that the reflectance spectra can be well explained by a dispersionless effective optical refractive index rather than a constant optical conductivity. Furthermore, it was found that each few-layer possesses a unique optical index, as tabulated in We performed reflectance spectroscopy on exfoliated monolayer, bilayer, and trilayer graphene coupled to a Fabry-Pérot resonator by means of a laser scanning microscope and a supercontinuum laser over the wavelengths of 545 nm to 700 nm, corresponding to photons of energy 1.77 eV to 2.28 eV. The optical index of the few-layer graphene flakes were determined based on their contrast to the bare Si-SiOHow to cite this article: Ghamsari, B. G. et al. Measuring the Complex Optical Conductivity of Graphene by Fabry-Pérot Reflectance Spectroscopy. Sci. Rep.6, 34166; doi: 10.1038/srep34166 (2016).


The ionic liquid-based electrolyte containing ring-like Pyr1,2O1TFSI and chain-like DMS exhibits good overall performance in lithium-ion batteries. N-methoxyethyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)-imide  and lithium difluoroborate (LiODFB) lithium salt, with ethylene sulphite (ES) or dimethyl sulphite (DMS) as a cosolvent. The mixed electrolyte system exhibits good ion transport properties (a conductivity of 8.163 mS cm–1), a wide electrochemical window (5.2 V), non-flammability, the ability to form films to protect the anode and a large operating temperature range (–40 °C to 60 °C). We compare the performance and function of the new mixed electrolyte system with a variety of ionic liquid/cosolvent electrolyte systems developed in previous studies. The ring-chain synergy takes advantage of the availability of both high permittivities based on the ring-like components and low viscosities based on the chain-like components in the mixed electrolyte system and causes the electrolyte to exhibit a good overall performance in safety, ion transport and compatibility with electrodes.Lithium-ion batteries have been attracting much attention which enables the revolution of wireless global communication. Ionic liquids are regarded as promising candidates for lithium-ion battery electrolytes because they can overcome the limitations of high operating temperatures and flammability concerns of traditional electrolytes. However, at low temperatures they suffer from low ionic conductivity and phase transition. In this paper mixed electrolyte systems are described based on  With increasing global concerns about climate change and the environment and a growing scarcity of traditional fossil fuels, substantial efforts have been focused on the development of new and renewable energy sources.–1 at 40 °C.2/Li cells reaches up to 102 mA h g–1 at 10 °C with negligible damage to the safety characteristics.23In lithium-ion batteries, a variety of liquid solvents can be used as electrolytes to produce batteries with excellent ionic conductivity, and the use of organic carbonates as solvents for electrochemical applications is well established.N-methoxyethyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)-imide . The ether-functionalised cation  and chain-like dimethyl sulphite (DMS) in electrochemical and physicochemical performance for the electrolyte based on Pyr+ in the electrolyte depends upon the interaction of Li+ and the solvent molecules.1,2O1TFSI  scale" fill="currentColor" stroke="none"><path d="M0 1440 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z M0 960 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z"/></g></svg>O become weaker. Consequently, the bond energy of O–S–O becomes stronger and the peak is red shifted to a lower frequency. The O–S–O stretching bands varying in ES (910 cm–1 and 654 cm–1) and DMS (953 cm–1 and 692 cm–1) indicates that the enhancement of Li+ solvation is more obvious in DMS.Solvation of LiI Fig. S1 are show1,2O1TFSI electrolyte with and without sulphites over a temperature range of –40 °C to 80 °C are given in –1) is not yet comparable to that of traditional carbonate electrolytes (5–10 mS cm–1).1,2O1TFSI is mixed with sulphites, a significant increase (3–4 times) in the ionic conductivity is observed. LiODFB–Pyr1,2O1TFSI/DMS possesses an ionic conductivity at room temperature of 8.163 mS cm–1 with a relative standard departure of 4.14% among permitted error bars after testing 5 times .1,2O1TFSI exhibits a large exothermal crystallisation peak (at –43 °C) due to incomplete crystallization of the sample prior to the DSC heating scan. It becomes lower (–51 °C) when DMS is introduced, which suggests that the addition of DMS makes the electrolyte useful at low temperatures.The ionic conductivity and the Arrhenius plots of the ionic conductivity of the LiODFB–Pyrs Fig. S2. The conA is assumed to be proportional to the number of carrier ions and T0 is the temperature at which the configurational entropy becomes zero. The VTF parameters for this system are presented in B relating to the apparent activation energy shows the energy to overcome association among the ions of the ionic liquid to become free conductive ions. The modest ion association in the ionic liquid owing to the resultant effect of electrostatic forces, hydrogen bonds and van der Waals force brings about ion pairs and ion networks causing high viscosity and low conductivity. The large van der Waals force due to the long side-chain in Pyr1,2O1+ and strong hydrogen bond resulting from TFSI– with a big size leads to the high apparent activation energy. The addition of sulphites with good dielectric properties and a low viscosity contributes to the dissociation between the positive and negative ions in the ionic liquid, resulting in B with relatively low value. The T0 of LiODFB–Pyr1,2O1TFSI/DMS is –125 °C, which is lower than that of ionic liquid electrolytes with carbonates (–103 °C),The relationship between temperature and ionic conductivity is described by the Vogel–Tamman–Fulcher (VTF) equation,1,2O1TFSI becomes significant, suggesting oxidative decomposition at a potential of 5.2 V (as compared to Li/Li+). The addition of sulphites only has a small influence on the oxidation potentials of the electrolytes; for all cases the oxidation potential exceeded 5 V (vs. Li/Li+). On the basis of molecular orbital theory, the difference between the calculated energies of the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) determine the vertical electron affinity (VEA) and the vertical ionisation potential (VIP).To clarify the influence of the sulphites on electrochemical stability, the cyclic voltammograms (CVs) determining the oxidation/reduction potentials of the electrolytes are shown in The flammability of the electrolytes based on either ionic liquids or carbonates was tested, and the results are shown in 1,2O1TFSI do not feature a stable plateau, and the CV  and (c)A mesocarbon microbead (MCMB) is chosen as the electrode to evaluate the electrochemical properties of cells with the electrolytes because it is abundant, inexpensive and has a high specific energy. In V Fig. S5 without 1,2O1TFSI exhibit a limited reversible charge capacity below 100 mA h g–1. The initial discharge of cells with LiODFB–Pyr1,2O1TFSI/ES are about 313.9 mA h g–1. Compared with ES, the cells upon addition of DMS acquire a higher charge capacity of 376.2 mA h g–1 in the first cycle and retain a value of 345.0 mA h g–1 after 50 cycles. The coulombic efficiency is 99.6%, which is higher than that of cells containing electrolytes of disiloxane-functionalised phosphonium,1,2O1TFSI/DMS because DMS is beneficial for SEI forming on the surface of the MCMB.The cycling performances of the Li/MCMB cells containing the electrolytes are demonstrated in Rb), the resistance to Li+ migration through the SEI layer (Rsei), and the charge transfer resistance (Rct).Rb and Rct values are much smaller for electrolytes with sulphites than for those of LiODFB–Pyr1,2O1TFSI. The Rct value of cells containing LiODFB–Pyr1,2O1TFSI/ES is higher than that of cells containing LiODFB–Pyr1,2O1TFSI/DMS, which might be attributed to the excessively thick SEI layer formed in ES and the consequent difficulty for Li+ to transfer through the electrode–electrolyte interface.The Nyquist plots of AC impedance spectra of cells containing different electrolytes are shown in Fig. S6.2B[ox]– anions may contribute to the formation of the inorganic inner layer of the SEI:45A combination of density functional theory (DFT) modelling, electrochemical testing and scanning electron microscopy (SEM) analysis reveals the film-forming mechanisms of the mixed electrolytes. LiODFB can facilitate the formation of a SEI by electrochemical redox reactions.2 gas which is noxious and causes the swelling of cells is negligible because the reactions are endergonic to produce the SO2 gas.The [ox]B˙ radical can react with sulphite molecules, and the reactions with the energy change obtained by DFT calculations are shown in 1,2O1TFSI. Moreover, the film grown in the electrolyte containing ES is thicker and has a lower S content than in DMS  and schematic illustration of the synthesis route to the SEI layer with prime reactions in the electrolytes are shown in  Table S1, which i4 has been developed with a low toxicity, low cost and high safety4 containing the traditional electrolyte, cannot operate at low temperatures below –20 °C according to observations reported by Wang Y.464 cells in LiODFB–Pyr1,2O1TFSI/ES, LiODFB–Pyr1,2O1TFSI/DMS, the traditional electrolyte (1 M LiPF6–EC/DEC (1 : 1 by volume)) and the 1 M LiODFB–EC/DEC (1 : 1 by volume) at temperatures ranging from –40 °C to 60 °C. The cells with the traditional electrolyte exhibit poor low temperature performance. LiODFB provides some improvement in the electrochemical performance of the lithium-ion cells at low temperatures,4 cells containing LiODFB–Pyr1,2O1TFSI/DMS are 354.2 mA h g–1 and 130.3 mA h g–1 at –10 °C with average voltages of 0.306 V and 3.283 V, respectively. Additionally, these cells are able to operate with acceptable electrochemical performance at temperatures as low as –40 °C.The olivine LiFePO2 has been widely used in lithium-ion batteries as a cathode material. To ensure the effect of the developed electrolyte on the electrochemical performance of lithium-ion cells, the rate capability of the LiODFB–Pyr1,2O1TFSI/DMS electrolyte in Li/LiFePO4, Li/LiCoO2 and Li/MCMB cells are shown in 4 and Li/LiCoO2 cells containing LiODFB–Pyr1,2O1TFSI/DMS at 1C (150 mA g–1) are around 129 and 106.7 mA h g–1, respectively, and the charge capacity for the Li/MCMB cells at 0.5C (150 mA g–1) is about 206.5 mA h g–1. A good rate performance depends on both satisfactory ion transport and acceptable interfacial reaction resistance in the cells.LiCoO1,2O1TFSI offer some support for this relationship.To clarify if the ring-chain synergy in the carbonate electrolytes used in lithium-ion batteries is also applicable for the ionic liquid electrolytes, a summary of representative electrolyte systems of ionic liquids with organic cosolvents for lithium-ion batteries and the corresponding characteristics and properties are given in Generally, a safe electrolyte should satisfy several requirements such as non-flammability, good ion transport and compatibility with both the cathode and anode in lithium-ion batteries. The electrolytes based on imidazolium are electrochemically unstable at high potential.Safety is related to the flammability of the electrolyte and can be improved using combined ionic liquid/cosolvent electrolyte systems. For the electrolyte systems investigated in the present work, the non-flammability is retained when the amount of cosolvent added is kept below approximately 40 wt%. The electrolytes containing chain-like components require higher concentrations of ionic liquid, as the chain-like cosolvent is more thermally unstable.80+ conductivity greater than 10–1 mS cm–1.–1 at room temperature. To reach this target, the amount of ring-like and chain-like cosolvents introduced into the ring-like ionic liquid pyrrolidinium or piperidinium should be approximately 25–35 wt% or 15–25 wt%, respectively. The most conventional tetra-alkylammonium cations are seldom selected to form electrolytes for lithium batteries, mainly because of their high melting temperatures.–1 is lower than that in ring-like pyrrolidinium or piperidinium.In this study, the ionic conductivity of the electrolyte with DMS is higher than that with ES because the chain-like DMS possesses a lower viscosity, which is beneficial for ionic mobility. A satisfactory electrolyte for a battery cell should have a LiThe electrochemical window is an important index related to the compatibility of the electrolyte with the electrodes in a battery cell. A high-voltage cathode material requires an electrolyte with a high oxidation potential, which restricts the composition of the electrolyte systems. As shown in + to transfer through the electrode–electrolyte interface. Moreover, the calculated [ox]B˙ radical releases more energy when reacting with DMS than with ES, so DMS is more prone to form an SEI. Meanwhile, a larger mass of product is introduced by the reduction of ES, making the SEI thicker. These results confirm that in electrolytes containing a ring-like ionic liquid, the chain-like DMS is more beneficial as the cosolvent than the ring-like ES. An optimal proportion of cosolvents should be chosen such that they form a SEI layer that is neither too thick (leading to high resistance in the battery) nor too thin (providing no protection for the electrodes).Carbon is widely used as an anode which requires cosolvents with a suitable reduction potential to form the SEI layer. In this study, both higher capacities and better cycle stability are obtained in Li/MCMB cells with an electrolyte containing DMS rather than ES. This could be due to one of two reasons: (1) the reduction peak corresponding to the formation of an SEI with the electrolyte containing DMS is weaker, indicating a thinner SEI layer; (2) the electrolyte with DMS has a low viscosity and high separator wettability. An excessively thick SEI layer would result in a high resistance, making it difficult for Li–1. The amount of cosolvents added depends on the nature of the specific components. For systems exhibited in the present and previous studies, it should be more than 25–35 wt% (purple zone).4, LiCoO2, LiNi1/3Mn1/3Co1/3O2, and Li1.2Ni0.2Mn0.6O2. Besides, the contents of the cosolvents should be chosen to form a suitable SEI layer to protect the carbonaceous anodes, which is about 20 wt% (blue zone) in accordance with the previous studies. The performances of the electrolyte systems containing “ring-like ionic liquid and chain-like cosolvent”, “chain-like ionic liquid and ring-like cosolvent” and “chain-like ionic liquid and chain-like cosolvent” are analogously summed up to search for the optimal proportion of the electrolyte components on the basis of this work and the reported studies.General performances of the electrolytes based on ionic liquids with cosolvents are divided into four factors: safety, conductivity, oxidation potential and SEI forming ability. They depend on the nature of the ionic liquids and the cosolvents. We tried to suggest how the electrochemical performances of the electrolyte systems varied with the contents of the cosolvents through analyzing research data from this work and previous studies and the results are shown in 1,2O1TFSI with ES and DMS reveals that the sulphites improve the electrolyte conductivity, compatibility with MCMB electrodes and cell performance at low temperatures. DMS with a lower viscosity and melting point can better enhance the cell performance than ES in the electrolyte with the main component of Pyr1,2O1TFSI. The conductivity of the LiODFB–Pyr1,2O1TFSI/DMS electrolyte was 8.163 × 10–3 S cm–1. The Li/MCMB and Li/LiFePO4 cells containing this electrolyte had good cycle performance and a normal charge curve in the temperature range of –40 °C to 60 °C.Study of the electrolytes based on the ring-like PyrFurthermore, this research identifies the relationship between ionic liquid/cosolvent electrolyte performances and the component structures. According to this work and previous studies, ionic liquid electrolyte systems consisting of both a ring-like component and a chain-like component in a specific ratio can offer good overall battery performance – measured in terms of safety, ionic conductivity and compatibility with cathode and anode materials. The ring-chain synergy that takes advantage of the availability of the two structures might offer a useful starting point to design mixed electrolytes in lithium-ion batteries. In addition, electrolytes with both ring-like components and chain-like components might be developed for applications under particular conditions due to their outstanding electrochemical window and ionic conductivity, respectively. The insight into the ring-chain synergy will allow further anticipation of the ionic liquid/cosolvent electrolytes. It is noteworthy that only the chemical structures of the cosolvent and the cations of ionic liquid were taken into consideration here. In order to gain a better understanding of a broader range of systems and to achieve an even better performance, further study should explore functional modifications and the effect of anions, which might further improve the properties of the electrolyte systems.Supplementary informationClick here for additional data file.


The method of TBLI gives the distribution of periodic dissociation energies for oxygen functional groups, which are capable to reduce the graphene oxide to hierarchical graphene nanostructures, which holds great promise for gaseous molecular adsorption. The fabricated reduced graphene oxide(RGO) sensor enhanced sensing response in NO2 and accelerated response/recovery rates. It is seen that, for 20 ppm NO2, the response (Ra/Rg) of the sensor based on RGO hierarchical nanostructures is 1.27, which is higher than that of GO (1.06) and thermal reduced RGO (1.04). The response time and recovery time of the sensor based on laser reduced RGO are 10 s and 7 s, which are much shorter than those of GO (34 s and 45 s), indicating that the sensing performances for NO2 sensor at room temperature have been enhanced by introduction of nanostructures. This mask-free and large-area approach to the production of hierarchical graphene micro-nanostructures, could lead to the implementation of future graphene-based sensors.We report on the fabrication of a NO Therefore, the development of high performance gas sensor to detect the gas of NO2 in an economic way is crucially important, for not only health protection but also environmental applications. Since the ability to detect individual gas molecules by graphene was demonstrated1, considerable numbers of research activities have been ignited for graphene-based gas sensors7, including flexible gas sensors for wearable sensing applications9, and NO2 detecting sensors13, because graphene and its derivatives exhibit great electronic conductivity, flexibility, low noise and good thermal stability, it has been generally considered as a promising gas-sensing material for various highly sensitive detections. But interaction between intrinsic graphene and gas molecules is weak, in contrast, the surface of graphene oxide contains a large number of chemically active defects, showing remarkably improvement in adsorption capacity and large-scale preparation18. However, the surface area is reduced due to the sheet stacking, which seriously restricts the development of graphene-based gas sensors. In order to make the interior sheet fully contact to the test gas, it is necessary to prepared micro-nano hierarchical structure on the film to expand the specific surface area of material, and then, to improve the performance of the device. Researchers have developed nanostructured materials such as a 3-dimensional (3D) graphene foam network and a graphene nanomesh to overcome low-level sensitivity and slow response of graphene-based gas sensors23. Han et al. reported porous grapheme oxide network for chemical sensing via steam etching20. Yavari et al. using the method of CVD fabricated 3-D grapheme foam network for gas detection21. Paul et al. fabricatied graphene nanomesh using reactive-ion-etching for NO2 and NH3 sensing22. Yun et al. presented 3D nanostructured RGO scaffold using method of electrostatic self-assembly23. The method of freeze drying was also reported for the fabricating of 3D graphene/SnO2 structure24 and 3D SnO2/RGO structure25. Lupan et al. reported a low-powered sensor based on a microtube network26. These methods are limited by restricted temperature, mask, requirement of special equipment and substrate transfer or difficulty in mass production. Here we propose a strategy on the regulation of surface characteristics of graphene oxide using laser micro-nanofabrication technology, to build a high specific surface area of micro-nanostructures and fabricate graphene-based NO2 sensor. Because GO has good solution process compatibility, the device can be implemented on any substrate, this method does not require a substrate transfer process. Laser micro-nanofabrication can be carried out in the air at room temperature, and it has the advantage of rapid preparation of large areas. By Two-beam-laser Interference method, surface area of the film is increased, the sensitivity of the device towards NO2 has been enhanced, meanwhile, the response and recovery time is reduced to varying degrees.Nitrogen dioxide . The variety of response range is caused by two factors together, the increased specific surface area and the reduced oxygen containing groups. We can speculate that in the case of functional groups are invariant, the hierarchical nanostructures would improve the sensitivity of the device to a greater extent. As shown in Fig. 2, indicating the reliability of our RGO NO2 sensor. Figure 2 of the sensor based on GO and RGO hierarchical nanostructures at room temperature. The resistances of the devices were decreased upon exposure to NO2 gas, indicating NO2 doped the RGO film with holes, as RGO film exhibited the electrical behavior of a p-type semiconductor28. It is seen that the response of the sensor based on RGO hierarchical nanostructures is 1.27, which is higher than that of GO (1.06), indicating the enhanced sensing response by laser reduction of GO nanostructures. The response time and recovery time of the sensor based on nanostructured RGO are 10 s and 7 s, respectively, which are much shorter than that of GO (34 s and 45 s). Figure 2 for 15 days. It is seen that the response of the sensor floats slightly. The observed results reveal that RGO sensor exhibits good stability. The selectivity of the RGO sensor towards NO2 is also examined, as shown in Fig. 2 is 1.2, which is much larger than those of the sensor to 4 ppm other gases, such as CO2, CH4, H2 and CO, indicating that the NO2 sensor exhibits good selectivity and can be used for selective detection of NO2. The sensing performances of the sensor were also compared with the previously reported sensors based on micro-nano structured graphene materials, as shown in Table Figure 2, the value of Ra/Rg is 1.04, lower than that of reduced RGO by laser, which confirms the importance of nanostructures in the NO2 sensor. Based on the above results, the fabricated RGO sensor shows improved sensing response in NO2 and accelerated response/recovery rates. We also tested the response of gas sensors based on GO and RGO ethanol gas. When expose thermal reduced RGO to 20 ppm NOasFigure . Differe2 molecule and graphene is 78 meV, which is smaller than the interaction of NO2 and hydroxyl groups of graphene oxide. For epoxy group, a negative binding energy of −144 meV indicating a coulomb repulsion between epoxy and NO2 will push the molecules away from the GO sheet. Overall, according to other studies29, the oxygen functional groups on GO would hold significantly larger ability to absorb NO2 molecules than pure graphene. In this work, the RGO film shows a stronger response than GO film under the influence of the formation of nanostructure and the reduction of oxygen-containing functional groups. However, as shown in Figure To get further insight into the different mechanisms of the gas sensors, first principle study was carried out to give an essential explanation Figure  and S4. 2 sensor has been successfully fabricated by TBLI reduction and nanostructuring of GO film. The presence of nanostructure increases the surface area and thus significantly improves the sensitivity of the device towards NO2, meanwhile, the response and recovery time is reduced to varying degrees at room temperature, compared to GO and thermal reduced RGO, this method was proved to be a novel approach to simultaneous reduction and nanostructuring of GO in a surfactant-free, mask-free and large-area manner. Our present study shows great potential for fabrication of high-performance room temperature graphene gas sensors.A graphene-based NOGO was produced via the Hummers method from natural graphite . The GO films were prepared by spin-coating GO solution on ceramic substrates with interdigital electrodes, at 1000 rpm for 30 s, dried at room temperature. The contacts are interdigital Ag-Pd electrodes as shown in the Figure a/Rg) of the sensor resistance in air (Ra) to that in the NO2 (or ethanol) gas (Rg). The time taken by the sensor to achieve 90% of the total resistance change was defined as the response time in the case of adsorption and recovery time in the case of desorption. X-ray photoelectron spectroscopy (XPS) was performed using an ESCALAB 250 spectrometer. Scanning electron microscope (SEM) experiments were performed on a Hitachi S-4800 electron microscope. Optical microscope images were obtained from a Motic BE400 microscope. Raman spectra were measured with a Renishaw Raman microscope using 514 nm wavelength laser.The dilute tested gas was air. Gas sensing properties were measured using a static test system. Saturated target vapor was injected into a test chamber (about 1 L in volume) by a microinjector through a rubber plug. After fully mixed with air (relative humidity was about 25%), the sensor was put into the test chamber. When the response reached a constant value, the sensor was taken out to recover in air. The electrical properties of the sensor were measured by CGS-8 intelligent test meter  <250 mA. The response of a sensor was defined as the ratio  decorated with oxygen group is used to simulate the graphene oxide. In order to avoid the interaction with neighboring images, a vaccum layer of 20 Å is used. Cutoff energy with 500 eV for plane wave expansion and 2 × 2 × 1 Monkhorst-Pack mesh grid for Brillouin zone sampling are carried out for the calculations.Supporting Information


We studied the spin-transfer torque (STT) in graphene based normal-metal/topological-insulator/ferromagnet heterostructures (N/TI/F), which is induced by the helical spin-polarized current in the quantum spin Hall insulator. We found that the STT is comparable in magnitude to the STT in ferromagnetic-normal- ferromagnetic graphene junction, while not requiring additional ferromagnetic layer with fixed magnetization, which makes it advantageous for the manipulation of magnetic devices in spintronics. More interestingly, the STT is very robust in our proposed nanostructure, as it is immune to changes in the geometry due to an asymmetrically notch or the presence of random nanopores in the quantum spin Hall insulator. Our theoretical prediction suggests that graphene based quantum spin Hall insulator could be used for very efficient magnetization manipulation for magnetic materials. The two-dimensional topological insulator, known as the quantum spin Hall insulator, was first predicted by Kane and Mele12 in graphene. The electrons can be transported in the gapless edge states while the bulk is insulating, and spin-polarized dissipationless currents are transported in the transport channels confined at the two edges without backscattering. However, the quantum spin Hall insulator can not be realized in graphene owing to the exceedingly weak spin-orbit interaction16. Recently, theoretical and experimental work suggested that spin-orbit interaction can be enhanced by appropriate substrates or adatom deposition25 which leads to the transition into the topological non-trivial phase. It is therefore useful to investigate how the topological non-trivial phase can be used in spintronic applications.The topological insulator is a new quantum state of matter characterized by an insulating bulk gap and gapless edge states topologically protected, which has been intensively studied owing to the new physical properties and potential technological applications26. When spin current flows into a ferromagnetic layer, the magnetization of the ferromagnetic layer exerts a torque on the electron spins and the spin current exerts an equal but opposite torque on the ferromagnetic layer, so the orientation of magnetization is modified27. This spintronic effect was predicted independently by Slonczewski28 and Berger29, and it has been confirmed in many experiments36. In spintronics, it is of great importance to reorient the magnetizations in magnetic memory and logic devices, and the STT effect offers us an efficient method to control magnetizations through current. The STT effect can be used to manipulate the magnetic device elements without external magnetic fields.Spin-transfer torque (STT) is an important spintronic phenomenon, in which a spin current injected into a ferromagnetic layer exerts a torque on the magnetic layer and may change its magnetization orientation39 and the nonlocal electrical spin transport at room temperature was first demonstrated in graphene40. Some work has been done to study the STT generation in graphene based F/N/F structure. Ding et al.41 investigated theoretically the current-induced STT in ferromagnetic-normal-ferromagnetic graphene nanoribbon junction, and Yokoyama et al.42 also considered the STT generation in ferromagnetic-normal-ferromagnetic bulk graphene junctions.Graphene has been proven to be a promising candidate for future practical applications in spintronics owing to the long spin relaxation time and length30, we theoretically study the generation of the STT in graphene nanoribbon through a quantum spin Hall insulator. It is found that reliable STT can be generated by a graphene based N/TI/F heterostructures, and the STT can not be affected by asymmetrically notched the ribbon or nanopores.Motivated by the successful idea of realizing quantum spin Hall insulator in graphene and the recent measurements of the STT induced by a topological insulatorHN, HTI and HF are Hamiltonians for the normal graphene, graphene based topological insulator and ferromagnetic graphene respectively. In the tight-binding approximation, the Hamiltonians for the three different regions can be written asε is the onsite energy, λSO is the spin-orbit interaction, M is the magnetization of the ferromagnetic electrode, θ and φ describes the direction of the magnetization, vij = +1(−1) if the electron makes a counterclockwise (clockwise) turn, with respect to the positive z axis, in going from site j to site i. The coupling between the leads and the TI region is represented by the operatorThe schematic view of the device under consideration is presented in Fig. 43,For a small bias voltage V and zero temperature, the STT per unit of the bias voltage can be obtained using the nonequilibrium Green’s function method asThere is an out-of-plane torque which is perpendicular to the plane defined by the z-axis and the magnetization, which is given by the expression4445. Kwant is a Python package which can be used to calculate quantities, such as the Green’s function and the scattering matrix, and determine the transport properties of tight-binding models. The technical details about how to use Kwant can be found in ref.45. Here we give a brief description of the steps we used to find the Green’s function and the self-energies using Kwant. First of all, we constructed the tight-binding model of the scattering region using the Kwant package by specifying the atomic sites of the scattering region, the site energies of the sites and the hopping strengths between sties. This is carried out in the form of a small Python program. The spin degree of freedom of the atomic sites is represented by 2 × 2 matrices. For example, the spin-independent site energy and neighboring sites hopping are represented by the two 2 × 2 matrices These expressions describe the STT exerted on the magnetization of the ferromagnetic electrode by the electrons injected from N region and spin polarized when travelling through the topological insulator region. Using the same noequilibrium Green’s function (NEGF) formalism, the conductance can be obtained within the Landauer-Buttiker framework, and expressed ase as Eq. . All num12 that graphene exhibits a quantum spin Hall effect in the presence of intrinsic spin-orbit interaction. The spin-orbit interaction can be described by a second neighbor tight-binding model . When the Fermi energy moves away from 0, the STT oscillates with the spin conductances. Zero STT is obtained when the Fermi energy coincides with a subband edge in the FM lead. The oscillation amplitude of the STT decreases with the Fermi energy, because the spin conductances decrease with increasing Fermi energy when there are more subbands in the FM lead into which the electrons can be scattered.Figure EF > 0.25t or EF > −0.25t), it can be noted in Fig. When the Fermi energy is outside the gap of TI  which is within this range. We have also considered other two values of strength within the range (280 meV and 56 meV). The results are similar to the present at most of the energies.According to ref.In Fig. Ly) of the square notch for the graphene based topological insulator, and the inset is a schematic illustration of the devices in our numerical calculation. Ly is the width of the square notch, and we have an ideal ribbon when Ly = 0. In our calculation, the width of the ribbon is chosen to be Ny = 200 which is around 21.2 nm. Here, the width of the square notch changes from 0 to 20.8 nm. As shown in the figure, the STT does not change much with the width of the notch until it is very close to the ribbon width. To be more specific, we calculate the STT for a fixed notched square Ly = 10.2 nm, and it is plotted as a function of the Fermi energy .We have also considered structures with armchair edges and random edges, which consist of random combination of armchair and zigzag edges with random lengths. The random edges are created by cutting triangles of random sizes from a zigzag edged structure. The STT obtained in these structures are close to the zigzag edged structure for low Eθ) angular dependence and the out-of-plane STT is very small in Fig. t, the in-plane STT does not reach its peak at θ = π/4 anymore, and there is a small deviation. We found that the amplitude of the in-plane STT increases with an increase in the magnetization intensity. For example, the amplitude for M = 0.005t is around 0.7, but is increased to be around 0.9 for the amplitude M = 0.003t. Figure φ. It is clear that the out-of-plane STT is small for these values of φ and the magnitude of the in-plane STT decrease with the increase in φ and then increase again but with a reverse in direction. So the in-plane STT has oppositie directions for φ = 0 and φ = π/2, while the magnitude are very similar.The angular dependence of the STT is shown in Fig. λSO. In Fig. λSO < 0.05t, because with this SOI strength the Fermi energy is not in the bandgap. When electrons move from the left lead to the right lead, there are electron scatterings, which cause the oscillations in conductance and STT. It is noted that both the STT and the conductance have very negligible changes when the Fermi energy is in the bandgap. The electrons can only move at the edges of the ribbon, and the spin-polarized dispationless currents induce a stable STT.It is known that the spin-orbit interaction can generate an energy gap in graphene, changing it into a quantum spin Hall insulator. The bulk bandgap is dependent on the value of the spin-orbit interaction, which is described by the formula Δ = 6√3e/4π which is comparable in magnitude to the conventional F/N/F junctions. The features of the STT can be explained through the analysis of the band structure of the right ferromagnetic graphene electrode. It is found that the STT obtained in our proposed nanostructure is immune to the changes in the geometry of the quantum spin Hall insulator, and it can not be changed by considering an asymmetric square notch or random nanopores in the quantum spin hall insulator. This offers us an efficient method to change the magnetization direction of magnetic materials without the help of a ferromagnetic layer.In summary, we have investigated the current induced STT in graphene based N/TI/F heterostructures using the nonequilibrium Green’s function method. It is found that the charge current becomes spin polarized, when it flows from the left lead (N) across the quantum spin Hall insulator layer (TI), and induced STT on the magnetization of the ferromagnetic layer (F). The STT per unit of the bias voltage can reach 0.8


A major challenge of agriculture is to increase food production to meet the needs of the growing world population, without damaging the environment. In current agricultural practices, the control of pests is often accomplished by means of the excessive use of agrochemicals, which can result in environmental pollution and the development of resistant pests. In this context, biopesticides can offer a better alternative to synthetic pesticides, enabling safer control of pest populations. However, limitations of biopesticides, including short shelf life, photosensitivity, and volatilization, make it difficult to use them on a large scale. Here, we review the potential use of neem oil in crop protection, considering the gaps and obstacles associated with the development of sustainable agriculture in the not too distant future. Attention is increasingly being paid to the use of natural compounds  as a promising option to replace agrochemicals in agricultural pest control. These odoriferous substances are extracted from various aromatic plants, which are rich sources of biologically active secondary metabolites such as alkaloids, phenolics, and terpenoids , using eAzadirachta indica Juss., a member of the Meliaceae family that originates from the Indian subcontinent and is now valued worldwide as an important source of phytochemicals for use in human health and pest control. Azadirachta is a fast-growing small-to-medium sized evergreen tree, with wide and spreading branches. It can tolerate high temperatures as well as poor or degraded soil. The young leaves are reddish to purple, while the mature leaves are bright green, consisting of petiole, lamina, and the base that attaches the leaf to the stem and may bear two small lateral leaf-like structures known as stipules , which appears to cause 90% of the effect on most pests. The compound has a melting point of 160°C and molecular weight of 720 g/mol. Other components present include meliantriol, nimbin, nimbidin, nimbinin, nimbolides, fatty acids , and salannin. The main neem product is the oil extracted from the seeds by different techniques. The other parts of the neem tree contain less azadirachtin, but are also used for oil extraction  Lepidoptera: antifeeding effect and increased larvae mortality ; (ii) HeFor centuries, neem has been used in folk medicine for the treatment of conditions such as malaria, ulcers, cardiovascular disease, and skin problems. Despite the limited existence of clinical trials to support therapeutic claims, the use of neem has expanded over time, and it is an important component of Ayurvedic medicine . In the cosmetics and hygiene sector, neem is used in the composition of face masks, lotions, sunscreens, soaps, and toothpastes  can be used as a biofertilizer, providing the macronutrients essential for plant growth .Nitrogen is one of the main nutrients required by plants for their development, and urea is the main source of nitrogen fertilizer used worldwide to supply the nitrogen demand of crops. The control of urea hydrolysis and nitrification is one of the principal strategies employed to avoid nitrogen losses in agriculture . Neem haDue to their compositional complexity, neem-based products can act as antifeedants, growth regulators, sterilants, anti-oviposition agents, and repellents . Other fThese features of neem support its contribution to organic agricultural production systems that are more sustainable and do not generate chemical residues . This method also helps to maintain soil productivity, ensuring longer production times. Organic agriculture can be a viable alternative production method for farmers, but there are numerous challenges to be overcome. A key to success is to be open to new approaches, and in this respect neem products can effectively contribute to organic agriculture, being used as organic pesticides and as soil fertilizers. In addition, growing concerns about conventional agriculture and the demand for products that do not generate waste justify increased adoption of the use of biopesticides by farmers, which contributes to the growth of organic agriculture .Neem has acquired commercial recognition due to its various beneficial properties, which have been extensively investigated over time. Compared to conventional chemicals, which are generally persistent in the environment and highly toxic, botanical pesticides are biodegradable and leave no harmful residues. Most botanical pesticides are non-phytotoxic and are also more selective toward the target pest. In terms of commercial applications, biopesticides can provide substantial economic advantages, since the infrastructure required is inexpensive, compared to conventional pesticides .This has resulted in the publication of numerous scientific research articles and books, as well as the organization of international conferences to discuss the benefits of the plant .Table 1 lists some of the main commercial products based on neem.Several patents related to processes and products based on neem have been deposited in the United States, India, Japan, Australia, and elsewhere. Many of the products derived from neem are manufactured by crushing the seeds and other plant parts, followed by the use of solvents to extract the active ingredients possessing pesticide activity. The different methods and techniques employed to obtain neem products can result in different concentrations of the active compounds, as well as different biological effectiveness . Table 1Despite its many promising properties, there are limitations that hinder effective large-scale use of neem. These impediments must be overcome and many uncertainties clarified so that the full potential of neem can be exploited. One of the main problems facing the commercial development of neem is a lack of industrial interest, largely due to the difficulty of patenting natural products, as well as a shortage of scientific evidence to support claims regarding the benefits of these substances. As a results, the products are not widely publicized in the farming community and elsewhere .Disadvantages of neem are its low stability under field conditions, due mainly to a high rate of photodegradation, as well as a short residence time and slow killing rates, compared to conventional pesticides . GeneticNeem oil contains a group of active ingredients with different chemical characteristics. It was therefore believed that the development of insect resistance would be virtually impossible. However, as studies have progressed, it has been observed that due to the low residual power of botanical insecticides, multiple applications are required in order to control pests, which can increase selection pressure on the pest population, possibly leading to resistance .Myzus persicae, which were exposed to pure azadirachtin or to refined neem seed extract at the same concentration as azadirachtin. It was found that after forty generations, the line treated with azadirachtin had developed ninefold greater resistance to azadirachtin, compared to a control line, whereas the line treated with the extract did not show resistance.Currently, most of the botanical insecticides that are being studied and that are effective against many pests are those with feeding deterrent action, so their indiscriminate use could result in the development of resistance . Feng anBiological control is defined as the action of natural enemies on a population of pests in order to keep it at a population density that does not cause economic damage to crops . NaturalThe biological control of insects and mites in agriculture can be achieved using small wasps or flies, known as parasitoids, which parasitize eggs, small caterpillars, and even adults. It can also be performed using predators such as ladybugs, bugs, predatory mites, and spiders, as well as parasitism by entomopathogenic microorganisms including fungi, bacteria, and viruses . AlthougBeauveria bassiana, Isaria fumosoroseus, and Lecanicillium lecanii, and the results showed that these entomopathogenic fungi were compatible with most products tested. There has recently been increased interest in the application of plant-based materials , such as neem oil, in pest control. Although these products are safer for the management of pests, compared to synthetic chemicals, their effects in IPM must be evaluated. Several studies have investigated the relationships between botanical insecticides and natural enemies of agricultural pests . SahayarThe integrated use of botanical insecticides associated with biological control (synergism) in IPM is becoming increasingly widespread in the farming and research communities. The advantage of this approach is that it offers the potential to control agricultural pests, without serious impacts on the environment, non-target organisms, and animal and human health.in vitro), due to the instability of this substance under field conditions. From these studies, it is not possible to draw firm conclusions concerning the in vivo biological efficacy of the formulations, due to the effects of numerous environmental variables.Botanical insecticides must meet the same criteria as conventional insecticides. In other words, they must be selective for the target pest and provide sufficient residual activity to protect the plant during the period of vulnerability. Over the past decade, there has been a significant increase in the number of publications concerning the use of neem oil to control agricultural pests . HoweverIn order to overcome the above-mentioned limitations, nanotechnology has emerged as a novel tool to address the problems of agricultural sustainability and food security . Many stFrom the point of view of sustainable agriculture, nanotechnology can help in the development of environmentally friendly agricultural inputs, improving the safety and stability of active agents, enhancing their activity in pest control, and, consequently, increasing their acceptance by producers . The useAlthough studies have demonstrated the beneficial effects of nanoencapsulation of neem oil, some issues need to be resolved so that the synergistic effect of nanoparticles associated with this botanical insecticide can significantly contribute to the control of insect pests. These issues include the need for: (a) regulation of the use of nanomaterials in agriculture; (b) nanoformulations that are easily scalable; (c) comparative studies employing neem formulations available commercially to prove the cost/benefit of nanoformulations; (d) detailed studies of the degradation and behavior of these nanopesticides in the environment; and (e) evaluation of toxicity toward non-target organisms .Given the importance of neem oil and its worldwide use for combating numerous pests in different crops, the nanoencapsulation of this oil should enable the production of more stable formulations for the control of insects that damage crops, especially those that are essential for human consumption. In addition, the use of nanotechnology is an excellent way to combat the development of resistance in insects due to the indiscriminate use of neem oil.EC, JdO, and MP wrote the manuscript. LF and RdL contributed to the discussion and revised the manuscript. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.