Programming is a skill that requires high levels of logical thinking and problem-solving abilities. According to the Curriculum Guidelines for the 12-Year Basic Education currently implemented in Taiwan, programming has been included in the mandatory courses of middle and high schools. Nevertheless, the guidelines simply recommend that elementary schools conduct fundamental instructions in related fields during alternative learning periods. This may result in the problem of a rough transition in programming learning for middle school freshmen. To alleviate this problem, this study proposes an augmented reality (AR) logic programming teaching system that combines AR technologies and game-based teaching material designs on the basis of the fundamental concepts for seventh-grade structured programming. This system can serve as an articulation curriculum for logic programming in primary education. Thus, students are able to develop basic programming logic concepts through AR technologies by performing simple command programming. This study conducted an experiment using the factor-based quasi-experimental research design and questionnaire survey method, with 42 fifth and sixth graders enrolled as the experimental subjects. The statistical analysis showed the following results: In terms of learning effectiveness, both AR-based and traditional learning groups displayed a significant performance. However, of the two groups, the former achieved more significant effectiveness in the posttest results. Regarding learning motivation, according to the evaluation results of the Attention, Relevance, Confidence, and Satisfaction (ARCS) motivation model, the AR-based learning group manifested significantly higher levels of learning motivation than the traditional learning group, with particularly significant differences observed in the dimension of Attention. Therefore, the experimental results validate that the proposed AR-based logic programming teaching system has significant positive effects on enhancing students’ learning effectiveness and motivation. Digital information technology has been perceived as an essential component of human society. In a highly digital environment, information science education has been gaining increasing importance. Accordingly, governments worldwide have begun promoting all kinds of information science education. Computational thinking has been identified as a significant core of information science education . It enabTeacher resources: This is the primary challenge faced by most counties and cities. Even in counties and cities that advocate programming courses in primary and secondary schools, teacher resources are still a challenge;Suitability of teaching materials: With rapid development of science and technology, if teachers simply lecture using paper teaching materials, there may be a disconnect from the current development of industrial technology;Insufficient information equipment: Programming relies on a large number of information equipment. Schools in rural and remote areas have relatively insufficient resources in this regard, and information equipment is relatively backward;Articulation of curricula: If students start to learn programming without any foundation, the learning process may add some burden on their study load. In addition to the regular basic courses, they also must learn and practice programming.In recent years, Taiwan has also been devoting increasing attention to programming education. As such, the 2019 Curriculum Guidelines included ‘programming’ in science and technology, and specified formal learning hours for the junior and senior high school stages. Because the knowledge involved in programming languages is relatively abstract and abstruse, beginners are more likely to encounter difficulties in learning, hence reducing learning motivation . Thus, mAs a result, for the implementation of programming education in Taiwan as per the 2019 Curriculum Guidelines, in the future, problems regarding teacher training, teaching material design, equipment prevalence and student curriculum articulation are to be resolved. Based on these possible challenges, this paper addresses the following research questions (RQs).RQ1: Does the augmented reality (AR) based teaching system effectively help teachers improve students’ learning effectiveness in primary logic programming courses?In response to the era of artificial intelligence (AI), Taiwan’s Ministry of Education (MOE) launched the General Implementation Strategy for Artificial Intelligence and New Technology Education in 2019. The MOE published the AI education plan for students at all levels from primary school to university and announced the adjustment to include ‘machine learning’ and ‘artificial intelligence’ as required courses in the pre-service teacher training program . The MOERQ2: Does the AR-based teaching materials effectively stimulate students’ learning motivation in primary logic programming courses?In the design of teaching materials, the literature  noted thRQ3: Does the AR-based teaching system simplify teaching equipment used in primary logic programming courses?Regarding teaching equipment, with the development of technology, smartphones and wireless networks have become increasingly prevalent. They have gradually become indispensable tools in modern life. In addition, with the improvement in mobile phone development technologies and the enhancement of hardware and software equipment, many AR or virtual reality (VR) mobile applications have emerged. Nowadays, almost everyone has a smartphone. With such a high prevalence, the entry barriers for AR and VR have been greatly lowered. AR and VR technologies enable users to operate and experience virtual objects through devices, giving them access to businesses and experiences that are normally not readily accessible. Many instances of applying AR or VR technologies to education have been observed domestically and abroad ,11,14,16In terms of assisting teachers in teaching, this study proposes an AR-based teaching system that allows users to learn logic programming through smartphones, thereby transforming teachers who originally served as the chief channel of knowledge impartation into a learning facilitator;In terms of teaching material design, this study validates that adding AR functions and appropriate gamification elements to the logic programming courses can effectively stimulate students’ learning motivation;In terms of simplifying teaching equipment, the proposed AR-based logic programming teaching system frees the learning of logic programming from the limitations of computer equipment. Students can learn with smartphones, which are very popular and easy to use.Based on the aforementioned challenges for programming education development and the relevant literature review, this study proposes a novel AR-based teaching system for basic logic programming, which combines AR technology and gamified designs of teaching materials on the basis of the fundamental concepts of the seventh-grade structured programming articulation curriculum . The comThe experimental results are as follows. In terms of learning effectiveness, both AR-based and traditional learning groups showed significant performance in the learning of logic programming. Of the two groups, the AR-based learning group achieved more significant learning effectiveness. Regarding learning motivation, according to the evaluation results of the ARCS Learning Motivation Questionnaire, the AR-based learning group manifested significantly higher levels of learning motivation than the traditional learning group, with particularly significant differences observed in the dimension of Attention.This study adopted a factorial experimental design to examine the differences in the learning motivation and learning effectiveness of eleven and twelve-year-old students who learned logic programming using the traditional paper-based learning method and those who used the AR-based learning method. The experimental subjects, research design, learning activities, and research instruments are explained below.The subjects of this experiment are mainly eleven and twelve-year-old students in two classes of a primary school in Hsinchu County. Students in each class were randomly grouped into AR-based and traditional learning groups for logic programming training. The total numbers of participants were 22 and 20 for the AR-based and traditional learning groups, respectively. The two classes had equal numbers of participants for both groups, i.e., 11 and 10 each for the AR-based and traditional learning groups, respectively. Note that, since there is no logic programming course in the formal curriculum of elementary schools, most of the participants have no relevant logic programming experience. In the pretest questionnaire, of the 42 students who participated in the experiment, 34 had never studied logic programming before.This study employed the self-developed mobile application, the AR-based logic programming teaching system, as a teaching aid for basic programming logic learning and cultivation. In terms of learning effectiveness, the analysis of covariance (ANCOVA) was employed as the experimental design method. The independent variables were the experimental subjects in the AR-based and traditional learning groups, whereas the pretest and posttest surveys were, respectively, used as the covariate and dependent variables of the analysis. Regarding learning motivation, the analysis of variance (ANOVA) was adopted as the experimental design method. The independent variables were the experimental subjects in the AR-based and traditional learning groups; the control variables comprised teaching methods, teaching materials, instructors, learning time, and pretest and posttest questions and the dependent variables were the four fundamental dimensions of the ARCS motivation model and theory proposed by M.J. Keller : AttentiThis study employed the Learning Effectiveness Questionnaire (LEQ) and the ARCS Learning Motivation Questionnaire (LMQ) as experiment questionnaires. Two groups of subjects were tested with two different logic program teaching aids and the same logic program teaching method. The two groups were required to receive pretests and posttests and fill out questionnaires.This study conducted a data analysis using IBM SPSS Statistics 28.0.0 to find out the effect of the AR-based teaching system for basic logic programming on students’ learning effectiveness and learning motivation. The results of the LEQ were analyzed using the ANCOVA approach. With the initial differences in students’ backgrounds removed, the effects of the teaching models on students’ learning effectiveness were examined. The data of the ARCS LMQ were analyzed using the ANOVA approach to compare the mean differences in the learning motivation of the two groups of students.The total time of the teaching experiment in this study was 50 min. The experiment process included an activity description and random grouping (approximately 5 min), pretest administration of the LEQ (approximately 10 min), logic programming curriculum experience (approximately 20 min), and posttest administration of the LEQ and administration of the ARCS LMQ (approximately 15 min).A total of three questionnaires were used in this study, i.e., the LEQ pretest, the LEQ posttest and the ARCS LMQ. Among these three, the LEQ pretest was administered before the logic programming training activity, and the other two were administered after the activity.The filling of demographic information;The logic programming integrating into life issues;The logic programming concepts;The application of logic programming concepts.As a method to assess learning effectiveness in this study, the LEQ was divided into four sections: This study preserves anonymity to protect the personal information of the subjects. Therefore, the experiment subjects only need to provide their grade, group code and number for the demographic information in the first section. All data were provided as statistical data and for academic research use only. The second to fourth sections are test papers. Through the test of logic programming questions, the study examined whether the subjects had improved concepts of logic programming after the activity. The test questions were designed for the following three dimensions, seeking to understand the level of subjects’ comprehension and application of logic programming.Logic programming integrated with life issues;Logic programming concepts;Application of logic programming concepts;The ARCS LMQ used in this study was based mainly on the ARCS motivation model proposed by John Keller and was specifically designed for the content of this thesis with references taken from the following ARCS-related academic theses ,20,21. TAccording to the reliability analysis of the ARCS LMQ data collected from the experiment, the ARCS LMQ achieved an overall reliability of 0.932. The Cronbach’s α value for the four dimensions, Attention, Relevance, Confidence and Satisfaction, arrived at 0.861, 0.889, 0.850, and 0.851 respectively, which indicated a medium-to-high level of reliability.This section explains the teaching concept of the proposed AR-based logic programming teaching system and introduces the functions of this teaching system and the focus of each learning topic.The AR-based teaching system for basic logic programming proposed in this study offers students a different learning method from traditional logic programming teaching methods. The differences between the two are shown in The proposed logic programming teaching system is a mobile application developed for the Android system. It enables students to autonomously learn the concepts of logic programming and operate in a visualized manner in the AR environment. https://youtu.be/-IpyBerj1C0 (accessed on 14 November 2021)Note that interested readers can refer to the following online video to watch the demonstration of the proposed teaching system: Demo video—This section presents the statistical analysis conducted based on the questionnaires recovered in the experiment and discusses the analysis results of learning effectiveness and learning motivation.The ANCOVA framework was conducted based on the results of LEQ pretests and posttest taken by the two groups of students to whom different teaching methods were applied. A total of 42 valid samples were recovered. ANCOVA was employed to compare the differences in learning effectiveness between the two groups.Before ANCOVA is performed, a test should be conducted on the two groups to see whether their pretest and posttest scores show the same regression slopes. If the results of data testing fulfil the premise of ANCOVA, i.e., high intra-group homogeneity of regression coefficients, the subsequent ANCOVA can be proceeded with. The results of the test of intro-group homogeneity of regression slopes in this study are shown in F-value achieved was 2.803, and the p-value of 0.102 (>0.05), hence fulfilling the premise of the ANCOVA . On this basis, the study could proceed with the ANCOVA analysis.The analysis results showed that the test of intro-group homogeneity of the learning effectiveness tests using different teaching methods did not reach the significant level of 0.05. The F-value reached 12.149, and the p-value reached 0.001 (<0.05). The AR-based learning group obtained higher posttest scores than the traditional learning group, indicating that when different teaching methods were employed, the students displayed significant differences in their pretest and posttest performances in terms of learning effectiveness.According to The ANOVA was conducted based on the results of the ARCS LMQ administered by the two groups of students to whom different teaching methods were applied. A total of 42 valid samples were recovered. ANOVA was adopted to compare the difference in learning motivation between the two groups. The analysis results are shown in The analysis of each question in the Attention dimension is shown in The analysis of each question in the Relevance dimension is shown in The analysis of each question in the Confidence dimension is shown in The analysis of each question in the Satisfaction dimension is shown in This study developed a primary logic programming teaching system that combines AR technologies and game-based teaching materials on the basis of the fundamental concepts for seventh-grade structured programming. The proposed teaching system can serve as an articulation curriculum for logic programming in primary education. After implementation and evaluation, the statistical analysis showed that the AR-based teaching system not only achieved more significant learning effectiveness, but also enabled students to show a higher level of learning motivation than the traditional teaching method based on the evaluation results of the ARCS motivation model. Therefore, the proposed AR-based teaching system has significant positive effects on enhancing students’ learning effectiveness and motivation. Note that, the small sample size may lead to biased results in the statistical analysis. Therefore, the sample size can be identified as a limitation of this study.Some previous studies also involved the development of teaching aids for different levels of logic programming education. For example, Evripidou et al.  proposedThe course lecturers who participated in this study also pointed out that when students experience AR-based teaching, they are much more active in the classroom than usual; while students using traditional teaching methods are not much different from ordinary classes. Since the proposed AR-based teaching system can be easily executed on mobile devices, students can engage effective logic programming learning in both formal and informal environments. This is one of the main contributions of the proposed teaching system for students to free the learning of logic programming from the limitations of computer equipment.In response to curriculum articulation problems in the information technology area encountered during the 2019 Curriculum Guidelines implementation, this study developed an AR-based logic programming teaching system, which enables eleven and twelve-year-old students to access logic programming early, thereby lessening the pressure middle school freshmen may experience in the face of required programming courses. In order to effectively improve the learning effectiveness and learning motivation of students, the proposed teaching system implements three modules based on AR technology, namely the application program, the ARCore cloud anchor, and the AR environment. Aside from the user interface, the application program module also includes the development of the block programming function, which enables users to learn basic logic programming. The ARCore cloud anchor module aims to store the virtual maps of different learning topics and the information on their locations in the real environment so that users can learn different topics in different environments and locations. The AR environment module covers multiple topic spaces and scene spaces. Through the AR environment, the block programming results developed by users will be displayed in the scene space where the phone is located, thereby transforming logic programming learning from abstract programming to visualized execution results.According to the experimental results and questionnaire analysis, the proposed AR-based teaching system has beneficial effects on students’ overall learning effectiveness and motivation in logic programming. In terms of learning effectiveness, although the AR-based learning group displayed greater improvements in test scores than the traditional learning group, all eleven and twelve-year-old students made significant progress in logic programming learning regardless of teaching methodology. Regarding learning motivation, because the AR-based teaching method is more likely to enhance students’ concentration and interest, the results of the ARCS LMQ revealed that the AR-based learning group obtained higher scores than the traditional learning group. The aforementioned results demonstrate that the AR-based logic programming teaching system proposed in this study has significant positive effects on enhancing students’ learning effectiveness and motivation.There remains a lot of room for development in the future. First, constructing an experiment that divides a large number of participants into multiple groups can improve the accuracy of statistical analysis and validate the current findings. In addition to increasing the depth of logic programming learning, the command blocks can be further expanded in the aspect of block programming. In addition, this system was developed using the development kit, Unity AR Foundation, which can support multiple platforms. This advantage can be leveraged in the future to broaden the coverage of programming. For example, future research may attempt to include the function of AR connections, allowing teachers and learners to simultaneously learn and interact in the AR environment.


Chronic low back pain (CLBP) is a prominent medical condition that can affect an individual at some point in their life time which could lead to poor quality of life (QOL). Low back pain has affected approximately 577 million individuals globally by 2017. The aim of the current systematic review is to synthesise the existing evidence on the factors influencing the QOL in individuals with CLBP and to identify strategies to improve their QOL.PubMed, ScienceDirect, PsychNet and Google Scholar were used to extract studies reporting quantitative relationships between QOL and its possible determinants in individuals having CLBP and the intervention strategies to improve QOL.10,851 studies were initially identified and twenty-six studies which met the inclusion criteria were selected for the review. 21 studies reported relationship between QOL and potential determinants and five studies assessed the influence of interventions on QOL. Determinants were classified as kinesiophobia, fear avoidance belief, or pain belief; occupation-related factors; pain and disability; activity; personal factors including age, gender, employment status; and other psychological factors including anxiety, quality of sleep, and health locus of control. Intervention strategies including MBSR, Pilates method and Back School Programme improved QOL in individuals with CLBP.Psychosocial factors as well as the physical status of the individual contributed to the QOL in individuals having CLBP. Low back pain is a prominent health condition that affects an individual at some point of their life  globally , mental quality of life, QOL, HRQOL. The search terms were combined differently for the databases. The search terms were kept as broad as possible to ensure the inclusion of a maximum number of relevant articles. For example; Science direct:  AND (Chronic Low back pain). A similar search strategy was executed for identifying the determinants as well as intervention strategies.The screening of the study titles and abstracts were done initially. After the initial screening, the full-text articles were assessed for selection. The criteria for inclusion were, (1) the study population exclusively concerned with chronic low back pain, (2) study that reported the relationship between possible determinants and QOL, (3) studies that reported interventions to improve quality of life and (4) articles published in the English language. The exclusion criteria include (1) use of a non-standardised measure of QOL, (2) pharmacological intervention studies, (3) articles published before 2010, and (4) Qualitative studies. Due to the higher number of quality of life research articles published every year, the article search was restricted to articles published in the previous 10 years and hence studies from 2010 were included in the review.The studies were extracted from quality assured databases such as ScienceDirect, PubMed and PsycNet which ensured access to high-quality peer-reviewed articles. Besides, for assessing the quality of the intervention studies, Revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used which ensured a low risk of bias for the studies included. RoB 2 tool was structured into five domains including; (1) bias arising from randomisation process, (2) bias due to deviation from intended intervention, (3) bias due to missing outcome data, (4) bias in the measurement of the outcome, and (5) bias in the selection of the reported result. The risk of bias assessment done for the five intervention studies is given in As the preliminary step, the obtained data were merged and de-duplicated. After the duplicates were removed, titles and abstracts were examined to remove the articles irrelevant to the current study. Thirty per cent of the same were randomly cross-verified by the co-authors. The full-text documents were retrieved and were examined in detail in compliance to the inclusion criteria.Information related to the research design, sample size, male-female ratio, duration of low back pain symptoms reported, the measurement tools used, and the assessed determinants of quality of life were collected and tabulated. All reported associations between factors and quality of life were taken into account. All the interventions other than the pharmacological interventions were taken into consideration. Correlation coefficients were the statistic that was mostly reported in the studies selected. Meta-analysis was not conducted, due to the diversity of the primary studies.1.Literature search was conducted in Science Direct (9848), PubMed (976) and PsycNet (4). The PRISMA 2009 flow diagram for the systematic search conducted is shown in 2.Study characteristics are summarised in 3.The possible factors determining the quality of life among patients with CLBP were assessed in 21 of the 26 studies considered for the review. All the determinants identified as a result of the review were listed by the first author initially and was later clubbed into categories depending on their relative similarities.3.1.Kinesiophobia, pain belief and fear avoidance belief (FAB) were assessed in six out of the 21 studies summarised in 3.1.1.Kinesiophobia refers to ‘avoidance behaviour due to fear’ or ‘an excessive, irrational, and debilitating fear of physical movement and activity resulting from a feeling of vulnerability to painful injury or re-injury’ . SES-6 measures two dimensions including self-efficacy for managing symptoms and self-efficacy to manage disease in general . The scale consists of 20 items with two dimensions including passive coping styles and active coping styles  scale. Patients with chance health locus of control (CHLC) had a negative impact on the quality of life . PCS is a 13-item self-report questionnaire consisting of three domains including rumination, helplessness and magnification . It is a 19-item self-report index having seen sub-scales evaluating sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications and day-time disturbances . Positive illness perception was related to improved QOL  intervention on improving QOL of individuals who have CLBP. MBSR is a mindfulness-based eight-week group programme for individuals having a wide range of stress-related conditions Baer, . MBSR ha4.2.Two studies assessed the effect of the Pilate exercise method on the QOL of individuals with CLBP. ‘Pilates method is a unique system of techniques including stretching and strengthening exercises developed to achieve better functioning of the body based on the strengthening of the lower trunk region’ (Natour, Cazotti, Ribeiro, Baptista, & Jones, 4.3.The Back school programme intervention was studied in one article. Back school is an exercise programme which is mostly used for the treatment of CLBP (Morone et al., Low back pain is one of the prominent health condition affecting the quality of life of the individuals. It affects various domains of daily life from basic self-care activities to advance and complex social interactions, work and leisure activities and eventually leading to poor quality of life (Montazeri & Mousavi, Considering the fear related to movement and associated factors, kinesiophobia, fear avoidance belief, and pain beliefs were identified to be significant predictors of QOL in individuals with CLBP. Studies revealed that kinesiophobia has a negative influence on QOL and is negatively associated with the dimensions of QOL. Excessive fear restricts them from creating further movements and restricting the activities of daily living (Alaca et al., Pain-related factors are highly contributing to the quality of life among individuals with CLBP. Pain severity is negatively influencing physical function and role functioning. Greater pain severity and greater disability are contributing to poor quality of life outcomes (Aminde et al., Physical activity is also an important determinant of quality of life. Studies revealed that an avoidant activity style (Huijnen et al., The current review is able to identify other personal factors contributing to the quality of life among individuals with CLBP. Sociodemographic factors influencing the quality of life are identified as part of the review including, gender, age, duration of illness, employability, and presence or absence of smoking. Studies reveal that mental health-related QOL was better among older individuals compared to younger patients (Wettstein et al., Other factors such as self-efficacy, coping styles and locus of control were also influencing the quality of life of CLBP patients (Du et al., These were the possible determinants of quality of life identified through the review. The psychological profile of the individuals having CLBP is one of the most important prognostic predictor. Studies revealed that patients’ cognitive behavioural profile predicts the prognosis and the extent of psychological distress within the individual indicating the QOL (Trocoli & Botelho, Five intervention studies were analysed during the review. MBSR was effective in improving the quality of life of CLBP patients. MBSR was identified to have a significant effect in reducing the fear avoidance belief (Masumian et al., Another intervention technique reviewed was the Pilates method. The review revealed that the Pilates method is contributing to improvement in quality of life and its various dimensions (Masumian et al., These were the major intervention strategies identified which were effective in improving the QOL of people who were diagnosed to have CLBP. These intervention strategies were successful in dealing with some of the possible determinants of QOL such as FAB, anxiety, disability and pain in CLBP patients. But the intervention strategies identified were not sufficient to cover all the possible determinants of quality of life. One among these interventions alone will not cover all the factors that are influencing the quality of life. Hence, it will be more useful if an intervention which covers all or most of the determining factors of QOL for individuals with CLBP is introduced as part of future exploration in this area. As there were only a few intervention studies identified, any conclusions regarding their efficiency on improving the quality of life could not be made.The current review also has some limitations. Firstly, heterogeneity in the sample studies in terms of research design, sample size and measurement instruments could have affected the results. Another limitation is that the literature search was limited to the English language and therefore the study might have overlooked similar studies published in other languages. Also, some studies included in the review had a low sample size and hence it can affect the conclusions drawn from the review. As the studies considered were conducted in different countries, the conclusions drawn could not be generalised while ignoring the cultural differences.As part of the future exploration, a cross-cultural exploration of the differences in the determinants of quality of life in the context of CLBP could be made. A met analysis could be done to combine the results and thus to derive statistically driven conclusions regarding the determinants of QOL.The current systematic review is successful in identifying the possible determinants of QOL in individuals having CLBP. The current review provides a valuable contribution to the literature by summarising the results of the studies investigating the determinants of QOL in the context of CLBP. The psychological status of the individual was a significant contributor to the QOL of individuals with CLBP. The review identified various psychological determinants of QOL in individuals having CLBP including kinesiophobia, pain belief and fear avoidance belief, self-efficacy, anxiety, coping styles, sleep quality, locus of control and catastrophising. Social factors including occupation and demographic characteristics were also key in determining the quality of life. Pain and health-related factors such as pain severity and disability experienced by the patient, involvement in physical activity and health status have also contributed to the QOL in individuals with CLBP. The psychological status of the individual significantly contributed to the quality of life in the individuals’ having CLBP along with their physical status. Identifying the possible determinant is helpful in planning the rehabilitation strategies and intervention plans. The review identified some intervention strategies which are reported to manage the pain and improving the QOL including MBSR, Pilates methods and Back School programme. Due to the methodological limitations, any conclusions regarding the effectiveness of the identified interventions couldn’t be made. More exploration in the area could facilitate understanding regarding the interventions which are effective in improving the QOL in the context of CLBP.


An electronic nose (Enose) relies on the use of an array of partially selective chemical gas sensors for identification of various chemical compounds, including volatile organic compounds in gas mixtures. They have been proposed as a portable low-cost technology to analyse complex odours in the food industry and for environmental monitoring. Recent advances in nanofabrication, sensor and microcircuitry design, neural networks, and system integration have considerably improved the efficacy of Enose devices. Here, we highlight different types of semiconducting metal oxides as well as their sensing mechanism and integration into Enose systems, including different pattern recognition techniques employed for data analysis. We offer a critical perspective of state-of-the-art commercial and custom-made Enoses, identifying current challenges for the broader uptake and use of Enose systems in a variety of applications. Olfaction is one of the most complex senses possessed by humans. From the second half of the 20th century, researchers have proposed the idea of creating an artificial olfactory system, commonly known as an electronic nose (Enose), to detect and distinguish between structurally similar volatile organic compounds (VOCs). VOCs are organic compounds having high vapour pressure and low water solubility. Featuring the capability to quantify concentrations from parts per billion (ppb) to parts per trillion (ppt), Enoses have the potential to replace canines, the current gold standard for portable vapour detection ,2.The earliest knowledge of an artificial mechanical nose was suggested by Zwaardemaker and Hogewind in 1920, but they were unable to develop the system due to the lack of appropriate electronic and computational infrastructure . In 1964Conventionally, gas mixtures have been analysed using techniques such as gas chromatography (GC) , ion mobThe state-of-the-art methodologies  adopted FET-based sensors respond to the target gas by either inducing a charge transfer or modifying the nature of the conductive channel to alter the electrical characteristics  .3PO4, and Na1+xZr2SixP3-xO12. MPSs are based on the competing catalytic reactions between the sensing material and the target gas and between the target gas and O2. Responses of the sensor are measured when the rate of both the reactions are equal. Impedometric gas sensors are similar to the previously mentioned techniques, however, the sensor response between the working and the reference electrode is measured in terms of impedance instead of voltage. Response is then analysed using the equivalent Randles circuit.Electrochemical sensors can further be classified into four categories: amperometric, impedometric, equilibrium potentiometric sensor (EPS), and mixed potentiometric sensor (MPS). Amperometric gas sensors contain a working, a reference, and a counter electrode, which are connected via an electrolyte. When the target gas/analyte is introduced into the electrolyte either directly or with the help of a transport barrier, current changes are monitored as a function of potential to build the analytical utility . EPSs caChemiresistive gas sensors function on Ohm’s Law; upon the catalytic reaction between the sensing material and the target gas, results in the change of the resistance in the setup, thereby generating a voltage signal. Amongst the different methodologies, chemiresistive is often preferable owing to advantages such as ease of fabrication, high sensitivity, and low cost and is the focus of this review.Chemiresistive sensors usually employ a two-electrode system where the resistance of the sensing layer in between the electrodes is monitored as a function of time upon gas exposure. This sensing layer can be composed of different materials such as conducting polymers , carbon-The use of conductive polymers (CP) and its derivatives such as poly  (PEDOT), polypyrrole (PPy), polyaniline (PANI), and polythiphene as the active layer in gas sensors dates back to the early 1980s  and has Pencillium digitatum in post-harvest oranges ..23]. Witn arrays . Subsequ2 and TiO2) on a circular alumina substrate using radio frequency magnetron sputtering for in-situ monitoring of VOCs in soil contamination . . 122]. SContamination of building materials by microbes is another environmental issue addressed by researchers. Suchorab et al. developed an Enose using eight commercial SMO based gas sensors to detect various microbial VOCs released by ten different genres of fungi . Using P4, natural gas, propane, methane, i-butane, hydrogen, and smoke  conditions, and stability. Incorporation of hetero-structures or new morphologies can enable new pathways for improving these challenges.Lack of stability due to long-term and short-term drifts is another commonly faced drawback of SMO-based Enose systems, leading to difficulty in comparing data obtained at different periods. One way to tackle this impending problem is the usage of highly advanced computational algorithms. Another issue with SMO Enoses is the flooding of response where exposure to high concentrations of analyte gas molecules can sometimes lead to sensor poisoning, resulting in slow recovery. This may be improved with the usage of nanomaterials as sensing agents .Another challenge that Enoses bring with the usage of many individual sensor elements is the issue of malfunctioning of one element in the whole sensor array system. This causes the Enose to fail, as most data analyses do not take this into consideration for their predictive algorithms. As a result, this requires implementation of a new Enose or a fresh algorithm, which are both expensive and time consuming. A fail-safe system built into Enoses will make them more robust. More research is required in implementing robust computational systems in order to increase the usage of Enoses for commercial applications.The combination of gas sensor arrays along with data acquisition systems provides Enoses with a potential for numerous applications in the food industry to differentiate between adulterants and establish quality. It can also be employed for environmental quality monitoring and detection of explosives and hazardous gases, paving a path for enhancement in the quality of life and ensuring public safety. Among different types of sensing materials and transduction mechanisms, chemiresistive SMO nanomaterials have shown potential for multiplexing, label-free, and real-time detection. Researchers have developed Enose systems either using commercially available or custom-made gas sensors for detection of various kinds of vapours. The majority of Enose systems consist of 3–38 sensors in the sensor array. In general, a minimum of 5–6 sensors are typically needed within an Enose to differentiate between the various groups of VOCs. Greater numbers of sensors increase sensitivity and selectivity but also increase cost and decrease portability. A great deal of research has gone into an assembly process where commercially available sensors are procured and then put together to form a custom-made device, thereby only needing to work on the analysis techniques for the development of Enoses. This is mainly due to the limitations in nanofabrication of multiple sensors on a small footprint together with the lack of facile deposition techniques to grow sensing layers on each individual sensor, which inherently limits the development of Enoses. The authors direct more research into this area to further fuel the development of advanced Enoses for improved quality of life. Choosing an appropriate data processing technique is also vital for proper analysis of data. Recently, there is an increased use of neural network analytical tools and neuro-fuzzy methods, as they have the capability to reliably quantify imprecise sets of data by eliminating drift and noise from sensors. Therefore, with the advancement in electronic architecture and computational infrastructure, the prospect of integrating these sensor systems into smaller devices with higher performances will be the driving force behind the research for commercial applications.


Lichen associations, a classic model for successful and sustainable interactions between micro-organisms, have been studied for many years. However, there are significant gaps in our understanding about how the lichen symbiosis operates at the molecular level. This review addresses opportunities for expanding current knowledge on signalling and metabolic interplays in the lichen symbiosis using the tools and approaches of systems biology, particularly network modelling. The largely unexplored nature of symbiont recognition and metabolic interdependency in lichens could benefit from applying a holistic approach to understand underlying molecular mechanisms and processes. Together with ‘omics’ approaches, the application of signalling and metabolic network modelling could provide predictive means to gain insights into lichen signalling and metabolic pathways. First, we review the major signalling and recognition modalities in the lichen symbioses studied to date, and then describe how modelling signalling networks could enhance our understanding of symbiont recognition, particularly leveraging omics techniques. Next, we highlight the current state of knowledge on lichen metabolism. We also discuss metabolic network modelling as a tool to simulate flux distribution in lichen metabolic pathways and to analyse the co-dependence between symbionts. This is especially important given the growing number of lichen genomes now available and improved computational tools for reconstructing such models. We highlight the benefits and possible bottlenecks for implementing different types of network models as applied to the study of lichens. Lichens are often seen as a typical example of successful and sustainable symbiotic interactions between micro-organisms . With th2via photosynthesis  and a microalgal partner , either an alga  or a cyanobacterium . Instead, previous studies have shown that lichens harbour a diverse microbiome e.g., , and morynthesis  as well ynthesis , althougynthesis . Lichensynthesis . All licynthesis . Cyanoliynthesis . Lichensynthesis . Many liynthesis .The establishment of the lichen symbiosis, or “lichenisation,” has been described as a four-stage process : (A) a p2 fixation processes  and computational tools  to gain a more holistic understanding of the inter-dependencies of system components and underlying system complexity. Hypotheses are generally tested using iterative cycles of ‘wet’ (lab-based) and ‘dry’ (simulation-based) experiments, by which systems-level data are generated, analysed, and then used to inspire new insights and hypotheses about the biological system at hand , b. For rocesses . A similIn this review, we summarise the current knowledgebase of signalling and recognition mechanisms in the lichen symbiosis. We then discuss the modelling of signalling networks as a tool to extend our understanding of such mechanisms in lichens. We review the literature on lichen metabolism and propose that modelling fluxes in metabolic networks could be a powerful tool for providing insights into lichen metabolism in particular, and the metabolic interplays between symbiotic partners in general. We provide a broad overview of metabolic network models and their applications in addition to a review of some of the symbiotic systems that have been studied through the lens of metabolic models. Finally, the opportunities and challenges of modelling both signalling networks and metabolic fluxes are discussed.Distinct small molecules are produced by lichen symbionts during symbiosis that are absent when mycobiont and photobiont are grown separately . WhetherXanthoria parietina and Evernia prunastri  was characterised and speculated to act as a ligand on the cell wall of the compatible photobiont of this lichen association  of Peltigera polydactyla compared with its free-living and cultured forms  could be recaptured by the photobiont for efficient carbon recycling within the lichen symbiosis , organic substances , inorganic molecules , or other proteins or biomolecules. Reactions connecting these molecules frame the underlying signalling mechanisms and the goal of signalling network modelling would be to predict such interactions and the emergent cascade of signalling events that can explain or predict the behaviour of the signalling network. Signalling network models are often divided into descriptive and predictive subtypes. Descriptive models are usually simpler and provide a qualitative overview of the signalling pathway structure , whereas predictive models may capture kinetics of the signalling pathway  and be capable of estimating system behaviours under new perturbations. The application of diverse descriptive and predictive modelling to signalling networks has been reviewed elsewhere . The scoIn symbiotic systems, signalling pathways have been a topic of particular focus for legumes-rhizobia and plants-root fungi (mycorrhiza) symbioses . HoweverFaced with the paucity of detailed mechanistic knowledge on signalling networks in lichens  may play roles in producing secreted extracellular polysaccharides, lichen nutrient acquisition, and secondary metabolite production , a more sophisticated understanding of the interactions between the host and gut microbiome was achieved, revealing how system responses depended upon the metabolic potential of each component species and the nutrients available . The AGOGenome-scale metabolic network models simulate the metabolism of a living cell as a collection of hundreds to thousands of biochemical reactions (forming metabolic pathways of an organism) and enable quantitative and gene-grounded predictions of phenotypes under different growth conditions . This seTechniques developed for the characterisation of metabolic interactions among members of microbial communities based on genome-scale metabolic modelling can be classified into two main groups: lumped  and comin vitro lichen re-synthesis is still hampered by the complexity of the lichenisation process, metabolic modelling could highlight potential metabolites that may need to be exchanged between symbionts as well as the metabolic pathways that may lead to successful differentiation and growth. Moreover, metabolic modelling could be used to examine the potential for symbiosis between various combinations of mycobionts and photobionts, and provide insights into the evolution of the lichen symbiosis. Validating predictions of flux distribution by community metabolic models could be a challenge, due to multi-compartmental nature of lichen symbiosis and difficulties in measuring fluxes through each compartment in vivo. However, recent advances in the field of metabolic flux analysis now make it possible to resolve fluxes by carefully designing the isotope labels and tracing them across different compartments  the signalling molecules and the roles they play at different stages of lichenisation, (2) how lichen symbionts benefit from the symbiosis with regards to carbon, nitrogen, and other limiting nutrients or environmental conditions, (3) which conditions allow lichens to produce secondary metabolites and the genes that are involved, and (4) how lichens manage to accumulate and tolerate high levels of toxic metals. Advances in DNA sequencing technologies in recent years have significantly reduced the cost of generating genome sequences. At the same time, improvements in high performance computing and development of more biologist-friendly tools for modelling and analysing ‘genome-scale’ metabolic networks have enabled the exploration of metabolically-coupled microbial communities. Combining these genome resources and systems biology tools could open up a whole new era for the study of the lichen symbiosis.HN-B and CG conceptualised and wrote the manuscript. HN-B and CG designed and created figures. EFYH, ACW, and SM revised the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Torpedo maculopathy (TM) is a rare congenital defect of the retinal pigment epithelium (RPE). The RPE is often evaluated clinically using fundus autofluorescence (AF), a technique that visualizes RPE structure at the tissue level from the intrinsic AF of RPE fluorophores. TM lesions typically emit little or no AF, but this macroscopic assessment is unable to resolve the RPE cells, leaving the organization of the RPE cell mosaic in TM unknown. We used fluorescence adaptive optics scanning laser ophthalmoscopy (AOSLO) to show here for the first time the microscopic cellular-level structural alterations to the RPE cell mosaic in TM that underlie the tissue-level changes seen in conventional clinical imaging. We evaluated two patients with TM using conventional clinical imaging techniques and adaptive optics (AO) infrared autofluorescence (IRAF) in AOSLO. Confocal AOSLO revealed relatively normal cones outside the TM lesion but altered cone appearance within it and along its margins in both patients. We quantified cone topography and RPE cell morphometry from the fovea to the margin of the lesion in case 1 and found cone density to be within the normal range across the locations imaged. However, RPE morphometric analysis revealed disrupted RPE cells outside the margin of the lesion; the mean RPE cell area was greater than two standard deviations above the normative range up to approximately 1.5 mm from the lesion margin. Similar morphometric changes were seen to individual RPE cells in case 2. Multi-modal imaging with AOSLO reveals that RPE cells are abnormal in TM well beyond the margins of the characteristic TM lesion boundary defined with conventional clinical imaging. Since the TM fovea appears to be fully formed, with normal cone packing, it is possible that the congenital RPE defect in TM occurs relatively late in retinal development. This work demonstrates how cellular level imaging of the RPE can provide new insight into RPE pathologies, particularly for rare conditions such as TM. Torpedo maculopathy (TM) is characterized by the presence of a well-circumscribed lesion of the macula featuring elements of hyperpigmentation and atrophy at the level of the retinal pigment epithelium (RPE) and named for its typical shape and orientation with respect to the fovea , 2. TM aIn TM, OCT sometimes reveals neurosensory retinal layers detached from the RPE, forming a cavity , 8. BaseIn recent years, OCT angiography (OCTA) has been used to evaluate flow profiles in the choriocapillaris and/or choroid in the lesions. Most of these studies have reported decreased flow in the choriocapillaris with vascular alterations at the site of the lesion , 14–16. in vivo in TM patients using any modality.Adaptive optics ophthalmoscopy (AOO) permits cellular level imaging of the retina , 20. RecGiven the well-circumscribed nature of TM, our hypothesis was that the transition from abnormal to normal cellular mosaics would be relatively abrupt, with abnormalities confined to the immediate vicinity of the lesion. Further, due to the non-progressive clinical course, we hypothesized that the demarcation between abnormal and normal photoreceptor and RPE mosaics would be approximately aligned, without one appearing to lead or lag the other in terms of distance from the lesion border.Clinical imaging included color fundus photography (Topcon/Canon), SLO/OCT , and a flood-illumination adaptive optics camera . Detailed OCT imaging parameters are presented in Adaptive optics scanning laser ophthalmoscopy imaging was carried out using a system that has been described in detail . BrieflyThe confocal images were used to co-register the weak signals in the AO-IRAF images using custom strip-based image registration software , permittPatients were recruited through the clinics of the UPMC Eye Center. Written informed consent was obtained from both subjects following an explanation of experimental procedures and risks both verbally and in writing. All experiments were approved by the University of Pittsburgh Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. To ensure safe imaging, all light levels were kept below the ANSI laser safety limits  and werePatient 1, a woman in her early 30s was found to have a pigmented lesion in her right eye during pre-screening for laser refractive surgery that was diagnosed later as TM. Best corrected visual acuity (BCVA) was 20/15 in each eye. The patient had no history of retinal laser nor injections prior to our imaging. Patient 2 was a woman in her early 20s diagnosed with TM. Her BCVA was 20/20 in each eye. The left eye had received a single intravitreal bevacizumab injection 2 years earlier for neovascularization within the lesion. Her angiography images have been published previously .The first patient exhibited a typical torpedo-shaped lesion  in the tSince the second patient  was treain vivo morphology of both the cone and RPE cell mosaics in TM for the first time. These findings suggest that outside the TM lesion, RPE morphometry is relatively normal. However, near the margin of the lesion, we see marked changes in RPE morphometry characteristic of a disrupted cell mosaic. Within the TM lesion, we observed differences between the two cases that may reflect differences between type I and type II lesions. In patient 1  and also drafted the manuscript. ER, KD, and KV analyzed and interpreted the results. VS conducted the clinical imaging. JM and AE critically revised the manuscript for important intellectual content. All co-authors carefully reviewed the final manuscript.This research was supported by departmental startup funds from the University of Pittsburgh to ER. This work was also supported by the NIH CORE Grant P30 EY08098 to the University of Pittsburgh, Department of Ophthalmology, the Eye and Ear Foundation of Pittsburgh, NVIDIA GPU Grant Program and from an unrestricted grant from Research to Prevent Blindness, New York, NY, USA.Some aspects of this work include technologies that ER is an inventor on for patents that are owned by the University of Rochester . The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure. Cancer diseases are one of the major health problems all over the world. As a cell cycle disease, cancer is associated with uncontrolled cell division. Cell therapy is still evolving and seems to be a promising therapeutic approach for the treatment of many diseases, including cancer. The unique biological characteristics of Mesenchymal Stem Cells (MSCs) makes them useful in many areas such as cardiovascular diseases, liver diseases, nervous system diseases and regenerative medicine. The results of MSC therapies achieved so far have been encouraging. Searching for new therapeutic solutions in the field of cancer treatment, scientists point to the important role of MSCs in tumorigenesis and metastasis. The broad distribution of MSCs in the human body causes close mutual contact between MSCs and other types of cells, including cancer cells. Many studies have indicated that MSCs exhibit tropism for sites of tumor microenvironment and interact with cancer cells through paracrine signaling. Due to the pro-oncogenic and anti-oncogenic properties of MSCs, understanding the mechanisms of the interplay between MSCs and tumor cells is of high interest to researchers .The abilMSCs were first isolated from adult bone marrow, described as non-hematopoietic stromal cells, in the late 1960s by Friedenstein et al. ,4. They It has been found that CD105 induces activation and proliferation of endothelial cells. This protein is expressed in haematological cancers and in the vessels of solid tumors. It is worth noting that endoglin is a transmembrane glycoprotein and one of the transforming growth factor β (TGF-β) co-receptors . TGF-β iMSCs express CD105, CD73 and CD90, while not expressing the markers of hematopoietic cells CD45 (a pan-leukocyte marker), CD34 , CD14 (marker of monocytes and macrophages), CD11b (marker of monocytes and macrophages), CD19 (marker of B cells), CD79α (marker of B cells) and HLA-D (marker expressed on MSC under INF-γ stimulation) . The maiDue to the traits of MSCs such as tumor tropism, deep migration into the tumor microenvironment, immune evasion, wide availability and expandability, there is a wide interest in the use of MSCs as tumor-specific therapeutic agent-loaded vehicles. MSCs have been considered as a convincing approach for drug and gene delivery in a variety of diseases and disorders, including cancer  31,32,3,48,49,50It is known that MSCs participate in the regeneration of damaged tissues and may be useful tools in regenerative medicine. Stem cell therapy may be applied in the treatment of various diseases, such as cardiovascular, digestive and nervous system diseases ,51. It iMSCs can affect tumor cells through secreted extracellular proteins triggering the activation of various cell signaling pathways, in particular those related to cell growth and apoptosis regulation in cancer cells. PI3K/AKT and Wnt pathways are signaling pathways that are similar for both MSCs and tumor cells. The role of these pathways is to regulate differentiation and self-renewal potential, and determine cell fate ,76. The The Wnt signaling pathway is one of the key cascades regulating cell survival, differentiation, morphogenesis and proliferation. Wnt activators are secreted Wnt proteins (a family of 19 secreted glycolipoproteins) that work in an auto-, para- and endocrine manner. Disruptions in Wnt signaling have been found in many pathophysiological states, including different types of cancer . Wang etHowever, the mechanisms of MSCs secreting molecules that promote or inhibit carcinogenesis have not been elucidated so far. Therefore, the role of recruited MSCs in tumor sites is still under discussion. A comprehensive understanding of the effects of MSCs on cancer cells is crucial for the development of treatment strategies using MSCs as vehicles of anticancer agents. Nevertheless, the results of research on MSC-based cell therapy are promising.One of the strategies of MSC-based cell therapy is the use of MSCs as direct carriers of therapeutic agents ,60. The Researchers tracked the anticancer agents in MSCs’ membrane and cytoplasm. It seems that there are three mechanisms of drug loading into MSCs: (1) simple diffusion based on the chemical nature of anticancer agent, (2) endocytosis, and (3) transport of the drug by hCNT1 and hENT1 transporters . Some tyThe use of MSCs as vehicles of anticancer agents is an opportunity to minimize the unexpected side effects of chemotherapeutic drugs and to improve clinical outcomes. MSCs can release anticancer agents in a time-dependent manner. This makes them an excellent tool for the development of therapy in which drugs will be slowly released locally to ensure an effective concentration in the tumor site. However, the release capacity depends on both the MSCs and the properties of the therapeutic agents . TherefoMSCs are being genetically modified to convert inactive drugs, overexpress immunomodulatory molecules and induce cancer cells apoptosis. For instance, MSCs have been genetically manipulated to express specific enzymes to convert inactive systematically administered prodrugs like ganciclovir and fluorouracil (5-FU) into active cytotoxic agents ,96. ThisNevertheless, the challenge remains to match the type of therapy to the tumor type in order to obtain the best possible treatment results. MSC-based cell therapy also has several other limitations, including non-specific dissemination throughout the body and ineffective local concentration of therapeutic agents in cancer niches . MoreoveAlthough a deeper understanding of the cellular and molecular interactions between MSCs and the tumor microenvironment is necessary, the immune privilege, plasticity and migratory potential of MSCs, have made them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery in a wide range of diseases and disorders, including cancers  9,28].,28.9,28]One of the potential chemotherapeutic agents that can potentially be delivered by MSCs to tumor sites are quinazoline derivatives. The importance and application of these compounds and MSCs in cancer therapy has so far been independently investigated, but the results of these studies are encouraging in both subjects. Quinazolines are a group of compounds whose ability to be loaded and released by MSCs has not yet been of significant interest to scientists. However, research on other anti-cancer agents, on MSCs which have an ability to tropic tumor site, and the discovered mechanisms of small-molecules anticancer agents uptake by MSCs and their release into the tumor microenvironment support the possibility of using quinazoline derivatives in MSC-based cell therapy. To confirm this, research is needed to reveal the existing interactions between quinazolines and MSCs, and to determine the ability of MSCs to load and release these small-molecule anticancer agents.1) ..8), erlo17 [18 is a cyclin-dependent kinase 4 (Cdk4) and tubulin 653 polymerization inhibitor  (The inhibitory effects of quinazolines on voltage-dependent sodium channels (VDSCs) can lead to antiangiogenic and analgesic effects . VDSCs a19  132]. O. O19   134]..19 (20 [Another ability of quinazolines is to overcome multidrug resistance (MDR) in tumors by inhibiting ATP-Binding cassette (ABC) transporters. The overexpression of ABC transport proteins such as ABCB1 or ABCG2 causes the efflux of harmful substances out of cells at the cost of ATP hydrolysis. Inhibition of the ABC transporters by potent and selective inhibitors may increase the efficacy of cancer therapy. The expression of ABC transporters is often associated with the occurrence of MDR in chemotherapy of multiple cancers ,136. QuiCurrently, it is also indicated that multifunctional hybrid compounds containing quinazoline/quinazolinone and other biologically active pharmacophores can potentially significantly increase the effectiveness of pharmacotherapy . Osipov In light of the proven properties of quinazoline derivatives in relation to different cancer cell lines, they seem to be an attractive choice for new therapeutic solutions in the treatment of neoplasms and metastases. The drugs currently used in cancer diseases give hope that the synthesis of new quinazoline derivatives and the development of new methods of their application may contribute to the establishment of effective and low-toxic therapies for oncological patients. MSCs seem to be a promising therapeutic tool to achieve this goal. Systematically applied conventional cancer treatment agents are characterized by the lack of tumor specificity. They cause insufficient concentration of the chemotherapeutic agent in tumor cells and toxic effects in normal cells. These obstacles in cancer treatment can be overcome by using the migratory capacity of MSCs. A more accurate characterization of the subtypes of MSCs and a better understanding of the specific molecular mechanisms underlying their pro-tumorigenic properties could enable the development of highly effective therapeutic strategies based on MSCs. There is also a need to find therapeutic drugs that can be successfully used in this type of therapy. Quinazolines are potential candidates for this purpose due to their biological and pharmacological anticancer properties. Therefore, researching and understanding the interactions between MSCs and quinazoline derivatives may show new perspectives in cancer treatment. The use of MSCs as a delivery vehicle of small-molecule anticancer agents with activities such as quinazolines may turn out to be a milestone in the treatment of cancer patients.


Tick-borne encephalitis (TBE) virus is a human pathogen that is expanding its endemic zones in Europe, emerging in previously unaffected regions. In Austria, increasing incidence in alpine regions in the west has been countered by a decline in traditional endemic areas to the east of the country.To shed light on the cause of this disparity, we compared the temporal changes of human TBE incidences in all federal provinces of Austria with those of Lyme borreliosis (LB), which has the same tick vector and rodent reservoir.This comparative analysis was based on the surveillance of hospitalised TBE cases by the National Reference Center for TBE and on the analysis of hospitalised LB cases from hospital discharge records across all of Austria from 2005 to 2018.The incidences of the two diseases and their annual fluctuations were not geographically concordant. Neither the decline in TBE in the eastern lowlands nor the increase in western alpine regions is paralleled by similar changes in the incidence of LB.The discrepancy between changes in incidence of TBE and LB support the contributions of virus-specific factors beyond the mere availability of tick vectors and/or human outdoor activity, which are a prerequisite for the transmission of both diseases. A better understanding of parameters controlling human pathogenicity and the maintenance of TBE virus in its natural vector−host cycle will generate further insights into the focal nature of TBE and can potentially improve forecasts of TBE risk on smaller regional scales. Tick-borne encephalitis (TBE) is a viral disease that occurs in many parts of Europe and northern Asia . AccordiIxodes ricinus - primarily in Europe and Ixodes persulcatus - primarily in Asia) to small mammals that serve as reservoir hosts [In its natural cycle, the TBE virus is transmitted from infected hard ticks  as TBE and is maintained in the same rodent reservoir [Since Lyme borreliosis (LB) is transmitted by the same vector . All individuals with a place of residence in Austria were included. The incidences in federal provinces were derived from the postal code of patient’s home address.https://www.qgis.org/). Spatially close sites were aggregated using a 2 km grid for Austria, and centroids were calculated for each square. The centroids formed the centre of circles with diameters proportional to the number of documented sites within this area. The base map was generated with open access data from Statistik Austria , Natural Earth Data  and Global Multi-Resolution Topography (GMRT) synthesis data of the Marine Geoscience Data System (MGDS) [http://www.marine-geo.org/tools/GMRTMapTool).Probable TBE virus infection sites were geocoded and processed for spatial mapping with quantum geographic information system (QGIS) (m (MGDS)  , an institute for market and opinion research in Vienna [Population data were obtained from Statistik Austria and data on TBE vaccination coverage in each federal state were obtained through postal surveys conducted by Growth from Knowledge (GfK) Austria GmbH , geometric mean of TBE incidences were computed by weighting so that the annual population size replaced 0 with half the expectancies from cubic spline fits.Geometric mean incidences from 2005 to 2018  were calThis study was based on aggregated surveillance data and ethical approval was not required.The analysis of probable infection sites in Austria confirmed a previously observed trend, i.e. the establishment of new endemic foci in alpine regions in the west, and almost complete disappearance of infection sites in regions in the east . These eSupplementary Tables S1 and S2).In the next step, we compared the incidences of hospitalised cases of TBE and LB between 2005 and 2018. Since the incidence of TBE in Austria has declined strongly thanks to vaccination ,29, we cThe mean incidence of hospitalised LB cases country-wide during the study period was about twice as high as that of TBE (11.3 vs 6.0). However, this ratio varied strongly in different federal provinces, with the lowest incidence of 0.8 in Tyrol and highest incidence of 4.9 in Vienna/Lower Austria . IndepenWe further analysed the extent of variation of incidences among individual federal provinces and quantified their deviation from the mean incidence in the whole country. The observed shifts in TBE virus epidemiology may be the result of several mutually interacting factors including climate change, environmental change, abundance of ticks and their hosts, economic fluctuations and social habits ,22,30. OI. ricinus ticks with Borrelia in Austria appears to be constant over the years (ca 26%). The most frequently detected Borrelia genospecies are Borrelia afzelii (ca 56%), B. burgdorferi sensu stricto (ca 27%), B. valaisiana (ca 25%), and B. garinii (ca 20%) [Borrelia genospecies is B. afzelii in skin manifestations (ca 90%), B. garinii predominates in Lyme neuroborreliosis (ca 67%) [We found countercurrent trends for these two pathogens both geographically and on a temporal scale, although they are transmitted by the same vector and depend on the same natural host system . One of (ca 20%) . The mos(ca 67%) . It is uA possible explanation for the discrepancies observed would be the proposed dependency of TBE virus on so-called non-viraemic co-feeding transmission, which refers to the transmission of TBE virus from infected nymphs to uninfected larvae feeding in close proximity on the same rodent host . This meAdditional factors can be hypothesised to be responsible for the discordant epidemiology of TBE and LB, or may act in concert with non-viraemic transmission of TBE virus. The infectious cycle of TBE virus in ticks involves replication in cells lining the midgut, dissemination to the haemolymph, and subsequent infection of cells of different tissues to reach the highest titres in the ticks’ salivary glands . In eachBorrelia) can have specific effects on tick behaviour (e.g. mobility) [In addition to direct temperature effects on virus-host interactions, the microbiome in the midgut of the vector may exert important influences on pathogen replication and transmission . Studiesobility)  and affeobility) . It is cobility) . Since iOur findings are relevant for studies that attempt to forecast incidence of TBE ,41. The Our study has several limitations. Specifically, we did not study environmental changes that might affect tick habitats and abundance as well as human risk behaviour. We also did not assess pathogen factors that contribute to severe disease requiring hospitalisation.Although we believe it unlikely, we cannot exclude that TBE virus strains circulating in the east have acquired mutations that reduce transmission or pathogenicity for humans. In any case, the decline in TBE in the eastern part of the country despite a continuing high prevalence of LB indicates that other factors beyond the prevalence of ticks and human exposure, which are common to both pathogens, underlie the epidemiological phenomena observed.Our study points to ongoing changes in virus-specific factors of TBE that control the circulation and maintenance of TBE virus in its natural cycle and/or affect disease in humans. These factors might be responsible for the upsurge in TBE hospitalisations in newly endemic areas and declining hospitalisations or disappearance of TBE in regions with a history of high disease incidence.Since the changing patterns observed for hospitalised cases of TBE do not mirror those seen for LB, it is likely that parameters beyond those influencing tick abundance in general and/or human exposure to tick bites are responsible.Future studies to elucidate the unknown phenomena underlying the pathogenicity, ecological cycle and transmission efficiency of TBE virus may help to improve methods of disease forecasting and to resolve the conundrum of TBE focality and divergent developments on a small geographical scale.


The model established in this paper is also applicable to other material simulation processes, as long as the corresponding parameters and potential functions are available. This study will provide inspiration for the optimized design and preparation of highly efficient cladding materials in nuclear reactors.Owing to the excellent thermal properties of graphene, silicon carbide (SiC) combined with graphene is expected to obtain more outstanding thermal performance and structural stability at high temperatures. Herein, the thermal conductivity of graphene/SiC heterostructures (GS-Hs) with different structures and atomic orientations was calculated through non-equilibrium molecular dynamics (NEMD) simulations. The temperature dependence and size effect on the thermal transport properties of GS-Hs were systematically investigated and discussed. The continuous addition of graphene layers did not always have a positive effect. The thermal transport performance of GS-Hs approached the intrinsic thermal conductivity of SiC when the interaction gradually decreased with the distance between SiC and graphene. Studies on temperature and size dependence show opposite trends. The enhancement effect of graphene was limited at small distances. The thermal conductivity of GS-Hs had a negative correlation with temperature and increased with the system size. Meanwhile, the thermal conductivity of GS-Hs was predicted to be 156.25 (W·m Similar to solar, hydro, wind and other renewable energy sources, nuclear energy is a low-carbon and environmentally friendly energy source ,2. Compa−1·K−1 by the measurement of single-layer graphene using the photo Raman technique. In the application field of graphene, it is often used as an additive for composite materials to improve thermal transport properties [2 heterostructures to enhance the electrochemical and thermal transport properties of MoS2. Chu et al. [In recent years, graphene has attracted extensive attention both from the scientific community and the industry, owing to its unique thermal properties, showing huge potential to address the thermal adjustment challenge in material design . Balandioperties . For exaoperties  built gru et al.  reportedu et al.  studied 2-SiC via discharge plasma sintering on the microstructure and thermal conductivity of the composite material. In order to improve the fracture toughness of Si3N4/SiC ceramics, Yang et al. [In addition, the study of the composite of SiC and graphene has also received some attention in recent years. Cheng et al.  synthesig et al.  added 0.Herein, we propose to construct a graphene/SiC heterojunction structure (GS-Hs) to obtain an effective thermal conductive composite. The great thermal conductivity and thermal stability of graphene are expected to further improve the thermal properties of SiC and thus to achieve excellent structural stability and safety reliability under high-temperature conditions. In this work, we quantitatively and systematically investigated the thermal transport properties of GS-Hs with different structures and atomic orientations via the non-equilibrium molecular dynamics (NEMD) method. The effects of various numbers of graphene and SiC layers on the thermal properties of heterojunction structures were investigated using the pair potential (Lennard-Jones and Airebo) and many-body potential (Tersoff) models. In addition, the influences of temperature and simulation system size on the heat transport performance of GS-Hs were studied. Providing valuable suggestions toward optimizing the effective thermal transport properties in the novel SiC composite material, the modeling of the thermal performance of GS-Hs accomplished in this study will inspire the better design of cladding materials in nuclear reactors.All the simulations were conducted using Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS), which is an open-source code developed by Sandia National Laboratory in America . LAMMPS In order to investigate the effects of different structure of GS-Hs, we performed NEMD simulations using LAMMPS. Kawamura et al.  studied In molecular dynamics (MD) simulation, the potential function is primally used to describe the interaction between atoms (molecules) . In thisIn NEMD simulation, the extensive linear response theory is used to calculate the thermal conductivity by using the system nonequilibrium response caused by external disturbance . The indyJ is one component of thermal current, dT/dy is the temperature gradient along the y direction and κ is the thermal conductivity. Because of the specific composition surface, the thermal conductivity in the y direction was selected as the calculation of thermal conductivity. The temperature distribution can be simulated by the traditional NEMD at a certain temperature. However, due to the large difference between the structure scale of the computable system and the actual material, the calculated results of thermal conductivity will change with the increase in the simulation scale when the scale is close to or less than the mean free path of crystal phonons [α is the lattice constant; ν is the group velocity of phonons; l∞ is the mean free path of phonons; and bL is the length of heat flow transfer direction. By changing the scale size of the simulated structure, the influence of size effect on the thermal conductivity was explored. By analyzing the above equation, it can be concluded that: 1/κ and 1/bL present an approximate linear relationship. Furthermore, the thermal conductivity at the microscopic size was processed by least squares to draw a linear image. When bL extended to the macroscopic size, 1/bL approached 0. The value of 1/κ was equal to the intercept of the vertical axis, which was the reciprocal of the actual thermal conductivity.When the system reached the steady state, the thermal conductivity of finite length L was calculated according to Fourier’s law by measuring the heat flux (flux) and temperature gradient. Fourier’s law of thermal conductivity states that in a given material, there is a positive relationship between the heat flux density and the corresponding temperature gradient, and the proportional coefficient is the thermal conductivity . Fourier phonons . The relThe thermal conductivity of GS-Hs with different composite structures was calculated at 300 K, as shown in As shown in In addition, the effect of interatomic interactions between graphene and SiC was studied on Si-terminated surfaces. Different substrate temperatures  were analyzed in this study. Temperature in NEMD simulations is typically calculated based on the mean kinetic energy of the system . The temThe thermal conductivity of GS-Hs monotonically decreased with increasing temperature as shown in In order to investigate the finite-size effect of thermal conductivity, systems with different simulation lengths  were studied, and the results are presented in −1·K−1) was the actual thermal conductivity of the composite. Some predictable difficulties can be encountered in the extrapolated process at a finite size system. Even though NEMD is widely used to calculate microscale thermal conductivity, its results sometimes serve as references [However, the values of thermal conductivity for simulated systems containing a finite number of atoms were significantly different from the actual values, indicating that the thermal conductivity of these systems are affected by the finite size. For the biggest simulation system, the finite-size effect had crucial influence on the thermal conduction, even with the periodic boundary conditions . Thus, iferences .−1·K−1) was predicted for the heterojunctions at the macro-scale. It is valuable to introduce carbon materials such as graphene into the design of cladding tubes, which can be used as references to improve performance. It was determined that the thermal properties of GS-Hs depend on the interatomic interaction, temperature and simulation size based on the simulation results in this research. The computational model can also be applied to the design and conception of other materials. This quantitative study reveals the thermal transport phenomenon and limitations in graphene/SiC heterojunctions, which may guide the design of highly efficient cladding materials for different nuclear energy plants. In this work, the thermal transport properties of different composite structure GS-Hs were systematically investigated using NEMD simulations and potential functions . The influences of the interatomic interaction, temperature and simulation size were investigated systematically. It was found that interatomic interaction has a significant effect on the thermal conductivity of heterojunctions. The interaction was removed when the inter-layer distance exceeded the cut-off distance and the thermal transport performance of the heterojunction approached the intrinsic value of SiC. However, since the application of SiC in nuclear reactors is still immature, we mainly focused on the thermal properties of materials. The evaluation standard is simplified to be the enhancement of thermal conductivity. The temperature dependence of the GS-Hs shows a negative tendency, and the inelastic scattering of phonons plays a significant role in thermal diffusion. The study of size effects demonstrated that the thermal conductivities of GS-Hs are a function of the system size with a positive correlation. The thermal conductivity of 156.25 (W·m


Case Report. We report a case of a 65-year-old lady who has systemic lupus erythematosus with acute pyogenic osteomyelitis of the pubic bone who presented initially with a suspicious healing pubic rami fracture and periprosthetic infection of the hip joint.  Pubic bone osteomyelitis is atypical, and the diagnosis is often overlooked. It may present as osteitis pubis, fracture, or noninfectious inflammation of the pubic symphysis.  Acute osteomyelitis of the pubic bone has often an infrequent and delayed presentation. Clinical awareness, early diagnosis, and appropriate treatment including surgical debridement and long-term antibiotics can prevent ongoing morbidities such as chronic osteomyelitis, pain, and deformities of pelvic bone and joints. Osteomyelitis of the pubic bone is a rare clinical condition and accounts for 2% of all haematogenous osteomyelitis in bone , 2. RiskA 65-year-old female was admitted with a one-week history of general malaise, decreased appetite, fever, lethargy, and progressively worsening pain in her right hip and groin. She had a history of a fall 4 weeks prior to presentation but had been mobilised with some discomfort following the fall. Past medical and surgical history included SLE, managed through regular corticosteroids and intermittent courses of hydroxychloroquine, and bilateral hip and knee replacements. On examination, she was unable to weight bear on the right lower limb. She had tachycardia and a temperature of 38.5°. There was severe tenderness to the right groin, a restricted range of movement, and a 20° fixed flexion deformity. The examination of the left hip and both knees was unremarkable.Inflammatory markers were raised with WCC 19.83 and a raised CRP of 215. Plain radiographs of the pelvis showed bilateral total hip replacements in situ and an irregularity of the cortex of the superior pubic rami with evidence of new bone formation . A proviArthrocentesis of the right hip under the image intensifier was dry . A contrThe patient underwent exploration of the right pubic region under general anaesthesia by a joint team of orthopaedic and general surgeons. Exploration revealed abscess formation around the right pubic bone with destruction of the cortex of the superior pubic ramus and evidence of osteomyelitis and the collection extending into the adductor compartment. The pus and tissue samples were sent for culture and sensitivity, identifying E.coli sensitive to cefuroxime. She was treated with intravenous cefuroxime for two weeks, later receiving a further four weeks of oral cefuroxime at the time of discharge from the hospital. An outpatient follow-up at three months indicated that inflammatory markers had settled, and she was mobilising pain-free. Repeat CT scan and inflammatory markers confirmed resolution of the osteomyelitis and persisting normalisation of her CRP.This case presents a uniquely difficult diagnostic challenge, requiring the discrimination between three distinct pathologies in an anatomically and functionally intertwined region: septic arthritis of the hip and fracture and osteomyelitis of the pubic bone. In all these pathologies, the patient can present with atraumatic hip or groin pain that is insidious in onset, unremitting, and exacerbated by movement. Features of septic shock with leucocytosis are suggestive of an infective pathology, namely, septic arthritis of the hip or osteomyelitis.Differentiating between septic arthritis of the hip and osteomyelitis of the pubic bone is inherently difficult. Appropriate imaging has a fundamental role in the diagnosis of osteomyelitis. In our case, early plain radiographs indicated an irregularity of the cortex of the superior pubic rami with evidence of new bone formation and radiolucency. While affordable and quick, plain radiographs have low sensitivity and specificity for detecting osteomyelitis with as many as 80% of patients showing no radiographic changes within the first two weeks of infection . TypicalMRI imaging remains the gold standard for investigating osteomyelitis. It is highly sensitive for osteomyelitis due to its ability to detect bone marrow oedema, detecting infection as early as one to two days after the onset . In our The precise aetiology of our patient's presentation still remains unclear. The mechanisms of action of glucocorticosteroids consist of genomic and nongenomic pathways triggered following the activation of intracellular glucocorticoid receptors. These result in a breakdown of the inflammatory cascade through reduction of T and B cell proliferation, immunoglobulin and cytokine synthesis, and inhibition of mononuclear cell and neutrophil leucocyte migration . ConsequThe immunomodulatory properties of hydroxychloroquine have also been well researched ; howeverSLE has been shown to predispose patients to osteonecrosis. Intraosseous adipocyte hypertrophy, fat conversion of red marrow, and subsequent raised bone marrow pressure have been hypothesised as a mechanism with glucocorticoids causing these . A role Osteomyelitis of the pubic bone is a rare but serious life-threatening condition. It can mimic traumatic or stress fracture of the pubic bone and septic arthritis of the hip. Early diagnosis with either MRI or CT scan is indicated. Treatment includes debridement and long-term antibiotics. Patients with autoimmune diseases such as SLE on glucocorticoids and other immunomodulators are at risk of opportune osteomyelitis.