P = 0.110) and was significantly lower at high ambient humidity . The multivariable analysis also showed that high ambient humidity was independently associated with low sensitivity of FIT . In conclusion, high ambient humidity decreased the sensitivity, while high ambient temperature along with high ambient humidity decreased the positivity rate of FIT.Although it is known that ambient temperature can affect the diagnostic performance of the fecal immunochemical test (FIT), the impact of other weather parameters, including humidity, on the sensitivity of FIT remains to be further investigated. We aimed to evaluate the impact of ambient temperature and humidity on the performance of FIT for screening for advanced colorectal neoplasia (ACRN). We included asymptomatic individuals who had undergone both screening colonoscopy and FIT. The diagnostic performance of FIT, including its sensitivity, was analyzed according to the ambient temperature and humidity on the day that FIT was performed. Temperature and humidity were divided into five levels. Among 35,461 participants, 589 (1.7%) had ACRN. The positivity rate of FIT was lower at ≥24 °C (3.1%) than at <0 °C (3.9%), 0–8 °C (4.3%), and 8–16 °C (3.9%). It was also lower at 80–90% humidity (3.1%) than at < 60% humidity (3.9%). Multivariable analysis showed that high ambient temperature (≥24 °C) with high ambient humidity (≥80%) was associated with a low positivity rate of FIT . Sensitivity tended to decrease at high ambient temperature (<24 °C vs. ≥24 °C; 20.8% vs. 14.6%,  The US Preventive Services Task Force recommends screening for CRC starting at 50 years of age and continuing until age 752. In addition, the US Multi-Society Task Force strongly recommends colonoscopy every 10 years or an annual fecal immunochemical test (FIT) as first-tier options for screening individuals at average risk of colorectal neoplasia (CRN)3. Although colonoscopy can effectively prevent CRC through resection of colorectal adenoma, colonoscopic screening has not been popular worldwide owing to limited medical resources5. FIT is now regarded as the best noninvasive tool for CRC screening6. The Asia Pacific guideline indicates FIT as the first choice for CRC screening in resource-limited countries7. FIT has been adopted as a population-based screening program in many countries, including Korea8.Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related mortality in the world11. The sensitivity and specificity of FIT are maintained across individuals with different clinical risk factors12. However, there is concern that the performance of FIT is influenced by seasonal variations. Several studies from different countries, including Korea, France, Italy, and Netherlands, reported that the positivity rate of FIT is lower in summer16. High ambient temperature is suggested as a possible factor that lowers the positivity rate of FIT17. This is an important issue, because the exposure of fecal samples to a high ambient temperature may be unavoidable in population-based screening13.It is well known that FIT is superior to the guaiac test in terms of efficacy in preventing CRC, through enhanced detection of advanced adenomas15. In addition, a contradictory study shows that ambient temperature alone does not affect the performance of FIT18. Not only ambient temperature but also other weather parameters, such as humidity, may affect seasonal variation in the performance of FIT. In an experimental study, high humidity was associated with an increased rate of hemoglobin degradation19. In this study, we aimed to evaluate the impact of weather parameters, including ambient humidity as well as ambient temperature, on the performance of FIT using a large cohort of asymptomatic individuals who underwent both colonoscopy and FIT. The positivity rate, sensitivity, and specificity of FIT for ACRN were assessed according to ambient temperature and humidity.However, the impact of high ambient temperature on the performance of FIT is yet to be further investigated. The positivity rate of FIT depends on the prevalence of CRC or advanced CRN (ACRN); therefore, it is better to evaluate the performance of FIT in terms of sensitivity and specificity rather than its positivity rate. In most studies, however, sensitivity and specificity could not be assessed because only participants who showed positive results for FIT were offered colonoscopyThe medical records of 46,654 participants who underwent both screening colonoscopy and FIT were reviewed. Of these participants, 5,544 were excluded because they had previously undergone a colonic examination, colorectal surgery, or surgery for CRN. In addition, 74 participants with inflammatory bowel disease were excluded. Of the remaining 41,036 participants, 3,171 were excluded due to poor bowel preparation and 2,404 because of incomplete data. A final total of 35,461 participants was included in this study.Table The monthly average temperature and relative humidity during the study period (from 2004 to 2015) are shown in Fig. Figure The positivity rate, sensitivity, and specificity of FIT for ACRN were assessed according to ambient temperature and humidity Fig. . The posSensitivity tended to decrease at temperatures above 24 °C, although no statistical difference was identified. Moreover, sensitivity decreased at 80–90% humidity compared to 60–70% humidity. Although there was no statistical difference, ≥90% humidity tended to be related with low sensitivity.In contrast, specificity increased at high ambient temperature and humidity. Specificity at an ambient temperature ≥24 °C was higher than at 0–8 °C or 8–16 °C. Specificity at 80–90% ambient humidity was higher than at <60% ambient humidity.To assess the impact of ambient temperature and humidity on the sensitivity of FIT, we further performed a subgroup analysis of participants with CRC. Among 27 participants with CRC, 21 showed a positive result on FIT, and the sensitivity was 77.8%. The sensitivity was 100% in 3 participants who underwent FIT at a high ambient temperature (≥24 °C), while it was 50% in 4 participants who underwent FIT at high humidity (≥80%).The results of subgroup analyses according to the type of FIT device (HM-JACK and OC-SENSOR DIANA) are shown in Table Results of logistic regression analysis for the positivity rate, sensitivity, and specificity of FIT for ACRN are presented in Table In the univariable analysis, high ambient humidity was associated with low sensitivity, but high ambient temperature was not. However, in the multivariable analysis, high ambient humidity was also associated with low sensitivity .In the univariable logistic regression model for specificity, both high ambient temperature and high ambient humidity were significant factors. In the multivariable analysis, high ambient temperature and humidity (temperature ≥24 °C and humidity ≥80%) were associated with high specificity  of FIT. Neither high ambient temperature alone nor high ambient humidity alone was associated with specificity in the multivariable analysis.Figure 20. The sensitivity and specificity of FIT are unaffected by the characteristics of the individuals undergoing screening. Our previous study on the performance of FIT showed that the sensitivity was not affected by age, sex, smoking history, or obesity12. Although specificity decreased in individuals with diverticula or hemorrhoids, it was not influenced by clinical risk factors for ACRN, including male sex, obesity, and smoking12. Owing to these characteristics, FIT can be used for population-based screening regardless of the characteristics of the individuals being screened.FIT is a widely accepted noninvasive tool for screening for CRC20. Several studies have reported that the positivity rate of FIT was relatively low in the summer months16. In addition, a recent study by Cha et al. showed that the risk of interval cancer was 16% higher in individuals who underwent FIT in summer as opposed to in winter13.However, there is concern regarding the performance of FIT when fecal samples are obtained during the warm summer months15. Although the sensitivity and specificity of FIT were assessed in the study by Cha et al., only individuals who were diagnosed with CRC within 1 year after undergoing FIT were regarded as true-positive cases13. Given that some of the individuals with false-negative results on FIT may not be diagnosed within 1 year, the sensitivity of FIT may have been overestimated in that study. In the current study, the sensitivity and specificity of FIT could be calculated accurately, because our cohort underwent both colonoscopy and FIT. In addition, our study showed that the sensitivity and specificity as well as the positivity rate of FIT were influenced by high ambient temperature and high humidity. The multivariable analysis demonstrated that high ambient temperature (≥24 °C) and humidity (≥80%) decreased the positivity rate and increased the specificity of FIT. In addition, high ambient humidity decreased the sensitivity of FIT. This is the first clinical study to show that high humidity and high temperature can reduce the quality of FIT. Our findings suggest that optimal humidity and temperature are important in maintaining the quality of FIT.Whether ambient temperature actually affects sensitivity and specificity remains unclear, because most previous studies evaluated the performance of FIT based on its positivity rateet al.21, in which degradation of the fecal hemoglobin level was facilitated when samples were stored at 28 °C rather than at 4 °C and 20 °C. In addition, delayed return of fecal samples may cause false-negative results owing to hemoglobin degradation22. Another experimental study showed that minimizing both temperature and humidity is essential to maintain the integrity of the hemoglobin tetramer molecules19. When fecal samples were stored for 1 month at 37 °C, almost 100% of hemoglobin degraded at high humidity (>50%), whereas only 33–36% of hemoglobin degraded at low humidity (<30%)19. This result implies that not only temperature but also humidity is very important in maintaining the performance of FIT.The impact of ambient temperature on the performance of FIT is supported by a previous experimental study by Vilkin et al. from Germany reported that the sensitivity and specificity of FIT did not differ between low-temperature and high-temperature groups18; this might be attributable to the different geographic areas, with different climate signatures, where the studies were conducted. In southern Germany, where the study by Niedermaier et al. was conducted, the summers are not very humid23. Relatively low humidity in summer might prevent deterioration of the sensitivity of FIT. In contrast to the study from Germany, a study performed in Florence, Italy and a nationwide Korean study showed seasonal variation in the diagnostic performance of FIT14, and Italy and Korea are not only very hot, but also very humid in summer25. In particular, Korea has a regional climate characteristic of the rainy season, and typhoons are frequent from July to September; therefore, there are many hot and humid days in summer. In summary, the diagnostic performance of FIT may be influenced by humidity as well as by temperature. This impact of humidity on the sensitivity of FIT seemed to be seen even in participants diagnosed with CRC. Although tests of statistical significance were not conducted due to the very small sample size, sensitivity for CRC tended to decrease at high humidity.In addition, the impact of humidity on the performance of FIT may explain the contradictory results in previous studies focusing on the impact of ambient temperature on FIT. For example, Niedermaier Considering that the hemoglobin level might be decreased on humid days, it may be reasonable to lower the cut-off values of FIT on such days. We therefore investigated the changes in the diagnostic performance of FIT by reducing the cut-off values in humid environments, and we found that the sensitivity of FIT increased from 12.5% to about 20% by reducing the cut-off value to 10 μg hemoglobin/g feces . However, at the same time, the specificity decreased from about 97% to 95.5–95.9%. Given that the specificity was 96.3–96.8% at low humidity, 95.5–95.9% specificity seemed to be relatively poor. Therefore, lowering the cut-off value for FIT performed on humid days is not the perfect solution. Performance of FIT should preferably be avoided on humid days, such as those in the rainy season in Korea. However, if carrying out the test is unavoidable on humid days, it should be kept in mind that the sensitivity of FIT may be decreased. In this situation, reinterpretation of the results of FIT based on the reduced cut-off value may be considered.21. Van Rossum et al. reported that delays of more than 5 days in returning fecal samples increased false-negative results22. In our study, however, fecal samples were usually collected on the day before FIT was carried out or on the day of FIT. Second, two different devices were used for FIT, depending on the study period, and the performance of FIT may differ according to the type of device used. In the subgroup analyses, however, similar tendencies were observed in the diagnostic performance of FIT. In addition, there has been no evidence that the impact of seasonal variation differs according to the FIT device. The Korean study by Cha et al. showed that both types of tests  had lower positivity rates in the summer months than in winter13. The type of buffer formulation used in the FIT may be an additional issue. Recently, a novel buffer formulation for the OC-Sensor FIT has been developed, to minimize hemoglobin degradation of fecal samples exposed to high temperatures. An in vitro study showed that the new formulation buffer enhanced hemoglobin-stabilizing properties in high temperature environments (>22 °C)26. However, the clinical implications of the use of this new buffer on CRC screening should be further evaluated in a subsequent study. Third, the number of participants with ACRN was relatively small, although our study included a large number of participants. Therefore, the statistical power in the analysis of sensitivity was relatively low, and we could not identify the impact of high ambient temperature on the sensitivity of FIT. Although ambient temperature was not independently associated with low sensitivity in our study, the influence of ambient temperature may not be completely ruled out, considering the results of previous studies. Larger studies may be required for reaching a definitive conclusion. Finally, this study was performed in Korea, which has a characteristic climate; therefore, it is difficult to generalize our findings worldwide. However, our results can be generalized to countries or regions with a climate similar to that of Korea.Although our study demonstrated the impact of ambient temperature and humidity on the performance of FIT for ACRN, it has several limitations. First, we could not investigate the return time of fecal samples, and it is well known that degradation of hemoglobin is influenced by timeDespite the limitations, our research enhances the understanding of the impact of weather parameters on the diagnostic performance of FIT. Ambient temperature and humidity may affect the performance of FIT for ACRN. High ambient humidity decreased the sensitivity of FIT. In addition, a high ambient temperature with high ambient humidity decreased the positivity rate of FIT. These results have important implications for FIT-based screening programs in countries where temperature and humidity vary widely by season. In countries with such a climate, FIT-based screening may have to be avoided during hot and humid seasons.The Kangbuk Samsung Health Study is a prospectively established cohort study of South Korean men and women aged ≥18 years, who underwent a comprehensive annual or biennial health examination at two large health checkup centers, namely the Kangbuk Samsung Hospital Total Healthcare Center in Seoul and in Suwon, South Korea. The current study participants are a subset of the population in the Kangbuk Samsung Health Study conducted between 2004 and 2015, and included participants who underwent both screening colonoscopy and FIT as part of a comprehensive health checkup.27. In brief, according to the Industrial Safety and Health Law in Korea, employees should undergo a health checkup every one or two years. In addition, as part of the welfare policy, Korean companies often support the cost of health examinations, including CRC screening programs, regardless of the guidelines27. At our health checkup centers, a comprehensive health examination program includes screening colonoscopy and FIT. Although some participants chose either FIT or colonoscopy as a CRC screening modality, others prefer to undergo both examinations. The examinations carried out  depend on individual preference.Reasons for the large number of participants in this cohort who underwent both colonoscopy and FIT have been described previously28.Among participants aged ≥30 years, those who met the following criteria were excluded: (i) previous colonic examination, colorectal surgery or CRN; (ii) history of inflammatory bowel disease; (iii) poor bowel preparation; and (iv) incomplete data for analysis. Poor bowel preparation was defined as “large amounts of solid fecal matter found, precluding a satisfactory study; unacceptable preparation; <90% visible mucosa”This study was approved by the institutional review board of Kangbuk Samsung Hospital. The requirement for informed consent was waived since only de-identified data were retrospectively assessed. All experiments were performed in accordance with relevant guidelines and regulations.29. Body mass index (BMI) was calculated as measured weight (kg) divided by the square of the height (/m2), and obesity was defined as a BMI ≥ 25 kg/m2, which is the proposed cut-off value for Asian populations31.Demographic data, including age, sex, height, weight, family history of CRC, smoking habits, underlying diseases, and medications, were retrieved from an electronic medical database. Data on family history of CRC, smoking habits, and underlying diseases had been collected based on a self-administered questionnaire method. A family history of CRC was defined as the presence of the disease in first-degree relatives at any age. Participants were considered as having a history of smoking if they were former or current smokers who had smoked ≥100 cigarettes in their lifeOnly board-certified endoscopists were involved in carrying out the colonoscopic examinations, which were performed using an EVIS LUCERA CV-260 colonoscope . Four liters of polyethylene glycol solution were used for bowel cleansing. Suspicious neoplastic lesions were biopsied or removed by polypectomy or endoscopic mucosal resection.32.CRN was defined as cancer or adenoma, and ACRN was defined as cancer or advanced adenoma. Advanced adenoma was defined as the presence of one of the following features: tumor diameter ≥10 mm, tubulovillous or villous structure, and high-grade dysplasiaA single fecal sample was collected at home, using a sampling tube containing buffer designed to minimize hemoglobin degradation, on the day before FIT was performed or on the day of FIT. After being sealed in a plastic bag, the fecal sample in the tube was hand-delivered to the laboratory on the day of FIT. Date of FIT was defined as the date on which the fecal sample arrived in the laboratory. The fecal hemoglobin level was determined using the HM-JACK test  from 2004 to 2009, and the OC-SENSOR DIANA test  from 2010 to 2015. The cut-off value of FIT was 20 μg hemoglobin/g feces.www.weather.go.kr/weather/climate/past_table.jsp). As two centers, one in Seoul and the other in Suwon, were included in this study, weather information was collected for each of these locations. In this study, ambient temperature was defined as the average temperature of the day. The daily weather information was then merged into the clinical dataset of each participant, based on the date of FIT.Data about daily air temperature and relative humidity during the study period were collected from the official website of the Korea Meteorological Administration  was also included in the model, in order to consider the rainy season in Korea , with high temperatures and high humidity.Finally, to evaluate whether poor sensitivity of FIT in summer (or on hot and humid days) would improve by adjusting the cut-off value of FIT, we assessed changes in sensitivity and specificity when the cut-off value was reduced.P-value < 0.05 was regarded as being significant in group comparisons. Statistical analyses were performed using statistical software R .A Table S1. Diagnostic performance of the fecal immunochemical test according to the type of device used, ambient temperature, and ambient humidity.


Nanog, are dependent on the direct association of Sin3 for active transcription to occur. Sin3 appears to have properties of a co-repressor, co-activator and general transcription factor, and has thus been termed a co-regulator complex. Through a series of unique domains, Sin3 is able to assemble HDAC1/2, chromatin adaptors and transcription factors in a series of functionally and compositionally distinct complexes to modify chromatin at both gene-specific and global levels. Unsurprisingly, therefore, Sin3/HDAC1 have been implicated in the regulation of numerous cellular processes, including mammalian development, maintenance of pluripotency, cell cycle regulation and diseases such as cancer.At face value, the Sin3 histone deacetylase (HDAC) complex appears to be a prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression. While this is almost certainly part of its role, Sin3 stubbornly refuses to be pigeon-holed in quite this way. Genome-wide mapping studies have found that Sin3 localises predominantly to the promoters of actively transcribed genes. While Sin3 knockout studies in various species result in a combination of both up- and down-regulated genes. Furthermore, genes such as the stem cell factor,  One of  I) . The ELM2-SANT domain of MTA1 (part of the NuRD complex) contains specific and highly conserved basic residues which help co-ordinate the negatively charged phosphates in InsP6 [in vitro [The highly related deacetylases, HDAC1 and HDAC2 (HDAC1/2) share 82% amino acid identity and form the catalytic core of numerous co-repressor complexes, which account for ∼50% of all cellular deacetylase activity in embryonic stem (ES) cells  and T-cein InsP6 . These rin InsP6 . The Sinin vitro . NonetheIn many regards, Sin3 is the prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression –23. WhilO-GlcNAc transferase, OGT [The central platform of the complex is the Sin3 protein, which binds directly to HDAC1/2 and many other adaptors ,21,22, tase, OGT ; althougase, OGT ,40,42–44Understanding how different SAPs co-operate to recruit the Sin3 complex to chromatin is a crucial step towards understanding its functions in cells. With a dozen or more different SAPs it raises the question: are they all bound at the same time? And if not, how many different variants of the Sin3 complex are there? To address these questions Streubel et al.  employedOne well-studied sub-division among Sin3 complexes comes from work in yeast. Purification of Sin3/Rpd3(HDAC1) complexes identified two distinct biochemical entities of different apparent molecular mass, termed Rpd3 large  and Rpd3 small  ,53. Rpd3The domain structure of Sin3A/B is highly conserved from yeast to man . From N-The three PAH domains are imperfect ∼100 amino acid repeats with a conserved fold, consisting of four α-helices separated into pairs by a central loop ,61,64–66Kd in the sub-micromolar region, 50–200 nM) are guided by long-range electrostatic interactions. van Ingen et al. [Kd from 1.4 µM (Mxd1 5–20aa) to 0.4 µM (Mxd1 5–24aa). The increased affinity was the result of a long-range electrostatic attraction between Sin3B Lys165 (which sits above the hydrophobic cleft) and Mxd1 Glu23. An N:O bridge forms through hydrogen bonding which orients the SID for binding and brings it close enough to the PAH domain for the relatively short range hydrophobic interaction to occur. Sin3A-PAH2 contains an equivalent Lys residue, Lys315, whose charge also contributes to the binding of the Mxd1-SID [All three PAH domains show a significant degree of similarity and yet the specificity of interacting partners is quite distinct. The Mxd1-SID binds PAH2 but does not interact with PAH1 or 3 ,68; whiln et al.  observedMxd1-SID , suggestMxd1-SID ,64,70.in silico screen of small molecule inhibitor mimetics identified FDA-approved avermectin derivatives as PAH2 binders [In closing this section, it may be useful to reflect on the usage of the PAH domains. Data from Streubel et al. show that Sap30 is present in a 1 : 1 complex with Sin3A suggesting that PAH3 may be permanently occupied . This wo binders  which ph binders .Saccharomyces cerevisiae, which contains a single Suds3 gene, deletion causes dissociation of Sin3 and HDAC1 (Rpd3), and the remaining HDAC1 is enzymatically inactive [The binding site for HDAC1 in Sin3A was initially mapped between PAH3 and PAH4 (still a domain in 1997) and duly named the HID . This isinactive . Deletioinactive , indicatinactive . Dimerisinactive , which mA solution structure of the Suds3-SID bound to a portion of the HID (Sin3A 601–742 aa) has been described with a sub-micromolar affinity . CharactThe Sin3/HDAC complex is abundant, stable and ubiquitously expressed in mammalian tissues and cells. The temporal and cell type-specific nature of its activity, in numerous cellular processes, is mediated via transient association with transcription factors. Sin3 can therefore be viewed as a permanent tool in the chromatin toolbox, which can be recruited to specific loci and then applied to regulate chromatin accessibility in particular pathways by tissue-specific factors which interact with PAH, HID or Sin3a_C domains. Since its initial discovery as a transcriptional repressor of Myc target genes, via the association of PAH2 and Mxd1, Sin3 has been associated with numerous cellular processes, including mammalian development, maintenance of pluripotency, cell survival, cell cycle regulation  and Sin3 appears to play a role in each of them. The implication that Sin3 had a role to play in cell cycle was clear from the outset. Mxd1 (formerly Mad1) and Mxi1 are repressor proteins which compete with Myc for their common heterodimeric partner, Max, and form an anti-proliferative counter-weight to the pro-growth role of Myc . Yeast tSchizosaccharomyces pombe [Replication of the genome is an essential and rate-limiting phase of cell cycle. Critically, new DNA requires new chromatin. Histone H4 is initially deposited on nascent DNA in an acetylated form  whices pombe , with boes pombe . In summAlthough Sin3A and Sin3B are 57% identical  and sharConsistent with early embryonic lethality in mice, Sin3A has been reported to be crucial for the maintenance of pluripotency in ES cells ,100,101.Sin3A and Sin3B are highly expressed in all tissues . As permanent members of the chromatin toolbox, they can be recruited by a wide variety of tissue-specific transcription factors during tissue development. It is therefore unsurprising that KO studies have identified key roles for both proteins in a variety of tissue types. Sin3A/B are critical for the maintenance of haematopoietic stem cell homeostasis, with the different isoforms of Sin3 potentially regulating alternative pathways via unique interactions with transcription factors. Loss of Sin3A in the bone marrow of mice results in a reduction in haematopoietic stem cells and subsequent lineages indicating a defect in early haematopoiesis . DeletioAs both global chromatin regulator and gene-specific transcriptional co-regulator, the Sin3 complex, or rather complexes, play roles in all nuclear processes. The flexibility of multiple direct protein–protein interfaces  and a multitude of cofactors  allow its recruitment for the regulation of chromatin homeostasis throughout the cell cycle. Any process which requires access to DNA  will require the manipulation of histone acetylation and as a major HDAC complex, Sin3 will likely play a role. Understanding the complex set of protein–protein interactions, and perhaps teasing these apart as a targeted therapy, will drive Sin3 biology for many years to come.


Case-based learning (CBL) is a highly interactive instructional format widely used in medical education. One goal of CBL is to integrate basic biomedical knowledge and its application to concrete patient cases and their clinical management. In this context, we focus the role of teacher questions as triggers for reproductive vs. elaborative student responses. Specifically, our research questions concern the kinds of questions posed by clinical teachers, the kinds of responses given by students, the prediction of student responses based upon teacher questions, and the differences between the two medical disciplines in focus of our study, internal medicine and surgery.We analyse 19 videotaped seminars  taught by clinicians and attended by advanced medical students. Multiple raters performed a low-inference rating process using a theory-based categorical scheme with satisfactory interrater-reliability.We found that medical teachers mostly posed initial (instead of follow-up) questions and that their questions were more often closed (instead of open). Also, more reasoning (than reproductive) questions were posed. A high rate of student non-response was observed while elaborative and reproductive student responses had a similar prevalence. In the prediction context, follow-up reasoning questions were associated with low non-response and many elaborative answers. In contrast, the highest student non-response rate followed open reproduction questions and initial reasoning questions. Most reproductive statements by students were made following closed reproduction questions.These results deepen our understanding of interactive, questions-driven medical teaching and provide an empirical basis for clinical teachers to use questions in didactically fruitful ways. The application of basic biomedical knowledge to specific patient cases is a core element of medicine, as a discipline and practice. Instructional approaches such as case-based learning (CBL) have hence become essential elements of many medical curricula and they represent “fundamental ways in which future practitioners are educated for their new profession” , p. 52)..2–5], a dialogic teaching. This thriving strand of educational research capitalises upon the idea that didactically orchestrated classroom discussion is a contemporary and powerful pedagogic strategy )Mangold Interact [who was speaking  and what kind of utterance was made by students (reproductive statement / elaborative statement / content-related question / other statement) and by teachers . This means we segmented the entire video into consecutive time intervals of varying length representing specific activities by teachers and students and breaks which occurred between these activities. In coding round two, we further categorized these activities as is elaborated in the following section categorical scheme (whereby we only specify the codes relevant in the present study). For an initial training phase, two videos of case-based seminars were coded by all four raters. These videos had been recorded in a pilot study and were not part of sample for this study. We calculated interrater agreement between pairs of raters and simultaneously visualised different raters’ coding solutions. On this basis, passages in the seminars in which differences between coders had emerged could be identified easily. These passages were discussed, differences in agreement were resolved, and coding rules refined. This was done in an iterative manner until overall interrater agreement between all four coders, measured by Cohen’s Kappa, reached a satisfactory value of .80 . The main study videos were divided between the four raters. Two of the main study videos were analysed by all four coders, resulting in an overall IRR-value of Cohen’s Kappa = 0.65 and pairwise values between .59 and .66, which can be regarded as satisfactory [Coding was done by four researchers  from our group using the software Interact . In rounsfactory .didactically irrelevant teacher questions are unrelated to the learning goals of the seminar and were hence not considered in the further analyses. Didactically relevant teacher questions were further described by the coding schemes type of question, openness of question, and cognitive level of question [type of question, we differentiated initial and follow-up questions  questions. The former are intended to elicit information that should already be known to students, e.g. from pre-clinical medical education. The latter are asked to elucidate cause-effect relationships, differentiate intended from unintended consequences of therapeutic measures, or compare advantages and disadvantages of different therapies and their relevance for the particular case at hand.We analysed the video material using a hierarchical categorical scheme which was based upon published rating schemes , 37. Thequestion . Regardiother. As this was the case in a very small number of instances, we excluded these utterances from all further analyses (cf. results section).Further, we coded different types of student statements made in response to teacher questions. The main categories here were reproductive / elaborative statements and non-response . Boxplots are used to display the distribution of the relative frequencies of the categorised question characteristics within seminars. Corresponding hypothesis testing on the differences between seminars from internal medicine and surgery was performed by two-sided Mann-Whitney U tests on exploratory 5% significance levels. Teacher questions were investigated as predictors of student answers by evolutionary learning of globally optimal classification trees . This maThe current study was approved by the ethics committee of the TUM Rechts der Isar University Hospital (Application code 400/16 S). All teachers and students were informed about the study prior to the seminar via email. One physician refused to take part, so we did not record that respective seminar. At the beginning of each seminar (before starting the video recording), one person from the research team was present to inform all participants about the study, answer open questions, and obtain consent in written from all individuals. We started the video recording only after consent had been declared by all individuals in the room. In one seminar, one student declared unwillingness to be filmed. The student was offered to be seated right beside camera one . In contrast, students made more responses in internal medicine (p = 0.17 for absolute numbers and p = 0.12 for questions per minute).Table To answer this question, we describe the prevalence of the different qualities of teacher questions in our video data. Each single teacher question is characterized by a combination of categories, hence a separate analysis of the prevalence of different combinations is reported below. Figure MD = 6%) or were organizational questions (MD = 7%). However, there were outliers in organizational questions, indicating a relatively high prevalence  of such questions in two seminars. Regarding teacher questions posed with a didactical intention, we first look at the categorical scheme type of question, comprising initial and follow-up questions. As is apparent from Fig. openness of questions, we found that clinical teachers asked much more closed (70%) than open questions (28%). Looking at the cognitive level of teacher questions, the clinical teachers in our sample asked more than two times as many reasoning questions (67%) than reproduction questions (31%). One discipline difference emerged in the area of comprehension questions (p = 0.05) with physicians from internal medicine having asked more questions of this kind than their colleagues from surgery.As was expected, few of the questions posed by clinical teachers were simply focused upon comprehension of student statements , whereas the amount of elaborative and reproductive responses was almost equal (MD = 17%). Very few student responses were concerning organizational matters (3%) or were content-related questions (1%).If looking at the median values reported in Fig. To answer research question 3, we used the evolutionary trees method as explicated in the methods section.cognitive level of teacher questions makes a difference, i.e. whether teacher questions are reproductive or reasoning-oriented. Reproductive questions are associated with a higher amount of reproductive answers (nodes 3 and 4) while reasoning-oriented questions trigger more elaborative answers (nodes 6 and 7). A further difference (node 2) can be found between open and closed reproduction questions. Open vs. closed reproductive questions are associated with a lower degree of reproductive student responses (31% vs. 53%), more elaborative student responses (11% vs. 5%), and a higher student nonresponse (57% vs. 42%). Regarding absolute amounts, closed reproduction questions are posed much more frequent (more than 14 times more often) than open reproduction questions. The right branch originating from node 1, reasoning questions, is indirectly connected to nodes 6 and 7 at the bottom. Overall, these are characterized by higher levels of elaborative answers compared to nodes 3 and 4. The highest degree of elaborative student answers—50% in node 6—is associated with follow-up reasoning questions. Node 6 is also characterised by the lowest rate of student non-response in our analysis (30%) and by a comparatively low degree of reproductive student answers (21%). Finally, node 7 is connected to initial reasoning questions and is characterised by a comparatively high degree of student nonresponse (61%). Such questions also trigger elaborative (23%) and reproductive (23%) student answers. As is apparent, node 7 summarises as much as 945 teacher question-student (non-)response sequences. So, the pattern described here is very frequent in our sample of CBL seminars, even more frequently than closed reproduction questions posed by the teachers followed by student (non-)responses. Finally, we found no evidence for a differential functioning of specific question types in the two disciplines.Starting from node 1, it is apparent that the internal medicine and surgery. Thereby, we have analysed how students’ responses to teacher questions (reproductive and elaborative responses vs. student non-response) depend upon different qualities of questions posed by clinical teachers . In the literature, CBL is mostly described as a format which gives students high degrees of freedom to reflect and to engage in clinical thinking . O–6. OinteRegarding teacher questions associated with a high degrees of student elaboration, our results show that reasoning questions are powerful in this respect cf. Fig. . Also, fhow clinical teaching actually works and is practiced by clinical teachers. It can help strengthen a descriptive perspective in clinical teaching research and better understand how certain teaching methods are implemented [In theorizing about what makes CBL effective, authors have provided elaborate, yet often quite general, descriptions of the behaviours of both teachers and learners, e.g. “the facilitator orchestrates the discussion to maximize the breadth and depth of the dialogue” or “advances the learning objectives for which the case was designed by formulating a sequence of trigger questions” lemented  while noout-talked their students [teacher wait time  is a is aout-e . Seconde  clinicae  was rather small in these seminars – which also means that these seminars were not very interactive, but were more like lectures anchored in example cases with occasional episodes of student-teacher interaction. A critical concern which could be connected to this observation is whether it is legitimate to consider the seminars we observed as valid examples of CBL in the first place. We argue that it can be seen as a strength of the present study to include a broad range of ways in which CBL was implemented (from more teacher-guided to more-student centred). Due to this heterogeneity, our study might not reflect the concept of CBL as discussed in the literature in its purest form. However, we argue that our research has high ecological validity in that it reflects that CBL might be interpreted and practiced by different clinical teachers in very different ways.Regarding the comparison between internal medicine and surgery, we only found minor differences. On this basis, it does not seem justified to conclude that CBL works different in various medical disciplines. However, our findings indicate that there is substantial heterogeneity between how different teachers practice case-based teaching (regardless of discipline). This is apparent from several outcomes; overall, the CBL-teachers posed quite few didactically irrelevant questions. However, we had seven seminars in our sample in which between 20% and just over 50% of the questions posed were focused upon organisational aspects response dyads. By pursuing a more high-inference analytic strategy, longer passages and several turns of teacher-student interactions could have been analysed. This surely is a promising idea for future research. In the field of empirical educational research, a certain trend away from low-inference analytic approaches in video studies is apparent . A furthThe present study gives detailed insights into associations between clinical teacher questions and medical student responses in CBL. They are relevant for medical teaching practice and professional development. Some concrete recommendations to clinical teachers can be deducted: When seeking to make students elaborate, teachers should primarily ask reasoning questions or follow-up questions. For eliciting reproductive answers from students, closed reproduction question are suitable. To increase student participation, teachers should strive for low student non-response rates. This can be achieved in different ways. Henning et al.  recommen


Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, progressive scarring of the lungs and the pathological hallmark of usual interstitial pneumonia. Current paradigms suggest alveolar epithelial cell damage is a key initiating factor. Globally, incidence of the disease is rising, with associated high morbidity, mortality, and economic healthcare burden. Diagnosis relies on a multidisciplinary team approach with exclusion of other causes of interstitial lung disease. Over recent years, two novel antifibrotic therapies, pirfenidone and nintedanib, have been developed, providing treatment options for many patients with IPF, with several other agents in early clinical trials. Current efforts are directed at identifying key biomarkers that may direct more customized patient-centred healthcare to improve outcomes for these patients in the future. The interstitial lung diseases (ILDs) are a heterogeneous group of parenchymal lung diseases characterised by varying degrees of inflammation and fibrosis. Some of these may occur secondary to a known precipitant such as drugs, autoimmune connective tissue disease, hypersensitivity to inhaled organic antigens, or sarcoidosis, whilst others, the idiopathic interstitial pneumonias (IIPs), have no identifiable cause . IdiopatIPF is the most common form of ILD. Reported incidence rates for IPF vary considerably depending on the method of data collection and diagnostic case definition. A systematic review of the global incidence of IPF estimated a rate of 2.8–9.3 per 100,000 per year in North America and Europe with significantly lower rates in Asia and South America. Regional variation within countries has also been observed, possibly reflecting exposure to environmental or occupational risk factors ,5,6. EviMortality in IPF is high, with a reported median survival of 2–3 years from diagnosis, based on historical data . More reInternational consensus guidelines recommend that the diagnosis of IPF be made at a multi-disciplinary level, requiring the exclusion of known causes of ILD and the presence of a usual interstitial pneumonia (UIP) pattern on high resolution computer tomography (HRCT) or surgical lung biopsy . A radioDespite evolution of diagnostic criteria, the process remains challenging and can be lengthy and stressful for patients . There iUIP is the characteristic histopathological hallmark of IPF. Features include temporal and spatially heterogeneous fibrosis, clusters of fibroblasts and myofibroblasts (fibroblastic foci), and excessive deposition of disorganised collagen and extracellular matrix (ECM), with resulting distortion of the normal lung architecture, with or without honeycomb cyst formation . Whilst Studies of familial interstitial pneumonia ,31 and lThe surfactant proteins are alveolar epithelial type II cell (AEC type II)-specific proteins considered to be essential for normal lung function and homeostasis. Variants of surfactant proteins C (SP-C) and A2 (SP-A2) have been implicated in the development of familial pulmonary fibrosis (FPF) ,34,35,36Studies suggest that these mutations prevent correct folding of proteins within the endoplasmic reticulum (ER), leading to ER stress and initiation of the unfolded protein response (UPR) ,40. The Interestingly, markers of UPR activation are also elevated in the alveolar epithelial type II cells of patients with IPF ,46, althMUC5B promoter single-nucleotide polymorphism (SNP) has been identified as a strong risk factor for the development of both familial and sporadic idiopathic interstitial pneumonias. Odds ratios for disease in subjects heterozygous (GT) and homozygous (TT) for the minor allele of this MUC5B polymorphism (rs35705950) have been quoted as 6.8 , 3.9–12.0) and 20.8  for familial cases, and 9.0  and 21.8  for IPF [The  for IPF , with va for IPF ,50, alth for IPF . The role of this gene in the pathogenesis of IPF has not been fully elucidated, although mechanistic studies suggest that overexpression of MUC5B, driven by the promoter polymorphism, increases chronic mucus hypersecretion, impairs mucociliary clearance in the broncho-alveolar region, and potentiates chronic inflammation and injury . InteresTOLLIP) gene [GWAS have also identified three single nucleotide polymorphisms (SNPs) in the toll-interacting protein (IP) gene  in assocIP) gene .Telomeres are specialised loop structures of repeating 5′-TTAGGG-3′ DNA units and associated binding proteins (the shelterin complex) that cap the tips of chromosomes, protecting chromosomal DNA from degradation. Progressive shortening of the telomere occurs during each cycle of DNA replication until a critical telomere length is reached, triggering cell senescence or chromosomal degradation and cell death . TelomerAccelerated telomere shortening has been associated with premature ageing and abnormal tissue repair . In precTERT [TERC [DKC1 [TINF2 [RTEL1 [PARN [TERT mutations are most frequent, occurring in approximately 15% of those with affected kindreds [Six telomere-related genes have been linked to FPF ; TERT [3TERT , TERC [5RT [TERC , DKC1 [5RC [DKC1 , TINF2 [1 [TINF2 , RTEL1 [2 [RTEL1 , and PARL1 [PARN , althougkindreds .There appears to be poor genotype-ILD phenotype correlation across patients with telomere-related gene mutations and indeed within families that have the same genetic mutation ,65. CaseINK4a positive) and similarly the use of pharmacological drivers of senescent cell apoptosis, improved lung function and fitness of animals in pre-clinical models of pulmonary fibrosis [The concept of removing senescent cells as a form of therapy for those with telomere-dysfunction or age-related diseases is a rapidly evolving area of research. Genetic deletion of specific senescent cells  family have been the most widely studied, albeit in small, retrospective studies ,82,83,84A role for bacteria in the initiation and progression of IPF has developed as a more novel concept in recent years, challenging current paradigms of acute exacerbations of IPF (AE-IPF), that by definition requires the exclusion of an infective trigger . In a stShulgina et al. evaluated the benefit of 12 months of prophylactic co-trimoxazole in patients with IPF in a large multicentre, randomised controlled trial . AlthougCampylobacter in the AE-IPF microbiota strengthens this association [There is growing consensus on the role of chronic gastric fluid microaspiration as the initial AEC insult driving aberrant tissue remodelling in IPF . In pre-ociation .A recent meta-analysis suggested pharmacological management of gastro-oesophageal reflux (GER) was associated with a significant reduction in IPF-related mortality, although these conclusions were drawn from observational studies in the absence of any available RCT data . Indeed,The inability of the dysfunctional epithelium to regenerate following repetitive injury is a significant juncture in the propagation of IPF ,96. DamaExpansion of the resident fibroblast population is thought to be the predominant source of collagen producing cells in the lung during the development of fibrosis , but bonEpithelial–mesenchymal transition (EMT) is the process by which epithelial cells acquire phenotypic characteristics of mesenchymal cells , a proceThe treatment approach to IPF has evolved considerably over the last two decades. A typical regimen in the year 2000 involved immunosuppression with prednisolone and azathioprine (2000). The Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual (IFIGENIA) study , publishPirfenidone is a novel compound with anti-inflammatory and anti-fibrotic properties ,115. EarNintedanib, a tyrosine kinase inhibitor initially developed as an anti-tumour agent , was notMeta-analysis indicates similar efficacy between both antifibrotics ,134. TreThe IPF disease course and response to anti-fibrotic therapy demonstrates marked heterogeneity, making individual prognostication difficult. Progression towards more customized patient-centred healthcare is essential to achieve better outcomes in the future ,146.Many biological markers or biomarkers have been explored with respect to predicting prognosis or treatment response in IPF, with several blood biomarkers showing promise with regards to the emerging concept of precision medicine ,148. WhiLCO (% predicted) [The matrix metalloproteinases (MMPs) are proteases involved in the remodelling of extracellular matrix components . MMP-7 aedicted) . Furtheredicted) ,155.LCO), and change in FVC [The alveolar epithelial markers surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6), also known as mucin 1 (MUC-1), have been widely used in clinical practice in Japan as part of the diagnostic work-up for ILD for more than 10-years, although evidence from clinical trials validating their clinical efficacy in IPF remains limited . Signifie in FVC . Furthere in FVC ,147 nor e in FVC  significGiven the complexity of IPF disease pathogenesis it is unlikely that a single biomarker will prove to be sufficiently specific to IPF and also be able to predict disease evolution; a panel of biomarkers is likely to be more successful. Gene expression profiling of several IPF cohorts has identified a collection of 52 specific peripheral blood mononuclear cell genes that when interpreted together predicts poor outcomes in IPF ,162. AltInternationally it has been recognised that to drive the concept of ‘patient-centred healthcare delivery’ in the future, an investigational approach of integrated systems biology is required, bringing together cellular, molecular, clinical, and environmental research to provide a more comprehensive understanding of disease development, progression and response to therapy . Fibrogenesis represents the final common pathway of disequilibrium in several processes that represents the complex interplay of cellular mechanisms, growth factors, cytokines and signalling pathways.Growing understanding of the pathogenesis of IPF has enabled the identification of a variety of putative molecular targets and has led to the development of multiple novel agents, many of which are in early clinical trials. Whilst a comprehensive review of all emerging therapies in IPF is beyond the scope of this article, we focus on recent and exciting advancements .Connective tissue growth factor (CTGF) is normally expressed at low levels in healthy adults, but when expressed in excess it is thought to co-ordinate the upregulation of several pro-fibrotic growth factors (including TGF-β1), promote ECM production, and inhibit ECM degradation . FG-3019In addition to targeting the circulating growth factors themselves, the corresponding cell surface receptors are also potential targets. Integrin αvβ6, a key mediator of TGF-β activation, is known to be involved in the regulation of fibrogenesis and epithelial injury . In a muAutotaxin is an enzyme that plays a central role in the production of bioactive lysophosphatidic acid (LPA). Levels of LPA and autotaxin have been found to be elevated in bronchoalveolar lavage fluid and exhaled breath condensate in patients with IPF, with several reports suggesting a role of the autotaxin-LPA pathway in fibrogenesis ,169,170.Interleukin-13 (IL-13) is a T-helper type 2 (Th2) cell cytokine that promotes lung fibrogenesis in a number of experimental settings ,173,174.Monocytes and macrophages have a key role in regulating tissue repair and fibrosis, and several molecular pathways regulating their activity are being investigated as potential treatments in IPF. Pentraxin-2 (PTX-2), also known as serum amyloid P, is a circulating protein which binds to Fc-gamma receptors on monocytes and promotes epithelial healing . Low circulating levels of PTX-2 have been found in IPF . PRM-151Galectin-3 is another circulating protein which plays a key role in fibrosis development through the activation of macrophages and myofibroblasts ,179. TD1There is growing evidence that an adaptive immune response to exposed autoantigens, notably collagen proteins, may play a role in the progression of IPF . SpecifiWhilst progress has been made over recent years to improve our understanding of this condition and provide therapeutic options, there is still much work to be done to identify key targets that may allow preventative interventions and to develop strategies and/or biomarkers to aid early diagnosis or even to suspend fibrogenesis in this devastating condition.


We calculated the band structures of a variety of N- and S-doped graphenes in order to understand the effects of the N and S dopants on the graphene electronic structure using density functional theory (DFT). Band-structure analysis revealed energy band upshifting above the Fermi level compared to pristine graphene following doping with three nitrogen atoms around a mono-vacancy defect, which corresponds to p-type nature. On the other hand, the energy bands were increasingly shifted downward below the Fermi level with increasing numbers of S atoms in N/S-co-doped graphene, which results in n-type behavior. Hence, modulating the structure of graphene through N- and S-doping schemes results in the switching of “p-type” to “n-type” behavior with increasing S concentration. Mulliken population analysis indicates that the N atom doped near a mono-vacancy is negatively charged due to its higher electronegativity compared to C, whereas the S atom doped near a mono-vacancy is positively charged due to its similar electronegativity to C and its additional valence electrons. As a result, doping with N and S significantly influences the unique electronic properties of graphene. Due to their tunable band-structure properties, the resulting N- and S-doped graphenes can be used in energy and electronic-device applications. In conclusion, we expect that doping with N and S will lead to new pathways for tailoring and enhancing the electronic properties of graphene at the atomic level. It e [2 g−1 ,5, whiche [2 g−1 . Graphenm2 V s−1 , good th1 [−1K−1  and high1 [−1K−1 . Due to 1 [−1K−1 , optoele1 [−1K−1 , energy-1 [−1K−1 ,13,14, s1 [−1K−1 , and cat1 [−1K−1 . It is e1 [−1K−1 ,31,32,331 [−1K−1 ,29,30,331 [−1K−1 ,23,24. T1 [−1K−1 ,31,32,33−6 eV per atom and the maximum force converged to below 0.05 eV Å−1. The graphene model used in our simulation consisted of a 12.3 × 12.3 × 15.0 Å, 5 × 5 supercell with a vacuum thickness of 15 Å, which avoids interference between adjacent graphene layers. Brillouin-zone integrations were carried out using a 4 × 4 × 1 Monkhorst–Pack Κ-point grid. The effects of van der Waals (vdW) interactions were included using the empirical DFT-D3 correction within the Grimme scheme [First-principles density functional theory (DFT) calculations were carried out using the Vienna Ab Initio Simulation Package (VASP) ,35. Geome scheme . All atoe scheme ,46.2-hybridized N atoms bonded to two neighboring sp2-hybridized C atoms. Using this configuration as the starting point, different configurations of N- and S-doped graphene with mono-vacancy defects were built as simulation models. Three C atoms around a mono-vacancy defect were substituted with different numbers of atomic N and/or S dopants. Regarding model structures in this investigation, research groups successfully reported the synthesis of N- and S-doped graphene [Various configurations exist for the doped and defective graphene chosen as the anode material in a lithium-ion battery (LIB). For instance, N-doped graphene exists in distinct forms that include graphitic, pyridinic, and pyrrolic N atoms . Among tgraphene ,62,63,64graphene .The bandgap clearly opens after doping with N or S, and/or the introduction of a mono-vacancy defect, which is ascribable to the effects of the atomic dopant and/or vacancy defect on the π electrons in the hexagonal rings. Mono-vacancy defects lead to shortages of whole charges compared to pristine graphene, which downshift the Fermi energy, indicating that the mono-vacancy defect acts as a hole dopant with missing π electrons. As shown in On the other hand, N and S atoms have one and two additional valence electrons, respectively; hence, doping with N or S results in an upward shift in the Fermi energy. N1′ and CN1′′ atoms, and +0.143e and +0.082e on the CN2′ and CN2′′ atoms, respectively. The charges on the C atoms on each side of the N atom are almost identical. On the other hand, the C atoms bonded to the S atom exhibit negative charges, at −0.242e on CS1′, and −0.246e on CS1′′. Likewise, the 1N2S-gra system showed a similar trend. As shown in N1′ and CN2′′, bear charges of +0.109e and +0.110e, which are almost identical. The C atoms adjacent to the S atoms exhibit negative charges, with charges of −0.248e and −0.240e on CS1′ and CS1′′, and −0.238e and −0.250e on the CS2′ and CS2′′ atoms, respectively. Finally, the 3S-gra system exhibited charges on the C atoms bonded to the S atoms that were in the −0.245e to −0.233e range. It seems that polarization in the doped region increases with increasing S concentration. The transformed charge-density distribution following doping, as well as the vacancy defect, affects the electronic properties of the graphene system.Finally, we studied the charge-density distribution of each atom around the mono-vacancy defect for each N- and S-doped graphene system by Mulliken population analysis because the charge distributions on the carbon, nitrogen, and sulfur atoms are important for determining the origin of the alternating electronic properties. The present density functional theory study aimed to reveal details of the electronic structures of several N- and S-doped graphenes in order to understand the effects of the N and S dopants on the graphene electronic structure. We found that the band structure of graphene can easily be tuned by doping with N and S atoms. The roles of the atomic N and S dopants on the band energies were clearly revealed; these dopants noticeably perturb the band shapes and open the bandgap at the Dirac point, compared to graphene itself. The band energies of 3N-doped graphene were upward shifted below the Fermi level compared with those of pure graphene, and showed p-type behavior. The band structure exhibits a remarkable electronic transition, from “p-type” to “n-type”, in moving from 3N-gra to 3S-gra (with increasing numbers of S atoms) with a downshifting of the band energy below the Fermi level. Moreover, Mulliken population analysis revealed that the atomic N dopants bear negative charges, whereas the atomic S dopants bear positive charges in N- and/or S-co-doped graphene systems, which is ascribable to differences in the electronegativities and numbers of valence electrons among the C, N, and S atoms. In each N- and/or S-co-doped graphene system, all of the N atoms bear negative charges, whereas all of the S atoms bear positive charges. The average charge on the N atoms gradually increases with decreasing numbers of N atoms in the N- and/or S-co-doped graphene system. In contrast, the average charge on the S atoms decreases with increasing numbers of S atoms in the co-doped graphene system. Due to their tunable band-structure properties, the resulting N- and S-co-doped graphenes can be used in energy and electronic-device applications. In conclusion, we expect that doping with N and S will lead to new pathways for tailoring and enhancing the electronic properties of graphene at the atomic level.


Moreover, the significant enhancement of photoluminescence can be ascribed to the coupling of the light emitters in multiple quantum wells with the surface plasmon Ag NPs and the EIT effect.In this work, the synthesis and characterization ofgraphene-metal nanocomposite, a transparent conductive layer, is examined. This transparent conductive layer is named graphene-Ag-graphene (GAG), which makes full use of the high electron mobility and high conductivity characteristics of graphene, while electromagnetically induced transparency (EIT) is induced by Ag nanoparticles (NPs). The nanocomposite preparation technique delivers three key parts including the transfer of the first layer graphene, spin coating of Ag NPs and transfer of the second layer of graphene. The GAG transparent conductive nanocomposite layer possess a sheet resistance of 16.3 ohm/sq and electron mobility of 14,729 cm However, the GAG transparent conductive layer would increase the optic power due to plasma-induced enhancement which can be seen in GAG must be GAG (MAX) = 7 × 105, JGA (MAX) = 5.9 × 105)  [A question to consider is why the effective radiated power of GAG is better than GA. If the simple transparency (T) formula (9 × 105) . The ele106 S/m) ,55. This2/(v s),and its sheet resistances are 16.3 ohm/sq. The PL of LED has significantly improved due to the performance of the GAG transparent conductive layer. In conclusion, GAG is a sounded, promising, transparent conductive layer to meet the future demand of light devices.Based on the study of materials of theindex dielectric layer to cover NPs andthe radius of nanoparticles and period of the plasmon, a graphene-metal nanocomposite transparent conductive layer of GAG was designed.Due to the plasma excited effect of Ag NP and double-layer graphene electromagnetically induced effect, the effective radiated power of the GAG transparent conductive layer is reaching 1.33, its carrier motilities are 14,729 cm


Damage to the corticospinal pathway often results in weak dorsiflexion of the ankle, thereby limiting the mobility of people with multiple sclerosis (MS). Thus, strengthening corticospinal connectivity may improve locomotion. Here, we investigated the feasibility of tibialis anterior (TA) motor-evoked potential (MEP) operant conditioning and whether it can enhance corticospinal excitability and alleviate locomotor problems in people with chronic stable MS. The protocol consisted of 6 baseline and 24 up-conditioning sessions over 10 weeks. In all sessions, TA MEPs were elicited at 10% above active threshold while the sitting subject provided 30–35% maximum voluntary contraction (MVC) level of TA background EMG. During baseline sessions, MEPs were simply measured. During conditioning trials of the conditioning sessions, the subject was encouraged to increase MEP and was given immediate feedback indicating whether MEP size was above a criterion. In 3/4 subjects, TA MEP increased 32–75%, MVC increased 28–52%, locomotor EMG modulation improved in multiple leg muscles, and foot drop became less severe. In one of them, MEP and MVC increases were maintained throughout 3 years of extensive follow-up sessions. These initial results support a therapeutic possibility of MEP operant conditioning for improving locomotion in people with MS or other CNS disorders, such as spinal cord injury and stroke. Transcranial magnetic stimulation (TMS) and its motor-evoked potential (MEP) have been widely used to study corticospinal excitability and connectivity noninvasively . GeneralOperant conditioning is a powerful method for modifying a behavior based on its consequences. The past 35 years of spinal reflex operant conditioning studies in monkeys, rats, mice, and humans show that even a simple spinal reflex behavior can be gradually changed through learning and practice –31. AnimThe purpose of this study was to investigate the feasibility and a therapeutic possibility of MEP operant conditioning for improving locomotion in people with chronic stable MS.The MEP operant conditioning protocol used in this study is a modified version of the conditioning protocols developed and used in human subjects with and without spinal cord injury , 37, 38.At the beginning of the study, the subject was familiarized with the protocol and TMS in several preliminary sessions. Then, each subject completed 6 baseline sessions and 24 up-conditioning sessions that occurred at a pace of 3 times per week . In one M-wave threshold to just above the maximum M-wave (Mmax) [Mmax measurement was followed by control MEP trials  were placed over the muscle bellies of TA and soleus for EMG recording , 41. EMGe (Mmax) . This TAP trials . In all P trials . The cri∗; (3) ability to ambulate with or without an assistive device  2 to 6 [∗Except for subject A, who had been taking 4-aminopyridine (Ampyra®) for 5 years at the time of enrollment, none were on neuromodulatory medication . These subjects maintained their long-term MS medication, such as beta interferons , rituximab (Rituxan®), and dimethyl fumarate (Tecfidera®), throughout the 10 weeks of main study period.Four women (age: 47–56 years) with chronic foot drop due to secondary progressive MS participated. Inclusion criteria were (1) neurologically stable for >6 months; (2) medical clearance to participate (with the expectation that current medication and therapy schedule would be maintained without change for at least 4 months)) 2 to 6 ); and  or a bat-wing coil (in subject A) with radii of 9 cm , held over the scalp such that the induced current flowed in the posterior–anterior direction in the brain. When the absolute TA EMG level was maintained within the preset range , anre study , 45–47. Along with control and conditioned MEP size measurements, we also measured the silent period (SP) as the period from the end of the MEP to the recovery of background EMG activity in 50% of the responses , 46, 48.Overground locomotor EMG activity was measured before and after the 24 conditioning sessions. Subject B, who wore an ankle foot orthosis on her unconditioned leg, was asked to remove it for this measurement. Surface EMG was recorded from the TA, soleus, biceps femoris, and vastus lateralis bilaterally. To detect foot contact for each leg, foot-switch cells were inserted between the subject's shoes and feet. For analysis, the foot-contact signal was used to define the beginning of the step cycle. Rectified EMG signals from individual steps were normalized to the mean step cycle time and averaged together to obtain the locomotor EMG activity over the step cycle , 49, 50.For each session of each subject, we calculated average MEP sizes for the 20 within-session control trials and for all three 75-trial blocks together. For these calculations, MEP size was defined as average absolute EMG in the MEP interval minus average background EMG. Changes in these MEP sizes across sessions were quantified in percent of their average values for the 6 baseline sessions. We also determined for each subject the final effects of conditioning on the conditioned MEP by averaging the MEPs for the 75-trial conditioning blocks of conditioning sessions 22–24 and expressing the result in % of the average MEP for the 75-trial blocks of the 6 baseline sessions.  The final effect on the control MEP was calculated by averaging the MEPs for the 20 within-session control trials of conditioning sessions 22–24 and expressing the result in % of the average MEP for the first 20 trials of the 6 baseline sessions (see ).t-test (two-tailed) [Mmax and background EMG levels over all sessions and assess changes in MVC and SP, a factorial ANOVA was used across successive 6-session blocks  [Mmax and TA and soleus background EMG levels in control and conditioning trials remained stable throughout the study . Typically, TA Mmax remained within ±15% to the mean across all the sessions, TA background EMG remained within ±5%, and soleus background EMG remained under 5 μV  throughout the study.To determine for each subject whether MEP up-conditioning was successful, the average conditioned MEPs of the final 6 conditioning sessions were compared to the average MEPs of the 6 baseline sessions by unpaired -tailed) , 37. To In 3 of the 4 subjects, TA MEP increased significantly, together with the TA MVC; and at the end of conditioning, all three spontaneously reported better leg movement in their daily walking. Here, we describe each subject's results individually.Over the course of conditioning, her left TA MEP increased progressively. Her final conditioned MEP size was 175% of the baseline value . This inThere were several noteworthy observations over the course of study. First, this subject had no visible voluntary ankle dorsiflexion at the beginning and needed a cane to compensate for the limited motion in the left leg. After 24 conditioning sessions, she was able to flex the left ankle even against resistance ; and at Mmax remained around 3.8 mV for the entire 172 weeks of her study). An increased MEP and decreased SP duration were also present in most of the follow-up sessions. At the study conclusion , voluntary ankle dorsiflexion remained visible and improved.In this subject, 66 follow-up sessions were performed over 161 weeks (3 years) after the last conditioning session . During The TA MEP increased over the course of study . Her finAfter conditioning, the conditioned leg's TA burst in the late swing phase of walking and soleus burst during the stance phase were clearly increased . LocomotHer final conditioned MEP size was 172% of the baseline value , which cThe TA burst in the swing phase of locomotion increased after conditioning in both the conditioned and the contralateral legs . LocomotMEP up-conditioning did not increase her MEP . Her finIn three of 4 subjects with MS, up-conditioning successfully increased MEP over the course of 24 conditioning sessions, supporting the possibility and feasibility of MEP operant conditioning in people with chronic stable MS.In two of the 3 successfully conditioned subjects, the conditioned MEP increase consisted of within-session task-dependent adaptation and cumulative long-term change, similar to previous studies of H-reflex operant conditioning , 37, 38.B receptor agonist and known to prolong the SP duration [B-mediated intracortical inhibition [In all of these subjects with MS, we noticed that the SP duration was very long  during the baseline sessions. Since baclofen, a common antispastic medication for people with MS, spinal cord injury, and cerebral palsy –53, is aduration , 55, onehibition –58. The hibition  that mayhibition . In subjhibition ). ConsidIn 3 of the 4 subjects, operant up-conditioning of TA MEP was successful and was accompanied by increased MVC, increased TA burst during the swing-phase of locomotion, and improved EMG modulation during locomotion. In 2 of the 3 subjects, the ankle dorsiflexor strength and walking speed also improved; in the third subject, disease progression near the end of the study may have prevented walking speed improvement despite significant increases in MEP, MVC, and locomotor EMG modulation. The increased corticospinal drive to the conditioned TA may explain increases in TA MEP, TA MVC, and TA burst amplitude during the swing phase of walking , 26, butOne of the cases presented here (subject A) has an important implication for future therapeutic applications. Over 3 years of follow-up sessions, her TA MEP, MVC, and SP improvements and the voluntary ankle dorsiflexion that she had not had before conditioning were essentially maintained , despiteThe present study investigated the feasibility of MEP operant conditioning in a small number of individuals with MS. Thus, while the initial results support a therapeutic possibility of this approach for improving locomotion in people with MS , its wider applicability is yet to be confirmed through future clinical studies of larger scales.


A method was developed to pattern the surface of perfluorinated materials with graphene oxide thin film, and various biological applications of the patterned perfluorinated surface were illustrated. Perfluorinated surfaces such as Teflon, Cytop, and other perfluorinated materials are known to be both hydrophobic and oleophobic, with low adhesion for most materials. Modifying the perfluorinated surfaces has been difficult due to the extraordinary chemical inertness, which limits the applications of perfluorinated materials as anti-fouling substrates. Herein we successfully patterned Cytop surfaces with graphene oxide. Patterns of the graphene oxide thin film with feature dimension down to 40 microns were formed and remained stable on the Cytop surface against washing with water, ethanol and acetone. The graphene oxide thin film on the Cytop surface allowed non-specific protein adsorption. To illustrate the applications of the patterned Cytop surface, we used the patterned Cytop surface as the substrate to study the protein-protein interactions, stem cell culture, and stem cell proliferation. Perfluorinated materials are a group of organofluorine compounds in which all the C–H bonds are replaced by C–F bonds. The perfluorinated materials share the well-known properties of extraordinary thermal and chemical stability due to the strong C–F and C–C bonds . Most pe2 C basal plane [To improve the polydopamine coating method, we turned our attention to graphene oxide, which can be stocked in solution for a long time before the coating application. Graphene oxide is the oxidized form of graphene with the oxygen-containing function groups decorating the spal plane . We hypoal plane ,16,17. Gal plane ,19,20,21al plane ,22,23. BTM (CTL-809M) and the fluorinated solvent CT-Solv.180 were purchased from Asashi Glass Co . Graphite was from International Laboratory, USA . AZ P4620 photoresist was from MicroChemicals GmbH . Sodium nitrate and hydrogen peroxide were from Scharlab S. L . Sulfuric acid (98%) was from RCI Labscan Limited . Hydrochloric acid was from Fisher Scientific . Potassium permanganate, ZONYL FSO-100 fluorosurfactant, trichloro  silane (97%) were from Sigma-Aldrich . β-human chorionic gonadotrophin (β-hCG) and fluorescein isothiocyanate (FITC) labeled anti-β-hCG were from Abcam . Mesenchymal stem cells were from mouse bone marrow . Dulbecco’s phosphate buffered saline (DPBS 1X), minimum essential medium (MEM) alpha (1X), and trypsin were from Gibco .CytopGraphene oxide was synthesized using the modified Hummer’s method . Five grGlass slides were cleaned with piranha solution, a mixture of 98% sulfuric acid and 30% hydrogen peroxide with 3:1 volume ratio, and were dried in the oven. The glass slides were then spin coated with 1% Cytop solution (1% in CT-Solv.180) at a 500 rpm for 30 s and heated at 180 °C for 1 h. After cooling down naturally, Cytop formed a uniform layer on the glass slide. The Cytop surface was then spin coated with AZ photoresist  at a speed of 2000 rpm for 30 s. The coated AZ photoresist was heated in the 100 ℃ heater for 5 min. Then a photomask containing two types of surface, transparent to pass the light and black to block the light, was placed onto the AZ photoresist. UV irradiation at 365 nm above the photomask was turned on for 30 s. A 0.02 M NaOH solution was used to wash the AZ photoresist. The area on the AZ photoresist irradiated with UV light became soluble in the NaOH solution while the non-irradiated area was insoluble and remained on the substrate, and AZ patterns corresponding to the photomask were created on the Cytop surface. A graphene oxide solution with 0.025% ZONYL FSO-100 fluorosurfactant was added onto the AZ-patterned Cytop surface to form graphene oxide thin films. Afterwards, the graphene oxide-patterned Cytop surface was placed in a vacuum desiccator which contained saturated vapor of trichlorosilane. After the fluorosilane treatment, the graphene oxide patterned Cytop surface was then treated by oxygen plasma (SPI Plasma Prep II) for 2 min. In the final step, acetone developing or peeling using adhesive tape was performed to remove the AZ photoresist from the Cytop surface. Aqueous solution of rhodamine with the concentration of 0.50 mg/mL was prepared to test the surface property of the graphene oxide patterned Cytop surface. A large drop of rhodamine solution was placed on top of the patterned Cytop surface, followed by tilting the surface so that the drop of rhodamine solution flowed off the surface.Three Cytop surfaces presenting the graphene oxide patterns, the fluorosilane treated graphene oxide patterns, the fluorosilane and plasma treated graphene oxide patterns, were placed onto a flat surface of the optical tensiometer . The optical tensiometer produced a water droplet onto each surface. A camera then took a photo of the water droplet resting on each surface. By manually selecting the highest point of the water droplet and two contacting points of water/air/solid interfaces, the tensiometer calculated the water contact angles.The graphene oxide solution was deposited onto a silicon substrate, which was then treated by freeze drying to remove the solvent and form the graphene oxide thin film. The silicon substrate was then loaded into a thermal evaporator and coated by a thin layer of Au. Finally, the silicon substrate was loaded into the scanning electron microscopy (SEM) to observe the micro structures of the graphene oxide.The stem cells microarray supported by the graphene oxide patterned Cytop substrate was put onto the holder of the confocal microscope . A 488 nm excitation laser was used to obtain the fluorescence image.Graphite and graphene oxide samples were ground into fine powders and then casted onto the glass slides. The casted powders were then pressed to form flat sample surface for X-ray diffraction (XRD) measurement. The samples were scanned from 5–40 degrees in XRD. To prepare the samples for XPS characterization, the graphene oxide solution with 0.025% ZONYL FSO-100 fluorosurfactant was deposited on the Cytop coated glass slide to form graphene oxide thin films. The thin film was treated with saturated vapor of trichlorosilane in a vacuum desiccator for the fluorosilane treatment. In the final step, the graphene oxide thin film was peeled off by conductive tape and loaded into the X-ray photoelectron spectroscopy (XPS) spectrometer  for XPS characterization. For infrared (IR) spectroscopy, graphite and graphene oxide samples were ground into fine powders and dried in a 70 ℃ oven. Two-gundred milligram KBr and 2 mg graphite or graphene oxide powders were mixed together and ground in one direction. The ground powders were put into the mold and pressed to become the sample tablet, which was used in the IR spectrometer for IR testing.g for 3 min to remove the liquid. Five milliliters of new growth media was added into the tube to suspend the MSCs. Afterwards, the MSCs suspension was uniformly added into 100 mm petri dish containing 5 mL new growth media. The petri dish was put into a 37 ℃ incubator for the MSCs proliferation. After two days, the petri dish was taken out from the incubator and observed under microscope. A 70% to 80% coverage ratio of the MSCs would represent nearly one million cells inside the petri dish. The growth media inside the petri dish was removed by pipetting, followed by rinsing with 5 mL phosphate-buffered saline (PBS) buffer twice. Two milliliters of trypsin solution was added into the petri dish. The petri dish was then put into 37 ℃ incubator for 5 min, followed by the addition of 4 mL growth media. Pipette was used to blow the wall of the petri dish to completely detach the MSCs. The solution containing the MSCs inside the petri dish was transferred into the centrifugal tube and underwent centrifugation at 500× g for 3 min. 0.5 mL new growth media was added into the tube after the supernatant was removed. The collected stem cells were mixed with the newly added growth media. Fifteen microliters of mixed solution was taken out and mixed with 15 μL trypan blue, followed by injection into the hemocytometer. A total of 0.78 million MSCs were harvested as a result. Mesenchymal stem cells (MSCs) derived from green fluorescent protein (GFP) transgenic mice were used for the low-level laser irradiation study. The MSCs were taken out from liquid nitrogen and quickly warmed up at 37 ℃ water bath. Then the MSCs were added into a 15 mL centrifugal tube containing 5 mL growth media. The tube was centrifuged at 500× The graphene oxide patterned Cytop surface was sterilized under ultraviolet (UV) irradiation in the fume hood. A total of 0.2 million MSCs from the 0.78 harvested MSCs were uniformly distributed onto this sterilized surface. After one day’s culture in the 37 ℃ incubator, the Cytop surface was washed with PBS buffer for three times to remove the MSCs on the unmodified Cytop surface. The MSCs remained only on the graphene oxide coated area. The remaining stem cells were then irradiated for 10 min using the low-level 633 nm laser  was optimal to promote the proliferation of the mouse mesenchymal stem cells. The patterned Cytop surface also facilitated the fabrication of cell microarrays. Previously, researchers demonstrated that low-level laser irradiation could stimulate the proliferation of many different types of cultured cells, including stem cells . For exaand mice ,35. The and mice . Despiteand mice . Graphenand mice ,39 but band mice ,41. In tand mice . The proIn conclusion, we have developed a new gentle method of modifying perfluorinated surfaces with graphene oxide thin film. The chemically inert and hydrophobic perfluorinated material surface can be patterned through photolithography with functionalized and hydrophilic graphene oxide thin film. The graphene oxide thin film on the perfluorinated material surface was stable against washing with water, ethanol, and acetone. Owing to the high adsorption capacity for serum proteins, the patterned graphene oxide presented the potential to be an excellent substrate for the stem cells culture. We applied this patterned perfluorinated surface to screening the conditions of the stem cells’ proliferation under the low-level laser irradiation. The graphene oxide-patterned perfluorinated materials could potentially be useful as a substrate for microarray fabrication in applications, such as high throughput bioanalysis.


A surface plasmon resonance (SPR) liquid refractive index sensor based on photonic crystal fiber (PCF) is proposed. The PCF is made of the exposed core structure, and the gold film is formed by electron beam evaporation within its defects. The sensitivity of the sensor is improved by coating graphene on the surface of the gold film. The experimental results show that the sensitivity of the sensor is increased by 390 nm/RIU after the introduction of graphene, and finally to 2290 nm/RIU. The experiment and simulation have a good consistency. Significantly, the sensor can be reused, and the measurement accuracy can be maintained. Since the first report of optical fiber surface SPR sensor, many scholars have devoted themselves to the research of biosensors . When itSensitivity is one of the most important performance parameters of sensors, which affects the accuracy and resolution of sensor detection. The sensitivity of the optical fiber SPR sensor can be improved by special treatment of the metal film, such as coating functional materials or specific materials. Since the sensor is approaching the upper limit of its sensitivity when the SPR is produced by the metal film, we continue to have difficulty in improving the performance of the sensor. For example, simply increasing the thickness of the metal film increases the cost or broadens the spectrum. Despite recent reports, the photonic crystal fiber (PCF) sensor designed by Islam et al. can obtain a spectral sensitivity of 25,000 nm/RIU with a gold SPR ,7,8. As Graphene as a coating must be in contact with the detection liquid to be effective. Therefore, many types of PCF structures have been proposed by some scholars. Rifat et al. proposed that the gold film be covered in the specific pore inside PCF, and then graphene is coated on the surface of the gold film . Using tThe proposed sensor model structure is shown in Through software simulation, we can get the effective refractive index and confinement loss of PCF, etc. In order to analyze the performance of the sensor. The existence of scattering boundary conditions and perfectly matched layer (PML) can be used to absorb the energy of outward radiation . In the λ is wavelength in μm, m = 3. B1, B2, B3 are 0.6961663, 0.407926 and 0.8974794, respectively. λ1, λ2 and λ3 are 4.67914826 × 10−3 μm2, 1.35120631 × 10−2 μm2 and 97.9340025 μm2, respectively. Which permittivity of Au is expressed by the Drude-Lorentz model, Equation (2)  is the imaginary part of the refractive index of the fundamental mode. Usually, we can get the spectral sensitivity (λS) of the sensor Equation (4) [tion (4) :(4)Sλ=Δλpeakλ is used to define the displacement of resonance wavelength. Δn is employed for changes in the refractive index.Δn′ expression of the complex refractive index of graphene in the simulation:According to the work of Nair  et al., By analyzing the results of numerical simulation, as shown by the black curve in n = 1.33, the corresponding resonance wavelengths are 570, 586 and 597 nm, respectively. When the refractive index n = 1.3402, the resonance wavelengths are 580, 600 and 610 nm, respectively. According to the spectral sensitivity equation, the spectral sensitivity of the sensor increases from about 1000 nm/RIU to 1400 nm/RIU and then decreases to 1300 nm/RIU. Therefore, we find that increasing the thickness of the gold film can improve the spectral sensitivity of the sensor.For the optical fiber sensor using SPR, the thickness of metal material has a great influence on its performance. In this paper, we mainly analyze the influence of the thickness of the gold film on the confinement loss of PCF and the resonance wavelength of SPR. As shown in However, the loss peak at 35 nm is sharper than that at 40 nm. Considering the full width at half maximum (FWHM) and sensitivity, the following simulation parameters of the gold film thickness are set to 35 nm. According to our assumption, graphene can be coated on a 35 nm thick gold film to achieve the best results. However, there may be an interaction between the gold film and graphene, which results in that the thickness of the gold film does not obtain the maximum sensitivity. Therefore, the data we get through simulation is not necessarily the best.As mentioned earlier, graphene as a plasma material can enhance the evanescent field. If graphene is coated on the gold film, the resonance wavelength position can be adjusted by enhancing SPR, and finally, the sensitivity of the sensor can be improved. Because the fabrication of the sensor failed to transfer graphene with fixed layers, the effects of graphene films with different thickness on the performance of the sensor were simulated. As can be seen from In order to show whether graphene can improve the performance of the sensor, we simulated the confinement loss of PCF in the range of 1.33–1.3688. If the liquid refractive index sensor is used to measure the actual data, it should pay great attention to the accuracy of the sensor measurement and the reliability of the measurement results at the beginning of the design.2 closer to 1. This proves that the linear regression equation has reference value.The black curve in After completing the simulation, we made the PCF included in the sensor system. All parameters are consistent with the simulation settings as far as possible. After that, we successfully deposited the gold film with a thickness of 35 nm in the depression of PCF by electron beam evaporation. Electron beam evaporation is a kind of physical vapor deposition. It evaporates gold into the film by accelerating electron bombardment of the pure gold source. It can accurately achieve high purity and high precision metal deposition by using electromagnetic field. Electron beam evaporator can control the thickness of the gold film. As the gold film we steamed is very thin, the thickness may be limited by the sensitivity of the machine sensor with an error of 1–2 nm. Due to the limitation of experimental equipment, we can only observe the side of PCF through 500 times magnification of the optical microscope. In Afterwards, we treated graphene ethanol dispersions with 1–10 layers and a concentration of 1 mg/mL with ultrasound in order to eliminate agglomeration. The solution was purchased by a commercial company. Considering the feasibility of different transfer methods of graphene, we decided to deposit graphene in defects of PCF by multiple pull-up and dry PCF. The number of pull-ups is 20. Of course, this method is not perfect. It is easy to bend the optical fibers, which may lead to uneven distribution and different thickness of graphene films. Therefore, the experimental results may be affected and need further improvement. However, according to our simulation results of graphene thickness, we can find that the thicker the graphene film, the more the resonance wavelength shifts. We believe that the thickness of graphene film can be increased by increasing the number of pull-ups. But for a single sensor, it has its own graphene film thickness and measurement standards. This must be taken into account.We have built a detection system, as shown in In order to complete the experiment, we configure different mass fractions of glucose solution. The refractive index of glucose solution measured by refractometer is shown in Finally, we have completed the sensor detection experiments by two methods: Only gold plating and coating graphene after gold plating. The obtained transmission spectrum is filtered and redrawn, as shown in Considering that the sensor should be durable, we have tested the graphene-coated sensor repeatedly. It is assumed that if the sensor is stable for a long time, its resonance wavelength should be constant. Therefore, we have experimented on the same gold film sensor coated with graphene. In this test, we measure the refractive index of water every 24 h and record its resonance wavelength. PCF is washed and dried after each measurement. And the experiment is repeated five times. The red curve represents the test curve, and the green curve represents the test completion curve. As we can see from the red curve in Similarly, we also fitted the data of the two groups, as shown in An SPR liquid refractive index sensor based on PCF is proposed in this paper. Firstly, SPR is generated by gold film, and a high linearity sensor with an average spectral sensitivity of 1900 nm/RIU is obtained in the range of liquid refractive index from 1.3330 to 1.3688. After that, we coated graphene on the gold film and obtained a graphene optical fiber sensor with an average spectral sensitivity of 2290 nm/RIU. The sensitivity of 390 nm/RIU is improved on the basis of the original sensor. In this paper, the thickness of the gold film is precisely controlled by electron beam evaporation, and the spectral sensitivity of the sensor is successfully improved by coating graphene layer. The sensor designed has low cost and good reusability. It has potential practical application value.