Search results for: Mengmeng Xiao

Authors: Xiao-Yan Li, Takashi Hashimoto, Guanhong Li, Shuo Yang

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In Japanese, onomatopoeia is an important element in the lively expression of feelings and experiences. It is very difficult for students of Japanese to acquire onomatopoeia, especially, its nuances. In this paper, based on traditional L2 learning theories, we propose a new method to improve the efficiency of teaching the nuances – both explicit and tacit - to non-native speakers of Japanese. The method for teaching the tacit nuances of onomatopoeia consists of three elements. First is to teach the formal rules representing the explicit nuances of onomatopoeic words. Second is to have the students create new onomatopoeic words by utilizing those formal rules. The last element is to provide feedback by evaluating the onomatopoeias created. Our previous study used five-grade relative estimation. However students were confused about the five-grade system, because they could not understand the evaluation criteria only based on a figure. In this new system, then, we built an evaluation database through native speakers’ narrative interpretation. We asked Japanese native speakers to describe their awareness of the nuances of onomatopoeia in writing. Then they voted on site and defined priorities for showing to learners on the system. To verify the effectiveness of the proposed method and the learning system, we conducted a preliminary experiment involving two groups of subjects. While Group A got feedback about the appropriateness of their onomatopoeic constructions from the native speakers’ narrative interpretation, Group B got feedback just in the form of the five-grade relative estimation. A questionnaire survey administered to all of the learners clarified our learning system availability and also identified areas that should be improved. Repetitive learning of word-formation rules, creating new onomatopoeias and gaining new awareness from narrative interpretation is the total process used to teach the explicit and tacit nuances of onomatopoeia.

Keywords: onomatopoeia, tacit nuance, narrative interpretation, e-learning system, second language teaching

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Authors: Irshad Ali Khan, Jian-Ping Lu, Xiao-Hong Liu, Fu-Cheng Lin

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This study reports the functional analysis of a gene MoNUC1 in M. oryzae, which is homologous to the Saccharomyces cerevisiae NUC1 encoding a mitochondrial nuclease protein. The MoNUC1 having a gene locus MGG_05324 is 1002-bp in length and encodes an identical protein of 333 amino acids. We disrupted the gene through gene disruption strategy and isolated two mutants confirmed by southern blotting. The deleted mutants were then used for phenotypic studies and their phenotypes were compared to those of the Guy-11 strain. The mutants were first grown on CM medium to find the effect of MoNUC1 gene disruption on colony growth and the mutants were found to show normal culture colony growth similar to that of the Guy-11 strain. Conidial germination and appressorial formation were also similar in both the mutants and Guy-11 strains showing that this gene plays no significant role in these phenotypes. For pathogenicity, the mutants and Guy-11 mycelium blocks were inoculated on blast susceptible barley seedlings and it was found that both the strains exhibited full pathogenicity showing coalesced and necrotic blast lesions suggesting that this gene is not involved in pathogenicity. Mating of the mutants with 2539 strain formed numerous perithecia showing that MoNUC1 is not essential for sexual reproduction in M. oryzae. However, the mutants were found to form reduced conidia (1.06±8.03B and 1.08±9.80B) than those of the Guy-11 strain (1.46±10.61A) and we conclude that this protein is not required for the blast fungus to cause pathogenicity but plays significant role in conidiation. Proteins of signal transduction pathways that could be disrupted/ intervened genetically or chemically could lead to antifungal products of important fungal cereal diseases and reduce rice yield losses. Tipping the balance toward understanding the whole of pathogenesis, rather than simply conidiation will take some time, but clearly presents the most exciting challenge of all.

Keywords: appressorium formation, conidiation, NUC1, Magnaporthe oryzae, pathogenicity

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Authors: Haider Al-Zubaidy, Xiao-Ling Zhao, Riadh Al-Mahaidi

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In recent years, the technique adhesively-bonded fibre reinforced polymer (FRP) composites has found its way into civil engineering applications and it has attracted a widespread attention as a viable alternative strategy for the retrofitting of civil infrastructure such as bridges and buildings. When adopting this method, adhesive has a significant role and controls the general performance and degree of enhancement of the strengthened and/or upgraded structures. This is because the ultimate member strength is highly affected by the failure mode which is considerably dependent on the utilised adhesive. This paper concerns with experimental investigations on the effect of the adhesive used on the bond between CFRP patch and steel plate under medium impact tensile loading. Experiment were conducted using double strap joints and these samples were prepared using two different types of adhesives, Araldite 420 and MBrace saturant. Drop mass rig was used to carry out dynamic tests at impact speeds of 3.35, 4.43 and m/s while quasi-static tests were implemented at 2mm/min using Instrone machine. In this test program, ultimate load-carrying capacity and failure modes were examined for all loading speeds. For both static and dynamic tests, the adhesive type has a significant effect on ultimate joint strength. It was found that the double strap joints prepared using Araldite 420 showed higher strength than those prepared utilising MBrace saturant adhesive. Failure mechanism for joints prepared using Araldite 420 is completely different from those samples prepared utilising MBrace saturant. CFRP failure is the most common failure pattern for joints with Araldite 420, whereas the dominant failure for joints with MBrace saturant adhesive is adhesive failure.

Keywords: CFRP/steel double strap joints, adhesives of different ductility, dynamic tensile loading, bond between CFRP and steel

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Authors: Lanlan Xiao, Yang Liu, Shuo Chen, Bingmei Fu

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Most cancer-related deaths are due to metastasis. Metastasis is a complex, multistep processes including the detachment of cancer cells from the primary tumor and the migration to distant targeted organs through blood and/or lymphatic circulations. During hematogenous metastasis, the emigration of tumor cells from the blood stream through the vascular wall into the tissue involves arrest in the microvasculature, adhesion to the endothelial cells forming the microvessel wall and transmigration to the tissue through the endothelial barrier termed as extravasation. The narrow slit between endothelial cells that line the microvessel wall is the principal pathway for tumor cell extravasation to the surrounding tissue. To understand this crucial step for tumor hematogenous metastasis, we used Dissipative Particle Dynamics method to investigate an individual cell passing through a narrow slit numerically. The cell membrane was simulated by a spring-based network model which can separate the internal cytoplasm and surrounding fluid. The effects of the cell elasticity, cell shape and cell surface area increase, and slit size on the cell transmigration through the slit were investigated. Under a fixed driven force, the cell with higher elasticity can be elongated more and pass faster through the slit. When the slit width decreases to 2/3 of the cell diameter, the spherical cell becomes jammed despite reducing its elasticity modulus by 10 times. However, transforming the cell from a spherical to ellipsoidal shape and increasing the cell surface area only by 3% can enable the cell to pass the narrow slit. Therefore the cell shape and surface area increase play a more important role than the cell elasticity in cell passing through the narrow slit. In addition, the simulation results indicate that the cell migration velocity decreases during entry but increases during exit of the slit, which is qualitatively in agreement with the experimental observation.

Keywords: dissipative particle dynamics, deformability, surface area increase, cell migration

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Authors: Adefarati Oloruntoba, Yongmin Zhang, Hongliang Xiao

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An annular fluidized bed (AFB) is gaining extensive application in the process industry due to its efficient gas-solids contacting. But a direct evaluation of its reaction performance is still lacking. In this paper, comparative 3D Euler–Lagrange multiphase-particle-in-cell (MP-PIC) computations are performed to assess the reaction performance of AFB relative to a bubbling fluidized bed (BFB) in an FCC regeneration process. By using the energy-minimization multi-scale (EMMS) drag model with a suitable heterogeneity index, the MP-PIC simulation predicts the typical fountain region in AFB and solids holdup of BFB, which is consistent with an experiment. Coke combustion rate, flue gas and temperature profile are utilized as the performance indicators, while related bed hydrodynamics are explored to account for the different performance under varying superficial gas velocities (0.5 m/s, 0.6 m/s, and 0.7 m/s). Simulation results indicate that the burning rates of coke and its species are relatively the same in both beds, albeit marginal increase in BFB. Similarly, the shape and evolution time of flue gas (CO, CO₂, H₂O and O₂) curves are indistinguishable but match the coke combustion rates. However, AFB has high proclivity to high temperature-gradient as higher gas and solids temperatures are predicted in the freeboard. Moreover, for both beds, the effect of superficial gas velocity is only conspicuous on the temperature but negligible on combustion efficiency and effluent gas emissions due to constant gas volumetric flow rate and bed loading criteria. Cross-flow of solids from the annulus to the spout region as well as the high primary gas in the AFB directly assume the underlying mechanisms for its unique gas-solids hydrodynamics (pressure, solids holdup, velocity, mass flux) and local spatial homogeneity, which in turn influence the reactor performance. Overall, the study portrays AFB as a cheap alternative reactor to BFB for catalyst regeneration.

Keywords: annular fluidized bed, bubbling fluidized bed, coke combustion, flue gas, fountaining, CFD, MP-PIC, hydrodynamics, FCC regeneration

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Authors: Xiao Wen Xu

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There exists a challenge of accommodating/integrating people at risk and those from various backgrounds in urban areas. The success of interdependence as a tool for survival largely rests on the mutually beneficial relationships amongst individuals within a given society. One approach to meeting this challenge has been written by Ivan Illich in his book, Tools for Conviviality, where he defines 'conviviality' as interactions that help individuals. With the goal of helping the community and applying conviviality as a principle to actors in both natural and social realms of Moss Park in Toronto, the proposal involves redesigning the park and buildings as a series of different health care, extended learning, employment support, armoury, and recreation facilities that integrate the exterior landscape as treatment, teaching, military, and recreation areas; in other words, the proposal links services with access to park space. While buildings are traditionally known to physically provide shelter, parks embody shelter and act as service, as people often find comfort and relief from being in nature, and Moss Park, in particular, is home to many people at risk. This landscape is not only an important space for the homeless community but also the rest of the neighborhood. The thesis proposes that the federal government rebuilds the current armoury, as it is an obsolete building while acknowledging the extensive future developments proposed by developers and its impact on public space. The neighbourhood is an underserved area, and the new design develops not just a new armoury, but also a complex of interrelated services, which are completely integrated into the park. The armoury is redesigned as an integral component of the community that not only serves as training facilities for reservists but also serves as an emergency shelter in sub-zero temperatures for the homeless community. This paper proposes a new design for Moss Park through examining how 'park buildings', interconnected buildings and parks, can foster empowering relationships that create a supportive public realm.

Keywords: conviviality, natural, social, Ivan Illich

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Authors: Ningfei Xiao, Simon Twose, Hannah Hopewell

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In urban settings worldwide, artists and researchers have drawn from shamanic healing, providing insightful responses to the environment. This project is a transdisciplinary creative research project where architecture and art practice draw from shamanic healing and provide the potential to expand knowledge of public space and inspire more aesthetic explorations of public spatial visions. The research started from the encounters with the Ewengki/Evenki shaman tribe in settlement areas of northern China in 2019 and extended through the partnerships with Maori artists in Poneke Aotearoa, New Zealand, in 2023. Based on the learnings and collaborations with female indigenous tradition practitioners and the healing that the researcher received from the land, a spatial installation exhibition was developed in this project. Indigenous practices are intricately woven with contemporary technology, merging visuals, soundscapes, and other non-visual aesthetics influenced by the researcher's personal experiences of embodied shamanic healing with brainwave generative technology. This synthesis seeks to ritualize and reimagine future public spaces, encompassing streetscapes and greenscapes from China to Aotearoa, and fostering connections between urbanized human body, mind, spirit, and land. In doing so, the project presents a feminist posthuman inquiry into how individuals perceive materiality within the context of a future city. Grounded in creative research and embodied methodologies, this paper focuses on the conceptual and autoethnographic aspects of visual-non-visual aesthetics and their creative representation. Through the exploration of aesthetics beyond the visual realm within urban and spatial contexts, this project showcases the spatial installation exhibition as an example of shamanic influence and related response to public space through embodied artistry and transdisciplinary creative inquiry.

Keywords: aesthetic, embodiment, visual and/or non-visual, spatial installation, shamanic healing, public space

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Authors: Xiao Yang, Ji Zhang, Yingli Song, Hui Huang, Jing Zhang, Yan Wang, Rongrong Han, Zhixuan Xiang, Lu Chen, Lingling Gao

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Aim and Objectives: To examine physical activity self-efficacy, identify its predictors, and further explore the mechanism of action among the predictors in mainland Chinese pregnant women with high risk for gestational diabetes mellitus (GDM). Background: Physical activity could protect pregnant women from developing GDM. Physical activity self-efficacy was the key predictor of physical activity. Design: A cross-sectional study was conducted from October 2021 to May 2022 in Zhengzhou, China. Methods: 252 eligible pregnant women completed the Pregnancy Physical Activity Self-efficacy Scale, the Social Support for Physical Activity Scale, the Knowledge on Physical Activity Questionnaire, the 7-item Generalized Anxiety Disorder scale, the Edinburgh Postnatal Depression Scale, and a socio-demographic data sheet. Multiple linear regression was applied to explore the predictors of physical activity self-efficacy. Structural equation modeling was used to explore the mechanism of action among the predictors. Results: Chinese pregnant women with a high risk for GDM reported a moderate level of physical activity self-efficacy. The best-fit regression analysis revealed four variables explained 17.5% of the variance in physical activity self-efficacy. Social support for physical activity was the strongest predictor, followed by knowledge of the physical activity, intention to do physical activity, and anxiety symptoms. The model analysis indicated that knowledge of physical activity could release anxiety and depressive symptoms and then increase physical activity self-efficacy. Conclusion: The present study revealed a moderate level of physical activity self-efficacy. Interventions targeting pregnant women with high risk for GDM need to include the predictors of physical activity self-efficacy. Relevance to clinical practice: To facilitate pregnant women with high risk for GDM to engage in physical activity, healthcare professionals may find assess physical activity self-efficacy and intervene as soon as possible on their first antenatal visit. Physical activity intervention programs focused on self-efficacy may be conducted in further research.

Keywords: physical activity, gestational diabetes, self-efficacy, predictors

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Authors: Xiao Chen, Alice Ho, Mabel Tie, Xiaoheng Xu

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Background and Significance of the Study: School-enterprise cooperation has been the cornerstone of vocational education in China and many other countries. Researchers and policymakers have paid much attention to ensuring the implementation and improving the quality of school-enterprise cooperation. However, many problems still exist on the implementation level of the cooperation. On the one hand, the enterprises lack the motivation to participate in the cooperation. On the other hand, there is a lack of effective guidance and management during the cooperation. Furthermore, the current literature focuses greatly on policy recommendations on the national level while failing to provide a detailed practical understanding of how school-enterprise cooperation is carried out on the ground level. With emerging social problems, such as the aging population in China, there is an increasing need for diverse nursing services and better nursing quality. Methodology: To gain a deeper understanding of the influencing factors of the implementation of school-enterprise cooperation, this work conducted 37 exploratory interviews in four Chinese cities spanning first-tier to fourth-tier cities with hospital department directors, vocational school deans, nurses, and vocational students. Multiple critical policy documents that founded the current vocational education system in China were analyzed, along with the data collected from the interviews. Major Findings: Based on the policy and interview analyses, this work reveals a set of influencing factors for school-enterprise cooperation implementation. Findings from each region contribute to an overall model of influencing factors for implementing school-enterprise cooperation in vocational nursing education in China, which leads to practical insights for policy recommendation. The key influencing factors are found based on the policy, hospital, school, and social levels. Following practical policy recommendations were presented. Moving forward, further research on the implementation of school-enterprise cooperation in specific industries will become increasingly critical to improving the effectiveness of educational policies and the quality of vocational education.

Keywords: nursing, policy recommendation, school-enterprise cooperation, vocational education

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Authors: Qunying Yuan, Manjula Bomma, Adrian Rhoden, Zhigang Xiao

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Selenium is an essential micronutrient for all mammals and plays an important role in maintaining human physiological functions. The potential applications of selenium as food supplements, cancer-prevention, antimicrobial and anti-inflammatory agents have been investigated in biomedicine and food sciences. Nanoscale of selenium is of particular interest due to its better biocompatibility, higher bioavailability, lower toxicity, more homogeneous distribution, and presumptive controlled release of substances. The objective of this study is to explore whether selenium nanoparticle (SeNP) has the potential to be used as a food preservative to reduce food spoilage. SeNPs were synthesized through ascorbic acid reduction of sodium selenite using the bovine serum albumin (BSA) as capping and stabilizing agent. The chemically synthesized SeNPs had a spherical conformation and a size of 22.8 ± 4.7 nm. FTIR analysis confirmed that the nanoparticles were covered with BSA. We further tested the antimicrobial activity of these SeNPs against common food-borne bacteria. Colony forming unit assay showed that SeNPs exhibited good inhibition on the growth of Listeria Monocytogens (ATCC15313), Staphylococcus epidermidis (ATCC 700583) starting at 0.5µg/mL, but only a moderate inhibitory effect on the growth of Staphylococcus aureus (ATCC12600) and Vibrio alginolyticus (ATCC 33787) at a concentration higher than 10µg/mL and 2.5µg/mL, respectively. There was a mild effect against the growth Salmonella enterica (ATCC19585) when the concentration reached 15µg/mL. No inhibition was observed in the growth of Enterococcus faecalis (ATCC 19433). Surprisingly, SeNPs appeared to promote the growth of Vibrio parahaemolyticus (ATCC43996) and Salmonella enterica (ATCC49284) at 30 µg/mL and above. Our preliminary data suggested that the chemically synthesized SeNPs may be able to inhibit some food-borne bacteria, and SeNP as a food preservative should be used with caution. We will explore the mechanisms of the inhibitory action of chemically synthesized SeNPs on bacterial growth and whether the SeNPs are able to inhibit the development of biofilm and antibiotic resistance.

Keywords: antimicrobial, food-borne bacteria, nanoparticles, selenium

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Authors: Kan Yu, Khui Hung Lee, Eben Afrifa-Yamoah, Jing Guo, Katrina Harrison, Jack Goldblatt, Nicholas Pachter, Jitian Xiao, Guicheng Brad Zhang

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Background and Significance of the Study: Congenital Heart Defects (CHDs) are the most common malformation at birth and one of the leading causes of infant death. Although the exact etiology remains a significant challenge, epigenetic modifications, such as DNA methylation, are thought to contribute to the pathogenesis of congenital heart defects. At present, no existing DNA methylation biomarkers are used for early detection of CHDs. The existing CHD diagnostic techniques are time-consuming and costly and can only be used to diagnose CHDs after an infant was born. The present study employed a machine learning technique to analyse genome-wide methylation data in children with and without CHDs with the aim to find methylation biomarkers for CHDs. Methods: The Illumina Human Methylation EPIC BeadChip was used to screen the genome‐wide DNA methylation profiles of 24 infants diagnosed with congenital heart defects and 24 healthy infants without congenital heart defects. Primary pre-processing was conducted by using RnBeads and limma packages. The methylation levels of top 600 genes with the lowest p-value were selected and further investigated by using a random forest approach. ROC curves were used to analyse the sensitivity and specificity of each biomarker in both training and test sample sets. The functionalities of selected genes with high sensitivity and specificity were then assessed in molecular processes. Major Findings of the Study: Three genes (MIR663, FGF3, and FAM64A) were identified from both training and validating data by random forests with an average sensitivity and specificity of 85% and 95%. GO analyses for the top 600 genes showed that these putative differentially methylated genes were primarily associated with regulation of lipid metabolic process, protein-containing complex localization, and Notch signalling pathway. The present findings highlight that aberrant DNA methylation may play a significant role in the pathogenesis of congenital heart defects.

Keywords: biomarker, congenital heart defects, DNA methylation, random forest

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Authors: Jin Liang, James H. Liu, Ti-Jun Xiao

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It is known that there exist many physical phenomena where abrupt or impulsive changes occur either in the system dynamics, for example, ad-hoc network, or in the input forces containing impacts, for example, the bombardment of space antenna by micrometeorites. There are many other examples such as ultra high-speed optical signals over communication networks, the collision of particles, inventory control, government decisions, interest changes, changes in stock price, etc. These are impulsive phenomena. Hence, as a combination of the traditional initial value problems and the short-term perturbations whose duration can be negligible in comparison with the duration of the process, the systems with impulsive conditions (i.e., impulsive systems) are more realistic models for describing the impulsive phenomenon. Such a situation is also suitable for the delay systems, which include some of the past states of the system. So far, there have been a lot of research results in the study of impulsive systems with delay both in finite and infinite dimensional spaces. In this paper, we investigate the periodicity of solutions to the nonautonomous impulsive evolution equations with infinite delay in Banach spaces, where the coefficient operators (possibly unbounded) in the linear part depend on the time, which are impulsive systems in infinite dimensional spaces and come from the optimal control theory. It was indicated that the study of periodic solutions for these impulsive evolution equations with infinite delay was challenging because the fixed point theorems requiring some compactness conditions are not applicable to them due to the impulsive condition and the infinite delay. We are happy to report that after detailed analysis, we are able to combine the techniques developed in our previous papers, and some new ideas in this paper, to attack these impulsive evolution equations and derive periodic solutions. More specifically, by virtue of the related transition operator family (evolution family), we present a Poincaré operator given by the nonautonomous impulsive evolution system with infinite delay, and then show that the operator is a condensing operator with respect to Kuratowski's measure of non-compactness in a phase space by using an Amann's lemma. Finally, we derive periodic solutions from bounded solutions in view of the Sadovskii fixed point theorem. We also present a relationship between the boundedness and the periodicity of the solutions of the nonautonomous impulsive evolution system. The new results obtained here extend some earlier results in this area for evolution equations without impulsive conditions or without infinite delay.

Keywords: impulsive, nonautonomous evolution equation, optimal control, periodic solution

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Authors: Abdul Ghaffar Memon, Xiao Hong Zhou, Yunpeng Xing, Ruoyu Wang, Miao He

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Due to deleterious environmental and health effects of the Hg²⁺ ions, various online, detection methods apart from the traditional analytical tools have been developed by researchers. Biosensors especially, label, label-free, colorimetric and optical sensors have advanced with sensitive detection. However, there remains a gap of ultrasensitive quantification as noise interact significantly especially in the AuNP based label-free colorimetry. This study reported an amplification strategy using Exo-III enzyme for target recycling of Hg²⁺ ions in a T-rich hairpin loop metallobase label-free colorimetric nanosensor with an improved sensitivity using unmodified gold nanoparticles (uGNPs) as an indicator. The two T-rich metallobase hairpin loop structures as 5’- CTT TCA TAC ATA GAA AAT GTA TGT TTG -3 (HgS1), and 5’- GGC TTT GAG CGC TAA GAA A TA GCG CTC TTT G -3’ (HgS2) were tested in the study. The thermodynamic properties of HgS1 and HgS2 were calculated using online tools (http://biophysics.idtdna.com/cgi-bin/meltCalculator.cgi). The lab scale synthesized uGNPs were utilized in the analysis. The DNA sequence had T-rich bases on both tails end, which in the presence of Hg²⁺ forms a T-Hg²⁺-T mismatch, promoting the formation of dsDNA. Later, the Exo-III incubation enable the enzyme to cleave stepwise mononucleotides from the 3’ end until the structure become single-stranded. These ssDNA fragments then adsorb on the surface of AuNPs in their presence and protect AuNPs from the induced salt aggregation. The visible change in color from blue (aggregation stage in the absence of Hg²⁺) and pink (dispersion state in the presence of Hg²⁺ and adsorption of ssDNA fragments) can be observed and analyzed through UV spectrometry. An ultrasensitive quantitative nanosensor employing Exo-III assisted target recycling of mercury ions through label-free colorimetry with nanomolar detection using uGNPs have been achieved and is further under the optimization to achieve picomolar range by avoiding the influence of the environmental matrix. The proposed strategy will supplement in the direction of uGNP based ultrasensitive, rapid, onsite, label-free colorimetric detection.

Keywords: colorimetric, Exo-III, gold nanoparticles, Hg²⁺ detection, label-free, signal amplification

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Authors: Yahoel Van Essen, Gordon Ho, Brett Russell, Hans-Georg Worms, Xiao Lin Long, Edward David Cooper, Avner Bachar

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Weeds reduce farm and forest productivity, invade crops, smother pastures and some can harm livestock. Farmers need to spend a significant amount of money to control weeds by means of biological, chemical, cultural, and physical methods. To solve the global agricultural labor shortage and remove poisonous chemicals, a fully autonomous, eco-friendly, and sustainable weeding technology is developed. This takes the form of a weeding robot, ‘Roboweeder’. Roboweeder includes a four-wheel-drive self-driving vehicle, a 4-DOF robotic arm which is mounted on top of the vehicle, an electromagnetic wave generator (magnetron) which is mounted on the “wrist” of the robotic arm, 48V battery packs, and a control/communication system. Cameras are mounted on the front and two sides of the vehicle. Using image processing and recognition, distinguish types of weeds are detected before being eliminated. The electromagnetic wave technology is applied to heat the individual weeds and clusters dielectrically causing them to wilt and die. The 4-DOF robotic arm was modeled mathematically based on its structure/mechanics, each joint’s load, brushless DC motor and worm gear’ characteristics, forward kinematics, and inverse kinematics. The Proportional-Integral-Differential control algorithm is used to control the robotic arm’s motion to ensure the waveguide aperture pointing to the detected weeds. GPS and machine vision are used to traverse the farm and avoid obstacles without the need of supervision. A Roboweeder prototype has been built. Multiple test trials show that Roboweeder is able to detect, point, and kill the pre-defined weeds successfully although further improvements are needed, such as reducing the “weeds killing” time and developing a new waveguide with a smaller waveguide aperture to avoid killing crops surrounded. This technology changes the tedious, time consuming and expensive weeding processes, and allows farmers to grow more, go organic, and eliminate operational headaches. A patent of this technology is pending.

Keywords: autonomous navigation, machine vision, precision heating, sustainable and eco-friendly

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Authors: Wanru Huang, Fujun Wang, Chaoyue Wang, Yuan Tang, Zhifeng Yao, Ruofu Xiao, Xin Chen

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Rotating stall in centrifugal pump is an unsteady flow phenomenon that causes instabilities and high hydraulic losses. It typically occurs at low flow rates due to large flow separation in impeller blade passage. In order to reveal the influence of incoming flow conditions on rotating stall in centrifugal pump, a numerical method for investigating rotating stall was established. This method is based on a modified SST k-ω turbulence model and a fine mesh model was adopted. The calculated flow velocity in impeller by this method was in good agreement with PIV results. The effects of flow rate and sealing-ring leakage on stall characteristics of centrifugal pump were studied by using the proposed numerical approach. The flow structures in impeller under typical flow rates and typical sealing-ring leakages were analyzed. It is found that the stall vortex frequency and circumferential propagation velocity increase as flow rate decreases. With the flow rate decreases from 0.40Qd to 0.30Qd, the stall vortex frequency increases from 1.50Hz to 2.34Hz, the circumferential propagation velocity of the stall vortex increases from 3.14rad/s to 4.90rad/s. Under almost all flow rate conditions where rotating stall is present, there is low frequency of pressure pulsation between 0Hz-5Hz. The corresponding pressure pulsation amplitude increases with flow rate decreases. Taking the measuring point at the leading edge of the blade pressure surface as an example, the flow rate decreases from 0.40Qd to 0.30Qd, the pressure fluctuation amplitude increases by 86.9%. With the increase of leakage, the flow structure in the impeller becomes more complex, and the 8-shaped stall vortex is no longer stable. On the basis of the 8-shaped stall vortex, new vortex nuclei are constantly generated and fused with the original vortex nuclei under large leakage. The upstream and downstream vortex structures of the 8-shaped stall vortex have different degrees of swimming in the flow passage, and the downstream vortex swimming is more obvious. The results show that the proposed numerical approach could capture the detail vortex characteristics, and the incoming flow conditions have significant effects on the stall vortex in centrifugal pumps.

Keywords: centrifugal pump, rotating stall, numerical simulation, flow condition, vortex frequency

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Authors: Xiao-Hua Zhu, Xin Yuan, Yi-Ran Zhao

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High-cadmium pollution in rice is a serious problem in many parts of China. Many kinds of remediation technologies have been tested and applied in many farmlands. Because of the productive function of the farmland, most technologies are inappropriate due to their destruction to the tillage soil layer. And the large labours and expensive fees of many technologies are also the restrictive factors for their applications. The conception of 'Root Micro-Geochemical Barrier' was proposed to reduce cadmium (Cd) bioavailability and the concentration of the cadmium in rice. Remediation and mitigation techniques were demonstrated on contaminated farmland in the downstream of some mine. According to the rule of rice growth, Cd would be absorbed by the crops in every growth stage, and the plant-absorb efficiency in the first stage of the tillering stage is almost the highest. We should create a method to protect the crops from heavy metal pollution, which could begin to work from the early growth stage. Many materials with repair property get our attention. The materials will create a barrier preventing Cd from being absorbed by the crops during all the growing process because the material has the ability to adsorb soil-Cd and making it losing its migration activity. And we should choose a good chance to put the materials into the crop-growing system cheaply as soon as early. Per plant, rice has a little root system scope, which makes the roots reach about 15cm deep and 15cm wide. So small root radiation area makes it possible for all the Cd approaching the roots to be adsorbed with a small amount of adsorbent. Mixing the remediation materials with the seed-raising soli and adding them to the tillage soil in the process of transplanting seedlings, we can control the soil-Cd activity in the range of roots to reduce the Cd-amount absorbed by the crops. Of course, the mineral materials must have enough adsorptive capacity and no additional pollution. More than 3000 square meters farmlands have been remediated. And on the application of root micro-geochemical barrier, the Cd-concentration in rice and the remediation-cost have been decreased by 90% and 80%, respectively, with little extra labour brought to the farmers. The Cd-concentrations in rice from remediated farmland have been controlled below 0.1 ppm. The remediation of one acre of contaminated cropland costs less than $100. The concept has its advantage in the remediation of paddy field contaminated by Cd, especially for the field with outside pollution sources.

Keywords: cadmium pollution, growth stage, cost, root micro-geochemistry barrier

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Authors: Bi Xiao Fang, Tan Bao Zhen

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Soft skills, core competencies, and generic competencies are exchangeable terminologies often used to represent a similar concept. In the Singapore context, such skills are currently being referred to as Critical Core Skills (CCS). In 2019, SkillsFuture Singapore (SSG) reviewed the Generic Skills and Competencies (GSC) framework that was first introduced in 2016, culminating in the development of the Critical Core Skills (CCS) framework comprising 16 soft skills classified into three clusters. The CCS framework is part of the Skills Framework, and whose stated purpose is to create a common skills language for individuals, employers and training providers. It is also developed with the objectives of building deep skills for a lean workforce, enhance business competitiveness and support employment and employability. This further helps to facilitate skills recognition and support the design of training programs for skills and career development. According to SSG, every job role requires a set of technical skills and a set of Critical Core Skills to perform well at work, whereby technical skills refer to skills required to perform key tasks of the job. There has been an increasing emphasis on soft skills for the future of work. A recent study involving approximately 80 organizations across 28 sectors in Singapore revealed that more enterprises are beginning to recognize that soft skills support their employees’ performance and business competitiveness. Though CCS is of high importance for the development of the workforce’s employability, there is little attention paid to the CCS use and profiling across occupations. A better understanding of how CCS is distributed across the economy will thus significantly enhance SSG’s career guidance services as well as training providers’ services to graduates and workers and guide organizations in their hiring for soft skills. This CCS profiling study sought to understand how CCS is demanded in different occupations. To achieve its research objectives, this study adopted a quantitative method to measure CCS use across different occupations in the Singaporean workforce. Based on the CCS framework developed by SSG, the research team adopted a formative approach to developing the CCS profiling tool to measure the importance of and self-efficacy in the use of CCS among the Singaporean workforce. Drawing on the survey results from 2500 participants, this study managed to profile them into seven occupation groups based on the different patterns of importance and confidence levels of the use of CCS. Each occupation group is labeled according to the most salient and demanded CCS. In the meantime, the CCS in each occupation group, which may need some further strengthening, were also identified. The profiling of CCS use has significant implications for different stakeholders, e.g., employers could leverage the profiling results to hire the staff with the soft skills demanded by the job.

Keywords: employability, skills profiling, skills measurement, soft skills

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Authors: Domenica Bona

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Colin Chant and David Goodman argue that historians of Chinese pre-industrial cities tend to underestimate revolutions and overestimate cyclic patterns: periods of peace and prosperity in the earl part of each d nast , followed b peasants’ rebellions and upheavals. Boyd described these cyclic patterns as part of the background of Chinese town planning and architecture. Thus old ideals of city planning-square plan, southward orientation and a palace along the central axis - are revived again and again in the ascendant phases of several d nastic c cles (e.g. Chang’an, Kaifen, and Beijing). Along this line of thought, m paper questions the relationship between the “magic square rule” and modern Chinese urban- planning. As a matter of fact, the classical theme of “cosmic Taoist urbanism” is still a reference for planning cities and new urban developments, whenever there is the intention to express nationalist ideals and “cultural straightforwardness.” Besides, some case studies can be related to “modern d nasties”: the first Republic under the Kuo Min Tang, the red People’s Republic and the post-Maoist open country of Deng Xiao Ping. Considering the project for the new capital of Nanjing in the Thirties, Beijing’s Tianan Men area in the ifties, and Shenzhen’s utian CBD in late 20th century, I argue that cyclic patterns are still in place, though with deformations related to westernization, private interests and lack of spirituality. How far new Chinese cities are - or simply seem to be - westernized? Symbolism, invisible frameworks, repeating features and behavioural patterns make urban China just “superficiall” western. This can be well noticed in cities previousl occupied b foreigners, like Hong Kong, or in newly founded ones, like Shenzhen, where both Asians and non-Asian people can feel the gender-shift from New-York-like landscapes to something else. Current planning in main metropolitan areas shows a blurred relationship between public policies and private investments: two levels of decisions and actions, one addressing the larger scale and infrastructures, the other concerning the micro scale and development of single plots. While zoning is instrumental in this process, master plans are often laid out over a very poor cartography, so much that any relation between the formal characters of new cities and the centuries-old structure of the related territory gets lost.

Keywords: China, contemporary cities, cultural heritage, shenzhen, urban planning

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Authors: Xiao-Dong Wang, Wei-Mon Yan

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The flow field design in the bipolar plates affects the performance of the proton exchange membrane (PEM) fuel cell. This work adopted a combined optimization procedure, including a simplified conjugate-gradient method and a completely three-dimensional, two-phase, non-isothermal fuel cell model, to look for optimal flow field design for a single serpentine fuel cell of size 9×9 mm with five channels. For the direct solution, the two-fluid method was adopted to incorporate the heat effects using energy equations for entire cells. The model assumes that the system is steady; the inlet reactants are ideal gases; the flow is laminar; and the porous layers such as the diffusion layer, catalyst layer and PEM are isotropic. The model includes continuity, momentum and species equations for gaseous species, liquid water transport equations in the channels, gas diffusion layers, and catalyst layers, water transport equation in the membrane, electron and proton transport equations. The Bulter-Volumer equation was used to describe electrochemical reactions in the catalyst layers. The cell output power density Pcell is maximized subjected to an optimal set of channel heights, H1-H5, and channel widths, W2-W5. The basic case with all channel heights and widths set at 1 mm yields a Pcell=7260 Wm-2. The optimal design displays a tapered characteristic for channels 1, 3 and 4, and a diverging characteristic in height for channels 2 and 5, producing a Pcell=8894 Wm-2, about 22.5% increment. The reduced channel heights of channels 2-4 significantly increase the sub-rib convection and widths for effectively removing liquid water and oxygen transport in gas diffusion layer. The final diverging channel minimizes the leakage of fuel to outlet via sub-rib convection from channel 4 to channel 5. Near-optimal design without huge loss in cell performance but is easily manufactured is tested. The use of a straight, final channel of 0.1 mm height has led to 7.37% power loss, while the design with all channel widths to be 1 mm with optimal channel heights obtained above yields only 1.68% loss of current density. The presence of a final, diverging channel has greater impact on cell performance than the fine adjustment of channel width at the simulation conditions set herein studied.

Keywords: optimization, flow field design, simplified conjugate-gradient method, serpentine flow field, sub-rib convection

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Authors: Yitian Ren, Liyin Shen, Tao Zhou, Xiao Li

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The past urbanization process in China has brought out series of problems, the Chinese government has then positioned small towns in essential roles for implementing the strategy 'The National New-type Urbanization Plan (2014-2020)'. As the connector and transfer station of cities and countryside, small towns are important force to narrow the gap between urban and rural area, and to achieve the mission of new-type urbanization in China. The sustainable development of small towns plays crucial role because cities are not capable enough to absorb the surplus rural population. Nevertheless, there are various types of barriers hindering the sustainable development of small towns, which led to the limited development of small towns and has presented a bottleneck in Chinese urbanization process. Therefore, this paper makes deep understanding of these barriers, thus effective actions can be taken to address them. And this paper chooses the perspective of Southwest China (refers to Sichuan province, Yunnan province, Guizhou province, Chongqing Municipality City and Tibet Autonomous Region), cause the urbanization rate in Southwest China is far behind the average urbanization level of the nation and the number of small towns accounts for a great proportion in mainland China, also the characteristics of small towns in Southwest China are distinct. This paper investigates the barriers of sustainable development of small towns which located in Southwest China by using the content analysis method, combing with the field work and interviews in sample small towns, then identified and concludes 18 barriers into four dimensions, namely, institutional barriers, economic barriers, social barriers and ecological barriers. Based on the research above, questionnaire survey and data analysis are implemented, thus the key barriers hinder the sustainable development of small towns in Southwest China are identified by using fuzzy set theory, those barriers are, lack of independent financial power, lack of construction land index, financial channels limitation, single industrial structure, topography variety and complexity, which mainly belongs to institutional barriers and economic barriers. In conclusion part, policy suggestions are come up with to improve the politic and institutional environment of small town development, also the market mechanism are supposed to be introduced to the development process of small towns, which can effectively overcome the economic barriers, promote the sustainable development of small towns, accelerate the in-situ urbanization by absorbing peasants in nearby villages, and achieve the mission of new-type urbanization in China from the perspective of people-oriented.

Keywords: barrier analysis, sustainable development, small town, Southwest China

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Authors: Xiao Wang, Qinge Zhang

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Background: This randomized, open-label study examined the therapeutic effects of computerized cognitive training (CCT) combined with selective serotonin reuptake inhibitors (SSRIs) on cognitive impairment among patients with late-life depression (LLD). Method: Study data were collected from May 5, 2021, to April 21, 2023. Outpatients who met diagnostic criteria for major depressive disorder according to the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria (i.e., a total score on the 17-item Hamilton Depression Rating Scale (HAMD-17) ≥ 18 and a total score on the Montreal Cognitive Assessment scale (MOCA) <26) were randomly assigned to receive up to 12 weeks of CCT and SSRIs treatment (n=57) or SSRIs and Control treatment (n=61). The primary outcome was the change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores from baseline to week 12 between the two groups. The secondary outcomes included changes in the HAMD-17 score, Hamilton Anxiety Scale (HAMA) score and Neuropsychiatric Inventory (NPI) score. Mixed model repeated measures (MMRM) analysis was performed on modified intention-to-treat (mITT) and completer populations. Results: The full analysis set (FAS) included 118 patients (CCT and SSRIs group, n=57; SSRIs and Control group, n =61). Over the 12-week study period, the reduction in the ADAS-cog total score was significant (P < 0.001) in both groups, while MMRM analysis revealed a significantly greater reduction in cognitive function (ADAS-cog total scores) from baseline to posttreatment in the CCT and SSRIs group than in the SSRI and Control group [(F (1,115) =13.65, least-squares mean difference [95% CI]: −2.77 [−3.73, −1.81], p<0.001)]. There were significantly greater improvements in depression symptoms (measured by the HAMD-17) in the CCT and SSRIs group than in the control group [MMRM, estimated mean difference (SE) between groups −3.59 [−5.02, −2.15], p < 0.001]. The least-squares mean changes in the HAMA scores and NPI scores between baseline and week 8 were greater in the CCT and SSRIs group than in the control group (all P < 0.05). There was no significant difference between groups on response rates and remission rates by using the last-observation-carried-forward (LOCF) method (all P > 0.05). The most frequent adverse events (AEs) in both groups were dry mouth, somnolence, and constipation. There was no significant difference in the incidence of adverse events between the two groups. Conclusions: CCT combined with SSRIs was efficacious and well tolerated in LLD patients with cognitive impairment.

Keywords: late-life depression, cognitive function, computerized cognitive training, SSRIs

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Authors: Qing Zhang, Janak L. Pathak, Macro N. Helder, Richard T. Jaspers, Yin Xiao

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Introduction: Nanomaterial-based bone regeneration is greatly influenced by the immune microenvironment. Tissue-engineered nanomaterials mediate the inflammatory response of macrophages to regulate bone regeneration. Silica nanoparticles have been widely used in tissue engineering-related preclinical studies. However, the effect of topological features on the surface of silica nanoparticles on the immune response of macrophages remains unknown. Purposes: The aims of this research are to compare the influences of normal and pollen-like silica nano-surface topography on macrophage immune responses and to obtain insight into their potential regulatory mechanisms. Method: Macrophages (RAW 264.7 cells) were exposed to mesoporous silica nanoparticles with normal morphology (MSNs) and pollen-like morphology (PMSNs). RNA-seq, RT-qPCR, and LSCM were used to assess the changes in expression levels of immune response-related genes and proteins. SEM and TEM were executed to evaluate the contact and adherence of silica nanoparticles by macrophages. For the assessment of the immunomodulation-mediated osteogenic potential, BMSCs were cultured with conditioned medium (CM) from LPS pre-stimulated macrophage cultures treated with MSNs or PMSNs. Osteoimmunomodulatory potential of MSNs and PMSNs in vivo was tested in a mouse cranial bone osteolysis model. Results: The results of the RNA-seq, RT-qPCR, and LSCM assays showed that PMSNs inhibited the expression of pro-inflammatory genes and proteins in macrophages. SEM images showed distinct macrophage membrane surface binding patterns of MSNs and PMSNs. MSNs were more evenly dispersed across the macrophage cell membrane, while PMSNs were aggregated. PMSNs-induced macrophage anti-inflammatory response was associated with upregulation of the cell surface receptor CD28 and inhibition of ERK phosphorylation. TEM images showed that both MSNs and PMSNs could be phagocytosed by macrophages, and inhibiting nanoparticle phagocytosis did not affect the expression of anti-inflammatory genes and proteins. Moreover, PMSNs-induced conditioned medium from macrophages enhanced BMP-2 expression and osteogenic differentiation mBMSCs. Similarly, PMSNs prevented LPS-induced bone resorption via downregulation of inflammatory reaction. Conclusions: PMSNs can promote bone regeneration by modulating osteoimmunological processes through surface topography. The study offers insights into how surface physical contact cues can modulate the regulation of osteoimmunology and provides a basis for the application of nanoparticles with pollen-like morphology to affect immunomodulation in bone tissue engineering and regeneration.

Keywords: physical contact, osteoimmunology, macrophages, silica nanoparticles, surface morphology, membrane receptor, osteogenesis, inflammation

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Authors: Lei Li, Ming M. Chai, Xiao X. Lu, Jia W. Wang

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The mixing process of two liquid layers in a cylindrical container includes the upper liquid with higher density rushing into the lower liquid with lighter density, the lower liquid rising into the upper liquid, meanwhile the two liquid layers having interactions with each other, forming vortices, spreading or dispersing in others, entraining or mixing with others. It is a complex process constituted of flow instability, turbulent mixing and other multiscale physical phenomena and having a fast evolution velocity. In order to explore the mechanism of the process and make further investigations, some experiments about the interfacial instability and mixing behavior between two liquid layers bounded in different volumes are carried out, applying the planar laser induced fluorescence (PLIF) and the high speed camera (HSC) techniques. According to the results, the evolution of interfacial instability between immiscible liquid develops faster than theoretical rate given by the Rayleigh-Taylor Instability (RTI) theory. It is reasonable to conjecture that some mechanisms except the RTI play key roles in the mixture process of two liquid layers. From the results, it is shown that the invading velocity of the upper liquid into the lower liquid does not depend on the upper liquid's volume (height). Comparing to the cases that the upper and lower containers are of identical diameter, in the case that the lower liquid volume increases to larger geometric space, the upper liquid spreads and expands into the lower liquid more quickly during the evolution of interfacial instability, indicating that the container wall has important influence on the mixing process. In the experiments of miscible liquid layers’ mixing, the diffusion time and pattern of the liquid interfacial mixing also does not depend on the upper liquid's volumes, and when the lower liquid volume increases to larger geometric space, the action of the bounded wall on the liquid falling and rising flow will decrease, and the liquid interfacial mixing effects will also attenuate. Therefore, it is also concluded that the volume weight of upper heavier liquid is not the reason of the fast interfacial instability evolution between the two liquid layers and the bounded wall action is limited to the unstable and mixing flow. The numerical simulations of the immiscible liquid layers’ interfacial instability flow using the VOF method show the typical flow pattern agree with the experiments. However the calculated instability development is much slower than the experimental measurement. The numerical simulation of the miscible liquids’ mixing, which applying Fick’s diffusion law to the components’ transport equation, shows a much faster mixing rate than the experiments on the liquids’ interface at the initial stage. It can be presumed that the interfacial tension plays an important role in the interfacial instability between the two liquid layers bounded in finite volume.

Keywords: interfacial instability and mixing, two liquid layers, Planar Laser Induced Fluorescence (PLIF), High Speed Camera (HSC), interfacial energy and tension, Cahn-Hilliard Navier-Stokes (CHNS) equations

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Authors: Xiao-Mei Zhang, Sian-Hong Tseng, Ming-Yen Lu

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Two-dimensional (2D) transition metal dichalcogenides (TMDCs), such as MoS₂, have attracted considerable attention owing to the unique optical and electronic properties related to its 2D ultrathin atomic layer structure. MoS₂ is becoming prevalent in post-silicon digital electronics and in highly efficient optoelectronics due to its extremely low thickness and its tunable band gap (Eg = 1-2 eV). For low-power, high-performance complementary logic applications, both p- and n-type MoS₂ FETs (NFETs and PFETs) must be developed. NFETs with an electron accumulation channel can be obtained using unintentionally doped n-type MoS₂. However, the fabrication of MoS₂ FETs with complementary p-type characteristics is challenging due to the significant difficulty of injecting holes into its inversion channel. Plasma treatments with different species (including CF₄, SF₆, O₂, and CHF₃) have also been found to achieve the desired property modifications of MoS₂. In this work, we demonstrated a p-type multilayer MoS₂ enabled by selective-area doping using CHF₃ plasma treatment. Compared with single layer MoS₂, multilayer MoS₂ can carry a higher drive current due to its lower bandgap and multiple conduction channels. Moreover, it has three times the density of states at its minimum conduction band. Large-area growth of MoS₂ films on 300 nm thick SiO₂/Si substrate is carried out by thermal decomposition of ammonium tetrathiomolybdate, (NH₄)₂MoS₄, in a tube furnace. A two-step annealing process is conducted to synthesize MoS₂ films. For the first step, the temperature is set to 280 °C for 30 min in an N₂ rich environment at 1.8 Torr. This is done to transform (NH₄)₂MoS₄ into MoS₃. To further reduce MoS₃ into MoS₂, the second step of annealing is performed. For the second step, the temperature is set to 750 °C for 30 min in a reducing atmosphere consisting of 90% Ar and 10% H₂ at 1.8 Torr. The grown MoS₂ films are subjected to out-of-plane doping by CHF₃ plasma treatment using a Dry-etching system (ULVAC original NLD-570). The radiofrequency power of this dry-etching system is set to 100 W and the pressure is set to 7.5 mTorr. The final thickness of the treated samples is obtained by etching for 30 s. Back-gated MoS₂ PFETs were presented with an on/off current ratio in the order of 10³ and a field-effect mobility of 65.2 cm²V⁻¹s⁻¹. The MoS₂ PFETs photodetector exhibited ultraviolet (UV) photodetection capability with a rapid response time of 37 ms and exhibited modulation of the generated photocurrent by back-gate voltage. This work suggests the potential application of the mild plasma-doped p-type multilayer MoS₂ in UV photodetectors for environmental monitoring, human health monitoring, and biological analysis.

Keywords: photodetection, p-type doping, multilayers, MoS₂

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Authors: G. Cunningham, E. Cantor, X. Wu, F. Shen, G. Jiang, S. Philips, C. Bales, Y. Xiao, T. R. Cummins, J. C. Fehrenbacher, B. P. Schneider

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Background: Taxane-induced peripheral neuropathy (TIPN) is the most devastating survivorship issue for patients receiving therapy. Dose reductions due to TIPN in the curative setting lead to inferior outcomes for African American patients, as prior research has shown that this group is more susceptible to developing severe neuropathy. The mechanistic underpinnings of TIPN, however, have not been entirely elucidated. While it would be appealing to use primary tissue to study the development of TIPN, procuring nerves from patients is not realistically feasible, as nerve biopsies are painful and may result in permanent damage. Therefore, our laboratory has investigated paclitaxel-induced neuronal morphological and molecular changes using an ex vivo model of human-induced pluripotent stem cell (iPSC)-derived neurons. Methods: iPSCs are undifferentiated and endlessly dividing cells that can be generated from a patient’s somatic cells, such as peripheral blood mononuclear cells (PBMCs). We successfully reprogrammed PBMCs into iPSCs using the Erythroid Progenitor Reprograming Kit (STEMCell Technologiesᵀᴹ); pluripotency was verified by flow cytometry analysis. iPSCs were then induced into neurons using a differentiation protocol that bypasses the neural progenitor stage and uses selected small-molecule modulators of key signaling pathways (SMAD, Notch, FGFR1 inhibition, and Wnt activation). Results: Flow cytometry analysis revealed expression of core pluripotency transcription factors Nanog, Oct3/4 and Sox2 in iPSCs overlaps with commercially purchased pluripotent cell line UCSD064i-20-2. Trilineage differentiation of iPSCs was confirmed with immunofluorescent imaging with germ-layer-specific markers; Sox17 and ExoA2 for ectoderm, Nestin, and Pax6 for mesoderm, and Ncam and Brachyury for endoderm. Sensory neuron markers, β-III tubulin, and Peripherin were applied to stain the cells for the maturity of iPSC-derived neurons. Patch-clamp electrophysiology and calcitonin gene-related peptide (CGRP) release data supported the functionality of the induced neurons and provided insight into the timing for which downstream assays could be performed (week 4 post-induction). We have also performed a cell viability assay and fluorescence-activated cell sorting (FACS) using four cell-surface markers (CD184, CD44, CD15, and CD24) to select a neuronal population. At least 70% of the cells were viable in the isolated neuron population. Conclusion: We have found that these iPSC-derived neurons recapitulate mature neuronal phenotypes and demonstrate functionality. Thus, this represents a patient-derived ex vivo neuronal model to investigate the molecular mechanisms of clinical TIPN.

Keywords: chemotherapy, iPSC-derived neurons, peripheral neuropathy, taxane, paclitaxel

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Authors: Narin Ozturk, Xiao-Mei Li, Sylvie Giachetti, Francis Levi, Alper Okyar

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P-glycoprotein (P-gp, MDR1, ABCB1) is a transmembrane protein acting as an ATP-dependent efflux pump and functions as a biological barrier by extruding drugs and xenobiotics out of cells in healthy tissues especially in intestines, liver and brain as well as in tumor cells. The circadian timing system controls a variety of biological functions in mammals including xenobiotic metabolism and detoxification, proliferation and cell cycle events, and may affect pharmacokinetics, toxicity and efficacy of drugs. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is active against many cancers, and its pharmacokinetics depend on P-gp. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus with respect to the intestinal P-gp expression rhythms in mdr1a::Luc mice using Real Time-Biolumicorder (RT-BIO) System. Mdr1a::Luc male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding Light onset). After 1-week baseline recordings, everolimus (5 mg/kg/day x 14 days) was administered orally at ZT1-resting period- and ZT13-activity period- to mdr1a::Luc mice singly housed in an innovative monitoring device, Real Time-Biolumicorder units which let us monitor real-time and long-term gene expression in freely moving mice. D-luciferin (1.5 mg/mL) was dissolved in drinking water. Mouse intestinal mdr1a::Luc oscillation profile reflecting P-gp gene expression and locomotor activity pattern were recorded every minute with the photomultiplier tube and infrared sensor respectively. General behavior and clinical signs were monitored, and body weight was measured every day as an index of toxicity. Drug-induced body weight change was expressed relative to body weight on the initial treatment day. Statistical significance of differences between groups was validated with ANOVA. Circadian rhythms were validated with Cosinor Analysis. Everolimus toxicity changed as a function of drug timing, which was least following dosing at ZT13, near the onset of the activity span in male mice. Mean body weight loss was nearly twice as large in mice treated with 5 mg/kg everolimus at ZT1 as compared to ZT13 (8.9% vs. 5.4%; ANOVA, p < 0.001). Based on the body weight loss and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13. Both rest-activity and mdr1a::Luc expression displayed stable 24-h periodic rhythms before everolimus and in both vehicle-treated controls. Real-time bioluminescence pattern of mdr1a revealed a circadian rhythm with a 24-h period with an acrophase at ZT16 (Cosinor, p < 0.001). Mdr1a expression remained rhythmic in everolimus-treated mice, whereas down-regulation was observed in P-gp expression in 2 of 4 mice. The study identified the circadian pattern of intestinal P-gp expression with an unprecedented precision. The circadian timing depending on the P-gp expression rhythms may play a crucial role in the tolerability/toxicity of everolimus. The circadian changes in mdr1a genes deserve further studies regarding their relevance for in vitro and in vivo chronotolerance of mdr1a-transported anticancer drugs. Chronotherapy with P-gp-effluxed anticancer drugs could then be applied according to their rhythmic patterns in host and tumor to jointly maximize treatment efficacy and minimize toxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, mdr1a::Luc mice, p-glycoprotein

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