Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer.Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non–AE-IPF rate during postoperative days 0–30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee.p = 0.01]) in the FAS, and in 38/39 patients  occurred in 1 patient, after AE-IPF; no other grade 3–5 adverse events were observed.From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible . Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients .This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (Registration Number:  Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease, and has a histological appearance of usual interstitial pneumonia (UIP). IPF is known to be a risk factor for lung cancer  and is oThe Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study group recently reported that pirfenidone, oral anti-fibrotic agent, significantly reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in a phase III trial in patients with IPF , 12. HowPatients were required to have the UIP/possible UIP pattern criteria published by ATS/ERS/JRS/ALAT in 2011  by high-This was a multicenter, single-arm phase II study designed to evaluate the efficacy of perioperative pirfenidone treatment on the reduction of postoperative AE-IPF in Japanese patients with lung cancer. The primary endpoint was non–AE rate during postoperative days 0–30, and the secondary endpoint was safety. The expected non–AE rate was set at 95 %, and the non–AEthreshold was set at 80 %, because the non–AE rate in patients who did not receive perioperative pirfenidone treatment was assumed to be ≤80 % based on the literature , 15. A tRadiologic and pathologic diagnoses of IPF-AE were confirmed by a central review committee. To validate the institutional diagnosis of IPF, preoperative HR-CT and pathological samples obtained by surgery (non-cancerous lesions) were collected from each participating institute for central review. Two radiologists with expertise in interstitial lung disease (S.S. and T.I.) initially evaluated the HR-CT data independently and then developed a consensus report after discussion. Two pathologists with expertise in interstitial lung disease (J.F. and K.H.) initially evaluated the pathological samples independently and then developed a consensus report after discussion. These experts followed the international IPF diagnostic criteria published in 2011 . The repEach participating institute diagnosed AE-IPF according to the definition published by the Japanese Respiratory Society  as folloPirfenidone  at a dose of 600 mg/day was orally administered to patients who planned to undergo surgery for the first 2 weeks; the dose was then increased to 1200 mg/day for the next 2–4 weeks. The administration dose and dose-increase interval were established according to the protocol included in the Japanese pirfenidone package insert, which was based on the results of the Japanese pre-authorizing phase III trial . SurgeryP-values were calculated using binomial tests. A p-value <0.05 was considered significant. All statistical analysis was performed using SAS version 9.2 .In the primary analyses, the non–AE rate was based on the full-analysis set (FAS) following the intent-to-treat principle. n = 2), a history of chemotherapy (n = 1), and initiation of pirfenidone prior to registration (n = 1). Thus, 39 patients comprised the FAS. Patients included 33 males (84.6 %) with a median age of 68.0  years, and 38 patients had Hugh-Jones grade I/II activity (97.5 %). Among the FAS cases, two patients stopped pirfenidone administration before surgery due to patient request, and surgery was cancelled for one patient because metastatic lesions were identified on further examination. Therefore, both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). All of the PPS patients had received pirfenidone 1200 mg/day for >2 weeks at the time of surgery. The mean time at which pirfenidone was stopped around surgery was 18.4 h. Characteristics of FAS and PPS patients were very similar , adenocarcinoma , and other minor types. Pathological cancer stages included stage I/II . With respect to IPF diagnosis, the central review board diagnosed 39 of the 43 registered cases as IPF and the remaining 4 cases as not IPF . Compared to the central review by the professional radiologist/pathologist/respirologist, the accuracy of the preoperative radiological diagnosis of each institution was 90.7 %. Four not-IPF cases were included in the FAS and the PPS to adhere to the intent-to-treat principle. With respect to efficacy, we also selected the confirmed IPF cases from the PPS and analyzed them separately .From June 2012 to January 2014, 43 patients from 17 Japanese institutions were enrolled. Although all patients initiated pirfenidone therapy, 4 patients were deemed ineligible due to severe heart disease  (Table n = 1), anorexia (n = 4), nausea (n = 4), somnolence (n = 1), dizziness (n = 2), malaise (n = 2), anemia (n = 2), hypoalubuminemia (n = 2), alkaline phosphatase elevation (n = 2), aspartate aminotransferase elevation (n = 3), alanine aminotransferase elevation (n = 3), γ-glutamyltransferase (GGT) elevation (n = 5), creatinine elevation (n = 1), hyponatremia (n = 3), and hyperkalemia (n = 1); however, all of these events were grade 1 or 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. Safety in the postoperative phase was evaluated in 37 patients in the FAS who underwent surgery. Fewer patients than those in the FAS who underwent surgery were evaluated for postoperative safety, because we did not require reporting of clinical data, except for the occurrence of AE-IPF, for patients who quit pirfenidone administration prior to surgery. The following adverse events were observed postoperatively: anorexia (n = 6), nausea (n = 3), diarrhea (n = 1), dizziness (n = 1), malaise (n = 2), respiratory failure (n = 1), dyspnea (n = 6), pulmonary fistula (n = 2), postoperative hemorrhage (n = 1), cough (n = 1), atrial fibrillation (n = 1), wound dehiscence (n = 1), pneumonitis (n = 1), dysgeusia (n = 1), white blood cell decreased (n = 2), neutrophil count decreased (n = 1), anemia (n = 4), hypoalbuminemia (n = 19), alkaline phosphatase increased (n = 8), blood bilirubin increased (n = 1), aspartate aminotransferase increased (n = 8), alanine aminotransferase increased (n = 6), GGT increased (n = 6), hyponatremia (n = 8), hypokalemia (n = 3), and hypocalcemia (n = 3). Among these, 1 case of increased aspartate aminotransferase and 1 case of hyponatremia were reported as grade 3; 1 case of anorexia, 1 case of respiratory failure, and 1 case of dyspnea were reported as grade 4; and 1 case of pneumonitis was reported as grade 5. The grade 4 respiratory failure and dyspnea and the grade 5 pneumonitis were determined to be due to AE-IPF.The safety of pirfenidone treatment in the preoperative phase was evaluated in all patients who received pirfenidone . The reasons for the two surgery cancellations were discovery of metastatic lesions and necessity of cardiovascular surgery prior to lung surgery. Surgery was not cancelled in any patients due to pirfenidone-related adverse events.p = 0.01 under the null rate of 80 %]) in the FAS (Table p = 0.004 under the null rate of 80 %]) in the PPS. Among patients in the PPS, we also analyzed select IPF cases whose diagnoses were confirmed by the central review board (PPS-IPF). In the PPS-IPF, one of the 32 patients experienced AE-IPF . When compared to the threshold derived from historical controls, AE-IPF occurred at a significantly lower incidence in this study.AE-IPF was diagnosed in two patients : 82.7–99.4 %, The current study was designed to evaluate the safety and efficacy of perioperative pirfenidone treatment in the reduction of postoperative AE-IPF in patients with lung cancer. No serious adverse events caused by pirfenidone were observed, and the incidence of AE-IPF among patients treated with pirfenidone was significantly lower than the null hypothesis.The incidence of lung cancer have been reported to be >7-fold higher in IPF patients compared to the general population . ConversNo studies have yet demonstrated that any agents can prevent or decrease the incidence of postoperative AE-IPF . PirfeniAlthough AE-IPF is a well-known, life-threatening postoperative complication in patients with lung cancer accompanied by IPF, its reported incidence varies among studies; however, it generally ranges from 10 % to 20 % , 29, 30.Several studies have revealed that interstitial pneumonia subtype (UIP pattern or not) is a risk factor for postoperative AE-IPF , 31. HowThis study was not randomized but rather was a single-arm study in which historical data served as the control. When we combined the Japanese and international data for surgical lung cancer patients with idiopathic interstitial pneumonia published prior to the planning of the present study, the total incidence of AE was about 19 % (data not shown); therefore, we believe the null hypothesis set herein was appropriate. However, patient background and the influence of some types of patient management that may have been better than those reported in the literature could not be controlled in such a single-arm study. Because the reported background risks for AE also varied among studies, it is difficult to verify the difference between the background risk in this study and those of previous studies. For example, respiratory function and activity shown by Hugh-Jones classification of the registered patients were relatively good in the current study. Severe IPF is undoubtedly considered to be a high risk; however, functionally inoperable cases were not included in this surgical study, and in many cases IPF was newly detected by surgeons during preoperative examination. Perhaps due to such a situation bias, the previously reported preoperative respiratory functions were also almost normal –31. PostIn conclusion, this single-arm phase II study revealed that perioperative pirfenidone treatment is safe and promising for reducing AE-IPF after lung cancer surgery. These results encourage the planning of future confirmatory studies to compare pirfenidone to other treatments, such as nintedanib, for which the efficacy against progression of IPF has already been reported .AE: acute exacerbation; FAS: full analysis set; HR-CT: high-resolution computed tomography; IPF: idiopathic pulmonary fibrosis; JACS: Japanese Association of Chest Surgeons; PPS: per protocol set; UIP: usual interstitial pneumonia; WJOG: West Japan Oncology Group


Online communities are becoming increasingly important as platforms for large-scale human cooperation. These communities allow users seeking and sharing professional skills to solve problems collaboratively. To investigate how users cooperate to complete a large number of knowledge-producing tasks, we analyze Stack Exchange, one of the largest question and answer systems in the world. We construct attention networks to model the growth of 110 communities in the Stack Exchange system and quantify individual answering strategies using the linking dynamics on attention networks. We identify two answering strategies. Strategy A aims at performing maintenance by doing simple tasks, whereas strategy B aims at investing time in doing challenging tasks. Both strategies are important: empirical evidence shows that strategy A decreases the median waiting time for answers and strategy B increases the acceptance rate of answers. In investigating the strategic persistence of users, we find that users tends to stick on the same strategy over time in a community, but switch from one strategy to the other across communities. This finding reveals the different sets of knowledge and skills between users. A balance between the population of users taking A and B strategies that approximates 2:1, is found to be optimal to the sustainable growth of communities. Humans are unique in their ability to create public goods in non-repeated situations with non-kin. In larger groups cooperation is more difficult due to the higher temptation to free ride on the voluntary contributions of others . NeverthOnline communities are natural experiments that give us an opportunity to test possible mechanisms that explain cooperation in large groups. Controlled online experiments show that if participants can choose group members higher levels of cooperation can be derived . This suWe will demonstrate in this paper that assortment is not sufficient to derive high levels of contributions in online collaboration . Our anaFor our empirical analysis we investigate the answering records of nearly three million users over a period of six years from 110 online communities. We find that strategy A are important in decreasing the median waiting time for answers, while strategy B users help increase the acceptance rate of answers. Meanwhile, we find that users tend to use the same strategy over time within a communities, but may take different strategies across communities. This can be explained by the different skill sets between users. For example, an expert in science and engineering may try to answer challenging questions in the astronomy community, but only contributes to easy questions in the poker community see . The comWe propose “attention network” models to study the effect of answering strategies on the growth dynamics of communities. In attention networks nodes are questions and edges are the successive answering activities of users that connect two questions. We developed a theoretical network model in which the co-existence of two answering strategies B and A are represented by the mixture of two linking dynamics, i.e., preferential attachment  and its https://archive.org/details/stackexchange. This data set is a freely accessible, anonymized dump of all user-contributed content on the Stack Exchange network provided by Stack Exchange, Inc. under cc-by-sa 3.0 license (see https://creativecommons.org/licenses/by-sa/3.0/us/ for the explanation of this license). The downloaded data set contained the log files of 110 communities. The smallest community italian.stackexchange.com was created in November, 2013 and has 374 users, 194 questions, and 387 answers in our data set. The largest site stackoverflow.com (SO) was created in July, 2008 and has 2,728,224 users, 6,474,687 questions and 11,540,788 answers.Stack Exchange is a network of question and answer communities covering diverse topics in many different fields. We downloaded its database dump on January, 2014 from Stack Exchange uses a variety of methods to prevent spamming and malicious edits. These methods, including CAPTCHA (Completely Automated Public Turing test to tell Computers and Humans Apart) systems, script detection heuristics, new users limits, collective flagging of spam or offensive flags, auto-removal of items based on flags, and human moderators to handle flagged items, work together to form a human-machine combined system that keeps answers clean and effective . Before qij to a question j when a user i responds to it. Then we average this number over the m questions answered by user i to derive the average perceived difficulty as n users, which is qi < E(qi)) from users taking strategy B (qi ≥ E(qi)) (We use the number of existing answers as a proxy for the “perceived difficulty” of questions  in order≥ E(qi)) . To show≥ E(qi)) , the ave≥ E(qi)) , and the≥ E(qi)) .ρ = 0.29, p-value < 0.001), justifying the validity of using TrueSkill score as a measure of user skill level.The TrueSkill algorithm is a Bayesian ranking algorithm that estimates the skill levels of game players from competition results . Liu et Cik and Hi to quantify the strategic persistence of users within and across communities, respectively . We define Cik = 2/5 = 0.4. It is easy to know that Cik may take any values between 0 and 1 and a value close to 1 implies a high level of strategic persistence over time.We define two indices ectively . Cik meaHi = ((13/23) − 0.5)(1 − 0.5) = 0.13 so it is comparable with the other index Cik.We find that user 53 contributes to 23 communities during the time period under investigation. More specifically, he/she takes strategy A in 13 communities and strategy B in the remaining 10 communities. We identify A as the major strategy of user 53 and count the corresponding fraction 13/23. This variable varies from 0.5 (if a user randomly switches between the two strategies across communes) to 1 (if a user sticks to one strategy). We normalize it between 0 and 1 as The answering strategies of individual users can be understood from a network perspective, in which two questions are connected if they are answered sequentially by the same users  and edges (M), the daily increments of nodes (ΔN) and edges (ΔM), and the number of links per node (m = M/N) and its daily increments (Δm = ΔM/ΔN).From empirical data we construct a growing attention network for each of the 110 communities. The network properties we are interested in include the cumulative number of nodes  in each of the 110 communities and plot the two above discussed community performance indicators against a. It is observed that type A users help decrease waiting time and type B users contribute to the increase of answer acceptance rate. Therefore, a balance between these two types of users should be carefully chosen in order to optimize the community performance. In a approximates 0.63, i.e., the ratio of type A users to type B users is roughly 2:1. In As shown in We have shown a co-occurrence between an optimal ratio and the maximum community size. However, why a deviation from this optimal ratio leads to small community size remains unclear. Therefore, we develop a network model to quantify our assumptions on individual answering strategies in order to analyze the consequences of different ratios.We use “attention networks” to represent question and answer communities, in which nodes are questions and edges are the sequential answering activities of users. In attention networks, answering strategies based on the number of existing answers to questions can be interpreted as degree-based linking dynamics. As type A users prefer easy questions (low-degree nodes) and type B users favor difficult questions (high-degree nodes), when these two types of users move to a new question from old questions, they bring connections to the new node from old nodes of very different degrees. Therefore, we can naively assume that strategy A corresponds to “preferential attachment” , in whicf and 1 − f  to represent the probability of observing type A and B strategies, respectively. Note that f is different from the empirical value of a mentioned in the last section, as a was not the fraction of activities but the fraction of users. Using f as a parameter makes our model simple—so that we do not need to take care of the possible non-linear relationship between a and f, but our analysis can still provide insights into real systems, as it is easy to understand that a and f must be positively correlated. This is because f can be viewed as the multiplication between two variables, the fraction of users a and answering frequency distribution w. As w is always positive, f changes in the same direction as a.We use f, we quantify the probability p(k) of a new question being connected to a existing similar question of degree k asCombining “preferential attachment” and its revered version using the mixing ratio f = 0) and the “reversed preferential attachment” model (f = 1), respectively. Using the master equation technique [α has a minimum value 3 and always increases with f. We find that for a majority of communities the empirical value of α lies in the scope of [In two extreme cases this model degenerates to the “preferential attachment” model f = 0) anscope of , our modp(k) given by E(k)Ng, in which we use Ng to model the effect of network size. By summing E(k)Ng over all nodes in the network we obtain the total number of new nodes as ΔN = E(k)Ng+1. Substituting this condition into C. Putting these two conditions together, we derive the expected number of links obtained by a new node as Δm = CNh/E(k), in which Nh is the effect of network size. Using the conclusion of Besides degree distribution, the discussed linking rules also explain several scaling relationships observed in the growth dynamics of attention networks as presented by s degree . Meanwhi=N3-f2+g.Note tha=Nf-12+h.From Eqsδ); on the other hand, η). As a balance, f = 3 + 2g, is preferred in order to maximize the value of γ, i.e., to match the growth of answers with the growth of questions. As f and a are positively correlated, the derived optimimal value of f implies that there is also an optimal value of a, which is consistent with our empirical observation.To summarize, the above analysis explains why a balance between strategies A and B is crucial to the growth of communities. On one hand, We select three communities to compare the consequences of different mixing ratios between type A and B users, including a community for math questions , a community for questions about astronomy , and a community for questions about game development . As show by a = 0.67). According to our model, questions in ASTR will be addressed efficiently, but there will be a slow growth of new questions. This prediction is supported by a = 0.62) than the optimum. According to our model, in this community new questions will increase fast such that they can not be answered promptly. The fast increase of new questions is evidenced in The fraction of type A users in MATH is approximately 0.63, which is equal to the optimal value. In contrast, ASTR has more type A users Click here for additional data file.


Azadirachta indica) is a member of the Meliaceae family and its role as health-promoting effect is attributed because it is rich source of antioxidant. It has been widely used in Chinese, Ayurvedic, and Unani medicines worldwide especially in Indian Subcontinent in the treatment and prevention of various diseases. Earlier finding confirmed that neem and its constituents play role in the scavenging of free radical generation and prevention of disease pathogenesis. The studies based on animal model established that neem and its chief constituents play pivotal role in anticancer management through the modulation of various molecular pathways including p53, pTEN, NF-κB, PI3K/Akt, Bcl-2, and VEGF. It is considered as safe medicinal plants and modulates the numerous biological processes without any adverse effect. In this review, I summarize the role of Azadirachta indica in the prevention and treatment of diseases via the regulation of various biological and physiological pathways.Neem ( Azadirachta indica), a member of the Meliaceae family, commonly found in India, Pakistan, Bangladesh, and Nepal, has therapeutics implication in diseases cure and formulation based on the fact that neem is also used to treat various diseases. Azadirachta indica has complex of various constituents including nimbin, nimbidin, nimbolide, and limonoids and such types of ingredients play role in diseases management through modulation of various genetic pathways and other activities. Quercetin and ß-sitosterol were first polyphenolic flavonoids purified from fresh leaves of neem and were known to have antifungal and antibacterial activities [The plant product or natural products show an important role in diseases prevention and treatment through the enhancement of antioxidant activity, inhibition of bacterial growth, and modulation of genetic pathways. The therapeutics role of number of plants in diseases management is still being enthusiastically researched due to their less side effect and affordable properties. It has been accepted that drugs based on allopathy are expensive and also exhibit toxic effect on normal tissues and on various biological activities. It is a largely accepted fact that numerous pharmacologically active drugs are derived from natural resources including medicinal plants , 2. Varitivities . Numeroutivities , antifuntivities , and anttivities –12 and ativities . This re Azadirachta indica (neem) is classified in Neem tree belongs to the family Meliaceae which is found in abundance in tropical and semitropical regions like India, Bangladesh, Pakistan, and Nepal. It is a fast-growing tree with 20–23 m tall and trunk is straight and has a diameter around 4-5 ft. The leaves are compound, imparipinnate, with each comprising 5–15 leaflets. Its fruits are green drupes which turn golden yellow on ripening in the months of June–August. Taxonomic position ofAzadirachta indica L. (neem) shows therapeutics role in health management due to rich source of various types of ingredients. The most important active constituent is azadirachtin and the others are nimbolinin, nimbin, nimbidin, nimbidol, sodium nimbinate, gedunin, salannin, and quercetin. Leaves contain ingredients such as nimbin, nimbanene, 6-desacetylnimbinene, nimbandiol, nimbolide, ascorbic acid, n-hexacosanol and amino acid, 7-desacetyl-7-benzoylazadiradione, 7-desacetyl-7-benzoylgedunin, 17-hydroxyazadiradione, and nimbiol [ nimbiol –17. QuerAzadirachta indica), a member of the Meliaceae family, has therapeutics implication in the diseases prevention and treatment. But the exact molecular mechanism in the prevention of pathogenesis is not understood entirely. It is considered that Azadirachta indica shows therapeutic role due to the rich source of antioxidant and other valuable active compounds such as azadirachtin, nimbolinin, nimbin, nimbidin, nimbidol, salannin, and quercetin.Neem ( Azadirachta indica is presented as follows.Possible mechanism of action ofAzadirachta indica) plants parts shows antimicrobial role through inhibitory effect on microbial growth/potentiality of cell wall breakdown. Azadirachtin, a complex tetranortriterpenoid limonoid present in seeds, is the key constituent responsible for both antifeedant and toxic effects in insects [ in vitro antibacterial activity against both Staphylococcus aureus and MRSA with greatest zones of inhibition noted at 100% concentration [Neem plays role as free radical scavenging properties due to rich source of antioxidant. Azadirachtin and nimbolide showed concentration-dependent antiradical scavenging activity and reductive potential in the following order: nimbolide > azadirachtin > ascorbate .κB), and apoptosis .Neem ingredient shows effective role in the management of cancer through the regulation of cell signaling pathways. Neem modulates the activity of various tumour suppressor genes , angiogenesis (VEGF), transcription factors , and lipoxygenase (LOX) enzyme.Neem  and antioxidant capacity of different crude extracts was as follows: chloroform > butanol > ethyl acetate extract > hexane extract > methanol extract. Result of the current finding suggested that the chloroform crude extracts of neem could be used as a natural antioxidant [A valuable study was carried out to evaluateioxidant . Azadirachta indica A. Juss. and results revealed that ethanolic extract of flowers and seed oil at 200 μg/mL produced the highest free radical scavenging activity with 64.17 ± 0.02% and 66.34 ± 0.06%, respectively [Other results revealed that azadirachtin and nimbolide showed concentration-dependent antiradical scavenging activity and reductive potential in the following order: nimbolide > azadirachtin > ascorbate. Furthermore, administration of azadirachtin and nimbolide inhibited the development of DMBA-induced HBP carcinomas through prevention of procarcinogen activation and oxidative DNA damage and upregulation of antioxidant and carcinogen detoxification enzymes . Experimectively .μg/mL and total antioxidant activity of this extract was found to be 0.58 mM of standard ascorbic acid [The results of the study revealed that root bark extract exhibited higher free radical scavenging effect with 50% scavenging activity at 27.3 bic acid .Leaves, fruits, flowers, and stem bark extracts from the Siamese neem tree were evaluated for antioxidant and results of the study showed that leaf aqueous extract and flower and stem bark ethanol extracts showed higher free radical scavenging effect with 50% scavenging activity at 26.5, 27.9, and 30.6 microg/mL, respectively. Furthermore, total antioxidant activity of extracts was found to be 0.959, 0.988, and 1.064 mM of standard trolox, respectively .Cancer is multifactorial disease and major health problem worldwide. The alteration of molecular/genetic pathways plays role in the development and progression of cancer. The treatment module based on allopathic is effective on one side but also shows adverse effect on the normal cell. Earlier studies reported that plants and their constituents show inhibitory effects on the growth of malignant cells via modulation of cellular proliferation, apoptosis, tumour suppressor gene, and various other molecular pathways . Neem co50 values of 2.01 and 1.19 μM for 7 and 24 h, respectively [Neem oil holds various neem limonoids which prevents mutagenic effects of 7,12-dimethylbenz(a)anthracene . A studyectively . A studyectively .Azadirachta indica and their active compounds play pivotal role in the prevention of cancer development and progression. The exact molecular mechanism in this vista is not understood fully. Based on experimentation, it was considered that neem and its ingredients play role in the modulation of various cell signaling pathways. Azadirachta indica hold various ingredients and theses constituents activate the tumour suppressor genes and inactivate the activity of several genes involved in the cancer development and progression such as VEGF, NF-κB, and PI3K/Akt. Neem has been reported to be a good activator of tumour suppressor gene and inhibitor of VEGF and phosphoinositol PI3K/Akt pathways. It also activates apoptosis, suppression of NF-κB signaling, and cyclooxygenase pathway.Neem and its constituents play role in the prevention of malignancies through the modulation of molecular pathways which are described below.p53 is an important tumour suppressor gene and it plays role in the inhibition of the proliferation of abnormal cells, in that way inhibiting the development and progression of cancer. A study confirmed that ethanolic fraction of neem leaf (EFNL) treatment effectively upregulated the proapoptotic genes and proteins including p53, Bcl-2-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (pTEN), and c-Jun N-terminal kinase (JNK) . A findiNimbolide, a tetranortriterpenoid limonoid, is one of the important contributors to the cytotoxicity of neem extracts . NimbolipTEN activity is commonly lost via mutations, deletions, or promoter methylation silencing in various types of primary and metastatic cancers , 39. Ina in vivo 4T1 breast cancer model in mice and results confirmed that CN 250 and CN 500 groups had a higher incidence of apoptosis compared with the cancer controls [bcl2 and bax play an important role in the regulation of apoptotic process. Any alteration in bcl2 and bax causes the development and progression of tumours . Alteredcontrols . Anothercontrols .A study finding revealed that leaf extract downregulated Bcl-2 expression and upregulated Bim, caspase-8, and caspase-3 expression in the buccal pouch indicating that it has apoptosis inducing effects in the target organ  and studAngiogenesis is complex process that supplies blood to the tissue and that is essential for growth and metastasis of tumour. Angiogenesis is regulated by activators as well as inhibitors. The development of antiangiogenic agents to block new blood vessel growth is crucial step in the inhibition/prevention of tumour growth. Medicinal plants and their ingredients play role in prevention of tumour growth due to their antiangiogenic activity. in vitro and in vivo and also EENL suppressed the in vitro proliferation, invasion, and migration of HUVECs [An important study revealed that ethanolic fraction of neem leaf (EFNL) treatment effectively inhibited the expression of proangiogenic genes, vascular endothelial growth factor A, and angiopoietin, indicating the antiangiogenic potential of EFNL. Furthermore, inhibition of angiogenesis by ethanolic fraction of neem leaf (EFNL) could be a reason for reduction in mammary tumour volume and for blocked development of new tumours as observed in current studies . Anotherf HUVECs . A studyf HUVECs .An oncogene is a mutated gene that plays significant role in the development and progression of tumours. Experiment was performed to investigate effect of leaf extract on c-Myc oncogene expression in 4T1 breast cancer BALB/c mice and results revealed that 500 mg/kg neem leaf extract (C500) group showed significant suppression of c-Myc oncogene expression as compared to the cancer control group .PI3K/Akt pathways show pivotal effect in the promotion of tumour. However, inhibition of PI3K/Akt pathways is one of the important steps towards regulation of tumour development. Effect of leaf extract on PI3K/Akt and apoptotic pathway in prostate cancer cell lines (PC-3 and LNCaP) was investigated and results suggested that effect of leaf extract induces apoptosis and inhibits cell proliferation through inhibiting PI3K/Akt pathway in both PC-3 and LNCaP cells .Another study was performed to evaluate the molecular mechanisms involved in the induction of apoptosis and antiproliferative activity exerted by leaf extract on the human breast cancer cell lines and results confirmed that extract treated cells significantly decreased the protein expression such as IGF signaling molecules IGF-1R, Ras, Raf, p-Erk, p-Akt, and cyclin D1  .Another study was carried out to evaluate the effects of nimbolide on apoptosis and insulin-like growth factor (IGF) signaling molecules in androgen-independent prostate cancer (PC-3) cells line and results of the study suggested that nimbolide acts as a potent anticancer agent by inducing apoptosis and inhibiting cell proliferation via PI3K/Akt pathway in PC-3 cells .κB transcription factor plays a major role in cancer and related diseases [κB action is a vital step in the prevention of cancer development and progression. An important study was performed to investigate the efficacy of bioactive phytochemicals in inhibiting radiotherapy- (RT-) induced NF-κB activity, signaling, and NF-κB-dependent regulation of cell death and results showed that curcumin, leaf extract, and black raspberry extract (RSE) significantly inhibited both constitutive and RT-induced NF-κB [κB and Wnt signaling and induces intrinsic apoptosis in human hepatocarcinoma (HepG2) cells [The NF-diseases . Howevered NF-κB  and othe2) cells . A. indica leaves at a dose of 200 mg/kg, p.o., showed significant anti-inflammatory activity in cotton pellet granuloma assay in rats [Plants or their isolated derivatives are in the practice to treat/act as anti-inflammatory agents. A study result has confirmed that extract of in rats . Other s in rats  and stud in rats .Earlier finding showed immunomodulator and anti-inflammatory effect of bark and leave extracts and antipyretic and anti-inflammatory activities of oil seeds , 59. ExpAnother study was made to investigate the anti-inflammatory effect of neem seed oil (NSO) on albino rats using carrageenan-induced hind paw edema and results revealed that NSO showed increased inhibition of paw edema with the progressive increase in dose from 0.25 mL to 2 mL/kg body weight. At the dose of 2 mL/kg body weight, NSO showed maximum (53.14%) inhibition of edema at 4th hour of carrageenan injection .−1 dose of carbon tetrachloride extract (CTCE) of Azadirachta indica fruit skin and isolated ingredient azadiradione showed significant antinociceptive and anti-inflammatory activities [Results of the study concluded that the treated animals with 100 mg kgtivities .4) induced hepatotoxicity in rats and histology and ultrastructure results confirmed that pretreatment with azadirachtin-A dose-dependently reduced hepatocellular necrosis [Medicinal plants and their ingredients play a pivotal role as hepatoprotective without any adverse complications. A study was performed to investigate the hepatoprotective role of azadirachtin-A in carbon tetrachloride (CClnecrosis . Furthernecrosis .4) induced liver toxicity in rats and results suggest that nimbolide possesses hepatoprotective effect against CCl4 induced liver damage with efficiency similar to that of silymarin standard [Another study was carried out to evaluate the protective effect of active constituent of neem such as nimbolide against carbon tetrachloride (CClstandard  and anotstandard . Azadirachta indica (AI) leaf extract on antitubercular drugs-induced hepatotoxicity and results confirmed aqueous leaf extract significantly prevented changes in the serum levels of bilirubin, protein, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and significantly prevented the histological changes as compared to the group receiving antitubercular drugs [ A. indica exhibited moderate activity over carbon tetrachloride treated animals [ Azadirachta indica leaves was evaluated in rats and study result established that the plant has good potential to act as hepatoprotective agent [A study assesses the hepatoprotective activity ofar drugs . Additio animals . Hepatopve agent .An experiment was made to investigate the protective effect of neem extract on ethanol-induced gastric mucosal lesions in rats and results showed that pretreatment with neem extract showed protection against ethanol-induced gastric mucosal damage . A. indica and T. cordifolia using excision and incision wound models in Sprague Dawley rats and results revealed that extract of both plants significantly promoted the wound healing activity in both excision and incision wound models [ Azadirachta indica promote wound healing activity through increased inflammatory response and neovascularization [Numerous plants/their constituents play an important role in the wound healing effect. A study was made to evaluate the wound healing activity of the extracts of leaves ofd models . Furtherd models . Other rrization . Azadirachta indica in diabetic rats and results showed that in a glucose tolerance test with neem extract 250 mg/kg demonstrated glucose levels were significantly less as compared to the control group and Azadirachta indica significantly reduce glucose levels at 15th day in diabetic rats [A study was undertaken to evaluate the 70% alcoholic neem root bark extract (NRE) in diabetes and results showed that neem root bark extract showed statistically significant results in 800 mg/kg dose . Anothertic rats . in vivo diabetic murine model, A. indica, and B. spectabilis chloroform, methanolic, and aqueous extracts were investigated and results showed that A. indica chloroform extract and B. spectabilis aqueous, methanolic extracts showed a good oral glucose tolerance and significantly reduced the intestinal glucosidase activity [ Azadirachta indica and Andrographis paniculata have significant antidiabetic activity and could be a potential source for treatment of diabetes mellitus [Studies usingactivity . Anothermellitus .Neem and its ingredients play role in the inhibition of growth of numerous microbes such as viruses, bacteria, and pathogenic fungi. The role of neem in the prevention of microbial growth is described individually as follows.A study was performed to evaluate antimicrobial efficacy of herbal alternatives as endodontic irrigants and compared with the standard irrigant sodium hypochlorite and finding confirmed that leaf extracts and grape seed extracts showed zones of inhibition suggesting that they had antimicrobial properties . FurtherThe antibacterial activity of guava and neem extracts against 21 strains of foodborne pathogens was evaluated and result of the study suggested that guava and neem extracts possess compounds containing antibacterial properties that can potentially be useful to control foodborne pathogens and spoilage organisms . Azadirachta indica (neem) on bacteria isolated from adult mouth and results revealed that bark and leaf extracts showed antibacterial activity against all the test bacteria used [Another experiment was made to evaluate the antibacterial activity of the bark, leaf, seed, and fruit extracts ofria used . Furtherria used .μg/mL [Results showed that neem bark (NBE) extract significantly blocked HSV-1 entry into cells at concentrations ranging from 50 to 100 μg/mL . Furtherμg/mL .Azadirachta indica A. Juss.) (NCL-11) has shown virucidal activity against coxsackievirus virus B-4 as suggested via virus inactivation and yield reduction assay besides interfering at an early event of its replication cycle [Leaves extract of neem  as the fungicide has MIC of 0.78 mg [Aqueous extracts of various parts of neem such as neem oil and its chief principles have antifungal activities and have been reported by earlier investigators –86. A st 0.78 mg . Plasmodium berghei infected albino mice and results revealed that neem leaf and stem bark extracts reduced the level of parasitemia in infected mice by about 51–80% and 56–87%, respectively, [Experiment was made to evaluate the antimalarial activity of extracts usingctively,  and othectively, –91. Plasmodium falciparum, in vitro and results showed that, in separate 72-hour cultures of both asexual parasites and mature gametocytes treated with IRAB (0.5 microg/mL), parasite numbers were less than 50% of the numbers in control cultures, which had 8.0% and 8.5% parasitemia, respectively [Another finding based on crude acetone/water (50/50) extract of leaves (IRAB) was performed to evaluate the activity against the asexual and the sexual forms of the malaria parasite,ectively . A. indica mouth rinse is equally effective in reducing periodontal indices as chlorhexidine [A study was made to assess the efficacy of neem based on mouth rinse regarding its antigingivitis effect and study confirmed thathexidine . S. mutans. Chloroform extract showed strong activity against Streptococcus salivarius and third strain Fusobacterium nucleatum was highly sensitive to both ethanol and water extract [ neem showed maximum antibacterial activity against S. mutans as compared to S. salivarius, S. mitis, and S. sanguis [Another study was carried out to evaluate the antimicrobial properties of organic extracts of neem against three bacterial strains causing dental caries and results showed that petroleum ether and chloroform extract showed strong antimicrobial activity against extract . Earlier sanguis . Azadirachta indica (MLEN) on cisplatin- (CP-) induced nephrotoxicity and oxidative stress in rats and results confirmed that extract effectively rescues the kidney from CP-mediated oxidative damage [An experiment was made to investigate the effects of methanolic leaves extract ofe damage . Furthere damage . Azadirachta indica leaves against cisplatin- (CP-) induced neurotoxicity and results showed that morphological findings of neem before and after CP injection implied a well-preserved brain tissue. No changes, in biochemical parameters, were observed with neem treated groups [A study was performed to investigate the neuroprotective effects ofd groups .Experiment was performed to investigate growth promoting and immunomodulatory effects of neem leaves infusion on broiler chicks and results showed that neem infusion successfully improved antibody titre, growth performance, and gross return at the level of 50 mL/liter of fresh drinking water . A. indica (AI) on humoral and cell mediated immune responses, in broilers and results showed that AI (2 g/kg) treatment significantly enhanced the antibody titres against new castle disease virus (NCDV) antigen [Another study investigated the effects of feeding of powdered dry leaves of antigen .The measurement of toxicities of natural compound is crucial before their application in health management. Various studies based on animal model and clinical trials confirmed the neem is safe at certain dose and on the other side neem and its ingredients showed toxic/adverse effect.Several studies reported, in children, neem oil poisoning causing vomiting, hepatic toxicity, metabolic acidosis, and encephalopathy –102 and 50 values of neem oil were found to be 31.95 g/kg [50 of 4800 mg/kg, and clinical signs were dose dependent [A study result showed that, in the acute toxicity test, the LD.95 g/kg . Anotherependent .50) recorded for neem leaf and stem bark extracts were 31.62 and 489.90 mg/kg body weight, respectively [50 of water extract of A. indica leaves and seeds were 6.2, 9.4 mL kg−1, respectively [50 and LD90 values were found to be 8.4 and 169.8 µg/fly of neem extract, respectively [50 value of approximately 13 g/kg body weight [A study reported that lethal median doses  of gastric acid secretion. The bark extract at the dose of 30–60 mg twice daily for 10 weeks almost completely healed the duodenal ulcers and one case of esophageal ulcer and one case of gastric ulcer healed completely when administrated at the dose of 30 mg twice daily for 6 weeks .A double blind clinical drug trial study was performed to check the efficacy of drug made up of aqueous extract of neem leaves in 50 cases of uncomplicated psoriasis taking conventional coal tar regime and results revealed that patients taking drug in addition to coal tar had shown a quicker and better response in comparison to placebo group . A cliniPopularity of natural products or their derivatives role in diseases cure and prevention is increasing worldwide due to less side effect properties. Neem and its ingredients have therapeutics implication and have been traditionally used worldwide especially in Indian Subcontinent since ancient time. Clinical based studies confirmed that neem plays pivotal role in prevention of various diseases. The role of active ingredients as chemopreventive effect has been noticed in various tumour via modulation of numerous cell signaling pathways. The detailed study should be made based on animal to know the exact mechanism of action in the diseases management.


It was observed that the lattice of Ni3C was quickly relaxed upon thermal annealing at high temperature, resulting in an amorphous Ni3C catalyst structure. With the aid of the mobile nickel atoms, inner layer carbon atoms precipitated rapidly out of the surface and then formed polyyne chains and Y-junctions. The frequent sinusoidal-like vibration of the branched carbon configurations led to the formation of nascent graphene precursors. In light of the rapid decomposition of the crystalline Ni3C, it is proposed that the crystalline Ni3C is unlikely to be a reaction intermediate in the CVD-growth of graphene at high temperatures. However, results present here indicate that Ni3C films can be employed as precursors in the synthesis of graphene with exciting possibility.Graphene nucleation from crystalline Ni The as-grown graphene usually displays multiple imperfections such as wrinkles and grain boundaries, due to the weak interaction between graphene and copper51612Among the substrates used in the CVD process, Cu7910117et al. concluded that bulk crystalline Ni carbide is not present during graphene growth26910113C and graphene was provided by Cao et al.3C phase accompanied by the decomposition of Ni3C, further indicating that Ni3C plays an important role during the formation of graphene on nickel catalystsPrevious studies demonstrated that the following steps are involved in the graphene growth process on Ni-based catalysts: (1) gaseous hydrocarbons are adsorbed and decompose on nickel surfaces; (2) carbon adatoms dissolve into the subsurface or bulk nickel; (3) carbon atoms precipitate back to the nickel surface at low temperature and graphene is formed12192021111223243C phase. In doing so, we will reveal the atomistic mechanism of this non-equilibrium process and elucidate the relationship between the nucleation of graphene and the crystalline Ni3C phase at high temperature.In this study, we present quantum chemical molecular dynamics (QM/MD) simulations of graphene nucleation from crystalline NiThe model structure studied in this work is shown in n units gradually coalesced with each other to form extended polyyne chains and Y-junctions, which are the prerequisite for the formation of the carbon network. Meanwhile, the Mermin free energy3C system drops substantially by ca. 3.0 eV per Ni3C unit, due to repeated C-C bond formation, making the entire system to be more stable. This minimization of free energy is the driving force for carbon diffusion from bulk Ni3C substrate, which is in line with the observations of carbon nanofiber growthIt can be seen from n chains was formed at 16.0 ps. A hexagon was formed preferentially after ca. 20 ps, which is different from “pentagon-first” mechanism that is usually observed during graphene and carbon nanotube nucleation23n chains branching out from the original hexagon, and additional graphene rings were added to the nucleus (at 47.2 ps). It is noted that the sp2-hybridized structure remained flat throughout this process. Three pentagons and two hexagons were generated sequentially in the immediate vicinity of the original hexagon by the end of the simulation time (at 200 ps). A geometry analogous to the core-shell structured C21, which was found to be the precursor in the initial graphene CVD growth35362-carbon polygon driven by the sinusoidal-like vibration of the polyyne chains . This is similar to the graphene hole-healing processWith the continuous precipitation of carbon, many nickel atoms were also pulled out. This phenomenon favored the subsequent precipitation of the inner layer carbon atoms by providing larger interspace. On the other hand, the Ni-C3C system. 3C and amorphous Ni3C systems, respectively. These processes are similar in the changing trend of the ratio of carbon atoms, i.e., a drastic increase in the ratio of surface carbon atoms was accompanied by a simultaneous decrease in the ratio of subsurface carbon atoms. In addition, their equilibrium was reached much earlier  method13Te is the electronic temperature, fi is the fractional occupation numbers of Kohn-Sham eigenstates (0 ≤ fi ≤ 1), and Se is electronic entropy, respectively. This method has been previously applied extensively in the investigations of carbon nanostructure growth232425where 3C have been proposed: orthorhombic and hexagonal structures5354553C unit, which was corroborated by experimental observation of the existence of only hexagonal Ni3C533C with the lattice parameter of a = 4.553 Å and c = 12.92 Å was used in this work553C (001) surface to form the nuclei of hexagonal Ni3C phase. For the QM/MD simulations, a 3 × 3 supercell consisting of Ni162C54 was employed .


To avoid metal diffusion through the organic film, the author used (i) nanoscale bottom electrodes to reduce the probability of defects on the bottom electrodes and (ii) molecular crosslinked technology to avoid metal diffusion through the SAMs. The properties of the crosslinked self-assembled monolayer were determined by XPS. I-V characteristics of the device show thermally activated hopping transport. The implementation of this type of architecture will open up new vistas for a new class of devices for transport, storage, and computing.A bottom-up approach was devised to build a crossbar device using the crosslinked SAM of the 5,5′-bis (mercaptomethyl)-2,2′-bipyridine-Ni Only the mutuality of the parts creates the whole and its ability to function. In the language of chemistry, this means that the self-organization of molecules engenders supramolecular systems and is responsible for their functions. The application of self-assembly technology has been extended to surface science during the last two decades. Self-assembled monolayers (SAMs) are highly ordered organic molecular aggregates that are chemisorbed on surfaces with the thickness of a single molecule [Self-ordering principle was a basic idea of ancient philosophers: molecule -6. The cmolecule .Modification of the conjugate SAMs by electron beam allows fabrication of the crosslinked aromatic SAM ,9. Low-eMetallization of SAMs to design top electrodes is a subject of long-standing interest. Many applications can be found in everyday life. This subject has attracted great attention recently because of interest in organic electronics and light emitting diodes . Metal dThe current flowing through junctions composed of assemblies of molecules depends on the energy gap separating the Fermi levels of the electrodes and the valence band of the molecules. A redox-active center (Ni) has been incorporated into the organic backbones to improve the charge-transfer processes. Different studies of molecular redox center immobilized on metallic substrate indicate them as good conductors .2+ (BPD-Ni2+) has been prepared on top of the pre-patterned Au bottom contacts. Then the top Au contacts were evaporated. A two-electrode probe station was used to assess the fidelity of the molecular junctions. Additionally, to elucidate the molecular transport in the device junctions, temperature-dependent I-V examinations were performed.As described in this paper, a crossbar device with molecules as interconnecting elements was fabricated on gold bars (100 nm) and thus the use of crosslinked molecular self-assembled monolayer is demonstrated as compatible with use in crossbar nanoelectronic devices. A crosslinked SAM of 5,5′-bis (mercaptomethyl)-2,2′-bipyridine-Ni2 substrate. Photoresist PMMA 950 was spin-coated on SiO2 at 2,000 rpm for 90 s and baked at 180°C for 3 min . The resist was developed in MIBK methyl isobutyl ketone + IPA isopropanol 1:3 solution (MIBK-IPA) for 30 to 40 s to remove the irradiated zones and to form a pattern for the bottom electrode bars -2,2′-bipyridine was purchased from Aldrich and used as received. The SAM of 5,5′-bismercaptomethyl-2,2′-bipyridine (BPD) was prepared by immersing the bottom electrodes in freshly prepared 1-mM solution of  studies ,6. Subsef, S 2p, C 1 s, N 1 s, and Ni 2p regions. Spectrum acquisition was done in normal emission geometry using the Al K radiation. The binding energy (BE) scale of each spectrum was calibrated individually to the Au 4f7/2 emission of an n-alkanethiol-covered gold substrate at 83.95 eV. In addition, XPS data were used to ascertain the effective thickness of the target SAMs. This assessment was done based on the Au 4f intensity, assuming standard exponential attenuation of the photoelectron signal and using the attenuation lengths described in an earlier report [The BPD SAM fabricated as above was characterized using X-ray photoelectron spectroscopy (XPS). XPS spectroscopy measurements were conducted at the MANA Foundry using an XPS spectrometer . The XPS spectra were recorded in the Au 4r report .2) in proximity printing geometry using a metal TEM mesh as a mask. The patterned template was etched in an I2/KI-etch bath. As Figure The exposure of BPD-Ni film to electron beams engenders the formation of crosslinked SAMs. As shown in Figure 2). Then the resist was developed in the MIBK-IPA solution for 30 to 40 s to form the pattern for the top electrode lines. Finally, 10 nm of titanium and 150 nm of gold were deposited by electron-beam evaporation on the photoresist-patterned wafer. The wafer was immersed in acetone to remove the photoresist and the excess metal which adhered on the resist  was spin-coated on top of the PMMA at 2,000 rpm for 60 s. The 100-nm bar patterns perpendicularly aligned with respect to the bottom electrodes were fabricated using the electron beam lithography  on a cryostat modulated between 8 K and room temperature to probe the respective pads for the top and bottom contacts to the molecule.Temperature-dependent df, 2pd)) [Density functional theory (DFT) calculations were conducted using ORCA . The PBEf, 2pd)) .s, N 1 s, S 2p, and Ni 2p XPS spectra are portrayed in Figure s spectrum shows that the main peak at 285.5 eV is a superposition of the contribution from different carbons: the aliphatic (CH2) and the C = C moieties at the low binding energy  is commonly assigned to the thiolate species, which indicates that the molecules in the BPD films are attached to the substrate via the thiolate. The second doublet is at about 163.5 eV S2 (S 2p3/2) corresponding to sulfur of the free thiol (SH) groups or S-S bonds [s XPS spectra of the BPD SAM are displayed in Figure The spectral deconvolution of the S 2M Figure b was per-S bonds ,5. The N2 brings a significant change in the S 2p and the N 1 s spectra. The S 2p spectra  at the SAM interface decreases in intensity after exposure to Ni, which is probably attributable to the formation of the Ni thiolate species at the SAM-ambient interface [2 was not achieved, which indicates a partial formation of the Ni thiolate species at the SAM-ambient interface. In addition, it is noteworthy that the dithiol SAMs are extremely sensitive to photo-oxidation [Treatment of the BPD SAM with NiCla Figure b show a nterface ,18. In txidation ,6. Soluts spectra , which happens at low bias where the I-V is rather insensitive to temperature. They only differ in terms of voltage dependence [The temperature-dependent pendence . The secI)-log(V) plot of the I-V characteristics and the d2i/d2v versus voltage provides key information related to the transport mode of the molecules on metallic junctions [d2i/d2v versus voltage and the log(I)-log(V) plot of the I-V characteristics of the crosslinked BPD-Ni2+ on the crossbar devices. It is possible to discern different transport regimes as a function of the voltage using the log(I)-log(V) plot of the I-V characteristics. At the low-voltage bias, the plots are linear with a slope of about 1.45 for the different temperature. The crossbar architectures exhibit a second regime at the voltage higher then 0.45 with slope of about 4.31.The study of log on a gold surface and (ii) by reducing the area of the bottom electrodes (100 nm), the probability of the SAM defects is reduced.This report presents a novel method to produce a molecular electronic crossbar device basing in two strategies to avoid penetration of the metal through the organic film: (i) using the crosslinked self-assembled monolayer of 5,5′-bis (mercaptomethyl)-2,2′-bipyridine-NiI-V characteristics of devices show thermally activated hopping transport excluding existence of spurious metal filament transport. Further studies are in progress in our institute to elucidate the electron transfer mechanism in junctions based on a crosslinked SAM.Temperature-dependent The author declares that he has no competing interest.


However, molecular fingerprinting at the nanoscale level still remains a significant challenge, due to weak light–matter interaction between micron-wavelengthed infrared light and nano-sized molecules. Here we demonstrate molecular fingerprinting at the nanoscale level using our specially designed graphene plasmonic structure on CaF2 nanofilm. This structure not only avoids the plasmon–phonon hybridization, but also provides in situ electrically-tunable graphene plasmon covering the entire molecular fingerprint region, which was previously unattainable. In addition, undisturbed and highly confined graphene plasmon offers simultaneous detection of in-plane and out-of-plane vibrational modes with ultrahigh detection sensitivity down to the sub-monolayer level, significantly pushing the current detection limit of far-field mid-infrared spectroscopies. Our results provide a platform, fulfilling the long-awaited expectation of high sensitivity and selectivity far-field fingerprint detection of nano-scale molecules for numerous applications.Infrared spectroscopy, especially for molecular vibrations in the fingerprint region between 600 and 1,500 cm Despite being a powerful tool for molecular vibrational mode detection, infrared spectrosocpy is limited by weak sensitivity. Here, the authors demonstrate a platform for enhanced molecular fingerprint sensing based on a graphene/CaF2 nanofilm plasmonic structure. This eliminates the strong plasmon–phonon coupling issue in conventional graphene plasmonic structures, and enables the first electrically tunable plasmon that covers the entire molecular fingerprint region for molecular detection with extremely high sensitivity down to sub-monolayer level. Highly selective average enhancement of up to larger than 20-fold is achieved for unambiguous identification of vibrational fingerprints in polymers at the nanoscale with a far-field Fourier transform infrared spectroscopy. In addition, our graphene plasmonic devices can simultaneously identify in-plane and out-of-plane vibrational modes in complicated molecules. Our results provide a route for highly sensitive and selective identification of molecular structure fingerprints for diverse applications in anti-terrorism, food and healthcare and bio-sensing.Here we demonstrate a hybrid graphene plasmonic structure on a CaF2 thin-film based dielectric supporting substrate for graphene  substrates produce strong phonon-related resonance peaks in this spectral region  was used to characterize the plasmonic response of graphene nanoribbons (see Methods for further details).  phonons . This in−1). Most absorption peaks cannot be distinguished from the background noise, which is expected from weak light–molecule interaction in this spectral range. In striking contrast to the noisy results without plasmon enhancement, the extinction spectrum  polyethylene oxide (PEO) films as analyte because infrared spectra of PEO bulk films are well-studied and feature fourteen well-characterized molecular vibrational modes in the fingerprint regionubstrate , which c−1  has been enhanced by more than ten times  with a 1:3 graphene ribbon-to-pitch ratio, and the plasmonic field enhancement is strongly concentrated at the ribbon edges, the enhancement factor at the ribbon edges should be substantially larger than the average enhancement factor. We also tested the reusability of our plasmonic sensors  of the mode F located at 1,123 cm sensors , which s−1 by changing ΔCNP from −6 to −21 V. The signal strengths of vibrational modes A and B gradually decrease when ΔCNP decreases from −6 to −21 V, which is expected because the graphene plasmon resonance frequency is tuned away from these modes. However, because the graphene plasmon resonance frequency is tuned towards the H, I, J and K modes, the signal intensities of these modes rapidly increase with a decrease in ΔCNP. To further investigate this frequency-selective function quantitatively, we fit the fourteen vibrational modes, extracted their peak areas and calculated their enhancement factors based on our experimental results  between the vibrational mode and graphene plasmon. As expected, these fitted curves follow the fundamental principle of plasmonic enhancement: molecular signal enhancement (ΔI) is inversely proportional to the frequency detuning Δf (ΔI ∼ 1/Δf)−1, an interaction mode between the symmetric stretching of the C-C group and anti-symmetric stretching of the C–O–C group in the PEO molecules) can be adjusted from 2.5 to 23 via graphene plasmon frequency tuning.The graphene plasmon broadband electrical tunability offers unique frequency-selective enhancement for individual vibrational modes in our molecular fingerprint sensor as demonstrated by the plasmon-enhanced molecular fingerprinting results . For exain situ frequency-selective enhancement and thus facilitate unambiguous identification of complex molecular compounds and structures through correlation with structural vibrational fingerprint detection.In addition, with the electrical tunability enhancement, we can distinguish the overlapping vibrational modes in the pristine absorption spectrum. For example, the E and F modes cannot be distinguished in the absorption spectrum . However−1 and the out-of-plane structure vibrational mode at ∼820 cm−1 cannot be detected using the conventional infrared microscopyx and z directions, and their enhancements are comparable  are not typically visible for conventional infrared microscopy because these vibrational modes cannot respond to incident light with a polarization direction perpendicular to its vibrational directionmparable . Therefod from the graphene ribbons . Thanks to the electrical tunability of graphene plasmon, we can tune its resonance with the gate voltage to selectively identify the vibrational fingerprints of sub-monolayer polymer . These observations clearly indicate that our molecular fingerprint sensor is highly sensitive and selective even for sub-monolayer molecules detection.In principle, highly confined graphene plasmons can facilitate high-sensitivity, sub-monolayer detection. On the basis of near-field distribution, we calculated near-field intensity confinement as a function of a given distance  ribbons . The dat ribbons . Such suIn conclusion, we demonstrate high sensitivity and selectivity molecular fingerprinting with a graphene plasmon based far-field Fourier transform infrared spectroscopy. We enhance ∼8-nm PEO film vibrational signatures up to larger than 20-fold. We also show that our method can detect structural vibrational modes  in molecules with a resolution previously unachievable using conventional mid-infrared absorption spectroscopy. Our graphene plasmon based far-field molecular fingerprint spectroscopy can facilitate various applications, such as functional studies on trace matter in biology and pharmacology.2 (285 nm)/Si substrate using the PMMA-assisted method. Nanoribbon arrays were patterned onto the graphene surface using electron beam lithography  in PMMA followed by oxygen plasma etching. An additional electron beam lithography process and electronic beam evaporation were used to define the electrodes. We deposited a 300-nm thick CaF2 film onto a low-doped Si substrate using electronic beam evaporation. The complete graphene device was then transferred onto the CaF2/Si substrate. A thin (∼8 nm) PEO polymer layer was spin-coated onto the sensor as a sensing sample.Graphene and monolayer h-BN were grown on copper foil through chemical vapour deposition methods and transferred onto a SiOPatterned graphene nanoribbons were characterized with scanning electron microscopy (Hitachi S-4800) and atomic force microscopy (Neaspec s-SNOM). The graphene quality was confirmed by Raman spectroscopy (Horiba Jobin Yvon LabRAM HR800) before and after oxygen ion bombardment under PMMA protection. The electrical transport properties were characterized using a semiconductor parameter analyser (Agilent 4294A) at room temperature.2/Si substrate was used to extract the background signal from the pristine PEO film absorption spectrum. The graphene nanoribbon array transmission spectra at CNP (TCNP) were used as background, and the transmission spectra (TEF) at certain Femi levels EF were collected to obtain the plasmonic extinction spectra by 1−TEF/TCNP. Thus, the extinction spectra are purely plasmonic signals excited by the incident light. Each measurement was repeated several times to confirm the extinction spectrum.Infrared transmission measurements were performed using a FTIR microscopy (Thermo Fisher Nicolet iN10). We generated a background spectrum for each measurement. A bare CaFt and imposed the relative permittivity The graphene plasmons were simulated by using the finite element method. The infrared lights impinge perpendicular on graphene nanoribbons. We modelled graphene as a thin film with a thickness of The data that support the findings of this study are available from the corresponding author upon request.How to cite this article: Hu, H. et al. Far-field nanoscale infrared spectroscopy of vibrational fingerprints of molecules with graphene plasmons. Nat. Commun. 7:12334 doi: 10.1038/ncomms12334 (2016).Supplementary Figures 1-15, Supplementary Notes 1-4, Supplementary ReferencesThe ChemDraw file for the chemical structure of the PEO molecule.


The XPS patterns revealed the formation of Sn-C-O bonds. Both SEM and TEM imaging of the electrode material showed that the three dimensional network of graphene aerogels and the SnO2 particles were distributed homogeneously on graphene sheets. Finally, the electrochemical properties of the samples as active anode materials for lithium-ion batteries were tested and examined by constant current charge–discharge cycling and the finding fully described in this manuscript.In this work it is shown how porous graphene aerogels fabricated by an eco-friendly and simple technological process, could be used as electrodes in lithium- ion batteries. The proposed graphene framework exhibited excellent performance including high reversible capacities, superior cycling stability and rate capability. A significantly lower temperature (75 °C) than the one currently utilized in battery manufacturing was utilized for self-assembly hence providing potential significant savings to the industrial production. After annealing at 600 °C, the formation of Sn-C-O bonds between the SnO With the development of new electrode materials and technology innovations, LIBs which have high charge-discharge rate and specific capacity, have shown great advantages in the electronic field1232/graphene composites used as anode material by a hydrothermal method with a process heating to 200 °C for 24 h. What is more, the composites were grinded into powder and then mixed with acetylene carbon black (15 wt%) and polyvinylidene fluoride(10 wt%) in N-methyl-2-pyrrolidone (NMP). Lastly, vacuum treatment for 12 h was required to prepare working electrods. Nonetheless, this strategy could not take full advantage of the virtues of GA as clearly the grinding process disrupts the natural GA’s 3D framework. Additionally, conductive agents and binders are indispensable in this type of manufacturing hence increasing the weight of the batteries and complicating the manufacturing process. Thus, such method not only has a lengthy manufacturing process, but also cannot take fully advantage of the aerogel as a three dimensional conductive network.Currently, most studies describe graphene hydrogels preparation by hydrothermal method516182-reduced graphene aerogels which have the merits of excellent cycling performance, environmental friendliness, and simple manufacturing process. In the synthesis process for graphene hydrogels, graphene oxide was reduced in a simple mold at low temperature (75 °C). Moreover, Sn-C-O bonds between SnO2 nanoparticles and GS were formed after annealing at 600 °C, which will initiate synergistic effect as well as improve the electrochemical performance. Graphene aerogels could then be used as LIBs electrode materials without any further processing or binder addition. Such freestanding and binder-less 3-D graphene with a remarkably high specific surface area and due to the porous structure and an excellent conductivity2221Herein, we proposed and developed a simple yet novel strategy to fabricate porous SnO2/graphene aerogels which could be used in LIBs without any conductive agent and binder was successfully prepared and characterized in this work. In the proposed manufacturing method, the significantly lower SnO2/graphene self-assembly temperature of 75 °C  tightly as a result of electrostatic attraction302 particles will remain anchored on the surface of graphene sheets after sonication and stirring. The dark brown color of the SnO2-GO dispersion suggested that the SnO2 nanoparticles were adhering directly onto the graphene sheets. Subsequently, L-ascorbic acid was used as reducing agent to transform in situ Graphene Oxide (GO) into reduced GO (rGO)2 particles was reduced to GS and self-assembled into a 3D hydrogel. Such reaction would result in the increase and enlargement of delocalized π-bond’s conjugative effect2 nanoparticles had polar surfaces, they interacted with functional groups via hydrogen bonding6272 and rGO by forming Sn-O-C bonds after annealing at 600 °C. Moreover, such bridges would stabilize the SnO2 nanoparticles on the graphene surface, moreover, facilitate the electron, transfer and improve the electrode stability4SnO2/Graphene hydrogels is schematically shown in It is known that graphene aerogels have excellent conductivity and mechanical strength which suggests that graphene aerogels could be directly used as electrodes without any additional additives132-GA were characterized both by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). 2 nanoparticles were approximately in the range of 4 nm to 10 nm, moreover, the nanoparticles appeared to anchor on the GS firmly and homogeneously.The morphologies of SnO2-rGA and SnO2-GA. For SnO2-rGA; the two prominent peaks at ~1339 cm−1 and ~1576.5 cm−1 corresponded to D and G bands, respectively. For SnO2-GA, the G-band was around 1338 cm−1 and the D bands was around 1577 cm−1. The intensity ration of the D to G peak (ID/IG) increased from 1.199 to 1.283, which could be explained by the size decrease of the sp2 domain and confirmed the reduction of graphene oxide after heat treatment355/2and Sn3d3/2. The peak at 487.2 eV of Sn3d5/2 belonged to Sn4+ in SnO27. This peak confirmed the presence of SnO2 on the surface of graphene layers. The peak of O1s was shown in 2 nanoparticles, which could initiate synergistic effect and improve the electrochemical properties382 nanoparticles and GS was physisorption. Without any chemical bonds, the interaction between SnO2 nanoparticles and GS was Van der Waals force and hydrogen bond, the SnO2 nanoparticles may separate form GS during Li+ insertion and extraction, resulting in the attenuation of capacity during charge/discharge cycling. After annealing at 600 °C, the hydrogen bonds transform into oxygen bridges and form Sn-C-O bonds, which would strongly anchor the SnO2 nanoparticles and initiate synergistic effect. The synergistic effect between GS and SnO2 nanoparticles was larger than the contribution of all constitutive componentsX-ray photoelectron spectroscopy (XPS) was carried out to confirm the surface chemical state and the chemical elements in the framework after annealing. According to the high-resolution scan spectrum , it was 302 anchored on the graphene sheets’ surface in the nano-composites was tested by thermogravimetric analysis (TGA) from 25 °C to 800 °C with a heating rate of 5 °C min−1  measurements with current density of 200 mA g−1 with voltage between 0.01 and 3 V, were carried out. It was noteworthy that the specific capacities were calculated on the basis of the weight of the active nanocomposites materials. 2-GA using charge-discharge repetition at a current density of 100 mA g−1, the typical charge-discharge profiles of SnO2-GA in the 1st, 2nd, 10th, 50th, 100th and 200th cycles are shown in 2-GA displays a discharging capacity of 1295.2 mAh g−1 and a reversible lithium de-intercalation charging capacity of 857.9 mAh g−1 with coulombic efficiency of 66.2%. In the second cycle, the reversible discharge capacity of SnO2-GA was found to be 866.6 mAh g−1. Subsequently the value decreases to 783.5 mAh g−1 in the 31th cycle and then increased to 867.3 mAh g−1 in the 99th cycle. Moreover, the coulombic efficiency was found to be higher than 96.5% after the 3rd cycle. Because the graphene structure was porous and elastic, when graphene nanostructure was compressed and used as electrodes, the porous structure prevented substantial shrinkage. Furthermore, the structure subsequently inflated during the charge/discharge cycles8292-GA at different current densities of 100 mA g−1, 200 mA g−1, 500 mA g−1,1500 mA g−1, 3000 mA g−1 are illustrated in −1. Furthermore, the capacity not only did not decrease, but even increased at higher current density of 200 mA g−1, 500 mA g−1, 1500 mA g−1 as well as 3000 mA g−1. When the current density returned to 100 mA g−1, the reversible capacity remained at 750 mAh g−1, indicating the nanocomposite displayed an excellent electro-chemical performance. One possible explanation for the superior capability and stable cycling performance of the material was that graphene wafer had a large contact surface area with the electrolyte. Moreover, the lithium ions could be adsorbed to the surface of graphene layers physically during the charging and discharging cycles because of the extensive surface area. The synergistic effect34432 nanoparticles and graphene layers as well as the decomposition of electrolyte could contribute to the increase in capacity452 nanoparticles, and the electrical conductivity, and mechanical flexibility of the graphene structure. The uniform distribution of SnO2 nanoparticles played a vital role in improving the electrochemical properties of LIBs. Since the graphene wafer prepared was porous and elastic, it could accommodate the volume expansion of SnO2 during charge/discharge cycles. In addition, the porous and interconnected graphene nanostructure could provide an effective conduction path for electron transfer and accommodate the mechanical strain caused by the Li+ insertion/extraction41To evaluate the electrochemical properties of SnO2-GA between 0 and 3 V vs. Li+/Li at a sweep rate of 0.5 mV s−1. In the first cycle, the electrode was unstable because no binder was used in the batteries and the contact did not reach an ideal state. After the first cycle, the curves were found to be more consistent. It could be seen from the curves that there were four reduction peaks at 1.21 V, 0.82 V, 0.45 V, ~0.2 V, respectively. Along with the formation of Li2O, the transition from SnO2 to Sn  measurements as shown in 2 adsorption-desorption isotherms exhibited a typical II hysteresis loop as a relative pressure between 0.45 to 0.96, characteristic of pores with different pore sizes. The nitrogen physisorption measurements traced the change of pore structure and the specific area was calculated to be 168 m2 g−1 while the pore diameter was distributed mainly at approximately 3 nm. These results demonstrated that it is feasible to obtain three dimensional graphene frameworks with solvothermal assembly approach. Moreover, the high porosity provided more surface area for lithium-ions insertion and extraction reactions as well as more room for SnO2 expansion.The porous nature of SnO2-rGA after 10 cycles and SnO2-rGA after 200 cycles as well as the equivalent circuit model. It was found that R2 and R3 were due to the solid electrolyte interface impedance and to the charge transfer resistance, respectively. Moreover, the liner part of the plot is likely due to the lithium diffusion in the 3D porous network462-rGA-20 was smaller than that of SnO2-rGA-10, implying that the prepared electrodes were stable during charge/discharge cyclesElectrochemical impedance spectroscopy (EIS) measurements were utilized to study the electrode’s superior electrochemical performance and the kinetics properties2/GA are shown in 2/GA and eliminated the volume expansion of SnO2 nanoparticles, which will lead to an excellent stability, resulting in excellent performance during discharge/charge cycling. Although a SEI layer  de-ionized water was added slowly. Then, 213 ml of warm (80 °C) water and 15 ml of H2O2 were added. The mixture was separated by centrifugation and washed by HCl solution (HCl/H2O = 1/10) three times. At last, the mixture was dissolved in de-ionized water and dispersed homogeneous by ultrasonic agitation for several hours.Graphene oxide (GO) dispersion was prepared by a modified Hummers method. Briefly, 3 g of graphite powder, 1.5 g of NaNO4·5 H2O was dissolved in 200 ml de-ionized water and then hydrothermally treated at 160 °C for 16 hours. The obtained white precipitate was washed by centrifugation three times and re-dispersed in 200 ml ethanol to form a suspension.2.325 g of SnCl2 dispersion was added drop-wise into 6 ml graphene oxide (2 mg ml−1) so that the mass ratio of graphene oxide and SnO2 was 1:1. In order to achieve homogeneous dispersion, additional stirring and ultrasonic agitation were carried out for more than 24 consecutive hours. Afterwards, 120 mg of ascorbic acid powder was added into the mixture and stirred for an additional 30 minutes. The dispersion was added into a mold and put into a draught drying cabinet at 75 °C for 4 hours to obtain 3D graphene hydrogels. Subsequently, the monolith was released from the mold and put in de-ionized water for 24 hours, and freeze-dried into graphene aerogel  analysis was conducted using a Kratos AXIS Ultra DLD spectrometer with a monochromatic AlKa X-ray source. Conductivity was measured by a four-point probe method in the van der Pauw configuration with an Accent HL5500 system. N2 adsorption/desorption isotherms were determined by an Auto sorb IQ instrument. The Brunauer-Emmett-Teller (BET) method was carried out to calculate the surface areas.The morphology of samples was characterized by transmission electron microscope . Field-emission scanning electron microscope (FE-SEM) analysis was performed on JSM-6700F at an acceleration voltage of 10.0 kV. X-ray photoelectron spectroscopic (XPS) measurements were performed on a Kratos AXIS Ultra DLD spectrometer with a monochromatic AlKa X-ray source. Thermal gravimetic analysis (TGA) was conducted in oxygen atmosphere at a heating rate of 5 °C minHow to cite this article: Chen, Z. et al. Three dimensional Graphene aerogels as binder-less, freestanding, elastic and high-performance electrodes for lithium-ion batteries. Sci. Rep. 6, 27365; doi: 10.1038/srep27365 (2016).


Investigation of the redox properties of drugs and their determination are performed by electrochemical techniques. Data obtained from electrochemical techniques are often correlated with molecular structure and pharmacological activity of drugs. In this regard, different modified electrodes were applied as sensors for quantification of different drugs.A nanocomposite of reduced graphene oxide-cobalt hexacyanoferrate was synthesized by a simple precipitation route. Scanning electron microscopy revealed that the nanocomposite comprised nanoparticles of cobalt hexacyanoferrate attached to the reduced graphene oxide nanosheets. A nanocomposite-modified carbon paste electrode was then fabricated. It represented prominent activity toward the electrocatalytic oxidation of ascorbic acid, and the kinetics of the electrooxidation process was evaluated. Finally, an amperometric method was developed for the quantification of ascorbic acid in different pharmaceutical formulations. Graphene is a single layer of carbon atoms arranged in a hexagonal lattice structure. It is the first two-dimensional crystalline material to be isolated, and owing to its single atom thick nature, it is of immense scientific and applied interest -2. Graphia+ [M’(CN)6]b. n H2O due to their attractive properties and applications in different devices  or vitamin C, as an essential water-soluble vitamin, represents an essential role in many important physiological and metabolic processes such as free radical scavenging, improving immunity and preventing cancer . AA whic In the present study, the capability of the reduced graphene oxide-CoHCF nanocomposite, prepared by simple precipitation method, as an amperometric sensor for the determination of ascorbic acid in different pharmaceutical formulation, was described. The amperometric method was based on the mediated electro oxidation of ascorbic acid.Chemicals and reagents All chemicals used were analytical grade from Merck (Germany) or Sigma (USA) and were used without further purification. Graphite fine powder with an average size of <50 μm was received from Merck (Germany). The AA pharmaceutical forms were obtained from a local drugstore. All solutions were prepared with redistilled water.Synthesis of reduced graphene oxide2O2 solution was added to the mixture until the color of the mixture changed into brilliant yellow. The suspension was filtered and the obtained graphene oxide was thoroughly washed by redistilled water. Then the graphene oxide was re-dispersed in redistilled water and exfoliated to generate graphene oxide nanosheets using an ultrasonic bath for 3 hours. The suspension gradually evolved into a brown solution during the ultrasonication, and the bulk graphene oxide powders were transformed into nanosheets. Finally, the exfoliated graphene oxide was reduced to graphene nanosheets by refluxing the graphene oxide solution with hydrazine monohydrate at 100 ºC for 2 hours, and the color of the solution turned into dark black. The final product (the reduced form of graphene oxide) was filtered, washed by redistilled water and ethanol and dried in an oven at 80 ºC.Graphene oxide was synthesized from natural graphite using a modified Hummer’s method  .In a tySynthesis of reduced graphene oxide-cobalt hexacyanoferrate nanocomposite3)2 containing 12.4 mM KCl and sonicated for 30 min. Then, 5 mL solution of 12.4 mM K3Fe (CN)6 was added drop-wise under vigorous stirring. Finally, the mixture was sonicated for 5 min to obtain a precipitate. The precipitate was centrifuged and firstly washed with 3% NaCl solution and then washed three times with redistilled water. The product was dried at room temperature. In order to synthesize the nanocomposite, CoHCF was deposited on the surface of the nanosheets of reduced graphene oxide via a solution-phase deposition. For the deposition, 50 mg graphene was firstly dispersed in 5 mL solution of 2.5 mM Co  powered by an μ-Autolab type III potentiostat/galvanostat (the Netherlands). An Ag/AgCl, 3M KCl, a platinum disk and a modified carbon paste electrode were used as the reference, counter and working electrodes, respectively. The system ran on a PC through GPES 4.9 software. In order to obtain information about the morphology and size of the graphene nanosheets, scanning electron microscopy (SEM) was performed using a X-30 Philips (Germany) instrument. SEM images were analyzed using manual microstructure distance measurement software .Working electrodes preparationUnmodified carbon paste electrode (UCPE) was prepared by hand-mixing carbon powder and mineral oil with an 80/20% (w/w) ratio. The paste was carefully mixed and homogenized in an agate mortar for 20 min. The resulting paste before use was kept at room temperature in a desiccator. The paste was ﬁrmly packed into a cavity (1.0 mm diameter and 2.0 mm depth) at the end of a Teflon tube. Electrical contact was established via a copper wire connected to the paste in the inner hole of the tube. The electrode surface was gently smoothed by rubbing on a piece of weighing paper just prior to use. This procedure was also used to regenerate the surface of the carbon paste electrodes. Modified carbon paste electrode (MCPE) was prepared by mixing weighed amounts of carbon powder, Nujol and the nanocomposite with ratios of 60:20:20, %w/w in a similar fashion.Analysis of AA pharmaceutical forms Different AA pharmaceutical forms were analyzed including effervescent and chewable tablets, ampoules and sachets. For analysis of the tablets, the average weight of ten tablets from each sample was determined; then, the tablets were finely powdered and homogenized in a mortar. Appropriate and accurately weighed amounts of the homogenized powder were transferred into 100 mL calibrated flasks containing 50 mL of PBS. The contents of the flasks were sonicated for 30 min, and then the undissolved excipients were removed by filtration and diluted to volume with PBS. Appropriate solutions were prepared by taking suitable aliquots of the clear filtrate and diluting them with PBS. For analysis of the sachets, the average weight of ten sachets was determined; then, the sachet contents were finely powdered and homogenized in a mortar and dissolved in 100 mL calibrated flasks containing 50 mL of PBS and diluted to volume with PBS. The ampoule contents were diluted by PBS and directly analyzed.Surface morphologies The surface morphology of reduced graphene oxide and the nanocomposite was evaluated by SEM micrographs. Electrocatalytic oxidation of AA on the MCPE surface-1 is shown in pa/Ipc) was almost equal to unity. Based on the direct evidence obtained from combined cyclic voltammetry and in situ IR spectroelectrochemistry techniques  involve cation insertion into the MHCF solid state and electron transfer within MHCF .-4 M AA in PBS is shown in  Cyclic voltammograms of UCPE and MCPE recorded in the absence and presence of 3.7510Kinetics of the AA electrooxidation process Chronoamperometry technique was also employed to study the mass transfer kinetics and obtain the heterogeneous catalytic rate constant in the electro catalytic mechanism )4110cat and Id are the currents in the presence and absence of AA, respectively, ζ=kcatCt is the argument of the error function, kcat is the catalytic rate constant, and t is the elapsed time (1/2) becomes almost unity and the above equation is simplified as:Where Ised time  .In the cat/Id versus t1/2 is shown in cat=8.87(±0.21)104 cm3 mol-1 s-1.The plot of IAmperometric determination of AA In order to develop an electrochemical sensor for the analysis of AA, an amperometric method was developed. Typical amperometric signals obtained during successive addition of AA to PBS are shown in Selectivity, durability and stability Selectivity of the amperometric sensor for the assay of AA was examined in the presence of some common excipients/ingredients in the same ratios usually used in pharmaceutical preparations. These interferences/ingredients include microcrystalline cellulose, magnesium stearate, phenyl alanine, aspartame, tartaric acid, sodium bicarbonate, citric acid, calcium carbonate, sucrose crystalline, polyethylene glycol, acetylsalicylic acid, acetylcysteine, sorbitol, lactose, and sodium saccharin. The results showed no significant interference from these compounds, because they are not electroreactive at the working potential, pH and the modified electrode. Therefore, the procedure is able to assay the drug in the presence of excipients/ingredients and, hence, it can be considered selective. In order to verify the durability and long-term stability of MCPE, 50 consecutive cyclic voltammograms using this electrode were recorded in PBS. The results showed that the peak currents changed slightly (<5%). In addition, the electrode was stored in PBS when not in use, retaining its electrochemical reactivity for four weeks.Determination of AA in pharmaceutical forms The applicability of the proposed amperometric method for the sample dosage form was examined by analyzing different AA pharmaceutical forms. It was found that the drug concentrations determined using this method were in good agreement with the reported values, as reported in  A nanocomposite of reduced graphene oxide-cobalt hexacyanoferrate was synthesized via a precipitation route. Cobalt hexacyanoferrate was deposited as nanoparticles of 50 nm on the graphene surface. This method would be useful for the synthesis of other MHCFs-graphene nanocomposites. The electrochemical behavior of the nanocomposite was studied by cyclic voltammetry and the kinetics of charge transfer and mass transport processes within the nanocomposite were evaluated. The nanocomposite has been applied to fabricate a modified carbon paste electrode and employed as an efficient electrocatalytic transducer for the electrocatalytic oxidation of AA. The AA electrooxidation process was diffusion-controlled, and the catalytic rate constant and diffusion coefficient involved in the reaction were reported. The amperometric responses of the electrode indicated that AA can be determined by high sensitivity in pharmaceutical formulations. The electrode can be applied in routine analysis of AA and as a detector in detecting systems.


Immunohistochemical detection of PD-L1 may be used in the future as a biomarker to help select an immunotherapeutic regimen for patients with advanced melanoma. For example, patients whose tumors are PD-L1+ may receive anti-PD-1 monotherapy, and those whose tumors are PD-L1(-) may receive combination anti-PD-1 and anti-CTLA-4. The evaluation of the utility of PD-L1 as a biomarker has been hampered by the different antibodies and assays used. The purpose of this study was to quantitatively compare staining properties of three different PD-L1 monoclonal antibodies that have been used in recent landmark publications.Immunohistochemistry for PD-L1 was performed on serial sections from fourteen formalin-fixed paraffin-embedded archival melanoma samples using three different monoclonal antibodies: 5h1, SP142, and E1L3N. Slides were imaged using the Vectra Automated Quantitative Pathology Imaging System, and using intensity thresholds set by two pathologists, were scored for the percentage of total cells (melanocytes and immune cells) demonstrating PD-L1 staining. The observed staining intensity in the samples below the threshold considered to be “positive” by the pathologists was used as a measure of background staining for each antibody.2 = 0.11, p = 0.25) or SP142 (Figure Membranous PD-L1 expression in melanoma samples detected with 5h1 and SP142 was highly correlated (Figure The commercially available clone SP142 demonstrates comparable staining properties to 5h1, while the E1L3N, at least under the conditions used in this study, does not. Similar comparisons including additional proprietary clones, such as 28-8 and 22C3, will be essential in understanding how best to use reported PD-L1 status from various assays to guide therapeutic selection in patients with advanced melanoma.