Nitrogen and phosphorus dual-doped multilayer graphene (NPG) was prepared by arc discharge process.NPG exhibits good rate capability and stable cycling performance in both lithium and potassium ion batteries.Full carbon-based lithium/potassium ion capacitors are assembled and show excellent electrochemical performance.The online version of this article (10.1007/s40820-019-0260-6) contains supplementary material, which is available to authorized users. 6‖active carbon (AC) LICs and NPG‖KPF6‖AC PICs are assembled and show excellent electrochemical performance, with competitive energy and power densities. This work provides a route for the large-scale production of dual-doped graphene as a universal anode material for high-performance alkali ion batteries and capacitors.Lithium/potassium ion capacitors (LICs/PICs) have been proposed to bridge the performance gap between high-energy batteries and high-power capacitors. However, their development is hindered by the choice, electrochemical performance, and preparation technique of the battery-type anode materials. Herein, a nitrogen and phosphorus dual-doped multilayer graphene (NPG) material is designed and synthesized through an arc discharge process, using low-cost graphite and solid nitrogen and phosphorus sources. When employed as the anode material, NPG exhibits high capacity, remarkable rate capability, and stable cycling performance in both lithium and potassium ion batteries. This excellent electrochemical performance is ascribed to the synergistic effect of nitrogen and phosphorus doping, which enhances the electrochemical conductivity, provides a higher number of ion storage sites, and leads to increased interlayer spacing. Full carbon-based NPG‖LiPFThe online version of this article (10.1007/s40820-019-0260-6) contains supplementary material, which is available to authorized users. Nevertheless, the production costs of LIBs show an increasing trend, due to the limited availability of lithium sources . Recentlcouple − .931 V [2−1) and poor rate performance cannot meet the increasingly high energy and power density demands of lithium ion capacitors (LICs) [Graphite is currently commercialized as an anode material for LIBs. However, its low theoretical specific capacity (372 mAh gs (LICs) . Graphens (LICs) . Recentls (LICs) , 7. For s (LICs) . The incs (LICs) . Moreoves (LICs) . Thus, d3 or another atmosphere. The rigorous reaction conditions and toxic reactants greatly limit the practical applications of this approach [π–π interactions, irreversible stacking of graphene invariably occurs in the direct thermal annealing process [Heteroatom-doped graphene is usually synthesized through post-thermal treatment and direct synthesis. In the case of post-treatment methods, graphene or graphene oxide has to be obtained first, followed by treatment in NHapproach , 12. Due process , 14. The2 atmosphere, with (NH4)3PO4 as the source of nitrogen and phosphorus. The large-scale NPG nanosheets are composed of 2–6 graphene layers, with P and N concentrations of about 1.3 and 3.2 at.%, respectively. Owing to its remarkable structure and uniform heteroatom doping, NPG displays an extraordinary electrochemical performance as an anode material for LIBs. The enhanced lithium storage properties of NPG are attributed to the synergistic effect of the nitrogen and phosphorus dopants. When employed as anode for PIBs, NPG also shows high capacity, good rate capability, and stable cycling performance. Moreover, full carbon-based LICs and PICs are assembled using the as-prepared NPG as anode and active carbon (AC) as cathode. Both LICs and PICs exhibit a high voltage window, high energy density, and remarkable power density, demonstrating their potential applications. This work introduces a facile arc discharge approach to prepare graphene doped with different heteroatoms, with promising potential as an anode material. In addition, the present work may provide a new route to design high-performance electrode materials for not only Li/K ion batteries or capacitors, but also other energy storage systems.Herein, a one-step arc discharge method is employed to obtain dual N, P heteroatom co-doped graphene (NPG) under He and H4)3PO4 powders were then loaded into the cavity of the graphite rod as the raw materials, and the resulting rod was used as the cathode. At the same time, a pure graphite rod served as the anode. The cathode and anode were placed in a vacuum chamber pumped to below 1 Pa. The arc discharge process was carried out in a water-cooled stainless-steel chamber under a steady current of 120 A and a voltage of 15 V. Hydrogen and helium were introduced into the pre-vacuumed chamber as working atmospheres at a volume ratio of 1:3; both gases had 99.99% purity. NPG was obtained after cooling the cavity to room temperature. For comparison, N-doped graphene (NG) was obtained by introducing NH3 into the reactant gas in the absence of (NH4)3PO4, while P-doped graphene (PG) was obtained by introducing the same number of moles of phosphate instead of (NH4)3PO4. Pure graphene was obtained under the same conditions, without (NH4)3PO4. Graphene sheets were exfoliated by arc discharge in a buffer gas mixture of H2 (10 kPa) and He (90 kPa).The NPG material was prepared by a one-step arc discharge method. In a typical procedure, graphite powders were first compressed into a rod, and an opening was drilled in the center of the rod. (NHX-ray diffraction (XRD) patterns were obtained with a Siemens D500 diffractometer, to investigate the crystal structure of the samples. The surface morphologies and detailed microstructures were analyzed by scanning electron microscopy  and transmission electron microscopy . The Raman spectra were obtained using a LabRAM HR800 confocal microscopic spectrometer with a laser excitation wavelength of 532 nm. The surface elemental composition and bonding configuration were determined by X-ray photoelectron spectroscopy . Thermogravimetric analysis (TGA) was carried out with a Netzsch STA 449C thermal analyzer.N-methylpyrrolidinone solution. The mixtures were mixed evenly, coated onto copper foil substrates and dried at 110 °C for 24 h in a vacuum oven; the cells were then assembled in an argon-filled glove box. The mass loading of the active material was about 1 mg cm−2. The electrolytes used for LIBs and PIBs were 1 M LiPF6 and 1 M KPF6, respectively, in ethylene carbonate/diethyl carbonate . Polypropylene film and lithium foil were used as the separator and counter electrode, respectively, for LIBs. A glass microfiber filter film and potassium foil were used as the separator and counter electrode, respectively, for PIBs. Charge/discharge tests were performed in the 0.01–3.0 V voltage window at various current densities, using a Neware battery tester. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) measurements of the electrodes were carried out on a Bio-Liogic VMP3 workstation. The CV measurements were conducted with a sweep rate of 0.1 mV s−1 in the range of 0.01–3.0 V. The frequency range of the EIS tests was set to 0.01–100 kHz, with a 5 mV amplitude.The electrochemical performances were tested using CR2032 coin-type cells. The electrode materials were prepared by mixing the active material, Super P conductive additive, and the polyvinylidene fluoride binder at 8:1:1 weight ratio in the −1 over five cycles, with a final lithiation at 1.0 V. LICs and PICs were then assembled with AC as the cathode and activated NPG as the anode in cathode/anode mass ratios of 1:1, 2:1, 4:1, 6:1, and 8:1.Before assembling the LICs and PICs, the NPG half-cells were tested by lithiation at 0.02 V followed by delithiation at 3.0 V and 100 mA gC, mAh g−1) of both half and full cells were derived from galvanostatic charge/discharge (GCD) curves according to Eq. I is the discharge current, t is the discharge time, and m is the mass of AC. The energy density  and power density  of the LIC and PIC systems were calculated from the GCD curves according to Eqs. V(t) is the potential of the device and m is the total mass of NPG and AC.The specific capacities C, mAh g− of both entclass1pt{minima4)3PO4, which was used as both nitrogen and phosphorus source. Due to the enormous cooling gradient under the arc discharge process, the nitrogen and phosphorus atoms could be isolated from (NH4)3PO4 and rapidly doped into the graphene structure. In the case of the NG and PG samples, nitrogen and phosphorus atoms were generated from NH3 and pure red phosphorus, respectively. Defect sites would be generated during the doping process, via the adsorption of dissociated oxygen atoms on the surface of graphene.The synthetic strategy for the preparation of NPG is schematically illustrated in Fig. The arc discharge exfoliation protocol is a fast and straightforward route to achieve mass production of doped graphene. The output depends on the size of the graphite rod and the reaction time. In this work, 1.0 g NPG Fig. a was preθ = 26.1° indicates a highly organized crystal structure, such as that of standard graphene [−1 can be assigned to the D, G, and 2D bands, respectively. The G band is ascribed to the zone center Eg2 mode related to phonon vibrations in sp2 carbon materials [IG/ID) corresponds to the amount of defects in graphene [IG/ID intensity ratios of the G, NG, PG, and NPG products are 2.26, 2.32, 2.38, and 2.31, respectively. The defects present in pristine graphene can be doped or replaced with nitrogen and phosphorus, resulting in little changes in the IG/ID ratio. Moreover, the IG/I2D ratio can be used to determine the number of graphene layers, with smaller IG/I2D values denoting fewer layers [IG/I2D intensity ratios of the four products are calculated to be ~ 0.75, suggesting that the obtained graphene sheets are mainly composed of 2–6 layers [s, O 1s, P 2p, and N 1s signals, respectively, indicating the successful P and N doping in graphene. The analysis shows that the amounts of nitrogen and phosphorus doped into graphene are 3.2 and 1.3 at.%, respectively. High-resolution C 1s, N 1s, and P 2p XPS spectra of NPG were also collected to gain further insight into the nitrogen and phosphorus doping. The peaks located at 284.6, 285.8, and 287.3 eV in Fig. S3 can be attributed to C–C, C–P, and C=N groups [s, N 1s, and P 2p XPS spectra of NG and PG are shown in Figs. S4, S5, respectively. The spectra of NG, PG, and G are identical in all respects, except for the presence of nitrogen and phosphorus in NG and PG. The amount of nitrogen and phosphorus doped into NG and PG, as estimated by the elemental analysis of the XPS data, are 3.31 and 1.18 at.%, respectively.The XRD analysis was used to characterize the crystal structure of NPG, NG, PG, and graphene sheets, as shown in Fig. graphene . Moreoveaterials . The D bgraphene . The intr layers . As show6 layers , which iN groups , 23, resN groups . The preN groups . For com−1, as shown in Fig. −1 in the voltage range from 0.01 to 3 V, measured in the 20th, 50th, 100th, 200th, and 500th cycle. In the first cycle, the NPG electrode delivers a lithiation capacity of 1383 mAh g−1 and a charge capacity 859 mAh g−1 at a current density of 100 mA g−1. The irreversible capacity is due to the SEI formation and to the irreversible lithium storage, in agreement with the CV results. For comparison, NG shows initial discharge and charge capacities of 982 and 636 mAh g−1, respectively, while the values obtained for PG are 913 and 576 mAh g−1, respectively , which are much lower than those of NPG. This suggests that co-doping with heteroatoms could provide a higher number of lithium ion storage sites and an improved capacity. In addition, the profiles largely maintain their shape with increasing number of discharge–charge cycles, demonstrating a good structural stability. Figure −1. A reversible discharge capacity of 758 mAh g−1 is obtained even at a high current density of 2000 mA g−1, denoting a high rate performance. A potential plateau is observed at under 0.5 V, which can enhance the working voltage of the full cell. Figure −1 at current densities of 100 and 2000 mA g−1, respectively, which is higher than those of undoped G, NG, and PG, respectively. Owing to the similar morphology and structure of NPG, G, NG, and PG, the enhancement of the reversible electrochemical performance observed for NPG should be attributed to the N and P doping. Furthermore, all samples exhibit a small capacity loss at each current density  and a nearly 100% recovery of discharge and charge capacities when the rate is restored to 100 mA g−1, demonstrating a remarkable rate capability. Moreover, the stable capacity of NPG obtained at each current rate is also higher than that of the G, NG, and PG samples. The enhanced capacity of NPG is ascribed to the synergistic effect of phosphorus and nitrogen co-doping in graphene. The capacity enhancement is closely related to the doping content of nitrogen or phosphorus. As shown in Fig. S7, the NPG sample displays not only an enhanced capacity upon doping with nitrogen and phosphorus, but also a further increase in capacity due to the synergistic effect of N and P co-doping. Figure −1. A reversible capacity of 798 mAh g−1 is achieved in the initial cycles. After 1000 cycles, NPG retains a capacity of 787 mAh g−1, corresponding to a retention of 98.6% and a fading of 0.0014% per cycle. Moreover, NPG displays a stable coulombic efficiency of ~ 100% during the whole cycling process, with the exception of the initial cycles. For comparison, Fig. S6 shows that the discharge capacities of G, PG, and NG are about 280, 570, and 627 mAh g−1, respectively, at the same current density, confirming that heteroatom doping can improve the capacity of graphene. The AC impedance of NPG before and after cycling is shown in Fig. To investigate the electrochemical performance, CV tests were carried out at a scan rate of 0.1 mV s+/K and Li+/Li couples, the irreversible peak is located at 0.6 V. In addition, the CV curves retain a similar shape in the second and third cycle, indicating a highly reversible potassium ion storage behavior in the NPG sample. Galvanostatic charge–discharge tests were carried out to further investigate the electrochemical performance of NPG in PIBs. As shown in Fig. −1, respectively. The large irreversible capacity is due to the formation of the SEI layer and the irreversible potassium ion storage on defect and edge sites of the NPG. Considering that the atomic radius of potassium ions (1.38 Å) is larger than that of lithium ions (0.76 Å), NPG provides a lower number of ion storage sites, leading to more potassium ions irreversibly binding to the defect and edge sites of NPG; thus, NPG shows a lower capacity and initial coulombic efficiency. A coulombic efficiency of 98% is obtained for the NPG electrode during cycling, except for the first cycle, indicating the high reversibility of the intercalation/extraction process of potassium ions. Moreover, the rate capability of the NPG sample is shown in Fig. −1 are 387, 324, 280, 247, and 194 mAh g−1, respectively. When the current density is switched back to 200 mA g−1, the discharge capacity returns to 270 mAh g−1, highlighting an outstanding rate capability . At the same time, the discharge–charge profiles maintain similar shapes at various current densities, confirming the good rate performance and structural stability. The NPG electrode also exhibits a remarkable cycling stability, as shown in Fig. −1 is achieved at the current density of 500 mA g−1. The capacity shows a slow decrease in the first 50 cycles, followed by a gradual increase due to the activation process during cycling. A discharge capacity of 242 mAh g−1 is obtained after 500 cycles. NPG also shows a stable coulombic efficiency of ~ 100%, except for the initial cycles. This indicates that potassium ions could be reversibly stored in NPG, which thus represents a promising anode material for PIBs [Potassium ion batteries have attracted considerable attention, due to their low cost and potential application in large-scale energy storage systems. Thus, the potassium storage behavior of NPG was also investigated by CV. As shown in Fig. for PIBs .Fig. 5a The high reversible capacity, rate performance, and cycling ability of NPG as the anode material for both LIBs and PIBs can be attributed to the intrinsic properties of graphene and the synergistic effect of N and P doping. First, the arc discharge method could produce high-quality and few-layer graphene nanosheets. The small thickness could provide shorter diffusion paths for lithium/potassium ions, and the large surface area enhances the contact between active materials and electrolyte. Second, doping with nitrogen atoms introduces active sites in graphene, providing additional storage sites for lithium/potassium ions , 31. At v)  at a given potential (V) can be determined from the diffusion-controlled and surface capacitive contributions  on the basis of the following equation: i(V) = k1v + k2v1/2 [k1 and k2 constants. The typical profile in Fig. −1 to a maximum value of 72.8% at 1 mV s−1  Fig. a. The cu+ k2v1/2 –28. The s−1 Fig. c. Simila −1 Fig. f. This fsite//AC , AC//sodsite//AC , graphitsite//AC , TiO2/rexide//AC , peanut  [2Ti3O7 , LiNi0.5.3O2//AC , nitroge.3O2//AC , and TiO−1 and outstanding cyclability over 1000 cycles at the current density of 1000 mA g−1. Moreover, NPG also shows remarkable electrochemical performance as the anode material for PIBs. A capacity of 194 mAh g−1 is obtained at the current density of 1000 mA g−1. Even at a high current density of 500 mA g−1, NPG exhibits a high reversible capacity along with a stable cycling performance after 500 cycles. In addition, full carbon-based NPG‖LiPF6‖AC LICs and NPG‖KPF6‖AC PICs show capacities of 98 and 56 mAh g−1 at 1 A g−1, respectively. Maximum energy densities of 195 and 104.4 Wh kg−1 and power densities of 14,983.7 and 14,976 W kg−1 can be achieved for the LICs and PICs, respectively, demonstrating the potential applications of NPG anodes. Thus, the arc discharge method is an effective way to prepare graphene doped with various heteroatoms, which can be used as promising electrode materials for high-performance energy storage systems. Moreover, multiple doping represents a smart option to improve the electrochemical performance of electrode materials, including not only graphene, but also other carbon-based materials.An anode material based on nitrogen and phosphorus dual-doped graphene has been successfully designed and synthesized via a one-step arc discharge method. NPG can be employed as a universal anode material for lithium ion and potassium ion batteries. As anode for LIBs, NPG displays a high specific capacity of 889 mAh gSupplementary material 1 (PDF 859 kb)Below is the link to the electronic supplementary material.


Patient-centric care entails optimising healthcare provision to patients based on their perspective and opinion. It involves appropriate treatment at a reasonable cost and a focus on patient characteristics in the decision-making process to make it more personally useful. The optimisation of medicines in the older population is a challenge due to physiological changes, comorbidity, and polypharmacy. Furthermore, patient-centric care is difficult to achieve due to the high proportion of patients with dementia and frailty. Decision support concerning the appropriateness of indication, formulation, dose, administration, co-prescribing, and length of treatment to older patients is frequently in demand. In the current study, we aimed to review clinical questions concerning administration and dosage to older patients of relevance to patient-centric care. We analysed questions concerning medicines to patients 65 years or older in the database of the network of Norwegian drug information centres from 2010 to 2020. The analysis included the distribution of drugs, diseases, and recurring topics among the questions. Through a Boolean search that combined the indexed categories of “older” and “administration and dosage”, we retrieved 84 question-answer pairs. Questions about psychotropic and cardiovascular drugs in relation to therapy, adverse drug reactions, and pharmacokinetics dominated, and more than 60% of the questions came from physicians. Topics relevant to patient-centric pharmacotherapy were drug withdrawal (10 questions), drug formulation (8 questions), drug initiation (8 questions), and switching drugs (5 questions). One question concerned drug withdrawal and switching, and one question drug formulation and switching. Answers provided decision support regarding appropriate formulations of drugs to patients with dementia who chew capsules or tablets, the use of parenteral administration in patients who refuse to take oral formulations, and the pharmacokinetics of transdermal or rectal drug administration. The results highlight the importance of including pharmacological factors in the assessment of the acceptability and appropriateness of oral and parenteral medicine to older patients. Patient-centric care entails optimising healthcare provision to patients based on their personal perspective and opinion ,2. In a The optimisation of medicines in the older population is a challenge due to physiological changes, comorbidity, and polypharmacy. Appropriate indication, formulation, dose, administration, co-prescribing, and length of treatment are frequent clinical issues. Patient-centric pharmaceutical drug product design, formulation, and optimisation for the older population is of current interest . HoweverNorwegian drug information centres provide decision support for drug-related questions from health care professionals in four health regions serving the total Norwegian population. In a previous study, we found frequent questions concerning psychopharmacology and cardiovascular pharmacology concerning older patients . In the Regional Medicines Information and Pharmacovigilance Centres (RELIS) is a Norwegian network of drug information centres providing decision support for health care professionals  in four health regions. The centres are associated with clinical pharmacology units in regional university hospitals, and pharmacists and physicians with expertise in searching and critically evaluating literature constitute the staff in the centres . RELIS pWe performed a Boolean search combining the category “older” with the category “administration & dosage” in the period 1 January 2010–30 September 2020. Q/As from all types of healthcare occupations and workplaces were included, since patient-centric care involves communication with, and observation of, patients in general practice, pharmacies, nursing homes, and hospitals . The WHODescriptive statistical analyses were performed with SPSS version 26 . Percentages were not rounded up to 100 in either text or tables. Notice that the same question can include several drugs, indexed categories, descriptive categories, and diseases. Several drugs in a question can belong to the same main ATC group (ATC 1st level). ICD-11 can also include symptoms, and some questions concern the use of drugs in relation to procedures such as surgery or diagnostic measures.The database contained 51,867 Q/As by the end of September 2020, and RELIS handled 3305 questions in 2019. In the study period, the size of the RELIS database increased from 19,785 to 51,867 Q/As. Two Q/As were excluded from the 86 Q/As retrieved by the Boolean search. In one Q/A, the patient was younger than 65 years, and in the other Q/A the category “older” was indexed when the appropriate category was “adverse drug reaction”. The final 84 Q/As were relatively evenly distributed (4–11 per year) over the study period, with the exception of a peak of 18 questions in 2015.Fifty-four questions (64%) came from physicians and 25 (30%) from pharmacists. Three questions (4%) came from nurses, one (1%) from a dentist, and one (1%) from a patient relative. The four major workplaces were general practice (GP) and pharmacies, with 24 questions (29%) each; nursing homes with 18 questions (21%); and hospitals with 14 questions (17%). Sixty-three questions (75%) were patient-related, and 21 (25%) were general. Among the patient-related questions, 35 questions (54%) concerned women, 13 questions (21%) concerned men, and in 16 questions (25%) gender was unknown. Regarding age, 18 (29%) of the 63 patient-related questions concerned patients in their eighties, 9 questions (14%) concerned patients in their seventies, 8 questions (13%) concerned patients in their nineties, and 5 questions (8%) concerned patients in their late sixties (≥65 years). In 23 (37%) patient-related questions, age was unknown. Three of the general questions (14%) concerned patients older than 80 years, and one question (5%) concerned a patient older than 95 years. In 17 general questions (81%), age was not described. The eighty-four questions concerned 129 brand drug names that involved 82 chemical or generic substances (ATC 5th level). The two most frequent generic substances were acetylsalicylic acid (6 questions) and metoprolol (5 questions). According to the WHO ATC system, the four most frequent ATC groups (ATC 1st level) were N (nervous system) with 53 counts, B (blood and blood-forming organs) with 24 counts, A  with 18 counts, and C (cardiovascular system) with 14 counts. The 84 questions concerned 104 diseases and three procedures . According to WHO ICD-11, the questions covered 13 codes, of which the majority concerned mental, behavioural, or neurodevelopmental disorders (24 questions), diseases of the circulatory system (20 questions), diseases of the digestive system (11 questions), and diseases of the genitourinary system (11 questions). See The 84 Q/As were indexed 90 times across eight categories , such asIn this descriptive study, we aimed to review clinical questions concerning the administration and dosage of medicines to older patients of relevance to patient-centric care. The search in the RELIS database showed that questions about psychotropic and cardiovascular drugs in relation to therapy, adverse drug reactions, and pharmacokinetics dominated. More than 60% of the questions came from physicians. Our results are in accordance with a previous study on questions concerning older patients in the same database from the period 2010–2015 ,21,22. WWe do not know to what degree the distribution of drugs in the questions is influenced by factors such as the availability of authorised product information, professional handbooks, other drug information sources or the size of the portfolio of drug products. Although the pharmacokinetic information on the formulations in the summaries of product characteristics (SmPCs) is quite comprehensive, physicians still infrequently use this source . FurtherAdverse drug reactions, treatment, and pharmacokinetics are frequent reasons for questions to drug information centres ,23,24. TOur examples reflect the problem with eating disturbances and drug intake among patients with dementia. Eating habits such as chewing or sucking without trying to eat is associated with mild to moderate dementia, while swallowing disturbance becomes critical in severe disease according to an observational study of 200 patients with Alzheimer’s disease . Our exaDysphagia is common in the elderly  and is aThe long-term use of prescribed and over-the-counter effervescent formulations is reported to be frequent among older people according to a study from the UK . A possiThe perception that the absorption and bioavailability of transdermal and rectal formulations are limited in older patients could potentially reduce the use of alternative routes of administration. Transdermal formulations are particularly useful for the administration of analgesic drugs to patients with dysphagia, and the formulations are now available in several strengths to allow titration of dose. RELIS have received questions about cutting patches to allow titration, but we warn against this practice. A case reported in 2013 to the Institute for Safe Medication Practices (ISMP) described a physician who instructed staff from a hospice health care agency to cut a 50 mcg/h fentanyl transdermal system patch in half and apply it to a patient to deliver a 25 mcg/h dose . A conseRELIS receive frequent questions concerning the switching of psychotropic drugs. In a commentary from 2016 we described several risk factors associated with this therapeutic intervention. Our experience is that physicians and other health care professionals are unaware of withdrawal reactions to old drugs, early-onset ADRs to new drugs, and that they lack knowledge about the role of active metabolites and interactions during switching . The queWhen interventions of treatment and care are carried out despite the resistance of the patient and/or against the patient’s will or knowledge, this is termed as coerced treatment and care. . A studyLength of prophylactic treatment in older patients is also a relevant ethical and clinical question. In our study, this issue concerned osteoporosis and dementia, among other diseases. A problem is that there are no clear age limits, and many of the drugs are proposed to be effective in old age. Thus, we receive numerous questions from physicians who want to discuss problems that the recommendations and clinical guidelines cannot answer. The example with intermittent use of acetylsalicylic acid where the physician was advised to weigh cardiovascular risk and strength of indication against acceptability on behalf of the patient, show that RELIS are aware of the principles of patient-centric care. The individual assessment of a patient and including the patient perspective is of importance in our work.The material in this study is naturalistic and descriptive, with a risk of biased interpretation. The great number of topics presented excludes a thorough discussion of each. Notice that the answers to the questions are related to the year they were provided. Furthermore, questions to RELIS are spontaneous, and do not necessarily represent drug problems perceived by the general population of health care professionals. However, in comparison to spontaneous ADR reports, a question to RELIS is in the context of clinical decision support, and as such a more deliberate action on behalf of a health care professional with a motivation to provide the best possible treatment of their patients.The examples from the recurring topics focused on pharmacological factors associated with different formulations and administration of generic substances. However, the RELIS database is searchable for brand names, and health care professionals often submit questions about choice or differences between brands. We are aware of potential differences between brands as well as generic copies, but RELIS are independent of the pharmaceutical industry and we usually avoid favouring any specific trademarks in our answers. The examples also raise several ethical issues, and RELIS use a disclaimer on all written answers to state that they are based on the available literature and other resources, and health care professionals have sole responsibility for using the content of the answers in their treatment of patients. Our credibility among health care professionals relies on the fact that they can safely ask us all sorts of drug-related questions knowing that RELIS have no control function with regard to their professional practice. If we receive questions from patients or relatives, we usually motivate them to discuss the questions with their treating physician. Accordingly, RELIS do not interfere in the physician–patient relationship.Although the problems presented are known in patient-centric care, a review of our database could be useful to find relevant topics for drug information activities for clinicians and patients. In particular, this is because the topics concern everyday, real-world problems not sufficiently described in recommendations and guidelines. Our selection of questions concerning the administration and dosage of medicines in older patients could be used to propose topics relevant to patient-centric medicine design. Furthermore, relevant stakeholders, including the pharmaceutical industry, should be aware of the specific drug information needs with regard to rational use in a patient population with specific challenges.Our review of the database of the Norwegian drug information centres highlights the importance of assessing pharmacological factors in decision support concerning the acceptability and appropriateness of oral and parenteral medicine in older patients. Drugs and diseases of priority include those concerning the nervous system, blood and blood-forming organs, the digestive system, and the cardiovascular system. Through examples, we have described practical solutions to drug-related problems. The practical solutions involve several principles of importance for patient-centric care and involve scenarios that could motivate patient-centric medicine design. Given the current focus on new design of medicine, our present topics with examples could generate hypotheses to be tested in clinical settings in future studies.


Affinity biosensors based on graphene field-effect transistor (GFET) or resistor designs require the utilization of graphene’s exceptional electrical properties. Therefore, it is critical when designing these sensors, that the electrical properties of graphene are maintained throughout the functionalization process. To that end, non-covalent functionalization may be preferred over covalent modification. Drop-cast 1,5-diaminonaphthalene (DAN) was investigated as a quick and simple method for the non-covalent amine functionalization of carbon-based surfaces such as graphene, for use in biosensor development. In this work, multiple graphene surfaces were functionalized with DAN via a drop-cast method, leading to amine moieties, available for subsequent attachment to receptor molecules. Successful modification of graphene with DAN via a drop-cast method was confirmed using X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and real-time resistance measurements. Successful attachment of receptor molecules also confirmed using the aforementioned techniques. Furthermore, an investigation into the effect of sequential wash steps which are required in biosensor manufacture, on the presence of the DAN layer, confirmed that the functional layer was not removed, even after multiple solvent exposures. Drop-cast DAN is thus, a viable fast and robust method for the amine functionalization of graphene surfaces for use in biosensor development. Graphene possesses exceptional electrical properties ,2 such a2 carbon bonds in the aromatic lattice and the subsequent introduction of sp3 bonds at these reaction sites, reducing the aromaticity of the graphene lattice and therefore affecting the properties of the graphene as electrical mobility is reduced −3/−4 in 1 × PBS (pH 7.4), at a scan rate of 50 mV/s. An increase in peak current is observed after DAN functionalization ,  Figure a in 5 mMlization a. This sTo ensure that the measured peak current changes were due to the presence of DAN on the graphene surface and not due to solvent interference, a control sample was measured using ethanol only in the place of DAN (using the same drop-cast method). A cyclic voltammogram for the ethanol only control can be seen in −1 can vary across the surface of the graphene device before modification, however, its intensity ratio to the G peak (ID/IG) is generally seen to increase after modification with DAN . The full width half maximum (FWHM) of the “D” peak broadens from ~34 cm−1 to ~190 cm−1 after surface modification. This broadening of the peak suggests that it contains a component from the C-N band at 1247 cm−1, from the DAN, as further evidenced by its asymmetric shape. The intensity ratio of the “2D” peak (~2678 cm−1) to the G peak changes dramatically following DAN modification, from 2D/IGI ~2.5 for unmodified graphene to ~0.3 following modification. This change in peak ratio is consistent with the addition of aromatic carbon-containing molecules to monolayer graphene surfaces [Raman spectroscopy was used to monitor the effects of surface modification of monolayer graphene with drop-cast DAN. Extended Raman scans were taken using a Renishaw inVia Raman system  with a 532 nm laser. Before surface modification, typical Raman spectra of graphene devices were obtained. Representative point spectra are shown in surfaces ,37.−1 and 2600 cm−1, in a grid pattern. Peak analysis based on previous reports [2 is typically p-doped [2) might be intrinsic or n-doped [2 substrate, The positions of the G and 2D peaks can be used to indicate doping and strain in graphene. Raman spectra were obtained, centered at 1600 cm reports ,38,39 wa p-doped , under a n-doped . A shift n-doped . Before 2/Si substrates, graphene with surface modification (DAN) and graphene with surface modification followed by attachment of an antibody (DAN + Ab), using a Kratos Axis Supra XPS system  using an Al Kα monochromatic X-ray source with an emission current of 15 mA at 20 eV pass energy. A minimum of three scan locations per sample were used to ensure the spectra were representative of the surface. 2 layer along with organic contaminants on the graphene surface (C-O/C=O) [2), corresponding to an atomic concentration of approximately 2.2%. Following the application of the antibody (and after standard wash steps), a further increase in the N 1s signal is evident (10.9 at. %), along with an attenuation of the Si 2s/2p and O 1s substrate signals, consistent with surface antibody coverage. The atomic concentrations for the samples are summarized in Functionalization with amine moieties should further allow for attachment of receptor molecules in affinity biosensors, e.g., antibody molecules. To that end, non-covalent functionalization of graphene with drop-cast DAN has been used for attachment of an antibody , providing evidence of its viability as a functional layer. X-ray photoelectron spectroscopy (XPS) measurements were performed, on unmodified graphene (before surface modification with DAN (blank graphene)) on SiOC-O/C=O) . Followi2/sp3 C-C contribution above the predominantly sp2 graphene blank , relaxation occurred over 5.5 h, this relaxation time occurs after any exposure of the graphene to solution and it is not a DAN specific effect. Long relaxation times occur with solution on bare graphene, e.g., 2/Si substrates [Real-time resistance data, bstrates ,46 and t2)) steps are also shown in 2. The I–V linear sweep measurements were therefore performed on dry samples. The ∆R/R0 for DAN functionalized resistor devices was + 0.078 ± 0.039 (SD of N = 13), and the ∆R/R0 for the ethanol only control resistor devices was −0.069 ± 0.043 (SD of N = 13), individual measurements can be found in 2 substrates [2/Si substrates). DAN is diluted in 70% ethanol, which has a slight p-doping effect; however, the final resistances increased above bare graphene (dry intrinsic resistance), meaning these changes in resistance are due to the likely electron donation from DAN and not due to solvent effects.As there is a resistance change after surface modification  which could affect device-to-device performance issues. Amorphous carbon made and deposited on the graphene during the growth process (CVD), residues left by fabrication chemicals or residual polymer left behind from the graphene transfer process [R/R0 of DAN functionalized graphene resistor devices. Whether the contaminants e.g., aromatic resist components, are electron acceptors or donors can affect doping of the graphene, and as the level of contamination varies with each manufacturing step, the level of doping will, therefore, show variation between batches but also between devices in the same batch.Variation in the final ∆ process  can all  process . Causes  process . The pre process  and can Exposure of the functionalization layer to multiple solvents is inevitable during affinity biosensor development, it is, therefore, essential to check the ability of the drop-cast DAN to withstand these multiple solvent exposures. The strength of the π-π stacking between the graphene surface and the aromatic molecules of the functionalization layer e.g., DAN can make the surface stacking quite stable against rinsing or other solution processing . An inveThe wash step investigation consisted of an initial ethanol wash to remove residual DAN from the surface , followed by 1, 2, or 3 DI water washes, to simulate further standard biosensor process steps. XPS analysis indicates that the DAN layer is not affected or removed by sequential wash steps. This is shown in 3 carbon, C-O and C=O bonds [2/Si substrate [After peak fitting, several additional peaks were found in the unmodified graphene sample at ~284.76, ~285.67, and ~286.27 eV, =O bonds . These bubstrate ,55. Afteubstrate . Followiubstrate ,57.−1, 1598 cm−1, and 2692 cm−1, respectively. After each successive DI water wash, the peaks red shift slightly until, after 3 DI water washes, the D-peak, G-peak, and 2D-peaks reach 1358 cm−1, 1603 cm−1, and 2700 cm−1, respectively. These shifts are consistent with graphene being p-doped with water [ID/IG), at ~1350 cm−1 and 1580 cm−1 respectively, are consistently around 0.2. Also, the I2D/IG ratio decreases from approximately 2 to approximately 0.55 for the modified samples, which is consistent for all wash steps. Both XPS and Raman results from subsequent wash steps of drop-cast DAN modified graphene demonstrate that the functionalized surface is robust for use in a biosensor process sequence after multiple solvent exposures.Raman spectra were also obtained following subsequent wash steps. Drop-cast DAN as a robust and facile method to amine functionalize carbon surfaces has been demonstrated. The addition of a functional layer containing amine groups allows for further bio-functionalization with specific receptors, using common crosslinking chemistries such as carbodiimide EDC-NHS, for the development of affinity biosensors. Real-time resistance measurements, cyclic voltammetry, XPS, and Raman analysis showed successful modification of graphene surfaces with DAN. As the purpose of surface modification with DAN was to provide amine moieties for further bio-functionalization with receptor molecules, the successful attachment of an antibody molecule was also confirmed, further demonstrating the viability of drop-cast DAN as a surface functionalization strategy. The robustness of the DAN and subsequently crosslinked antibody to withstand multiple washes was also demonstrated, with the presence of the DAN layer and successful antibody attachment confirmed via XPS, Raman spectroscopy, cyclic voltammetry, and real-time resistance measurements. The viability of drop-cast DAN as a surface functionalization method, providing available amine moieties was demonstrated with the resultant attachment shown to withstand multiple wash steps, therefore, providing a quick and simple route to prototype for biosensor development.


Reducing the capacitive opening between subwavelength metallic objects down to atomic scales or bridging the gap by a conductive path reveals new plasmonic spectral features, known as charge transfer plasmon (CTP). We review the origin, properties, and trending applications of this modes and show how they can be well-understood by classical electrodynamics and quantum mechanics principles. Particularly important is the excitation mechanisms and practical approaches of such a unique resonance in tailoring high-response and efficient extreme-subwavelength hybrid nanophotonic devices. While the quantum tunneling-induced CTP mode possesses the ability to turn on and off the charge transition by varying the intensity of an external light source, the excited CTP in conductively bridged plasmonic systems suffers from the lack of tunability. To address this, the integration of bulk plasmonic nanostructures with optothermally and optoelectronically controllable components has been introduced as promising techniques for developing multifunctional and high-performance CTP-resonant tools. Ultimate tunable plasmonic devices such as metamodulators and metafilters are thus in prospect. Plasmonics is a promising counterpart of nanophotonics which has witnessed major progresses in the control and manipulation of electromagnetic (EM) fields at extreme-subwavelength scales –3. CentrThere have been ongoing theoretical and experimental advancements to understand the possibility of direct dynamic charge transport between plasmonic objects in the absence of capacitive coupling between plasmonic particles. Relatively, researchers have shown the possibility of plasmon-driven charge transfer process in DNA-mediated metallic NP dimers , 34. In In spite of possessing interesting properties, CTPs are inherently suffering from lack of spectral tunability. Recent demonstrations that the functionality of CTP feature can be optimized by integrating bulk metallic systems with thermally and electronically controllable materials show why tunable CTP spectral features are important for implementing novel and advanced plasmonic tools , 43–46. In this review, we summarize recently introduced mechanisms that underpin the electron transition between plasmonic particles and trending applications of functional CTPs. One of the goals of this article is to present a comprehensive depiction of various modalities developed for the excitation of tunable CTPs. Besides, we explain the state-of-the-art approaches that have been proposed for enhancing the tunability of CTPs and the use of this spectral phenomenon in designing practical photonic tools such as modulators, switches, and nonlinear harmonic signal generators. Next, we illustrate how a careful integration of subwavelength plasmonic resonators with optically, thermally, and electronically functional materials leads to the emergence of multifunctional nanooptoelectronic and terahertz (THz) devices.via redistribution and transfer has been introduced as a simple approach to excite CTP spectral features and studied both theoretically and experimentally in nanoscale plasmonic systems  + Vxc[n(r)], where VH is the Hartree potential, n is the electronic density, Vxc is the exchange-correlation potential  to be able to have a proper electron spill-out. As plotted in VTLS = −4.6 eV. It is evident from z-axis): (a) the bare metallic dimer (gray line) and (b) the dimer with the TLS (red line). For the latter case, the background potential of the TLS is selected as equal to the NPs. In both cases, a bonding dipolar mode (BDP) [VTLS is varied to manipulate the position of the levels of the TLS. In this plot, each dot represents an energy level of the whole platform. Depending on the localization rate of the TLS levels, the size of the dot can be bigger, which is beneficial to differentiate localized levels in the TLS. A group of states are localized close to the Fermi level of the system, shown in black dashed line, for small numbers of VTLS. These states become more localized as the background potential is getting deeper and the states move to lower parts in the energy diagram. However, because of the strong localization, the interplay between the NPs is diminished. Particularly, when  VTLS is lower than -16.2 eV, an extra level starts to localize on the TLS. Lastly, in Figures VTLS values considered in In another recent study, Kulkarni and Manjavacas  investigximation ), n0 is de (BDP) , 76 appevia the direct transition of optically driven electrons across the bulk metallic paths between NPs suffer from the inherent lack of tunability. Recently, these challenges have effectively been addressed by using optoelectronically and optothermally tunable components in the purpose of the excitation of functional CTPs [As discussed in the previous section, in the quantum tunneling of energetic optically driven electrons, possessing an active control over the CTP spectral feature is limited to modifying the incident field intensity and/or morphological variations , 45. On nal CTPs –47, 77. sp2-hybridized carbon atoms, known as graphene, has received copious interest due to its significantly high electron mobility, mechanical flexibility, and exquisite optical properties [via modifying the generated carrier density [h is Planck's constant. Analogous to the plasmonic components, the spectral properties and plasmonic response of graphene sheet can be estimated by the Drude absorption model for a wide range of carrier densities [m is the electron mass and Γ is the transport scattering rate. The unprecedented levels of beam confinement and EM field enhancement by graphene allow for having electrostatic control over the plasmonic response in the absorption spectra [via adding small number of atoms. Using first-principle analyses, the plasmonic response of the entirely graphene-based dimer was studied for the intermediate junction with varying atomic row widths (4-8). The designed triangular structures forming the bowties are oriented with respect to the graphene lattice by assuming having armchair edges. This prevents the possible losses that can be naturally observed in zigzag-edge nanostructures, due to the presence of zero-energy electronic edge states [A one-atom thick layer of operties –82. Grapoperties , ultrafaoperties –87, nonloperties –90, and operties , 92. One density , 94. Thi density –95. This density –100. The density , 94(4)σensities , 94, 101ensities , 102(5) spectra . The suc spectra  demonstre states .3 atoms in each triangle), the researchers utilized the following settings: Fermi energy of the structures was to EF = 0.4 eV, the intrinsic damping as ħτ−1 = 1.6 meV, all corresponding to a DC mobility of 104 cm2/V·s [m = 0, 4, 8). It should be underlined that when m = 0, this means there is no atomically connection between proximal nanotriangles. Figures n). As shown in n resembles the number of carbon hexagons that are required to join the graphene triangles for m = 2. As can be explicitly seen in the extinction cross-section, by increasing the junction width, the spectral features show a trend from higher to lower energies. n. The size of the circles is prepared proportional to the intensity of the plasmon mode defined as the area under the corresponding plasmon peaks in the extinction profile. In the narrower junction limit, the spectra point out pronounced plasmonic features placed around ∼0.47 eV. On the other hand, when the junction becomes wider, the spectra are dramatically dominated by lower-energy plasmonic features around ∼0.22 eV. Finally, for the junction width intermediate geometries, there is a complex transition between the mentioned two regimes, with intermediate-energy features around ∼0.35 eV. As depicted in n) of the junction does not have a significant influence on the spectral changes. It is significant to note that the three distinguished behaviors of the plasmon energies declared before for all narrow, intermediate, and wide bridges perform for all sizes of the junction length.To begin with, Thongrattanasiri et al.  used the cm2/V·s .  Figuren) of the junction was fixed. Relatively, m = 0), validating a dipole-dipole interference that is not altered when a narrow junction (m = 2) is inserted between the two triangular resonators of the structure , one can see a distinct dipolar polarization pattern across the junction (see m = 8), similar to the fully metallic structures studied previously, the CTP becomes the dominant spectral response (see n) of the junction between neighbor graphene-based nanotriangles leads to effects that are consistent with the conclusions for the width of the bridge. Strictly speaking, Thongrattanasiri and teammates verified that the classical description of the investigated graphene nanostructures fails to regenerate the plasmonic behavior derived from first principles. This is obvious, for instance, for the junction width with intermediate sizes, the conventional computations oversight the intermediate-energy junction plasmons that have been observed in the quantum calculations. In addition, another disagreement between classical and quantum modes has been observed, in which the traditional approach predicted a smooth fadeout of the dipole-dipole mode exhibited by nonoverlapping triangles during insertion of the bridge, while the CTP shows a singular behavior, as it migrates towards zero energy in the limit of vanishing junction width.Further analyses help to understand the nature and properties of the plasmons in the graphene-based structures. In Figures ture see . Converstion see . In thisonse see . The sigIn T/T0 = 1 − 1/|1 + Z0σAC(ω)/(1 + ns)|2, where Z0 is the vacuum impedance, ns is the refractive index of the thin substrate, and the optical conductivity of graphene (σAC(ω)) can be taken by using the RPA principle. This leads to the strong capacitive coupling of plasmons at the charge neutrality point of graphene islands (resembling high resistance regime). This results in the excitation of a typical electric dipole. On the other hand, when the back-gate voltage is applied, the low resistance of graphene islands gives rise to the direct charge transition between the metallic resonators via the conductive atomic bridge and the excitation of THz-CTPs. 2/ITO substrate. Here, the ITO sublayer acts as a conductive surface for the applied voltages via the gate to control the AC photoconductivity of graphene islands. The resistance variations for graphene area in the presence of metallic objects are measured as a function of back-gate bias (Vbg), shown in Vbgcnp = 9.5 V). Moreover, the maximum resistance was measured around ~3.52 kΩ corresponding to the dielectric regime, while the lowest resistance was monitored for the graphene islands in the n-type phase correlating with the conductive regime. The geometrical parameters of the proposed unit cell are superimposed in the inset of this panel.To continue, we briefly consider the recent advances in enhancing the functionality of CTP resonances based on graphene-mediated metallic metastructures. Newly, Ahmadivand and colleagues have developed an approach to induce CTPs in gate-controlled graphene monolayer-integrated particle clusters in the THz spectra towards tailoring multifunctional metamodulators , where ħ is the reduced Planck's constant, vF is the Fermi velocity (106 m/s), and CA is the capacitance per unit area per charge of the multilayer substrate under the graphene islands. This enables active tuning of the frequency-dependent intraband photoconductivity of graphene by modifying the applied back-gate bias. Consequently, one can directly tune the conductance, resistance, and reactance of the graphene-enhanced bridge.To demonstrate the spectral properties of the device, firstly, the researchers computed and measured the spectral response under longitudinal polarized THz beam exposure at room temperature (300 K), as depicted in given by  EF = ħνF5 Hz, which led to a remarkable modulation depth up to 72% and fast operation speed with the rising and falling duration around 19 μs and 21 μs, respectively. From the modulation bandwidth principle, One other area that deserves special attention is that of optical modulation. Optical and optoelectronic metamodulators have previously been designed based on conventionally resonant structures such as Fano and EIT resonant metamolecules –117. The2Sb2Te5 (GST), have attained a copious interest for tailoring plasmonic and all-dielectric platforms from visible to infrared for various purposes, such as switching/modulation [As elaborated in Sections dulation , 122, sedulation , 124, andulation , 126, dudulation –130. In σGST(λ) = (c/2λ)(1 − εeff(λ)), where εeff(λ) is the effective permittivity of GST portion and c is the velocity of light in vacuum. Besides, depending on the crystallization level of the GST, the Lorentz-Lorenz effective-medium description can be performed using [εeff(λ) − 1)/(εeff(λ) + 2) = fc((εc(λ) − 1)/(εc(λ) + 2)) + fa((εa(λ) − 1)/(εa(λ) + 2)), where fi is the volume function of the ith phase as 0 ≤ fi = (ni/∑jnj) ≤ 1, where nj is the density of the jth phase. It is worth mentioning that to model the photothermal heating process, we utilized the multicapacitive cascading method [EH) in the platform can be defined as [EH = AQabsF(r), where Qabs is the numerical absorption coefficient, F(r) is the optical fluence of the impinging pulse, and A indicates the area of the dimer antenna (more comprehensive information can be obtained from the Supplementary Information file of the article). Furthermore, the normalized extinction spectra of the dimer system are presented for the following four different configurations of the bridge: full gold, air, amorphous GST (a-GST), and crystalline GST (c-GST)  is introduced to the monolithic gold nanowire, the charge transfer between the opposite sides of the system is hindered. Similar to the full gold case, a dipolar mode is appeared at higher energies, while a pronounced dipolar extreme is observed around 1.7 μm, owing to the strong capacitive coupling between gold nanorods. Moreover, when the gap area is filled up with GST , the dipolar peak around 1.7 μm is red-shifted to 2.2 μm with slightly increased intensity, due to negligible extinction coefficient (k ~ 0) of the a-GST in this regime [μm and its position is considerably red-shifted (δ ~ 100 nm) in comparison to the dipolar mode of a-GST, because of its absorptive behavior at low energies. It is significant to note that for all the studied conditions, the position and the amplitude of the induced dipolar mode shoulder are not affected by the changes made on the gold nanobridge. To verify this, the extinction profile of a bare gold dimer is plotted in E-field distributions are clearly demonstrated the presence of the CTP mode for the full gold structure. In the case of a-GST, opposite charges are accumulated around the dielectric region as well as in the surrounding gold nanodisks  88% of modulation depth at 1.55 μm, which is also known as the telecommunication band.In ed using –134  see . For coms regime . Once thidge see . Lastly,εeff(λ) of the GST sublayer for these calculations. Moreover, optically generated thermal power was quantified using the following equation: T = (AQaϕ/1.77ντ)/exp(−((t − t0)2/τ2)) [τ is the time constant of the incident light, ϕ is the beam fluence, r is the distance from the source, and t0 is the time delay. To verify the origin of the induced modes, the corresponding charge distribution profiles for the proposed device are investigated in In another recent study by Nooshnab and Ahmadivand , a novel0)2/τ2)) , where τIn recent years, the field of plasmonics has experienced rapid progresses in understanding the dynamics of conductively bridged and nearly touching metallic NPs. As we described in this focused review, many intriguing physical effects have been predicted in the systems supporting distinguished CTP excitations. So far, various theoretical and experimental investigations have been performed to realize oscillating electric current along the conductive junction, as a key principle of the CTP excitation, depending on the type of the nanosystem. However, related investigations have been limited to the excitation approaches and verifying this principle by standard measurements. Now that the CTP spectral feature has been reached in a broad range of platforms in modern nanophotonics, we believe that it is time to numerically and experimentally explore the modalities towards enhancing the functionality of this spectral phenomenon, eventually, to find its useful and practical applications. We also speculate that CTP states possess a strong potential to make a profound impact in the development of coming generation multifunctional nanophotonic instruments. More precisely, the transition between hybridized dipolar and distinct CTP modes have been explicitly demonstrated under capacitive and conductive coupling regimes, respectively. Highly attractive features of CTP resonances have opened the door for novel active devices and applications, including but not limited to surface-enhanced IR absorption (SEIRA), surface-enhanced Raman scattering (SERS), optical switching, modulation, and waveguiding; however, active manipulation of these resonances using functional materials is overlooked.In this review, we briefly presented the recent accomplishments in the use of versatile materials towards actively tunable CTP-based nanoscale tools. As indicated in the considered studies, having an active control on the CTP mode is possible using functional materials like graphene and GST, rather than applying morphological variations. The exceptional optical and electrical characteristics of these materials have allowed researchers to design active CTP-resonant devices. We envisage that this review will provide detailed understanding for the evolution from passive to active CTP-based platforms and pave the road for developing next-generation nanophotonic devices to reach new functionalities.


Bacillus subtilis with increased competitiveness towards other microorganisms. In particular, nonribosomal peptides (NRPs) have an enormous antimicrobial potential by causing cell lysis, perforation of fungal membranes, enzyme inhibition, or disruption of bacterial protein synthesis. This knowledge was primarily acquired in vitro when B. subtilis was competing with other microbial monocultures. However, our understanding of the true ecological role of these small molecules is limited. In this study, we have established soil-derived semisynthetic mock communities containing 13 main genera and supplemented them with B. subtilis P5_B1 WT, the NRP-deficient strain sfp, or single-NRP mutants incapable of producing surfactin, plipastatin, or bacillaene. Through 16S amplicon sequencing, it was revealed that the invasion of NRP-producing B. subtilis strains had no major impact on the bacterial communities. Still, the abundance of the two genera Lysinibacillus and Viridibacillus was reduced. Interestingly, this effect was diminished in communities supplemented with the NRP-deficient strain. Growth profiling of Lysinibacillus fusiformis M5 exposed to either spent media of the B. subtilis strains or pure surfactin indicated the sensitivity of this strain towards the biosurfactant surfactin. Our study provides a more in-depth insight into the influence of B. subtilis NRPs on semisynthetic bacterial communities and helps to understand their ecological role.Secondary metabolites provide  In nature, bacteria live in complex communities where they interact with various other microorganisms. Most microbial communities are influencing biochemical cycles and impact agriculture, from which the latter is primarily mediated due to plant-growth promotion –4. ExtenSecondary metabolites (SMs) are believed to be important mediators of the interactions between microorganisms . Many ofBacillus subtilis is a well-studied soil bacterium and is used as a model organism for biofilm formation and sporulation [B. subtilis species complex have exceptional plant growth promoting and plant health improving properties by suppressing plant pathogenic bacteria and fungi [Bacillus spp. affect the indigenous microbial communities. Gadhave et al. have shown that the supplementation of B. subtilis, Bacillus amyloliquefaciens (now identified as Bacillus velezensis), and Bacillus cereus to the roots of broccoli plants led to species-dependent changes in the diversity, evenness, and relative abundances of endophytic bacterial communities [B. subtilis and other Bacillus spp. produce various SMs [B. subtilis NRPs, the phosphopantetheinyl transferase Sfp is needed since it has been shown to activate the peptidyl carrier protein domains, converting it from the inactive apo-form to the active holo-form [B. subtilis has four sfp-dependent SMs, of which three are synthesised by NRPS gene clusters  and one by a hybrid NRPS–PKS gene cluster -based growth monitoring of the selected strain Lysinibacillus fusiformis M5 confirmed the impact of B. subtilis-produced surfactin on the growth.In this study, we focus on soil-derived semisynthetic bacterial mock communities and describe how these are affected by a libactin . It was B. subtilis WT P5_B1, the corresponding NRP-deficient strain sfp, or the single-NRP mutants srfAC, ∆ppsC, and ∆pksL, respectively, incapable of producing either surfactin, plipastatin, or bacillaene, and kept the untreated culture as a control , Candidatus Udaeobacter (7–10%), and Gaiella (3–4%). The communities of the 12 h precultivated soil suspension consisted primarily of the two genera Bacillus (56–65%) and Acinetobacter (29–34%). Additional genera with an abundance higher than 1% were Lysinibacillus (1.2–3.2%), Pseudomonas (1.0–2.2%), and Viridibacillus (0.6–1.5%). The genus richness of the four precultured soil suspensions was between 12 and 18 of the total 21 genera.We established soil-derived semisynthetic mock communities and supplemented them with  control . To inveeplicate . We inveDiversity analyses were performed to determine the overall impact of the NRPs on the diversity of the bacterial mock communities. The read numbers varied among the different samples  amplicon sequence variants (ASVs) to the nMDS ordination and plotted them as vectors to investigate the differences between the mock communities. The analysis indicated that three ASVs, taxonomically assigned to the genera Lysinibacillus, Acinetobacter, and Viridibacillus, correlated with the control and two sfp-treated communities. This observation suggests that the absence of NRP-producing B. subtilis resulted in an increased abundance of these. Furthermore, two ASVs of the genus Acinetobacter correlated best with the communities supplemented with the NRP-producing B. subtilis strains, hinting a higher frequency of these in NRP-treated communities. Additionally, three ASVs, identified as Pseudomonas, Citrobacter, and Sphingobacterium, correlated with two communities treated with the surfactin mutant. A similar but smaller correlation with two bacillaene mutant-treated communities was detectable as well. These results imply a negative impact of either surfactin or bacillaene on the four ASVs. Interestingly, the vector-based analysis suggests that, depending on the ASVs, the genus Acinetobacter is both positively and negatively affected by the NRPs.Therefore, we determined the beta diversity only for the treated and untreated mock communities cocultivated for 48 h. The analysis underlined a high similarity in the composition of the mock communities treated with  strains . HoweverB. subtilis strains on the diversity. However, the beta diversity results suggested that the addition of NRP-producing B. subtilis strains influenced the composition of the mock communities. Mainly ASVs belonging to the genera Lysinibacillus, Viridibacillus, and Acinetobacter were affected by the presence or absence of B. subtilis NRPs in the bacterial mock communities.In conclusion, the alpha diversity analyses revealed that species richness and evenness were reduced in the in vitro communities compared to the soil community. Furthermore, 12 h preincubated soil suspensions showed a reduced diversity compared to the mock communities incubated for 48 h. Nevertheless, we could not detect an effect of the supplemented B. subtilis-treated or untreated mock community were Acinetobacter, Lysinibacillus, Pseudomonas, Chryseobacterium, Bacillus, Sphingobacterium, Stenotrophomonas, Paenibacillus, Citrobacter, Serratia, Achromobacter, Viridibacillus, and Pantoea. Noteworthy, the prevalence of the Bacillus genus was comparable in the B. subtilis-treated communities (4–9%) and the control (5–10%). In the latter, the present Bacillus ssp. originated only from the soil suspension, highlighting that the additional supplementation of B. subtilis did not affect the relative abundance of the genus Bacillus after 48 h cocultivation. Interestingly, the only genera detected in both the in vitro mock communities and the soil samples were Bacillus, Lysinibacillus, and Paenibacillus. The remaining most abundant genera in the mock communities were below the detection limit.The diversity, in particular the species evenness, increased independently of the treatment in all established mock communities, compared to the precultivated soil suspensions and contained 11–18 genera . The mosB. subtilis WT-treated communities revealed that Lysinibacillus and Viridibacillus were significantly decreased 9.4-fold (P ≤ 0.001) and 8.3-fold (P ≤ 0.01), respectively, in the communities supplemented with B. subtilis WT  of Lysinibacillus in the sfp-treated communities compared to the untreated communities, and thus a greatly diminished effect compared to the WT-treated samples was evident  significantly reduced in these communities. The direct comparison of WT- and sfp-treated communities confirmed the NRP-dependent suppression of both Lysinibacillus and Viridibacillus in the WT-treated communities and the suppression of Stenotrophomonas in the sfp-treated communities , which was significantly different compared to all other B. subtilis-treated assays  of Lysinibacillus (1.2%) compared to the control communities was discovered. Furthermore, when we added the NRP-deficient strain sfp, we could notice a significantly higher abundance of Lysinibacillus (8.6%) compared to the WT-treated communities (P ≤ 0.001) but still a significantly lower prevalence compared to the control communities (P ≤ 0.05). Compared to the WT-treated communities, the frequency of Lysinibacillus was slightly but not significantly higher in the communities treated with the single-NRP mutants srfAC (2.0%) and ∆ppsC (3.3%). The abundance of Lysinibacillus in the assays containing the ∆pksL strain (5.3%) was significantly higher (P ≤ 0.01) than in the WT-treated assays. However, the Lysinibacillus abundance in ∆pksL-treated communities was not significantly different from the ∆ppsC- or sfp-treated communities. In summary, Lysinibacillus was affected by the addition of B. subtilis independent of the NRPs, but when B. subtilis strains capable of producing them were present, the impact on Lysinibacillus was enhanced. Furthermore, the results indicate that bacillaene had the strongest and surfactin the weakest effect on Lysinibacillus in the mock communities.Concentrating on d assays . HoweverB. subtilis was Viridibacillus, which had a very low abundance in the control mock communities (0.49%) compared to Lysinibacillus  abundance (0.03%) compared to the control communities. Notably, in two of the WT-treated community replicates, Viridibacillus was below the detection level. Nevertheless, the abundance of this genus in the sfp-treated communities (0.26%) was statistically not significant in comparison to the WT and the control communities. Furthermore, the addition of the single-NRP mutants srfAC, ∆ppsC, and ∆pksL resulted in communities with Viridibacillus frequencies similar to the WT-treated communities . Viridibacillus as well as Lysinibacillus was affected by the addition of B. subtilis to the communities. However, no particular NRP could be assigned to the reduced frequency of Viridibacillus.The second genus affected by the addition of Lysinibacillus was negatively affected by the addition of B. subtilis P5_B1 WT and that NRPs enhance the suppression. To dissect the direct impact of a particular NRP in this inhibition, we monitored the growth of L. fusiformis M5, a previously isolated Lysinibacillus species [B. subtilis WT and the corresponding NRP mutants  ,64. 1 g Environmental- and semisynthetic-community genomic DNA was extracted from either 250 mg soil or 250 µL bacterial culture, respectively, by using the DNeasy PowerSoil Pro Kit (QIAGEN) and following the manufacturer’s instructions.The V3-V4 region of the 16S rRNA gene was PCR-amplified from the extracted DNA samples using Fw_V3V4 (5’-CCTACGGGNGGCWGCAG-3’) and Rv_V3V4 (5’-GACTACHVGGGTATCTAATCC-3’) primers that were tagged with short barcodes with a length of eight nucleotides, listed in Table S2, The multiplexed sequencing data was imported into the QIIME 2 pipeline (version 2020.6) –66. The B. subtilis WT as well as in the communities supplemented with B. subtilis sfp, were investigated by calculating the abundance ratios of the different treated communities for each replicate. If species were not detected in some of the replicates, 0 values were replaced with the lowest detected value of the genus to avoid infinite values or 0 values in the ratio calculations. Rarefaction curves of the samples were calculated and visualised with the R package ranacapa [B. subtilis-treated and untreated samples were performed with ASV counts multiplied by factor 100,000 and transformed into integer proportions. The alpha diversity was estimated with the Shannon diversity index in the R package phyloseq [R2 > 0.6) ASVs were added to the nMDS ordination plot. All graphical visualisations were realised with ggplot2 [QIIME 2 artefacts were imported into the R software (4.0.2) with the R package qiime2R, and further analyses were conducted in the R package phyloseq –76. The ranacapa . Diversiphyloseq . The cor ggplot2 .The statistical significance was determined with the square roots of the tested values. The normality and equality of the variances were tested with the Shapiro–Wilk normality test and the Levene test, respectively. If one of the tests was rejected, the nonparametric Kruskal–Wallis rank sum test was performed instead. The statistical significance of pairs was determined with the Welch two-sample t-test, and the differences among groups >2 was determined with the one-way analysis of variance (ANOVA) test and the Tukey HSD test. The statistical significance was determined with an alpha level <0.05.B. subtilis strains were harvested from cultures grown in TSB medium at 37 °C and 250 rpm for 48 h immediately before the growth experiments. The cultures were adjusted to OD600 3.0 and centrifuged for 4 min at 5,000g. Subsequently, the supernatants were passed through 0.22 µm filters and stored at 4 °C. The growth experiments were performed in 96-well microplates. The wells of the first column were filled with 30 µL 10 × TSB, 30 µL L. fusiformis culture adjusted to OD600 0.1 in 1 × TSB, and 240 µL of the appropriate spent B. subtilis medium or water (untreated control). 100 µL L. fusiformis culture adjusted to OD600 0.01 in 1 × TSB was added to the wells of the remaining columns. A 1.5-fold serial dilution of the spent media was performed column-by-column. A surfactin stock solution was prepared by dissolving 10 mg of surfactin (Sigma-Aldrich) in 1 mL methanol (MeOH). The wells of the first column were filled with 170 µL 1 × TSB, 20 µL L. fusiformis culture adjusted to OD600 0.1 in 1 × TSB, and 10 µL surfactin, 10 µL MeOH (solvent control), or 10 µL 1 × TSB (untreated control). To the wells of the remaining columns, 100 µL L. fusiformis culture was added adjusted to OD600 0.01 in 1 × TSB. A 2-fold serial dilution of surfactin or MeOH was performed column-by-column. In both assays, the growth of L. fusiformis was monitored in a microplate reader (BioTek Synergy HTX Multi-Mode Microplate Reader). The microplates were incubated at 30 °C with continuous shaking , and the OD600 was measured in 15 min intervals over 24 h. All graphical visualisations were prepared using ggplot2 [Spent media of  ggplot2 .File 1Bacterial strains used in this study, 16S rRNA V3-V4 primer list, number of sequencing reads per sample, and supporting figures.


Aptamer-immobilized graphene field-effect transistors (GFETs) have become a well-known detection platform in the field of biosensing with various biomarkers such as proteins, bacteria, virus, as well as chemicals. A conventional aptamer immobilization technique on graphene involves a two-step crosslinking process. In the first step, a pyrene derivative is anchored onto the surface of graphene and, in the second step, an amine-terminated aptamer is crosslinked to the pyrene backbone with EDC/NHS (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide) chemistry. However, this process often requires the use of organic solvents such as dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) which are typically polar aprotic solvents and hence dissolves both polar and nonpolar compounds. The use of such solvents can be especially problematic in the fabrication of lab-on-a-chip or point-of-care diagnostic platforms as they can attack vulnerable materials such as polymers, passivation layers and microfluidic tubing leading to device damage and fluid leakage. To remedy such challenges, in this work, we demonstrate the use of pyrene-tagged DNA aptamers (PTDA) for performing a one-step aptamer immobilization technique to implement a GFET-based biosensor for the detection of Interleukin-6 (IL-6) protein biomarker. In this approach, the aptamer terminal is pre-tagged with a pyrene group which becomes soluble in aqueous solution. This obviates the need for using organic solvents, thereby enhancing the device integrity. In addition, an external electric field is applied during the functionalization step to increase the efficiency of aptamer immobilization and hence improved coverage and density. The results from this work could potentially open up new avenues for the use of GFET-based BioMEMS platforms by broadening the choice of materials used for device fabrication and integration. DS) of the GFET. A significant difference between GFETs and other conventional FETs is their ambipolar transfer (IDS-VGS) curve which results in a minimum channel current at the Dirac voltage also known as the charge neutrality point (VCNP). Any change in the electric field induced by the adsorption of the charged molecules at the graphene surface essentially causes a shift in the charge neutrality point enabling GFETs to be used for ultra-sensitive detection of the target biomolecules [In recent years, graphene-based field-effect transistors (GFETs) and their uses as sensing platforms have been greatly successful in developing various microfluidic and lab-on-a-chip-based biosensors ,2. Theirolecules ,6. To enhance the target selectivity in analyte detection, GFETs are commonly integrated with bioreceptors such as aptamers, antibodies and so forth. In this work, aptamers are used as representative target recognition probes. A major part of the implementation of such aptameric GFET devices is the reliable immobilization of aptamer probes onto the graphene channel of the device. In general, there are two main strategies for functionalizing aptamers on graphene, namely, the covalent and the non-covalent immobilization approaches. While the covalent approaches offer certain advantages over non-covalent methods in terms of stability and functionality, they unavoidably altar the physical properties of graphene. Hence, non-covalent modifications have been frequently used in order to maintain the inherent properties of a pristine graphene . A typicE. Coli with the aid of pyrene-tagged DNA aptamers [A commonly used pyrene-based crosslinker, such as PBASE (1-pyrenebutyric acid N-hydroxysuccinimide ester) as shown in aptamers . In theiaptamers . Howeveraptamers , the maiaptamers ,17. D = 5.4 nM) and the resuspension buffer were purchased from Base Pair Biotechnologies, Inc. . The aptamer’s affinity has been thoroughly characterized by the manufacturer and is shown to be specific toward IL-6 proteins. The predicted secondary structure of the aptamer sequence is presented in 2/Si was purchased from Graphenea, Inc. . The gold electrodes (source/drain) surrounding the graphene channel were passivated with insulating layers consisting of Al2O3 (50 nm)/Si3N4 (100 nm). A polydimethylsiloxane (PDMS) well (3 mm diameter) was then integrated in-house to contain the liquid gate on the passivated area of the electrode as well as to reduce liquid evaporation during measurements and incubation steps. The aminated aptamers having the specific affinity to mouse IL-6  was loaded into the well and a negative electric field (−400 mV) was applied to the solution using a wire inserted into the PTDA solution for 4 h as shown in 2 were exposed to the sensing area (PDMS well) for 10 min each. To investigate the selectivity and specificity, 100 nM of lysozyme (Lys) protein was also exposed to the IL-6 aptamer modified GFET in the same buffer for the same duration. After functionalizing the GFETs with IL-6 binding aptamers, various concentrations  of IL-6 protein in 0.01× PBS with 2 mM MgClD–VGS transfer characteristics. Voltage control and data acquisition were performed using a LabVIEW program. During the measurement, the drain–source voltage (VDS) was biased at 100 mV and the drain current (ID) was read while the liquid–gate voltage (VGS) was linearly scanned from 0 V to 1 V with a voltage step of 12.5 mV using the in-plane gold gate electrode. A scan rate of 12.5 mV/s was maintained so that ID is stabilized to ensure reliable measurements of the ID–VGS transfer curves. For electrical measurements, the devices were placed on a probe station  and a Keysight B2902A source/measure unit (SMU) was used to measure the ICNP) or the Dirac voltage (VDirac) [The transfer characteristics of a transistor in a linear region can be described as follows :IDS=WL.C(VDirac) . The sloessed as :gm=dIDSd2/V/s and 2/V/s, where 2 [Therefore, the average carrier mobilities for holes and electrons were calculated to be: 5 µF/cm2 . This hiON/IOFF) of the drain-source current. The larger the value of the on-off ratio, the better the sensitivity of the GFET since the device will exhibit better immunity to noise. An on-off ratio value of ~8 was calculated for the used devices which is above average for GFET devices grown by a CVD technique [Another important parameter that affects the sensitivity of the GFET devices is the on-off ratio (Iechnique . CNP) for the 6 GFET devices on a single chip. As seen in the figure, Ag/AgCl gate electrode gives the lowest VCNP among the three gate electrodes. However, the gold electrode provides the lowest device-to-device variations among the devices on a single chip. We also investigated the effects of different gate materials  on the GFET transfer characteristics illustrated in GS) calculated from the IGS-VGS curves  has been plotted in Although Ag/AgCl demonstrates the best performance in terms of the operating voltage, gate leakage and gate hysteresis, in-plane gold electrode was used throughout the experiments as it gives the highest uniformity of the charge neutrality point among the devices on a single chip. Moreover, the in-plane configuration of the gold electrode which can be fabricated at the same lithography step as the source and drain electrodes enhances the compactness of the setup and allows the potential integration with the microfluidic platform . −1 (C=O stretching in the amide I) and the broad stretching vibration peak around 3300–3550 cm−1  confirm the amide bond formation [The synthesized PTDAs were first characterized to verify the presence of an amide bond between the PBASE and the aminated aptamer. The amide bond was characterized using the Fourier-transform infrared (FTIR) spectroscopy as presented in −1 indicates the anchoring of the PTDAs by π-π stacking interaction between the pyrene ring of the PTDA and the basal plane of graphene [After the amide bond was confirmed by the FTIR spectroscopy, the PTDAs were immobilized on bare graphene. The presence of the PTDAs on graphene was confirmed by Raman spectroscopy. For Raman measurements, two samples were prepared, a blank graphene and a graphene functionalized with PTDAs. The Raman spectra for the PTDA-modified graphene were taken at 3 different spots on the surface. graphene .DS-VGS curves. CNP) compared to the case without the external electric field. With a negative potential at the gate, the negatively charged single-stranded PTDAs tend to migrate towards the graphene surface due to the electrostatic repulsion resulting in an increased density of the immobilized PTDA probes [CNP with respect to the blank GFET device for the two cases. With the electric field applied, the negative shift in the charge neutrality point was measured to be 123.53 mV which is approximately 2.5 times larger than that without the electric field.The anchoring of the PTDAs on graphene surface was also verified electrically by measuring the GFET transfer curves before and after the probe attachment. As shown in A probes . The bar2 for 10 min. Once the selectivity of the IL-6 binding aptamers was confirmed, the sensor was then exposed to various concentrations  of the target protein (IL-6) in the same buffer and for the same exposure time. After the successful functionalization of the GFET with the PTDAs, the device was exposed to IL-6 proteins to characterize its sensing performances. Prior to IL-6 exposure, in order to test the sensor’s selectivity to its target, the GFET-based IL-6 sensor was exposed to 100 nM of lysozyme protein (a model interfering species) in 0.01× PBS with 2 mM MgClAlso, the specificity of sensor was examined by functionalizing the GFET with a random sequence aptamer using the same protocol as the IL-6 aptamer and exposing different concentrations of IL-6 protein. The results are presented in CNP) using the formula ΔVCNP/ΔVCNP,max, where VCNP,max is the charge neutrality point corresponding to the maximum IL-6 concentration tested. With this detection method, the limit of detection of 100 pM was achieved. Although this detection limit is relatively higher than that achieved by the standard two-step immobilization of aptamers [2) but with the pH adjusted to ~3.64.aptamers , the benaptamers . As an eD is estimated to be 3.4 nM, similar to the value (5.4 nM) reported by the manufacturer for the aptamer-target pair. The limit of detection (LOD) of the GFET-based IL-6 sensor under this pH environment was calculated to be ~8 pM which is an order of magnitude larger than that under the physiological pH (pH ~7.4). We have developed a facile and rapid immobilization technique to attach target recognition probes on the GFET-based biosensing platform. The developed sensor was able to selectively measure IL-6 protein biomarker with the detection limit in the picomolar range. The sensitivity can be further improved by increasing the incubation time, purification steps as well as by adjusting the buffer pH to an acidic region. The proposed organic solvent-free aptamer immobilization technique is not only polymer friendly  but also simplifies and shortens the graphene modification process by eliminating the extra step needed for anchoring the linker molecules and the subsequent washing steps. We have also demonstrated that an external electric field can be used to enhance the efficiency (~2.5 times) of the aptamer immobilization on the graphene surface. Our proposed technology has the potential to be used in monitoring IL-6 from real physiologically relevant fluid samples such as sweat, serum and cerebrospinal fluid.


In our case, the NGr-1 sample which has the lowest doping level and the highest concentration of pyrrolic-N among all nitrogen-doped samples exhibits the best electrochemical parameters: a very small Rct (38.3 Ω), a large Kapp (13.9 × 10−2 cm/s) and the best electrochemical response towards 8-hydroxy-2′-deoxyguanosine detection (8-OHdG).Three nitrogen-doped graphene samples were synthesized by the hydrothermal method using urea as doping/reducing agent for graphene oxide (GO), previously dispersed in water. The mixture was poured into an autoclave and placed in the oven at 160 °C for 3, 8 and 12 h. The samples were correspondingly denoted NGr-1, NGr-2 and NGr-3. The effect of the reaction time on the morphology, structure and electrochemical properties of the resulting materials was thoroughly investigated using scanning electron microscopy (SEM) Raman spectroscopy, X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), elemental analysis, Cyclic Voltammetry (CV) and electrochemical impedance spectroscopy (EIS). For NGr-1 and NGr-2, the nitrogen concentration obtained from elemental analysis was around 6.36 wt%. In the case of NGr-3, a slightly higher concentration of 6.85 wt% was obtained. The electrochemical studies performed with NGr modified electrodes proved that the charge-transfer resistance (R Graphene, a single layer of graphite, possesses various interesting properties such as large surface area, high thermal and electrical conductivity and good optical transparency ,2,3. Curct) and large apparent heterogeneous electron transfer rate constant (Kapp). In addition, we originally proved the relationship between these two parameters and the electro-catalytic effect of N-doped graphene towards the detection of cancer biomarker, 8-hydroxy-2’-deoxyguanosine (8-OHdG).In this paper, we present for the first time the influence of the reaction time on the morphology, structure and electrochemical properties of nitrogen-doped graphenes. We show that the hydrothermal reaction may produce high quality nitrogen -doped graphene with very low charge-transfer resistance (R4[Fe(CN)6] and potassium chloride (KCl) were purchased from Merck (Germany). N,N-dimethylformamide (DMF) was bought from Sigma-Aldrich (Germany). 8-hydroxy-2’-deoxyguanosine (8-OHdG) was purchased from the Cayman Chemical Company. For the synthesis of nitrogen-doped graphene the following chemicals were used: graphene oxide, prepared using a modified Hummers method as previously reported  . In contrast, for the bare GC electrode the two waves were very broad and the peak potential separation large (400 mV)  in the presence of a redox indicator, K(400 mV) b. GO mod(400 mV) c.peak) vs. ʋ1/2 plot  (0.2 M KCl supporting electrolyte) at a bias corresponding to the peak potential of each electrode  within 0.1–106 Hz frequency range.Next, the interfacial properties of bare and N-doped graphene modified electrodes were evaluated using electrochemical impedance spectroscopy. The spectra were recorded in 10ct), and a straight line at low frequencies, characteristic to the diffusion of the electro-active species towards the electrode/solution interface (Warburg impedance). In the case of the GC/GO electrode, the semicircle is highly extended due to the insulating properties of graphene oxide. In contrast, for the electrodes modified with nitrogen-doped graphene the impedance values decreased by one order of magnitude, both the semicircle and the diffusive line (see the inset in In s), the charge-transfer resistance at the electrode/solution interface (Rct), the Warburg impedance due to the diffusion of ions in solution (ZW) and a constant phase element (CPE) that models a non-ideal capacitor.For the bare GC electrode, the best fit was obtained with a circuit containing the solution resistance , the surface is significantly different from that of bare GC. The successive GO layers deposited on top of the substrate were forming a porous structure where the insertion of ions from solution was hindered by the surface charges. Therefore, the equivalent circuit was a more complex one and contained the solution resistance, two RC parallel circuits (where the capacitances were replaced by CPEs) and the Warburg impedance . One of s, Rct and CPE1; In the case of electrodes modified with nitrogen-doped graphene, the surface is less hydrophilic but still has increased roughness compared with bare GC, and therefore, the best fit was obtained when the Warburg impedance was replaced with CPE, while the other circuit elements were preserved 6]3−, may easily transfer the electrons. The determined Rct values are indeed significantly lower for all GC/NGr electrodes, in comparison with the bare GC or GC/GO electrode. This is also in excellent agreement with the previous electrochemical measurements, where the CVs recorded with the GC/NGr electrodes exhibits the characteristics of a reversible redox process . According to the literature ,60, the cess see .app) calculated for each electrode (Equation (6)) [n is the number of electrons transferred during the redox reaction (n = 1); A is the active area of the electrode (cm2); Rct is the charge-transfer resistance obtained from the fitted Nyquist plots (Ω); C is the concentration of the redox species (mol/cm3).The value of apparent heterogeneous electron transfer rate constant (Kion (6))  gives al−4 cm/s) but is considerably higher for all NGr-modified electrodes (6.55−13.9 × 10−2 cm/s). The largest value was that corresponding to NGr-1 material, which had the lowest doping level and the highest concentration of pyrrolic-N, among all nitrogen-doped graphene.Its value has the same order of magnitude for GC/GO and bare GC (2.1−2.6 × 10c), which reflect the charge-storage capability of the synthesized materials. Hence, the graphene samples with the lowest doping level (GC/NGr-1 and GC/NGr-2) have the largest capacitive current, of 1.15 × 10−7 A and 1.01 × 10−7 A, respectively. In comparison, all the other samples have lower values, such as 5.58 × 10−8 A (GC/NGr-3), 1.48 × 10−8 A (GC/GO) and 2.39 × 10−8 A  and the results are shown in −7−10−3 M) in pH6 PBS supporting electrolyte . It is followed by GC/NGr-3, GC/NGr-2 and bare GC. The poorest electrochemical signal was obtained with the GC/GO electrode, due to the insulating properties of graphene oxide. The electrochemical parameters obtained from the calibration plots  for bare and graphene-modified electrodes are listed in Next, linear sweep voltammograms were recorded with each electrode in solutions containing various concentrations of 8-OHdG (10a)(L was obtained for GO (17.11 nm), followed by the NGr-1 (16.24 nm) and NGr-2 (16.16 nm) samples, which according to elemental analysis had similar amounts of nitrogen (6.36 wt%). For NGr-3 sample, the La value is slightly lower (16.12 nm), being in good agreement with the higher doping level (6.85 wt%). In addition, the EIS studies conducted with NGr-modified electrodes indicated that the sample with the lowest doping level and the highest concentration of pyrrolic-N among all nitrogen-doped graphene (NGr-1) exhibits the best electrochemical parameters: a very small Rct (38.3 Ω), a large Kapp (13.9 × 10−2 cm/s) and a low detection limit (9 × 10−8 M) for 8-OHdG.Nitrogen-doped graphenes with various concentrations of heteroatom  were prepared using the hydrothermal method with urea as reducing/doping source for graphene oxide. The structural characterization of the synthesized materials revealed that after doping, significant changes occurred in the XRD, Raman and XPS spectra, confirming the presence of heteroatom. For exemplification, the largest value for the in-plane crystallite size