Search results for: nonlinear partial differential equation

Authors: Pedro Felgueiras, Ana Miguel, Nélson Almeida, Raquel Silva

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Objective: Through the study of a clinical case of delusional somatic disorder secondary to phantogeusia, we aim to highlight the importance of considering psychosomatic conditions in differential diagnosis, as well as to emphasize the complexity of its comprehension, treatment, and respective impact on patients’ functioning. Methods: Bearing this in mind, we conducted a critical analysis of a case series based on patient observations, clinical data, and complementary diagnostic methods, as well as a non-systematic review of the literature on the subject. Results: A 61-year-old female patient with no history of psychiatric conditions. Family psychiatric history of mood disorder (depression), with psychotic features found in her mother. Medical history of many comorbidities affecting different organ systems (endocrine, gastrointestinal, genitourinary, ophthalmological). Documented neuroticism traits of personality. The patient’s family described a persistent concern about several physical symptoms across her life, with a continuous effort to obtain explanations about any sensation out of her normal perception. Since being subjected to endoscopy in 2018, she started complaints of persistent phantogeusia (acid taste) and developed excessive thoughts, feelings, and behaviors associated with this somatic symptom. The patient was evaluated by several medical specialties, and an extensive panel of medical exams was carried out, excluding any disease. Besides all the investigation and with no evidence of disease signs, acute anxiety, time, and energy dispended to this symptom culminated in severe psychosocial impairment. The patient was admitted to a psychiatric ward for investigation and treatment of this clinical picture, leading to the diagnosis of the delusional somatic disorder. In order to exclude the acute organic etiology of this psychotic disorder, an analytic panel was carried out with no abnormal results. In the context of a psychotic clinical picture, a CT scan was performed, which revealed a right cortical vascular lesion. Neuropsychological evaluation was made, with the description of cognitive functioning being globally normative. During treatment with an antipsychotic (pimozide), a complete remission of the somatic delusion was associated with the disappearance of gustative perception disturbance. In follow-up, a relapse of gustative sensation was documented, and her thoughts and speech were dominated by concerns about multiple somatic symptoms. Conclusion: In terms of abnormal bodily sensations, the oral cavity is one of the frequent sites of delusional disorder. Patients with these gustatory perception distortions complain about unusual sensations without corresponding abnormal findings in the oral area. Its pathophysiology has not been fully elucidated yet. In terms of its comprehensive psychopathology, this case was hypothesized as a paranoid development of a delusional somatic disorder triggered by a post-invasive procedure phantogeusia (which is described as a possible side effect of an endoscopy) in a patient with an anankastic personality. This case presents interesting psychopathology, reinforcing the complexity of psychosomatic disorders in terms of their etiopathogenesis, clinical treatment, and long-term prognosis.

Keywords: psychosomatics, delusional somatic disorder, phantogeusia, paranoid development

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Authors: Iacopo Odoardi, Emanuele Felice, Dario D'Ingiullo

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We investigate the role of human capital in the Chinese inland-coastal inequality and how the consequences of the 2007-2008 crisis may induce China to refocus its development path on human capital. We compare panel data analyses for two periods for the richer/coastal and the relatively poor/inland provinces. Considering the rapid evolution of the Chinese economy and the changes forced by the international crisis, we wonder if these events can lead to rethinking local development paths, fostering greater attention on the diffusion of higher education. We expect that the consequences on human capital may, in turn, have consequences on the inland/coastal dualism. The focus on human capital is due to the fact that the growing differences between inland and coastal areas can be explained by the different local endowments. In this respect, human capital may play a major role and should be thoroughly investigated. To assess the extent to which human capital has an effect on economic growth, we consider a fixed-effects model where differences among the provinces are considered parametric shifts in the regression equation. Data refer to the 31 Chinese provinces for the periods 1998-2008 and 2009-2017. Our dependent variable is the annual variation of the provincial gross domestic product (GDP) at the prices of the previous year. Among our regressors, we include two proxies of advanced human capital and other known factors affecting economic development. We are aware of the problem of conceptual endogeneity of variables related to human capital with respect to GDP; we adopt an instrumental variable approach (two-stage least squares) to avoid inconsistent estimates. Our results suggest that the economic strengths that influenced the Chinese take-off and the dualism are confirmed in the first period. These results gain relevance in comparison with the second period. An evolution in local economic endowments is taking place: first, although human capital can have a positive effect on all provinces after the crisis, not all types of advanced education have a direct economic effect; second, the development path of the inland area is changing, with an evolution towards more productive sectors which can favor higher returns to human capital. New strengths (e.g., advanced education, transport infrastructures) could be useful to foster development paths of inland-coastal desirable convergence, especially by favoring the poorer provinces. Our findings suggest that in all provinces, human capital can be useful to promote convergence in growth paths, even if investments in tertiary education seem to have a negative role, most likely due to the inability to exploit the skills of highly educated workers. Furthermore, we observe important changes in the economic characteristics of the less developed internal provinces. These findings suggest an evolution towards more productive economic sectors, a greater ability to exploit both investments in fixed capital and the available infrastructures. All these aspects, if connected with the improvement in the returns to human capital (at least at the secondary level), lead us to assume a better reaction (i.e., resilience) of the less developed provinces to the crisis effects.

Keywords: human capital, inland-coastal inequality, Great Recession, China

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Authors: Ting Lu, Ya-Ru Diao, Fei Fan, Ye Xue, Lei Shi, Xian-e Tang, Meng-jun Zhan, Zhen-hua Deng

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Accurate adult age estimation (AAE) is a significant and challenging task in forensic and archeology fields. Attempts have been made to explore optimal adult age metrics, and the rib is considered a potential age marker. The traditional way is to extract age-related features designed by experts from macroscopic or radiological images followed by classification or regression analysis. Those results still have not met the high-level requirements for practice, and the limitation of using feature design and manual extraction methods is loss of information since the features are likely not designed explicitly for extracting information relevant to age. Deep learning (DL) has recently garnered much interest in imaging learning and computer vision. It enables learning features that are important without a prior bias or hypothesis and could be supportive of AAE. This study aimed to develop DL models for AAE based on CT images and compare their performance to the manual visual scoring method. Chest CT data were reconstructed using volume rendering (VR). Retrospective data of 2500 patients aged 20.00-69.99 years were obtained between December 2019 and September 2021. Five-fold cross-validation was performed, and datasets were randomly split into training and validation sets in a 4:1 ratio for each fold. Before feeding the inputs into networks, all images were augmented with random rotation and vertical flip, normalized, and resized to 224×224 pixels. ResNeXt was chosen as the DL baseline due to its advantages of higher efficiency and accuracy in image classification. Mean absolute error (MAE) was the primary parameter. Independent data from 100 patients acquired between March and April 2022 were used as a test set. The manual method completely followed the prior study, which reported the lowest MAEs (5.31 in males and 6.72 in females) among similar studies. CT data and VR images were used. The radiation density of the first costal cartilage was recorded using CT data on the workstation. The osseous and calcified projections of the 1 to 7 costal cartilages were scored based on VR images using an eight-stage staging technique. According to the results of the prior study, the optimal models were the decision tree regression model in males and the stepwise multiple linear regression equation in females. Predicted ages of the test set were calculated separately using different models by sex. A total of 2600 patients (training and validation sets, mean age=45.19 years±14.20 [SD]; test set, mean age=46.57±9.66) were evaluated in this study. Of ResNeXt model training, MAEs were obtained with 3.95 in males and 3.65 in females. Based on the test set, DL achieved MAEs of 4.05 in males and 4.54 in females, which were far better than the MAEs of 8.90 and 6.42 respectively, for the manual method. Those results showed that the DL of the ResNeXt model outperformed the manual method in AAE based on CT reconstruction of the costal cartilage and the developed system may be a supportive tool for AAE.

Keywords: forensic anthropology, age determination by the skeleton, costal cartilage, CT, deep learning

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Authors: Yi-Hao Wong, Li-Li Chan, Chee-Onn Leong, Stephen Ambu, Joon-Wah Mak, Priyasashi Sahu

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Background: Acanthamoeba is a genus of amoebae which lives as a free-living in nature or as a human pathogen that causes severe brain and eye infections. Virulence potential of Acanthamoeba is not constant and can change with growth conditions. DNA methylation, an epigenetic process which adds methyl groups to DNA, is used by eukaryotic cells, including several human parasites to control their gene expression. We used qPCR, siRNA gene silencing, and RNA sequencing (RNA-Seq) to study DNA-methyltransferase gene family (DNMT) in order to indicate the possibility of its involvement in programming Acanthamoeba virulence potential. Methods: A virulence-attenuated Acanthamoeba isolate (designation: ATCC; original isolate: ATCC 50492) was subjected to mouse passages to restore its pathogenicity; a virulence-reactivated isolate (designation: AC/5) was generated. Several established factors associated with Acanthamoeba virulence phenotype were examined to confirm the succession of reactivation process. Differential gene expression of DNMT between ATCC and AC/5 isolates was performed by qPCR. Silencing on DNMT gene expression in AC/5 isolate was achieved by siRNA duplex. Total RNAs extracted from ATCC, AC/5, and siRNA-treated (designation: si-146) were subjected to RNA-Seq for comparative transcriptomic analysis in order to identify the genome-wide effect of DNMT in regulating Acanthamoeba gene expression. qPCR was performed to validate the RNA-Seq results. Results: Physiological and cytophatic assays demonstrated an increased in virulence potential of AC/5 isolate after mouse passages. DNMT gene expression was significantly higher in AC/5 compared to ATCC isolate (p ≤ 0.01) by qPCR. si-146 duplex reduced DNMT gene expression in AC/5 isolate by 30%. Comparative transcriptome analysis identified the differentially expressed genes, with 3768 genes in AC/5 vs ATCC isolate; 2102 genes in si-146 vs AC/5 isolate and 3422 genes in si-146 vs ATCC isolate, respectively (fold-change of ≥ 2 or ≤ 0.5, p-value adjusted (padj) < 0.05). Of these, 840 and 1262 genes were upregulated and downregulated, respectively, in si-146 vs AC/5 isolate. Eukaryotic orthologous group (KOG) assignments revealed a higher percentage of downregulated gene expression in si-146 compared to AC/5 isolate, were related to posttranslational modification, signal transduction and energy production. Gene Ontology (GO) terms for those downregulated genes shown were associated with transport activity, oxidation-reduction process, and metabolic process. Among these downregulated genes were putative genes encoded for heat shock proteins, transporters, ubiquitin-related proteins, proteins for vesicular trafficking (small GTPases), and oxidoreductases. Functional analysis of similar predicted proteins had been described in other parasitic protozoa for their survival and pathogenicity. Decreased expression of these genes in si146-treated isolate may account in part for Acanthamoeba reduced pathogenicity. qPCR on 6 selected genes upregulated in AC/5 compared to ATCC isolate corroborated the RNA sequencing findings, indicating a good concordance between these two analyses. Conclusion: To the best of our knowledge, this study represents the first genome-wide analysis of DNA methylation and its effects on gene expression in Acanthamoeba spp. The present data indicate that DNA methylation has substantial effect on global gene expression, allowing further dissection of the genome-wide effects of DNA-methyltransferase gene in regulating Acanthamoeba pathogenicity.

Keywords: Acanthamoeba, DNA methylation, RNA sequencing, virulence

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Authors: Matar Celine, Gaucel Sebastien, Gontard Nathalie, Guilbert Stephane, Guillard Valerie

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To increase the very short shelf life of fresh fruits and vegetable, Modified Atmosphere Packaging (MAP) allows an optimal atmosphere composition to be maintained around the product and thus prevent its decay. This technology relies on the modification of internal packaging atmosphere due to equilibrium between production/consumption of gases by the respiring product and gas permeation through the packaging material. While, to the best of our knowledge, benefit of MAP for fresh fruits and vegetable has been widely demonstrated in the literature, its effect on shelf life increase has never been quantified and formalized in a clear and simple manner leading difficult to anticipate its economic and environmental benefit, notably through the decrease of food losses. Mathematical modelling of mass transfers in the food/packaging system is the basis for a better design and dimensioning of the food packaging system. But up to now, existing models did not permit to estimate food quality nor shelf life gain reached by using MAP. However, shelf life prediction is an indispensable prerequisite for quantifying the effect of MAP on food losses reduction. The objective of this work is to propose an innovative approach to predict shelf life of MAP food product and then to link it to a reduction of food losses and wastes. In this purpose, a ‘Virtual MAP modeling tool’ was developed by coupling a new predictive deterioration model (based on visual surface prediction of deterioration encompassing colour, texture and spoilage development) with models of the literature for respiration and permeation. A major input of this modelling tool is the maximal percentage of deterioration (MAD) which was assessed from dedicated consumers’ studies. Strawberries of the variety Charlotte were selected as the model food for its high perishability, high respiration rate; 50-100 ml CO₂/h/kg produced at 20°C, allowing it to be a good representative of challenging post-harvest storage. A value of 13% was determined as a limit of acceptability for the consumers, permitting to define products’ shelf life. The ‘Virtual MAP modeling tool’ was validated in isothermal conditions (5, 10 and 20°C) and in dynamic temperature conditions mimicking commercial post-harvest storage of strawberries. RMSE values were systematically lower than 3% for respectively, O₂, CO₂ and deterioration profiles as a function of time confirming the goodness of model fitting. For the investigated temperature profile, a shelf life gain of 0.33 days was obtained in MAP compared to the conventional storage situation (no MAP condition). Shelf life gain of more than 1 day could be obtained for optimized post-harvest conditions as numerically investigated. Such shelf life gain permitted to anticipate a significant reduction of food losses at the distribution and consumer steps. This food losses' reduction as a function of shelf life gain has been quantified using a dedicated mathematical equation that has been developed for this purpose.

Keywords: food losses and wastes, modified atmosphere packaging, mathematical modeling, shelf life prediction

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Authors: Mingxin Li, Liya Ni

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Autonomous parking is a valuable feature applicable to many robotics applications such as tour guide robots, UV sanitizing robots, food delivery robots, and warehouse robots. With auto-parking, the robot will be able to park at the charging zone and charge itself without human intervention. As compared to self-driving vehicles, auto-parking is more challenging for a small-scale mobile robot only equipped with a front camera due to the camera view limited by the robot’s height and the narrow Field of View (FOV) of the inexpensive camera. In this research, auto-parking of a small-scale mobile robot with a front camera only was achieved in a four-step process: Firstly, transfer learning was performed on the AlexNet, a popular pre-trained convolutional neural network (CNN). It was trained with 150 pictures of empty parking slots and 150 pictures of occupied parking slots from the view angle of a small-scale robot. The dataset of images was divided into a group of 70% images for training and the remaining 30% images for validation. An average success rate of 95% was achieved. Secondly, the image of detected empty parking space was processed with edge detection followed by the computation of parametric representations of the boundary lines using the Hough Transform algorithm. Thirdly, the positions of the entrance point and center of available parking space were predicted based on the robot kinematic model as the robot was driving closer to the parking space because the boundary lines disappeared partially or completely from its camera view due to the height and FOV limitations. The robot used its wheel speeds to compute the positions of the parking space with respect to its changing local frame as it moved along, based on its kinematic model. Lastly, the predicted entrance point of the parking space was used as the reference for the motion control of the robot until it was replaced by the actual center when it became visible again by the robot. The linear and angular velocities of the robot chassis center were computed based on the error between the current chassis center and the reference point. Then the left and right wheel speeds were obtained using inverse kinematics and sent to the motor driver. The above-mentioned four subtasks were all successfully accomplished, with the transformed learning, image processing, and target prediction performed in MATLAB, while the motion control and image capture conducted on a self-built small scale differential drive mobile robot. The small-scale robot employs a Raspberry Pi board, a Pi camera, an L298N dual H-bridge motor driver, a USB power module, a power bank, four wheels, and a chassis. Future research includes three areas: the integration of all four subsystems into one hardware/software platform with the upgrade to an Nvidia Jetson Nano board that provides superior performance for deep learning and image processing; more testing and validation on the identification of available parking space and its boundary lines; improvement of performance after the hardware/software integration is completed.

Keywords: autonomous parking, convolutional neural network, image processing, kinematics-based prediction, transfer learning

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Authors: John Lachapelle

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Introduction: Neural stimulation is increasingly targeted toward treatment of back pain, PTSD, Parkinson’s disease, and for sensory perception. Sensory recording during stimulation is important in order to examine neural response to stimulation. Most neural amplifiers (headstages) focus on noise efficiency factor (NEF). Conversely, neural headstages need to handle artifacts from several sources including power lines, movement (EMG), and neural stimulation itself. In this work a layered approach to artifact rejection is used to reduce corruption of the neural ENG signal by 60dBv, resulting in recovery of sensory signals in rats and primates that would previously not be possible. Methods: The approach combines analog techniques to reduce and handle unwanted signal amplitudes. The methods include optimized (1) sensory electrode placement, (2) amplifier configuration, and (3) artifact blanking when necessary. The techniques together are like concentric moats protecting a castle; only the wanted neural signal can penetrate. There are two conditions in which the headstage operates: unwanted artifact < 50mV, linear operation, and artifact > 50mV, fast-settle gain reduction signal limiting (covered in more detail in a separate paper). Unwanted Signals at the headstage input: Consider: (a) EMG signals are by nature < 10mV. (b) 60 Hz power line signals may be > 50mV with poor electrode cable conditions; with careful routing much of the signal is common to both reference and active electrode and rejected in the differential amplifier with <50mV remaining. (c) An unwanted (to the neural recorder) stimulation signal is attenuated from stimulation to sensory electrode. The voltage seen at the sensory electrode can be modeled Φ_m=I_o/4πσr. For a 1 mA stimulation signal, with 1 cm spacing between electrodes, the signal is <20mV at the headstage. Headstage ASIC design: The front end ASIC design is designed to produce < 1% THD at 50mV input; 50 times higher than typical headstage ASICs, with no increase in noise floor. This requires careful balance of amplifier stages in the headstage ASIC, as well as consideration of the electrodes effect on noise. The ASIC is designed to allow extremely small signal extraction on low impedance (< 10kohm) electrodes with configuration of the headstage ASIC noise floor to < 700nV/rt-Hz. Smaller high impedance electrodes (> 100kohm) are typically located closer to neural sources and transduce higher amplitude signals (> 10uV); the ASIC low-power mode conserves power with 2uV/rt-Hz noise. Findings: The enhanced neural processing ASIC has been compared with a commercial neural recording amplifier IC. Chronically implanted primates at MGH demonstrated the presence of commercial neural amplifier saturation as a result of large environmental artifacts. The enhanced artifact suppression headstage ASIC, in the same setup, was able to recover and process the wanted neural signal separately from the suppressed unwanted artifacts. Separately, the enhanced artifact suppression headstage ASIC was able to separate sensory neural signals from unwanted artifacts in mouse-implanted peripheral intrafascicular electrodes. Conclusion: Optimizing headstage ASICs allow observation of neural signals in the presence of large artifacts that will be present in real-life implanted applications, and are targeted toward human implantation in the DARPA HAPTIX program.

Keywords: ASIC, biosensors, biomedical signal processing, biomedical sensors

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Authors: Ricardo Alberto Chiong Zevallos, Eduardo Moraes Rego Reis

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Pancreatic adenocarcinoma (PDAC) patients have a less than 10% 5-year survival rate. PDAC has no defined diagnostic and prognostic biomarkers. Gemcitabine is the first-line drug in PDAC and several other cancers. Long non-coding RNAs (lncRNAs) contribute to the tumorigenesis and are potential biomarkers for PDAC. Although lncRNAs aren’t translated into proteins, they have important functions. LncRNAs can decoy or recruit proteins from the epigenetic machinery, act as microRNA sponges, participate in protein translocation through different cellular compartments, and even promote chemoresistance. The chromatin remodeling enzyme EZH2 is a histone methyltransferase that catalyzes the methylation of histone 3 at lysine 27, silencing local expression. EZH2 is ambivalent, it can also activate gene expression independently of its histone methyltransferase activity. EZH2 is overexpressed in several cancers and interacts with lncRNAs, being recruited to a specific locus. EZH2 can be recruited to activate an oncogene or silence a tumor suppressor. The lncRNAs misregulation in cancer can result in the differential recruitment of EZH2 and in a distinct epigenetic landscape, promoting chemoresistance. The relevance of the EZH2-lncRNAs interaction to chemoresistant PDAC was assessed by Real Time quantitative PCR (RT-qPCR) and RNA Immunoprecipitation (RIP) experiments with naïve and gemcitabine-resistant PDAC cells. The expression of several lncRNAs and EZH2 gene targets was evaluated contrasting naïve and resistant cells. Selection of candidate genes was made by bioinformatic analysis and literature curation. Indeed, the resistant cell line showed higher expression of chemoresistant-associated lncRNAs and protein coding genes. RIP detected lncRNAs interacting with EZH2 with varying intensity levels in the cell lines. During RIP, the nuclear fraction of the cells was incubated with an antibody for EZH2 and with magnetic beads. The RNA precipitated with the beads-antibody-EZH2 complex was isolated and reverse transcribed. The presence of candidate lncRNAs was detected by RT-qPCR, and the enrichment was calculated relative to INPUT (total lysate control sample collected before RIP). The enrichment levels varied across the several lncRNAs and cell lines. The EZH2-lncRNA interaction might be responsible for the regulation of chemoresistance-associated genes in multiple cancers. The relevance of the lncRNA-EZH2 interaction to PDAC was assessed by siRNA knockdown of a lncRNA, followed by the analysis of the EZH2 target expression by RT-qPCR. The chromatin immunoprecipitation (ChIP) of EZH2 and H3K27me3 followed by RT-qPCR with primers for EZH2 targets also assess the specificity of the EZH2 recruitment by the lncRNA. This is the first report of the interaction of EZH2 and lncRNAs HOTTIP and PVT1 in chemoresistant PDAC. HOTTIP and PVT1 were described as promoting chemoresistance in several cancers, but the role of EZH2 is not clarified. For the first time, the lncRNA LINC01133 was detected in a chemoresistant cancer. The interaction of EZH2 with LINC02577, LINC00920, LINC00941, and LINC01559 have never been reported in any context. The novel lncRNAs-EZH2 interactions regulate chemoresistant-associated genes in PDAC and might be relevant to other cancers. Therapies targeting EZH2 alone weren’t successful, and a combinatorial approach also targeting the lncRNAs interacting with it might be key to overcome chemoresistance in several cancers.

Keywords: epigenetics, chemoresistance, long non-coding RNAs, pancreatic cancer, histone modification

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Authors: Omer Leshem, Michael F. Schober

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This paper introduces a new method for assessing how audience members and performers feel and think during live concerts, and how audience members' recognized and felt emotions are related. Two hypotheses were tested in a live concert setting: (1) that audience members’ cognitive perspective taking ability predicts their accuracy in identifying an emotion that a jazz improviser intended to express during a performance, and (2) that audience members' affective empathy predicts their likelihood of feeling the same emotions as the performer. The aim was to stage a concert with audience members who regularly attend live jazz performances, and to measure their cognitive and affective reactions during the performance as non-intrusively as possible. Pianist and Grammy nominee Andy Milne agreed, without knowing details of the method or hypotheses, to perform a full-length solo improvised concert that would include an ‘unusual’ piece. Jazz fans were recruited through typical advertising for New York City jazz performances. The event was held at the New School’s Glass Box Theater, the home of leading NYC jazz venue ‘The Stone.’ Audience members were charged typical NYC jazz club admission prices; advertisements informed them that anyone who chose to participate in the study would be reimbursed their ticket price after the concert. The concert, held in April 2018, had 30 attendees, 23 of whom participated in the study. Twenty-two minutes into the concert, the performer was handed a paper note with the instruction: ‘Perform a 3-5-minute improvised piece with the intention of conveying sadness.’ (Sadness was chosen based on previous music cognition lab studies, where solo listeners were less likely to select sadness as the musically-expressed emotion accurately from a list of basic emotions, and more likely to misinterpret sadness as tenderness). Then, audience members and the performer were invited to respond to a questionnaire from a first envelope under their seat. Participants used their own words to describe the emotion the performer had intended to express, and then to select the intended emotion from a list. They also reported the emotions they had felt while listening using Izard’s differential emotions scale. The concert then continued as usual. At the end, participants answered demographic questions and Davis’ interpersonal reactivity index (IRI), a 28-item scale designed to assess both cognitive and affective empathy. Hypothesis 1 was supported: audience members with greater cognitive empathy were more likely to accurately identify sadness as the expressed emotion. Moreover, audience members who accurately selected ‘sadness’ reported feeling marginally sadder than people who did not select sadness. Hypotheses 2 was not supported; audience members with greater affective empathy were not more likely to feel the same emotions as the performer. If anything, members with lower cognitive perspective-taking ability had marginally greater emotional overlap with the performer, which makes sense given that these participants were less likely to identify the music as sad, which corresponded with the performer’s actual feelings. Results replicate findings from solo lab studies in a concert setting and demonstrate the viability of exploring empathy and collective cognition in improvised live performance.

Keywords: audience, cognition, collective cognition, emotion, empathy, expressed emotion, felt emotion, improvisation, live performance, recognized emotion

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Authors: A.H.Y. Lai, C. Teyra

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In Taiwan, there are 16 official indigenous groups, accounting for 2.3% of the total population. Like other indigenous populations worldwide, indigenous peoples in Taiwan have poorer mental health because of their history of oppression and colonisation. Amid the negative narratives, the ethnic identity of cultural minorities is their unique psychological and cultural asset. Moreover, positive socialisation is found to be related to strong ethnic identity. Based on Phinney’s theory on ethnic identity development and social support theory, this study adopted a strength-based approach conceptualising ethnic identity as the central organising principle that linked perceived social support and mental health among indigenous adults in Taiwan. Aims. Overall aim is to examine the effect of ethnic identity and social support on mental health. Specific aims were to examine : (1) the association between ethnic identity and mental health; (2) the association between perceived social support and mental health ; (3) the indirect effect of ethnic identity linking perceived social support and mental health. Methods. Participants were indigenous adults in Taiwan (n=200; mean age=29.51; Female=31%, Male=61%, Others=8%). A cross-sectional quantitative design was implemented using data collected in the year 2020. Respondent-driven sampling was used. Standardised measurements were: Ethnic Identity Scale(6-item); Social Support Questionnaire-SF(6 items); Patient Health Questionnaire(9-item); and Generalised Anxiety Disorder(7-item). Covariates were age, gender and economic satisfaction. A four-stage structural equation modelling (SEM) with robust maximin likelihood estimation was employed using Mplus8.0. Step 1: A measurement model was built and tested using confirmatory factor analysis (CFA). Step 2: Factor covariates were re-specified as direct effects in the SEM. Covariates were added. The direct effects of (1) ethnic identity and social support on depression and anxiety and (2) social support on ethnic identity were tested. The indirect effect of ethnic identity was examined with the bootstrapping technique. Results. The CFA model showed satisfactory fit statistics: x^2(df)=869.69(608), p<.05; Comparative ft index (CFI)/ Tucker-Lewis fit index (TLI)=0.95/0.94; root mean square error of approximation (RMSEA)=0.05; Standardized Root Mean Squared Residual (SRMR)=0.05. Ethnic identity is represented by two latent factors: ethnic identity-commitment and ethnic identity-exploration. Depression, anxiety and social support are single-factor latent variables. For the SEM, model fit statistics were: x^2(df)=779.26(527), p<.05; CFI/TLI=0.94/0.93; RMSEA=0.05; SRMR=0.05. Ethnic identity-commitment (b=-0.30) and social support (b=-0.33) had direct negative effects on depression, but ethnic identity-exploration did not. Ethnic identity-commitment (b=-0.43) and social support (b=-0.31) had direct negative effects on anxiety, while identity-exploration (b=0.24) demonstrated a positive effect. Social support had direct positive effects on ethnic identity-exploration (b=0.26) and ethnic identity-commitment (b=0.31). Mediation analysis demonstrated the indirect effect of ethnic identity-commitment linking social support and depression (b=0.22). Implications: Results underscore the role of social support in preventing depression via ethnic identity commitment among indigenous adults in Taiwan. Adopting the strength-based approach, mental health practitioners can mobilise indigenous peoples’ commitment to their group to promote their well-being.

Keywords: ethnic identity, indigenous population, mental health, perceived social support

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Authors: Nien-Te Kuo, Yi-Sung Cheng, Kuo-Chien Chang

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Cultural festival tourism is now seen by many as an opportunity to facilitate community development because it has significant influences on the economic, social, cultural, and political aspects of local communities. The potential for tourist attraction has been recognized as a useful tool to strengthen local economies from governments. However, most community festivals in Taiwan are short-lived, often only lasting for a few years or occasionally not making it past a one-off event. Researchers suggested that most governments and other stakeholders do not recognize the importance of building a partnership with residents when developing community tourism. Thus, the sustainable community tourism development still remains a key issue in the existing literature. The success of community tourism is related to the attitudes and lifestyles of local residents. In order to maintain sustainable tourism, residents need to be seen as development partners. Residents’ support intention for tourism development not only helps to increase awareness of local culture, history, the natural environment, and infrastructure, but also improves the interactive relationship between the host community and tourists. Furthermore, researchers have identified the social capital theory as the core of sustainable community tourism development. The social capital of residents has been seen as a good way to solve issues of tourism governance, forecast the participation behavior and improve support intention of residents. In addition, previous studies have pointed out the role of community participation and place identity in increasing resident support intention for tourism development. A lack of place identity is one of the main reasons that community tourism has become a mere formality and is not sustainable. It refers to how much residents participate during tourism development and is mainly influenced by individual interest. Scholars believed that the place identity of residents is the soul of community festivals. It shows the community spirit to visitors and has significant impacts on tourism benefits and support intention of residents in community tourism development. Although the importance of community participation and place identity have been confirmed by both governmental and non-governmental organizations, real-life execution still needs to be improved. This study aimed to use social capital theory to investigate the social structure between community residents, participation levels in festival tourism, degrees of place identity, and resident support intention for future community tourism development, and the causal relationship that these factors have with cultural festival tourism. A quantitative research approach was employed to examine the proposed model. Structural equation model was used to test and verify the proposed hypotheses. This was a case study of the Kaohsiung Zuoying Wannian Folklore Festival. The festival was located in the Zuoying District of Kaohsiung City, Taiwan. The target population of this study was residents who attended the festival. The results reveal significant correlations among social capital, community participation, place identity and support intention. The results also confirm that impacts of social capital on support intention were significantly mediated by community participation and place identity. Practical suggestions were provided for tourism operators and policy makers. This work was supported by the Ministry of Science and Technology of Taiwan, Republic of China, under the grant MOST-105-2410-H-328-013.

Keywords: community participation, place identity, social capital, support intention

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Authors: Kaleeswari R. K., Seevagan L .

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Soil quality in an agroecosystem is influenced by the cropping system, water and soil fertility management. A valid soil quality index would help to assess the soil and crop management practices for desired productivity and soil health. The soil quality indices also provide an early indication of soil degradation and needy remedial and rehabilitation measures. Imbalanced fertilization and inadequate organic carbon dynamics deteriorate soil quality in an intensive cropping system. The rice soil ecosystem is different from other arable systems since rice is grown under submergence, which requires a different set of key soil attributes for enhancing soil quality and productivity. Assessment of the soil quality index involves indicator selection, indicator scoring and comprehensive score into one index. The most appropriate indicator to evaluate soil quality can be selected by establishing the minimum data set, which can be screened by linear and multiple regression factor analysis and score function. This investigation was carried out in intensive rice cultivating regions (having >1.0 lakh hectares) of Tamil Nadu viz., Thanjavur, Thiruvarur, Nagapattinam, Villupuram, Thiruvannamalai, Cuddalore and Ramanathapuram districts. In each district, intensive rice growing block was identified. In each block, two sampling grids (10 x 10 sq.km) were used with a sampling depth of 10 – 15 cm. Using GIS coordinates, and soil sampling was carried out at various locations in the study area. The number of soil sampling points were 41, 28, 28, 32, 37, 29 and 29 in Thanjavur, Thiruvarur, Nagapattinam, Cuddalore, Villupuram, Thiruvannamalai and Ramanathapuram districts, respectively. Principal Component Analysis is a data reduction tool to select some of the potential indicators. Principal Component is a linear combination of different variables that represents the maximum variance of the dataset. Principal Component that has eigenvalues equal or higher than 1.0 was taken as the minimum data set. Principal Component Analysis was used to select the representative soil quality indicators in rice soils based on factor loading values and contribution percent values. Variables having significant differences within the production system were used for the preparation of the minimum data set. Each Principal Component explained a certain amount of variation (%) in the total dataset. This percentage provided the weight for variables. The final Principal Component Analysis based soil quality equation is SQI = ∑ i=1 (W ᵢ x S ᵢ); where S- score for the subscripted variable; W-weighing factor derived from PCA. Higher index scores meant better soil quality. Soil respiration, Soil available Nitrogen and Potentially Mineralizable Nitrogen were assessed as soil quality indicators in rice soil of the Cauvery Delta zone covering Thanjavur, Thiruvavur and Nagapattinam districts. Soil available phosphorus could be used as a soil quality indicator of rice soils in the Cuddalore district. In rain-fed rice ecosystems of coastal sandy soil, DTPA – Zn could be used as an effective soil quality indicator. Among the soil parameters selected from Principal Component Analysis, Microbial Biomass Nitrogen could be used quality indicator for rice soils of the Villupuram district. Cauvery Delta zone has better SQI as compared with other intensive rice growing zone of Tamil Nadu.

Keywords: soil quality index, soil attributes, soil mapping, and rice soil

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Authors: Adriana Haulica

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Powered by Machine Learning, Precise medicine is tailored by now to use genetic and molecular profiling, with the aim of optimizing the therapeutic benefits for cohorts of patients. As the majority of Machine Language algorithms come from heuristics, the outputs have contextual validity. This is not very restrictive in the sense that medicine itself is not an exact science. Meanwhile, the progress made in Molecular Biology, Bioinformatics, Computational Biology, and Precise Medicine, correlated with the huge amount of human biology data and the increase in computational power, opens new healthcare challenges. A more accurate diagnosis is needed along with real-time treatments by processing as much as possible from the available information. The purpose of this paper is to present a deeper vision for the future of Artificial Intelligence in Precise medicine. In fact, actual Machine Learning algorithms use standard mathematical knowledge, mostly Euclidian metrics and standard computation rules. The loss of information arising from the classical methods prevents obtaining 100% evidence on the diagnosis process. To overcome these problems, we introduce MEDICOMPILLS, a new architectural concept tool of information processing in Precise medicine that delivers diagnosis and therapy advice. This tool processes poly-field digital resources: global knowledge related to biomedicine in a direct or indirect manner but also technical databases, Natural Language Processing algorithms, and strong class optimization functions. As the name suggests, the heart of this tool is a compiler. The approach is completely new, tailored for omics and clinical data. Firstly, the intrinsic biological intuition is different from the well-known “a needle in a haystack” approach usually used when Machine Learning algorithms have to process differential genomic or molecular data to find biomarkers. Also, even if the input is seized from various types of data, the working engine inside the MEDICOMPILLS does not search for patterns as an integrative tool. This approach deciphers the biological meaning of input data up to the metabolic and physiologic mechanisms, based on a compiler with grammars issued from bio-algebra-inspired mathematics. It translates input data into bio-semantic units with the help of contextual information iteratively until Bio-Logical operations can be performed on the base of the “common denominator “rule. The rigorousness of MEDICOMPILLS comes from the structure of the contextual information on functions, built to be analogous to mathematical “proofs”. The major impact of this architecture is expressed by the high accuracy of the diagnosis. Detected as a multiple conditions diagnostic, constituted by some main diseases along with unhealthy biological states, this format is highly suitable for therapy proposal and disease prevention. The use of MEDICOMPILLS architecture is highly beneficial for the healthcare industry. The expectation is to generate a strategic trend in Precise medicine, making medicine more like an exact science and reducing the considerable risk of errors in diagnostics and therapies. The tool can be used by pharmaceutical laboratories for the discovery of new cures. It will also contribute to better design of clinical trials and speed them up.

Keywords: bio-semantic units, multiple conditions diagnosis, NLP, omics

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Authors: Iñaki Iturria, Pasquale Russo, Montserrat Nacher-Vázquez, Giuseppe Spano, Paloma López, Miguel Angel Pardo

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Introduction: It is known that some Lactic Acid Bacteria (LAB) present an interesting probiotic effect. Probiotic bacteria stimulate host resistance to microbial pathogens and thereby aid in immune response, and modulate the host's immune responses to antigens with a potential to down-regulate hypersensitivity reactions. Therefore, probiotic therapy is valuable against intestinal infections and may be beneficial in the treatment of Inflammatory Bowel Disease (IBD). Several in vitro tests are available to evaluate the probiotic potential of a LAB strain. However, an in vivo model is required to understand the interaction between the host immune system and the bacteria. During the last few years, zebrafish (Danio rerio) has gained interest as a promising vertebrate model in this field. This organism has been extensively used to study the interaction between the host and the microbiota, as well as the host immune response under several microbial infections. In this work, we report on the use of the zebrafish model to investigate in vivo the colonizing ability and the immunomodulatory effect of probiotic LAB. Methods: Lactobacillus strains belonging to different LAB species were fluorescently tagged and used to colonize germ-free zebrafish larvae gastrointestinal tract (GIT). Some of the strains had a well-documented probiotic effect (L. acidophilus LA5); while others presented an exopolysaccharide (EPS) producing phenotype, thus allowing evaluating the influence of EPS in the colonization and immunomodulatory effect. Bacteria colonization was monitored for 72 h by direct observation in real time using fluorescent microscopy. CFU count per larva was also evaluated at different times. The immunomodulatory effect was assessed analysing the differential expression of several innate immune system genes (MyD88, NF-κB, Tlr4, Il1β and Il10) by qRT- PCR. The anti-inflammatory effect was evaluated using a chemical enterocolitis zebrafish model. The protective effect against a pathogen was also studied. To that end, a challenge test was developed using a fluorescently tagged pathogen (Vibrio anguillarum-GFP+). The progression of the infection was monitored up to 3 days using a fluorescent stereomicroscope. Mortality rates and CFU counts were also registered. Results and conclusions: Larvae exposed to EPS-producing bacteria showed a higher fluorescence and CFU count than those colonized with no-EPS phenotype LAB. In the same way, qRT-PCR results revealed an immunomodulatory effect on the host after the administration of the strains with probiotic activity. A downregulation of proinflammatory cytoquines as well as other cellular mediators of inflammation was observed. The anti-inflammatory effect was found to be particularly marked following exposure to LA% strain, as well as EPS producing strains. Furthermore, the challenge test revealed a protective effect of probiotic administration. As a matter of fact, larvae fed with probiotics showed a decrease in the mortality rate ranging from 20 to 35%. Discussion: In this work, we developed a promising model, based on the use of gnotobiotic zebrafish coupled with a bacterial fluorescent tagging in order to evaluate the probiotic potential of different LAB strains. We have successfully used this system to monitor in real time the colonization and persistence of exogenous LAB within the gut of zebrafish larvae, to evaluate their immunomodulatory effect and for in vivo competition assays. This approach could bring further insights into the complex microbial-host interactions at intestinal level.

Keywords: gnotobiotic, immune system, lactic acid bacteria, probiotics, zebrafish

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Authors: Mohammed S. Razali, Kamel Khimeche, Dahah Hichem, Ammar Boudjellal, Djamel E. Kaderi, Nourddine Ramdani

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The use of additive manufacturing technologies has revolutionized various aspects of our daily lives. In particular, 3D printing has greatly advanced biomedical applications. While fused filament fabrication (FFF) technologies have made it easy to produce or prototype various medical devices, it is crucial to minimize the risk of contamination. New materials with antibacterial properties, such as those containing compounded silver nanoparticles, have emerged on the market. In a previous study, we prepared a newly sintered seashell filler (SSh) from bio-based seashells found along the Mediterranean coast using a suitable heat treatment process. We then prepared a series of polylactic acid (PLA) and polybutylene succinate (PBS) biocomposites filled with these SSh particles using a melt mixing technique with a twin-screw extruder to use them as feedstock filaments for 3D printing. The study consisted of two parts: evaluating the antibacterial activity of newly prepared biocomposites made of PLA and PBS reinforced with a sintered seashell in the first part and experimental and modeling analysis of the non-isothermal crystallization kinetics of these biocomposites in the second part. In the first part, the bactericidal activity of the biocomposites against three different bacteria, including Gram-negative bacteria such as (E. coli and Pseudomonas aeruginosa), as well as Gram-positive bacteria such as (Staphylococcus aureus), was examined. The PLA-based biocomposite containing 20 wt.% of SSh particles exhibited an inhibition zone with radial diameters of 8mm and 6mm against E. coli and Pseudo. Au, respectively, while no bacterial activity was observed against Staphylococcus aureus. In the second part, the focus was on investigating the effect of the sintered seashell filler particles on the non-isothermal crystallization kinetics of PLA and PBS 3D-printing composite materials. The objective was to understand the impact of the filler particles on the crystallization mechanism of both PLA and PBS during the cooling process of a melt-extruded filament in (FFF) to manage the dimensional accuracy and mechanical properties of the final printed part. We conducted a non-isothermal melt crystallization kinetic study of a series of PLA-SS and PBS-SS composites using differential scanning calorimetry at various cooling rates. We analyzed the obtained kinetic data using different crystallization kinetic models such as modified Avrami, Ozawa, and Mo's methods. Dynamic mode describes the relative crystallinity as a function of temperature; it found that time half crystallinity (t1/2) of neat PLA decreased from 17 min to 7.3 min for PLA+5 SSh and the (t1/2) of virgin PBS was reduced from 3.5 min to 2.8 min for the composite containing 5wt.% of SSh. We found that the coated SS particles with stearic acid acted as nucleating agents and had a nucleation activity, as observed through polarized optical microscopy. Moreover, we evaluated the effective energy barrier of the non-isothermal crystallization process using the Iso conversional methods of Flynn-Wall-Ozawa (F-W-O) and Kissinger-Akahira-Sunose (K-A-S). The study provides significant insights into the crystallization behavior of PLA and PBS biocomposites.

Keywords: avrami model, bio-based reinforcement, dsc, gram-negative bacteria, gram-positive bacteria, isoconversional methods, non-isothermal crystallization kinetics, poly(butylene succinate), poly(lactic acid), antbactirial activity

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Authors: Hannah R. Devens, Phillip L. Davidson, Dione Deaker, Kathryn E. Smith, Gregory A. Wray, Maria Byrne

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Marine invertebrate species with calcifying larvae are especially vulnerable to ocean acidification (OA) caused by rising atmospheric CO₂ levels. Acidic conditions can delay development, suppress metabolism, and decrease the availability of carbonate ions in the ocean environment for skeletogenesis. These stresses often result in increased larval mortality, which may lead to significant ecological consequences including alterations to the larval settlement, population distribution, and genetic connectivity. Importantly, many of these physiological and developmental effects are caused by genetic and molecular level changes. Although many studies have examined the effect of near-future oceanic pH levels on gene expression in marine invertebrates, little is known about the impact of OA on gene expression in a developmental context. Here, we performed mRNA-sequencing to investigate the impact of environmental acidity on gene expression across three developmental stages in the sea urchin Heliocidaris erythrogramma. We collected RNA from gastrula, early larva, and 1-day post-metamorphic juvenile sea urchins cultured at present-day and predicted future oceanic pH levels (pH 8.1 and 7.7, respectively). We assembled an annotated reference transcriptome encompassing development from egg to ten days post-metamorphosis by combining these data with datasets from two previous developmental transcriptomic studies of H. erythrogramma. Differential gene expression and time course analyses between pH conditions revealed significant alterations to developmental transcription that are potentially associated with pH stress. Consistent with previous investigations, genes involved in biomineralization and ion transport were significantly upregulated under acidic conditions. Differences in gene expression between the two pH conditions became more pronounced post-metamorphosis, suggesting a development-dependent effect of OA on gene expression. Furthermore, many differences in gene expression later in development appeared to be a result of broad downregulation at pH 7.7: of 539 genes differentially expressed at the juvenile stage, 519 of these were lower in the acidic condition. Time course comparisons between pH 8.1 and 7.7 samples also demonstrated over 500 genes were more lowly expressed in pH 7.7 samples throughout development. Of the genes exhibiting stage-dependent expression level changes, over 15% of these diverged from the expected temporal pattern of expression in the acidic condition. Through these analyses, we identify novel candidate genes involved in development, metabolism, and transcriptional regulation that are possibly affected by pH stress. Our results demonstrate that pH stress significantly alters gene expression dynamics throughout development. A large number of genes differentially expressed between pH conditions in juveniles relative to earlier stages may be attributed to the effects of acidity on transcriptional regulation, as a greater proportion of mRNA at this later stage has been nascent transcribed rather than maternally loaded. Also, the overall downregulation of many genes in the acidic condition suggests that OA-induced developmental delay manifests as suppressed mRNA expression, possibly from lower transcription rates or increased mRNA degradation in the acidic environment. Further studies will be necessary to determine in greater detail the extent of OA effects on early developing marine invertebrates.

Keywords: development, gene expression, ocean acidification, RNA-sequencing, sea urchins

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Authors: Banu Pradheepa Kamarajan, Muthusamy Ananthasubramanian

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Biofilm forming Pseudomonads occupy the top third position in causing hospital acquired infections. P. aeruginosa is notoriously known for its tendency to develop drug resistance. Major classes of drug such as β-lactams, aminoglycosides, quinolones, and polymyxins are found ineffective against multi-drug resistance Pseudomonas. To combat the infections, rather than administration of a single antibiotic, use of combinations (tobramycin and essential oils from plants and/or silver nanoparticles, chitosan, nitric oxide, cis-2-decenoic acid) in single formulation are suggested to control P. aeruginosa biofilms. Conventional techniques to prevent hospital-acquired implant infections such as coatings with antibiotics, controlled release of antibiotics from the implant material, contact-killing surfaces, coating the implants with functional DNase I and, coating with glycoside hydrolase are being followed. Coatings with bioactive components besides having limited shelf-life, require cold-chain and, are likely to fail when bacteria develop resistance. Recently identified nano-scale physical architectures on the insect wings are expected to have potential bactericidal property. Nanopillars are bactericidal to Staphylococcus aureus, Bacillus subtilis, K. pnuemoniae and few species of Pseudomonas. Our study aims to investigate the survival rate of biofilm forming Pseudomonas aeruginosa strain over non-biofilm forming strain on the nanopillar architecture of dragonfly (Pantala flavescens) wing. Dragonflies were collected near house-hold areas and, insect identification was carried out by the Department of Entomology, Tamilnadu Agricultural University, Coimbatore, India. Two strains of P. aeruginosa such as PAO1 (potent biofilm former) and MTCC 1688 (non-weak biofilm former) were tested against the glass coverslip (control) and wings of dragonfly (test) for 48 h. The wings/glass coverslips were incubated with bacterial suspension in 48-well plate. The plates were incubated at 37 °C under static condition. Bacterial attachment on the nanopillar architecture of the wing surface was visualized using FESEM. The survival rate of P. aeruginosa was tested using colony counting technique and flow cytometry at 0.5 h, 1 h, 2 h, 7 h, 24 h, and 48 h post-incubation. Cell death was analyzed using propidium iodide staining and DNA quantification. The results indicated that the survival rate of non-biofilm forming P. aeruginosa is 0.2 %, whilst that of biofilm former is 45 % on the dragonfly wings at the end of 48 h. The reduction in the survival rate of biofilm and non-biofilm forming P. aeruginosa was 20% and 40% respectively on the wings compared to the glass coverslip. In addition, Fourier Transformed Infrared Radiation was used to study the modification in the surface chemical composition of the wing during bacterial attachment and, post-sonication. This result indicated that the chemical moieties are not involved in the bactericidal property of nanopillars by the conserved characteristic peaks of chitin pre and post-sonication. The nanopillar architecture of the dragonfly wing efficiently deters the survival of non-biofilm forming P. aeruginosa, but not the biofilm forming strain. The study highlights the ability of biofilm formers to survive on wing architecture. Understanding this survival strategy will help in designing the architecture that combats the colonization of biofilm forming pathogens.

Keywords: biofilm, nanopillars, Pseudomonas aeruginosa, survival rate

Procedia PDF Downloads 153

Authors: Ntandazo Dlatu, Benjamin Longo-Mbenza, Andre Renzaho, Ruffin Appalata, Yolande Yvonne Valeria Matoumona Mavoungou, Mbenza Ben Longo, Kenneth Ekoru, Blaise Makoso, Gedeon Longo Longo

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Background: The gap between complexities related to the integration of Tuberculosis /HIV control and evidence-based knowledge motivated the initiation of the study. Therefore, the objective of this study was to explore correlations between national TB management guidelines, multiple deprivation indexes, quantiles, components and levels of Tuberculosis control programme using mathematical modeling in rural O.R. Tambo District Health Facilities, South Africa. Methods: The study design used mixed secondary data analysis and cross-sectional analysis between 2009 and 2013 across O.R Tambo District, Eastern Cape, South Africa using univariate/ bivariate analysis, linear multiple regression models, and multivariate discriminant analysis. Health inequalities indicators and component of an impediment to the tuberculosis control programme were evaluated. Results: In total, 62 400 records for TB notification were analyzed for the period 2009-2013. There was a significant but negative between Financial Year Expenditure (r= -0.894; P= 0.041) Seropositive HIV status(r= -0.979; P= 0.004), Population Density (r = -0.881; P= 0.048) and the number of TB defaulter in all TB cases. It was shown unsuccessful control of TB management program through correlations between numbers of new PTB smear positive, TB defaulter new smear-positive, TB failure all TB, Pulmonary Tuberculosis case finding index and deprivation-concentration-dispersion index. It was shown successful TB program control through significant and negative associations between declining numbers of death in co-infection of HIV and TB, TB deaths all TB and SMIAD gradient/ deprivation-concentration-dispersion index. The multivariate linear model was summarized by unadjusted r of 96%, adjusted R2 of 95 %, Standard Error of estimate of 0.110, R2 changed of 0.959 and significance for variance change for P=0.004 to explain the prediction of TB defaulter in all TB with equation y= 8.558-0.979 x number of HIV seropositive. After adjusting for confounding factors (PTB case finding the index, TB defaulter new smear-positive, TB death in all TB, TB defaulter all TB, and TB failure in all TB). The HIV and TB death, as well as new PTB smear positive, were identified as the most important, significant, and independent indicator to discriminate most deprived deprivation index far from other deprivation quintiles 2-5 using discriminant analysis. Conclusion: Elimination of poverty such as overcrowding, lack of sanitation and environment of highest burden of HIV might end the TB threat in O.R Tambo District, Eastern Cape, South Africa. Furthermore, ongoing adequate budget comprehensive, holistic and collaborative initiative towards Sustainable Developmental Goals (SDGs) is necessary for complete elimination of TB in poor O.R Tambo District.

Keywords: tuberculosis, HIV/AIDS, success, failure, control program, health inequalities, South Africa

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Authors: Riadh Zorgati, Thomas Triboulet

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In quite diverse application areas such as astronomy, medical imaging, geophysics or nondestructive evaluation, many problems related to calibration, fitting or estimation of a large number of input parameters of a model from a small amount of output noisy data, can be cast as inverse problems. Due to noisy data corruption, insufficient data and model errors, most inverse problems are ill-posed in a Hadamard sense, i.e. existence, uniqueness and stability of the solution are not guaranteed. A wide class of inverse problems in physics relates to the Fredholm equation of the first kind. The ill-posedness of such inverse problem results, after discretization, in a very ill-conditioned linear system of equations, the condition number of the associated matrix can typically range from 109 to 1018. This condition number plays the role of an amplifier of uncertainties on data during inversion and then, renders the inverse problem difficult to handle numerically. Similar problems appear in other areas such as numerical optimization when using interior points algorithms for solving linear programs leads to face ill-conditioned systems of linear equations. Devising efficient solution approaches for such system of equations is therefore of great practical interest. Efficient iterative algorithms are proposed for solving a system of linear equations. The approach is based on a preconditioning of the initial matrix of the system with an approximation of a generalized inverse leading to a stochastic preconditioned matrix. This approach, valid for non-negative matrices, is first extended to hermitian, semi-definite positive matrices and then generalized to any complex rectangular matrices. The main results obtained are as follows: 1) We are able to build a generalized inverse of any complex rectangular matrix which satisfies the convergence condition requested in iterative algorithms for solving a system of linear equations. This completes the (short) list of generalized inverse having this property, after Kaczmarz and Cimmino matrices. Theoretical results on both the characterization of the type of generalized inverse obtained and the convergence are derived. 2) Thanks to its properties, this matrix can be efficiently used in different solving schemes as Richardson-Tanabe or preconditioned conjugate gradients. 3) By using Lp norms, we propose generalized Kaczmarz’s type matrices. We also show how Cimmino's matrix can be considered as a particular case consisting in choosing the Euclidian norm in an asymmetrical structure. 4) Regarding numerical results obtained on some pathological well-known test-cases (Hilbert, Nakasaka, …), some of the proposed algorithms are empirically shown to be more efficient on ill-conditioned problems and more robust to error propagation than the known classical techniques we have tested (Gauss, Moore-Penrose inverse, minimum residue, conjugate gradients, Kaczmarz, Cimmino). We end on a very early prospective application of our approach based on stochastic matrices aiming at computing some parameters (such as the extreme values, the mean, the variance, …) of the solution of a linear system prior to its resolution. Such an approach, if it were to be efficient, would be a source of information on the solution of a system of linear equations.

Keywords: conditioning, generalized inverse, linear system, norms, stochastic matrix

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Authors: Piotr Wadolowski, Grzegorz Krzesinski, Piotr Gutowski

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The aim of the presented work is to recognize the impact of mini-plate application approach on the stress and displacement within the stabilization devices and surrounding bones. The mini-plate osteosynthesis technique is widely used by craniofacial surgeons as an improved replacement of wire connection approach. Many different types of metal plates and screws are used to the physical connection of fractured bones. Below investigation is based on a clinical observation of patient hospitalized with mini-plate stabilization system. Analysis was conducted on a solid mandible geometry, which was modeled basis on the computed tomography scan of the hospitalized patient. In order to achieve most realistic connected system behavior, the cortical and cancellous bone layers were assumed. The temporomandibular joint was simplified to the elastic element to allow physiological movement of loaded bone. The muscles of mastication system were reduced to three pairs, modeled as shell structures. Finite element grid was created by the ANSYS software, where hexahedral and tetrahedral variants of SOLID185 element were used. A set of nonlinear contact conditions were applied on connecting devices and bone common surfaces. Properties of particular contact pair depend on screw - mini-plate connection type and possible gaps between fractured bone around osteosynthesis region. Some of the investigated cases contain prestress introduced to the mini-plate during the application, what responds the initial bending of the connecting device to fit the retromolar fossa region. Assumed bone fracture occurs within the mandible angle zone. Due to the significant deformation of the connecting plate in some of the assembly cases the elastic-plastic model of titanium alloy was assumed. The bone tissues were covered by the orthotropic material. As a loading were used the gauge force of magnitude of 100N applied in three different locations. Conducted analysis shows significant impact of mini-plate application methodology on the stress distribution within the miniplate. Prestress effect introduces additional loading, which leads to locally exceed the titanium alloy yield limit. Stress in surrounding bone increases rapidly around the screws application region, exceeding assumed bone yield limit, what indicate the local bone destruction. Approach with the doubled mini-plate shows increased stress within the connector due to the too rigid connection, where the main path of loading leads through the mini-plates instead of plates and connected bones. Clinical observations confirm more frequent plate destruction of stiffer connections. Some of them could be an effect of decreased low cyclic fatigue capability caused by the overloading. The executed analysis prove that the mini-plate system provides sufficient support to mandible fracture treatment, however, many applicable solutions shifts the entire system to the allowable material limits. The results show that connector application with the initial loading needs to be carefully established due to the small material capability tolerances. Comparison to the clinical observations allows optimizing entire connection to prevent future incidents.

Keywords: mandible fracture, mini-plate connection, numerical analysis, osteosynthesis

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Authors: Feyi Olorunshola

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Over the last few years, the senior travel market has been noted for its potential in the wider tourism industry. The tourism sector includes the hotel and hospitality, travel, transportation, and several other subdivisions to make it economically viable. In particular, the hotel attracts a substantial part of the expenditure in tourism activities as when people plan to travel, suitable accommodation for relaxation, dining, entertainment and so on is paramount to their decision-making. The global retail value of the hotel as of 2018 was significant for tourism. But, despite indications of the hotel to the tourism industry at large, very few empirical studies are available to establish how this sector can leverage on the senior demographic to achieve competitive advantage. Predominantly, studies on the mature market have focused on destination tourism, with a limited investigation on the hotel which makes a significant contribution to tourism. Also, several scholarly studies have demonstrated the importance of the senior travel market to the hotel, yet there is very little empirical research in the field which has explored the driving factors that will become the accepted new normal for this niche segment post-pandemic. Giving that the hotel already operates in a highly saturated business environment, and on top of this pre-existing challenge, the ongoing global health outbreak has further put the sector in a vulnerable position. Therefore, the hotel especially the full-service luxury category must evolve rapidly for it to survive in the current business environment. The hotel can no longer rely on corporate travelers to generate higher revenue since the unprecedented wake of the pandemic in 2020 many organizations have invented a different approach of conducting their businesses online, therefore, the hotel needs to anticipate a significant drop in business travellers. However, the rooms and the rest of the facilities must be occupied to keep their business operating. The way forward for the hotel lies in the leisure sector, but the question now is to focus on the potential demographics of travelers, in this case, the seniors who have been repeatedly recognized as the lucrative market because of increase discretionary income, availability of time and the global population trends. To achieve the study objectives, a mixed-method approach will be utilized drawing on both qualitative (netnography) and quantitative (survey) methods, cognitive and decision-making theories (means-end chain) and competitive theories to identify the salient drivers explaining senior hotel choice and its influence on their decision-making. The target population are repeated seniors’ age 65 years and over who are UK resident, and from the top tourist market to the UK (USA, Germany, and France). Structural equation modelling will be employed to analyze the datasets. The theoretical implication is the development of new concepts using a robust research design, and as well as advancing existing framework to hotel study. Practically, it will provide the hotel management with the latest information to design a competitive marketing strategy and activities to target the mature market post-pandemic and over a long period.

Keywords: competitive advantage, covid-19, full-service hotel, five-star, luxury hotels

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Authors: Ruth Leitch, Joanne Hughes

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This paper presents the findings of a three-year government-funded study (ILiAD) that aimed to understand the reasons for differential educational achievement within and between socially and economically deprived areas in Northern Ireland. Previous international studies have concluded that there is a positive correlation between deprivation and underachievement. Our preliminary secondary data analysis suggested that the factors involved in educational achievement within multiple deprived areas may be more complex than this, with some areas of high multiple deprivation having high levels of student attainment, whereas other less deprived areas demonstrated much lower levels of student attainment, as measured by outcomes on high stakes national tests. The study proposed that no single explanation or disparate set of explanations could easily account for the linkage between levels of deprivation and patterns of educational achievement. Using a social capital perspective that centralizes the connections within and between individuals and social networks in a community as a valuable resource for educational achievement, the ILiAD study involved a multi-level case study analysis of seven community sites in Northern Ireland, selected on the basis of religious composition (housing areas are largely segregated by religious affiliation), measures of multiple deprivation and differentials in educational achievement. The case study approach involved three (interconnecting) levels of qualitative data collection and analysis - what we have termed Micro (or community/grassroots level) understandings, Meso (or school level) explanations and Macro (or policy/structural) factors. The analysis combines a statistical mapping of factors with qualitative, in-depth data interpretation which, together, allow for deeper understandings of the dynamics and contributory factors within and between the case study sites. Thematic analysis of the qualitative data reveals both cross-cutting factors (e.g. demographic shifts and loss of community, place of the school in the community, parental capacity) and analytic case studies of explanatory factors associated with each of the community sites also permit a comparative element. Issues arising from the qualitative analysis are classified either as drivers or inhibitors of educational achievement within and between communities. Key issues that are emerging as inhibitors/drivers to attainment include: the legacy of the community conflict in Northern Ireland, not least in terms of inter-generational stress, related with substance abuse and mental health issues; differing discourses on notions of ‘community’ and ‘achievement’ within/between community sites; inter-agency and intra-agency levels of collaboration and joined-up working; relationship between the home/school/community triad and; school leadership and school ethos. At this stage, the balance of these factors can be conceptualized in terms of bonding social capital (or lack of it) within families, within schools, within each community, within agencies and also bridging social capital between the home/school/community, between different communities and between key statutory and voluntary organisations. The presentation will outline the study rationale, its methodology, present some cross-cutting findings and use an illustrative case study of the findings from a community site to underscore the importance of attending to community differences when trying to engage in research to understand and improve educational attainment for all.

Keywords: educational achievement, multiple deprivation, community case studies, social capital

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Authors: G. Hubert, S. Aubry

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The earth is constantly bombarded by cosmic rays that can be of either galactic or solar origin. Thus, humans are exposed to high levels of galactic radiation due to altitude aircraft. The typical total ambient dose equivalent for a transatlantic flight is about 50 μSv during quiet solar activity. On the contrary, estimations differ by one order of magnitude for the contribution induced by certain solar particle events. Indeed, during Ground Level Enhancements (GLE) event, the Sun can emit particles of sufficient energy and intensity to raise radiation levels on Earth's surface. Analyses of GLE characteristics occurring since 1942 showed that for the worst of them, the dose level is of the order of 1 mSv and more. The largest of these events was observed on February 1956 for which the ambient dose equivalent rate is in the orders of 10 mSv/hr. The extra dose at aircraft altitudes for a flight during this event might have been about 20 mSv, i.e. comparable with the annual limit for aircrew. The most recent GLE, occurred on September 2017 resulting from an X-class solar flare, and it was measured on the surface of both the Earth and Mars using the Radiation Assessment Detector on the Mars Science Laboratory's Curiosity Rover. Recently, Hubert et al. proposed a GLE model included in a particle transport platform (named ATMORAD) describing the extensive air shower characteristics and allowing to assess the ambient dose equivalent. In this approach, the GCR is based on the Force-Field approximation model. The physical description of the Solar Cosmic Ray (i.e. SCR) considers the primary differential rigidity spectrum and the distribution of primary particles at the top of the atmosphere. ATMORAD allows to determine the spectral fluence rate of secondary particles induced by extensive showers, considering altitude range from ground to 45 km. Ambient dose equivalent can be determined using fluence-to-ambient dose equivalent conversion coefficients. The objective of this paper is to analyze the GCR and SCR impacts on ambient dose equivalent considering a high number statistic of world-flight paths. Flight trajectories are based on the Eurocontrol Demand Data Repository (DDR) and consider realistic flight plan with and without regulations or updated with Radar Data from CFMU (Central Flow Management Unit). The final paper will present exhaustive analyses implying solar impacts on ambient dose equivalent level and will propose detailed analyses considering route and airplane characteristics (departure, arrival, continent, airplane type etc.), and the phasing of the solar event. Preliminary results show an important impact of the flight path, particularly the latitude which drives the cutoff rigidity variations. Moreover, dose values vary drastically during GLE events, on the one hand with the route path (latitude, longitude altitude), on the other hand with the phasing of the solar event. Considering the GLE occurred on 23 February 1956, the average ambient dose equivalent evaluated for a flight Paris - New York is around 1.6 mSv, which is relevant to previous works This point highlights the importance of monitoring these solar events and of developing semi-empirical and particle transport method to obtain a reliable calculation of dose levels.

Keywords: cosmic ray, human dose, solar flare, aviation

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Authors: Eiji Nakamachi, Tsuyoshi Eguchi, Sayo Yamamoto, Yusuke Morita, H. Sakamoto

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In this study, we aim to reveal the relationship between the meniscal tearing and the articular cartilage injury of knee joint by using the dynamic explicit finite element (FE) method. Meniscal injuries reduce its functional ability and consequently increase the load on the articular cartilage of knee joint. In order to prevent the induction of osteoarthritis (OA) caused by meniscal injuries, many medical treatment techniques, such as artificial meniscus replacement and meniscal regeneration, have been developed. However, it is reported that these treatments are not the comprehensive methods. In order to reveal the fundamental mechanism of OA induction, the mechanical characterization of meniscus under the condition of normal and injured states is carried out by using FE analyses. At first, a FE model of the human knee joint in the case of normal state – ‘intact’ - was constructed by using the magnetron resonance (MR) tomography images and the image construction code, Materialize Mimics. Next, two types of meniscal injury models with the radial tears of medial and lateral menisci were constructed. In FE analyses, the linear elastic constitutive law was adopted for the femur and tibia bones, the visco-hyperelastic constitutive law for the articular cartilage, and the visco-anisotropic hyperelastic constitutive law for the meniscus, respectively. Material properties of articular cartilage and meniscus were identified using the stress-strain curves obtained by our compressive and the tensile tests. The numerical results under the normal walking condition revealed how and where the maximum compressive stress occurred on the articular cartilage. The maximum compressive stress and its occurrence point were varied in the intact and two meniscal tear models. These compressive stress values can be used to establish the threshold value to cause the pathological change for the diagnosis. In this study, FE analyses of knee joint were carried out to reveal the influence of meniscal injuries on the cartilage injury. The following conclusions are obtained. 1. 3D FE model, which consists femur, tibia, articular cartilage and meniscus was constructed based on MR images of human knee joint. The image processing code, Materialize Mimics was used by using the tetrahedral FE elements. 2. Visco-anisotropic hyperelastic constitutive equation was formulated by adopting the generalized Kelvin model. The material properties of meniscus and articular cartilage were determined by curve fitting with experimental results. 3. Stresses on the articular cartilage and menisci were obtained in cases of the intact and two radial tears of medial and lateral menisci. Through comparison with the case of intact knee joint, two tear models show almost same stress value and higher value than the intact one. It was shown that both meniscal tears induce the stress localization in both medial and lateral regions. It is confirmed that our newly developed FE analysis code has a potential to be a new diagnostic system to evaluate the meniscal damage on the articular cartilage through the mechanical functional assessment.

Keywords: finite element analysis, hyperelastic constitutive law, knee joint injury, meniscal tear, stress concentration

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Authors: Suman Chaudhary, Rupinder K. Kanwar, Jagat R. Kanwar

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Azadirachta indica, also known as Neem belonging to the mahogany family is actively gaining interest in the era of modern day medicine due to its extensive applications in homeopathic medicine such as Ayurveda and Unani. More than 140 phytochemicals have been extracted from neem leaves, seed, bark and flowers for agro-medicinal applications. Among the various components, neem leaf protein (NLP) is currently the most investigated active ingredient, due to its immunomodulatory activities against tumor growth. However, these therapeutic ingredients of neem are susceptible to degradation and cannot withstand the drastic pH changes under physiological environment, and therefore, there is an urgent need of an alternative strategy such as a nano-delivery system to exploit its medicinal benefits. This study hypothesizes that guar gum (GG) derived biodegradable nano-carrier based encapsulation of NLP will improve its stability, specificity and sensitivity, thus facilitating targeted anti-cancer therapeutics. GG is a galactomannan derived from the endosperm of the guar beans seeds. Synthesis of guar nanocapsules (NCs) was performed using nanoprecipitation technique where the GG was encapsulated with NLP. Preliminary experiments conducted to characterize the NCs confirmed spherical morphology with a narrow size distribution of 30-40 nm. Differential scanning colorimetric analysis (DSC) validated the stability of these NCs even at a temperature range of 50-60°C which was well within the physiological and storage conditions. Thermogravimetric (TGA) analysis indicated high decomposition temperature of these NCs ranging upto 350°C. Additionally, Fourier Transform Infrared spectroscopy (FTIR) and the SDS-PAGE data acquired confirmed the successful encapsulation of NLP in the NCs. The anti-cancerous therapeutic property of this NC was tested on colon cancer cells (caco-2) as they are one of the most prevalent form of cancer. These NCs (both NLP loaded and void) were also tested on human intestinal epithelial cells (FHs 74) cells to evaluate their effect on normal cells. Cytotoxicity evaluation of the NCs in the cell lines confirmed that the IC50 for NLP in FHs 74 cells was ~2 fold higher than in caco-2 cells, indicating that this nanoformulation system possessed biocompatible anti-cancerous properties Immunoconfocal microscopy analysis confirmed the time dependent internalization of the NCs within 6h. Recent findings performed using Annexin V and PI staining indicated a significant increase (p ≤ 0.001) in the early and late apoptotic cell population when treated with the NCs signifying the role of NLP in inducing apoptosis in caco-2 cells. This was further validated using Western blot, Polymerase chain reaction (PCR) and Fluorescence activated cell sorter (FACS) aided protein expressional analysis which presented a downregulation of survivin, an anti-apoptotic cell marker and upregulation of Bax/Bcl-2 ratio (pro-apoptotic indicator). Further, both the NLP NC and unencapsulated NLP treatment destabilized the mitochondrial membrane potential subsequently facilitating the release of the pro-apoptotic caspase cascade initiator, cytochrome-c. Future studies will be focused towards granting specificity to these NCs towards cancer cells, along with a comprehensive analysis of the anti-cancer potential of this naturally occurring compound in different cancer and in vivo animal models, will validate the clinical application of this unprecedented protein therapeutic.

Keywords: anti-tumor, guar gum, nanocapsules, neem leaf protein

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Authors: Saif Al Ghafri, Thomas Hughes, Armand Karimi, Kumarini Seneviratne, Jordan Oakley, Michael Johns, Eric F. May

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Knowledge of the thermophysical properties of complex mixtures at extreme conditions of pressure and temperature have always been essential to the Liquefied Natural Gas (LNG) industry’s evolution because of the tremendous technical challenges present at all stages in the supply chain from production to liquefaction to transport. Each stage is designed using predictions of the mixture’s properties, such as density, viscosity, surface tension, heat capacity and phase behaviour as a function of temperature, pressure, and composition. Unfortunately, currently available models lead to equipment over-designs of 15% or more. To achieve better designs that work more effectively and/or over a wider range of conditions, new fundamental property data are essential, both to resolve discrepancies in our current predictive capabilities and to extend them to the higher-pressure conditions characteristic of many new gas fields. Furthermore, innovative experimental techniques are required to measure different thermophysical properties at high pressures and over a wide range of temperatures, including near the mixture’s critical points where gas and liquid become indistinguishable and most existing predictive fluid property models used breakdown. In this work, we present a wide range of experimental measurements made for different binary and ternary mixtures relevant to LNG processing, with a particular focus on viscosity, surface tension, heat capacity, bubble-points and density. For this purpose, customized and specialized apparatus were designed and validated over the temperature range (200 to 423) K at pressures to 35 MPa. The mixtures studied were (CH4 + C3H8), (CH4 + C3H8 + CO2) and (CH4 + C3H8 + C7H16); in the last of these the heptane contents was up to 10 mol %. Viscosity was measured using a vibrating wire apparatus, while mixture densities were obtained by means of a high-pressure magnetic-suspension densimeter and an isochoric cell apparatus; the latter was also used to determine bubble-points. Surface tensions were measured using the capillary rise method in a visual cell, which also enabled the location of the mixture critical point to be determined from observations of critical opalescence. Mixture heat capacities were measured using a customised high-pressure differential scanning calorimeter (DSC). The combined standard relative uncertainties were less than 0.3% for density, 2% for viscosity, 3% for heat capacity and 3 % for surface tension. The extensive experimental data gathered in this work were compared with a variety of different advanced engineering models frequently used for predicting thermophysical properties of mixtures relevant to LNG processing. In many cases the discrepancies between the predictions of different engineering models for these mixtures was large, and the high quality data allowed erroneous but often widely-used models to be identified. The data enable the development of new or improved models, to be implemented in process simulation software, so that the fluid properties needed for equipment and process design can be predicted reliably. This in turn will enable reduced capital and operational expenditure by the LNG industry. The current work also aided the community of scientists working to advance theoretical descriptions of fluid properties by allowing to identify deficiencies in theoretical descriptions and calculations.

Keywords: LNG, thermophysical, viscosity, density, surface tension, heat capacity, bubble points, models

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Authors: Sonia Sassi, Mostapha Tarfaoui, Hamza Benyahia

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Composite materials are increasingly being used as a substitute for metallic materials in many technological applications like aeronautics, aerospace, marine and civil engineering applications. For composite materials, the thermomechanical response evolves with the strain rate. The energy balance equation for anisotropic, elastic materials includes heat source terms that govern the conversion of some of the kinetic work into heat. The remainder contributes to the stored energy creating the damage process in the composite material. In this paper, we investigate the bulk thermomechanical behavior of adhesively-bonded composite assemblies to quantitatively asses the temperature rise which accompanies adiabatic deformations. In particular, adhesively bonded joints in glass/vinylester composite material are subjected to in-plane dynamic loads under a range of strain rates. Dynamic thermomechanical behavior of this material is investigated using compression Split Hopkinson Pressure Bars (SHPB) coupled with a high speed infrared camera and a high speed camera to measure in real time the dynamic behavior, the damage kinetic and the temperature variation in the material. The interest of using high speed IR camera is in order to view in real time the evolution of heat dissipation in the material when damage occurs. But, this technique does not produce thermal values in correlation with the stress-strain curves of composite material because of its high time response in comparison with the dynamic test time. For this reason, the authors revisit the application of specific thermocouples placed on the surface of the material to ensure the real thermal measurements under dynamic loading using small thermocouples. Experiments with dynamically loaded material show that the thermocouples record temperatures values with a short typical rise time as a result of the conversion of kinetic work into heat during compression test. This results show that small thermocouples can be used to provide an important complement to other noncontact techniques such as the high speed infrared camera. Significant temperature rise was observed in in-plane compression tests especially under high strain rates. During the tests, it has been noticed that sudden temperature rise occur when macroscopic damage occur. This rise in temperature is linked to the rate of damage. The more serve the damage is, a higher localized temperature is detected. This shows the strong relationship between the occurrence of damage and induced heat dissipation. For the case of the in plane tests, the damage takes place more abruptly as the strain rate is increased. The difference observed in the obtained thermomechanical response in plane compression is explained only by the difference in the damage process being active during the compression tests. In this study, we highlighted the dependence of the thermomechanical response on the strain rate of bonded specimens. The effect of heat dissipation of this material cannot hence be ignored and should be taken into account when defining damage models during impact loading.

Keywords: adhesively-bonded composite joints, damage, dynamic compression tests, energy balance, heat dissipation, SHPB, thermomechanical behavior

Procedia PDF Downloads 192

Authors: Anushka Naidoo, Veron Ramsuran, Maxwell Chirehwa, Paolo Denti, Kogieleum Naidoo, Helen McIlleron, Nonhlanhla Yende-Zuma, Ravesh Singh, Sinaye Ngcapu, Nesri Padayatachi

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Background: Despite efforts to introduce new drugs and shorter drug regimens for drug-susceptible tuberculosis (TB), the standard first-line treatment has not changed in over 50 years. Rifampicin, isoniazid, and pyrazinamide are critical components of the current standard treatment regimens. Some studies suggest that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic (PK) variability independent of adherence to treatment. Wide between-patient pharmacokinetic variability for rifampin, isoniazid, and pyrazinamide has been reported in prior studies. There may be several reasons for this variability. However, genetic variability in genes coding for drug metabolizing and transporter enzymes have been shown to be a contributing factor for variable tuberculosis drug exposures. Objective: We describe the pharmacokinetics of first-line TB drugs rifampicin, isoniazid, and pyrazinamide and assess the effect of genetic variability in relevant selected drug metabolizing and transporter enzymes on pharmacokinetic parameters of isoniazid and rifampicin. Methods: We conducted the randomized-controlled Improving retreatment success TB trial in Durban, South Africa. The drug regimen included rifampicin, isoniazid, and pyrazinamide. Drug concentrations were measured in plasma, and concentration-time data were analysed using nonlinear-mixed-effects models to quantify the effects of relevant covariates and single nucleotide polymorphisms (SNP’s) of drug metabolizing and transporter genes on rifampicin, isoniazid and pyrazinamide exposure. A total of 25 SNP’s: four NAT2 (used to determine acetylator status), four SLCO1B1, three Pregnane X receptor (NR1), six ABCB1 and eight UGT1A, were selected for analysis in this study. Genotypes were determined for each of the SNP’s using a TaqMan® Genotyping OpenArray™. Results: Among fifty-eight patients studied; 41 (70.7%) were male, 97% black African, 42 (72.4%) HIV co-infected and 40 (95%) on efavirenz-based ART. Median weight, fat-free mass (FFM), and age at baseline were 56.9 kg (interquartile range, IQR: 51.1-65.2), 46.8 kg (IQR: 42.5-50.3) and 37 years (IQR: 31-42), respectively. The pharmacokinetics of rifampicin and pyrazinamide was best described using one-compartment models with first-order absorption and elimination, while for isoniazid two-compartment disposition was used. The median (interquartile range: IQR) AUC (h·mg/L) and Cmax (mg/L) for rifampicin, isoniazid, and pyrazinamide were; 25.62 (23.01-28.53) and 4.85 (4.36-5.40), 10.62 (9.20-12.25) and 2.79 (2.61-2.97), 345.74 (312.03-383.10) and 28.06 (25.01-31.52), respectively. Eighteen percent of patients were classified as rapid acetylators, and 34% and 43% as slow and intermediate acetylators, respectively. Rapid and intermediate acetylator status based on NAT 2 genotype resulted in 2.3 and 1.6 times higher isoniazid clearance than slow acetylators. We found no effects of the SLCO1B1 genotypes on rifampicin pharmacokinetics. Conclusion: Plasma concentrations of rifampicin, isoniazid, and pyrazinamide were low overall in our patients. Isoniazid clearance was high overall and as expected higher in rapid and intermediate acetylators resulting in lower drug exposures. In contrast to reports from previous South African or Ugandan studies, we did not find any effects of the SLCO1B1 or other genotypes tested on rifampicin PK. However, our findings are in keeping with more recent studies from Malawi and India emphasizing the need for geographically diverse and adequately powered studies. The clinical relevance of the low tuberculosis drug concentrations warrants further investigation.

Keywords: rifampicin, isoniazid pharmacokinetics, genetics, NAT2, SLCO1B1, tuberculosis

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Authors: Hasmik V. Zanginyan, Gayane S. Ghazaryan, Laura M. Hovsepyan

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Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system that is induced in laboratory animals by developing an immune response against myelin epitopes. The typical clinical course is ascending palsy, which correlates with inflammation and tissue damage in the thoracolumbar spinal cord, although the optic nerves and brain (especially the subpial white matter and brainstem) are also often affected. With multiple sclerosis, there is a violation of lipid metabolism in myelin. When membrane lipids (glycosphingolipids, phospholipids) are disturbed, metabolites not only play a structural role in membranes but are also sources of secondary mediators that transmit multiple cellular signals. The purpose of this study was to investigate the effect of ganglioside as a therapeutic agent in experimental multiple sclerosis. The biological activity of a ganglioside-containing medicinal preparation (Cronassial) was evaluated in an experimental model of multiple sclerosis in laboratory animals. An experimental model of multiple sclerosis in rats was obtained by immunization with myelin basic protein (MBP), as well as homogenization of the spinal cord or brain. EAE was induced by administering a mixture of an encephalitogenic mixture (EGM) with Complete Freund’s Adjuvant. Mitochondrial fraction was isolated in a medium containing 0,25 M saccharose and 0, 01 M tris buffer, pH - 7,4, by a method of differential centrifugation on a K-24 centrifuge. Glutathione peroxidase activity was assessed by reduction reactions of hydrogen peroxide (H₂O₂) and lipid hydroperoxides (ROOH) in the presence of GSH. LPO activity was assessed by the amount of malondialdehyde (MDA) in the total homogenate and mitochondrial fraction of the spinal cord and brain of control and experimental autoimmune encephalomyelitis rats. MDA was assessed by a reaction with Thiobarbituric acid. For statistical data analysis on PNP, SPSS (Statistical Package for Social Science) package was used. The nature of the distribution of the obtained data was determined by the Kolmogorov-Smirnov criterion. The comparative analysis was performed using a nonparametric Mann-Whitney test. The differences were statistically significant when р ≤ 0,05 or р ≤ 0,01. Correlational analysis was conducted using a nonparametric Spearman test. In the work, refrigeratory centrifuge, spectrophotometer LKB Biochrom ULTROSPECII (Sweden), pH-meter PL-600 mrc (Israel), guanosine, and ATP (Sigma). The study of the process of lipid peroxidation in the total homogenate of the brain and spinal cord in experimental animals revealed an increase in the content of malonic dialdehyde. When applied, Cronassial observed normalization of lipid peroxidation processes. Reactive oxygen species, causing lipid peroxidation processes, can be toxic both for neurons and for oligodendrocytes that form myelin, causing a violation of their lipid composition. The high content of lipids in the brain and the uniqueness of their structure determines the nature of the development of LPO processes. The lipid layer of cellular and intracellular membranes performs two main functions -barrier and matrix (structural). Damage to the barrier leads to dysregulation of intracellular processes and severe disorders of cellular functions.

Keywords: experimental autoimmune encephalomyelitis, multiple sclerosis, neuroinflammation, therapy

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Authors: J. Desbrieres, M. Popa, C. Peptu, S. Bacaita

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Because of their favorable properties (non-toxicity, biodegradability, mucoadhesivity etc.), polysaccharides were studied as biomaterials and as pharmaceutical excipients in drug formulations. These formulations may be produced in a wide variety of forms including hydrogels, hydrogel based particles (or capsules), films etc. In these formulations, the polysaccharide based materials are able to provide local delivery of loaded therapeutic agents but their delivery can be rapid and not easily time-controllable due to, particularly, the burst effect. This leads to a loss in drug efficiency and lifetime. To overcome the consequences of burst effect, systems involving liposomes incorporated into polysaccharide hydrogels may appear as a promising material in tissue engineering, regenerative medicine and drug loading systems. Liposomes are spherical self-closed structures, composed of curved lipid bilayers, which enclose part of the surrounding solvent into their structure. The simplicity of production, their biocompatibility, the size and similar composition of cells, the possibility of size adjustment for specific applications, the ability of hydrophilic or/and hydrophobic drug loading make them a revolutionary tool in nanomedicine and biomedical domain. Drug delivery systems were developed as hydrogels containing chitosan or carboxymethylcellulose (CMC) as polysaccharides and gelatin (GEL) as polypeptide, and phosphatidylcholine or phosphatidylcholine/cholesterol liposomes able to accurately control this delivery, without any burst effect. Hydrogels based on CMC were covalently crosslinked using glutaraldehyde, whereas chitosan based hydrogels were double crosslinked (ionically using sodium tripolyphosphate or sodium sulphate and covalently using glutaraldehyde). It has been proven that the liposome integrity is highly protected during the crosslinking procedure for the formation of the film network. Calcein was used as model active matter for delivery experiments. Multi-Lamellar vesicles (MLV) and Small Uni-Lamellar Vesicles (SUV) were prepared and compared. The liposomes are well distributed throughout the whole area of the film, and the vesicle distribution is equivalent (for both types of liposomes evaluated) on the film surface as well as deeper (100 microns) in the film matrix. An obvious decrease of the burst effect was observed in presence of liposomes as well as a uniform increase of calcein release that continues even at large time scales. Liposomes act as an extra barrier for calcein release. Systems containing MLVs release higher amounts of calcein compared to systems containing SUVs, although these liposomes are more stable in the matrix and diffuse with difficulty. This difference comes from the higher quantity of calcein present within the MLV in relation with their size. Modeling of release kinetics curves was performed and the release of hydrophilic drugs may be described by a multi-scale mechanism characterized by four distinct phases, each of them being characterized by a different kinetics model (Higuchi equation, Korsmeyer-Peppas model etc.). Knowledge of such models will be a very interesting tool for designing new formulations for tissue engineering, regenerative medicine and drug delivery systems.

Keywords: controlled and delayed release, hydrogels, liposomes, polysaccharides

Procedia PDF Downloads 198