Search results for: Hiroaki Kodama

Authors: Futo Asano, Yusuke Yatsushiro, Hirokuni Miyamoto, Hiroaki Kodama

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A thermophile-fermented compost is produced using small fishes, crabs, and shrimps under a high temperature (approximately 75℃) by fermentation-associated self-heating. This compost has been used as a feed additive for pigs and hens in Japan, and the fecundity of this livestock is enhanced. Firmicutes is a dominant phylum in the microbial composition of the compost. We first reported that improvement of female larval fitness of Hercules beetle can be achieved by amendment of this compost to the humus. When the 90-d-old larvae were reared for subsequent 72 days in the humus with this compost, the growth of female larvae was significantly enhanced when compared with the growth of female larvae in the humus without the compost. In contrast, the growth of male larvae in the compost-free humus was the same as the larvae grow in the compost-amended humus. The bacterial composition of the feces of larvae was determined at 0 days and 46 days after transfer to the humus with or without the compost. The most dominant bacterium in the feces was Xylanimonas. Interestingly, the growth improvement of female larvae was associated with an increased abundance of Mollicutes in the fecal samples. These results indicate that the compost act as a probiotic material for enhancing the female larvae growth by supporting Mollicutes. Here, we tried to isolate Mollicutes from the contents of the midgut and hindgut of the 3rd instar female larvae of the Hercules beetle. These gut contents were spread onto a selective agar medium for Mollicutes (PPLO agar broth, BD Difco, NJ, USA). Although we isolated none of the Mollicutes until now, several bacteria that are closely related to Xylanimonas and Luteimicrobium were isolated. These isolates have xylanase and glucanase (CMCase) activities. We show the gut bacterial profiles of larvae and discuss how the fitness of female larvae of the Hercules beetle is improved by the compost.

Keywords: compost, beetle, mollicutes, woody biomass

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Authors: Hiroaki Sumi, Kiichiro Hayashi

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Now, the use of renewable energy power generation has been advanced. In this paper, we compared the expansion support policy of photovoltaic power generation which was researched using The internet and the amount of resource for photovoltaic power generation which was estimated using the NEDO formula in the municipality level in Hokkaido and Aichi Prefecture, Japan. This paper will contribute to grasp the current situation especially about the policy. As a result, there were municipalities which seemed to be no consideration of the amount of resources. We think it would need to consider the suitability between the policies and resources.

Keywords: photovoltaic power generation, dissemination and support policy, amount of resources, Japan

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Authors: Tetsuya Yabuki, Yasunori Arizumi, Tetsuhiro Shimozato, Samy Guezouli, Hiroaki Matsusita, Masayuki Tai

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The main object of this paper is to present the research results of the development of a hybrid stainless steel girder system for bridge construction undertaken at University of Ryukyu. In order to prevent the corrosion damage and reduce the fabrication costs, a hybrid stainless steel girder in bridge construction is developed, the stainless steel girder of which is stiffened and braced by structural carbon steel materials. It is verified analytically and experimentally that the ultimate strength of the hybrid stainless steel girder is equal to or greater than that of conventional carbon steel girder. The benefit of the life-cycle cost of the hybrid stainless steel girder is also shown.

Keywords: smart structure, hybrid stainless steel members, ultimate strength, steel bridge, corrosion prevention

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Authors: Fujio Akagi, Hiroaki Ito, Shin-Ichi Inage

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The aim of this study is to develop a combustion model that can be applied uniformly to laminar and turbulent premixed flames while considering the effect of the Lewis number (Le). The model considers the effect of Le on the transport equations of the reaction progress, which varies with the chemical species and temperature. The distribution of the reaction progress variable is approximated by a hyperbolic tangent function, while the other distribution of the reaction progress variable is estimated using the approximated distribution and transport equation of the reaction progress variable considering the Le. The validity of the model was evaluated under the conditions of propane with Le > 1 and methane with Le = 1 (equivalence ratios of 0.5 and 1). The estimated results were found to be in good agreement with those of previous studies under all conditions. A method of introducing a turbulence model into this model is also described. It was confirmed that conventional turbulence models can be expressed as an approximate theory of this model in a unified manner.

Keywords: combustion model, laminar flame, Lewis number, turbulent flame

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Authors: Vu Thu Trang, Lam Xuan Thanh, Samira Sarter, Tomoko Shimamura, Hiroaki Takeuchi　　

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Antimicrobial activities of aminoreductone (AR), a product formed in the initial stage of Maillard reaction, were screened against pathogenic bacteria. A significant growth inhibition of AR against all 7 isolates (Staphylococcus aureus ATCC® 25923™, Salmonella Typhimurium ATCC® 14028™, Bacillus cereus ATCC® 13061™, Bacillus subtilis ATCC® 11774™, Escherichia coli ATCC® 25922™, Enterococcus faecalis ATCC® 29212™, Listeria innocua ATCC® 33090™) were observed by the standard disc diffusion methods. The inhibition zone for each isolate by AR (2.5 mg) ranged from 15±0 mm to 28.3±0.4 mm in diameter. The minimum inhibitory concentration (MIC) of AR ranging from 20 mM to 26 mM was proven in the seven isolates tested. AR also showed the similar effect of growth inhibition in comparison with antibiotics frequently used for the treatment of infections bacteria, such as amikacin, ciprofloxacin, meropennem, and levofloxacin. The results indicated that foods containing AR are valuable sources of bioactive compounds towards pathogenic bacteria.

Keywords: pathogenic bacteria, aminoreductone, Maillard reaction, antimicrobial activity

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Authors: Selvan Bellan, Koji Matsubara, Nobuyuki Gokon, Tatsuya Kodama, Hyun Seok-Cho

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In concentrated solar thermal industry, fluidized-bed technology has been used to produce hydrogen by thermochemical two step water splitting cycles, and synthetic gas by gasification of coal coke. Recently, couple of fluidized bed reactors have been developed and tested at Niigata University, Japan, for two-step thermochemical water splitting cycles and coal coke gasification using Xe light, solar simulator. The hydrodynamic behavior of the gas-solid flow plays a vital role in the aforementioned fluidized bed reactors. Thus, in order to study the dynamics of dense gas-solid flow, a CFD-DEM model has been developed; in which the contact forces between the particles have been calculated by the spring-dashpot model, based on the soft-sphere method. Heat transfer and hydrodynamics of a solar thermochemical fluidized bed reactor filled with ceria particles have been studied numerically and experimentally for beam-down solar concentrating system. An experimental visualization of particles circulation pattern and mixing of two-tower fluidized bed system has been presented. Simulation results have been compared with experimental data to validate the CFD-DEM model. Results indicate that the model can predict the particle-fluid flow of the two-tower fluidized bed reactor. Using this model, the key operating parameters can be optimized.

Keywords: solar reactor, CFD-DEM modeling, fluidized bed, beam-down solar concentrating system

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Authors: Hiroaki Hirose, Hiroshi Ikeda, Isao Takeda

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The Japanese version of the SF-36 has been employed to assess individuals’ health-related QOL (HRQOL). This study aimed to clarify the HRQOL of motorists with a spinal cord injury, in order to compare these individuals' SF-36 scores and national standard values. A total of 100 motorists with a spinal cord injury participated in this study. Participants’ HRQOL was evaluated using the Japanese version of the SF-36 (second edition). The score for each subscale was standardized based on data on the Japanese population. The average scores for NPF, NRP, NBP, NGH, NVT, NSF, NRE, and NMH were 10.9, 41.8, 45.9, 47.1, 46.1, 46.7, 46.0, and 47.4 points, respectively. Subjects showed significantly lower scores for NPF and NRP compared with national standard values, which were both ≤ 45.0 points, but relatively normal scores for the other items: NBP, NGH, NVT, NSF, NRE and NMH (> 45.0 points). The average scores for PCS, MCS and RCS were 21.9, 56.0, and 50.0 points, respectively. Subjects showed a significantly lower PCS score (≤ 20.0 points); however, the MCS score was higher (> 55.0 points) along with a relatively normal RCS score in these individuals (= 50.0 points).

Keywords: health-related QOL, HRQOL, SF-36, motorist, spinal cord injury, Japan

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Authors: Takeyuki Suzuki, Ismiyarto, Da-Yang Zhou, Kaori Asano, Hiroaki Sasai

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The development of catalytic asymmetric reaction is important for the synthesis of natural products. To construct the multiple stereogenic centers, the desymmetrization of meso compounds is powerful strategy for the synthesis of chiral molecules. Oxidative desymmetrization of meso diols using chiral iridium catalyst provides a chiral hydroxyl ketone. The reaction is practical and an environmentally benign method which does not require the use of stoichiometric amount of heavy metals. This time we report here catalytic asymmetric synthesis of catalponol based on tandem coupling of meso-diols and an aldehyde. The tandem reaction includes oxidative desymmetrization of meso-diols, aldol condensation with an aldehyde. The reaction of meso-diol, benzaldehyde in the presence of a catalytic amount of chiral Ir complex and CsOH in tetrahydrofuran afforded the desired benzylidene ketone in 82% yield with 96% ee (enantiomeric excess). Next, we applied this benzylidene ketone derivative to the synthesis of catalponol. The corresponding benzylidene ketone was obtained in 87% yield with 99% ee. Finally, catalponol was synthesized by the regio- and stereo-selective reduction of dienone moiety in good yield.

Keywords: catalponol, desymmetrization, iridium, oxidation

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Authors: Kazui Sasakii, Seira Mormune-Moriya, Hiroaki Tanahashi, Shigeji Kongaya

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Poly (3.4-ethylenedioxythiophene) doped with poly (4-styrene sulfonate) (PEDOT: PSS) attracted a great deal of attention because of its unique characteristics of flexibility, optical properties, heat resistance and colloidal dispersion in water. It is well known that when high boiling solvents such as ethylene glycol or dimethyl sulfoxide are added as a secondary dopant to the micellar structure, PEDOT microcrystallizes and becomes highly conductive. In previous study bis(4-hydroxyphenyl) sulfone (BPS) was used as a secondary dopant for PEDOT:PSS and the enhancement of the conductivity was revealed. However, ductility is one of the serious issues which limited the application of PEDOT:PSS/BPS. So far, the composition with polymer binders has been conducted, however, polymer binders decrease the conductivity of the materials. In this study, PEDOT: PSS composites with polyester (PEs) were prepared by a simple aqueous process using PEs emulsion. The structural studies revealed that PEDOT:PSS and PEs were homogeneously distributed in the composites. It was found that the properties of PEDOT:PSS were remarkably enhanced by the incorporation of PEs. According to the tensile test, the ductility of PEDOT:PSS was remarkably improved. Interestingly, the conductivity of PEDOT:PSS/PEs composites was higher than that of neat PEDOT:PSS. For example, the conductivity increased by 8% at PEs content of 25 wt%. Since PEDOT:PSS were homogeneously dispersed on the surface of PEs particles, it was assumed that the conductive pathway was constructed by PEs particles in the nanocomposites. Therefore, a significant increase in conductivity was achieved.

Keywords: polymer composites, conductivity, PEDOT:PSS, polyester

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Authors: Robert Long, Hiroaki Watanabe

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This longitudinal study examines the grammatical errors of Japanese university students’ dialogues with a native speaker over an academic year. The L2 interactions of 15 Japanese speakers were taken from the JUSFC2018 corpus (April/May 2018) and the JUSFC2019 corpus (January/February). The corpora were based on a self-introduction monologue and a three-question dialogue; however, this study examines the grammatical accuracy found in the dialogues. Research questions focused on a possible significant difference in grammatical accuracy from the first interview session in 2018 and the second one the following year, specifically regarding errors in clauses per 100 words, global errors and local errors, and with specific errors related to parts of speech. The investigation also focused on which forms showed the least improvement or had worsened? Descriptive statistics showed that error-free clauses/errors per 100 words decreased slightly while clauses with errors/100 words increased by one clause. Global errors showed a significant decline, while local errors increased from 97 to 158 errors. For errors related to parts of speech, a t-test confirmed there was a significant difference between the two speech corpora with more error frequency occurring in the 2019 corpus. This data highlights the difficulty in having students self-edit themselves.

Keywords: clause analysis, global vs. local errors, grammatical accuracy, L2 output, longitudinal study

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Authors: Ankur Dixit, Hiroaki Wagatsuma

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The crack detection on a concrete bridge is an important and constant task in civil engineering. Chronically, humans are checking the bridge for inspection of cracks to maintain the quality and reliability of bridge. But this process is very long and costly. To overcome such limitations, we have used a drone with a digital camera, which took some images of bridge deck and these images are processed by morphological component analysis (MCA). MCA technique is a very strong application of sparse coding and it explores the possibility of separation of images. In this paper, MCA has been used to decompose the image into coarse and fine components with the effectiveness of two dictionaries namely anisotropic diffusion and wavelet transform. An anisotropic diffusion is an adaptive smoothing process used to adjust diffusion coefficient by finding gray level and gradient as features. These cracks in image are enhanced by subtracting the diffused coarse image into the original image and the results are treated by Sobel edge detector and binary filtering to exhibit the cracks in a fine way. Our results demonstrated that proposed MCA framework using anisotropic diffusion followed by Sobel operator and binary filtering may contribute to an automation of crack detection even in open field sever conditions such as bridge decks.

Keywords: anisotropic diffusion, coarse component, fine component, MCA, Sobel edge detector and wavelet transform

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Authors: Hiroaki Nasu, Ryota Miyamoto, Yuta Kodera, Yasuyuki Nogami

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To promote Industry 4.0 and Society 5.0 and so on, it is important to connect and share data so that every member can trust it. Blockchain (BC) technology is currently attracting attention as the most advanced tool and has been used in the financial field and so on. However, the data collaboration using BC has not progressed sufficiently among companies on the supply chain of manufacturing industry that handle sensitive data such as product quality, manufacturing conditions, etc. There are two main reasons why data utilization is not sufficiently advanced in the industrial supply chain. The first reason is that manufacturing information is top secret and a source for companies to generate profits. It is difficult to disclose data even between companies with transactions in the supply chain. In the blockchain mechanism such as Bitcoin using PKI (Public Key Infrastructure), in order to confirm the identity of the company that has sent the data, the plaintext must be shared between the companies. Another reason is that the merits (scenarios) of collaboration data between companies are not specifically specified in the industrial supply chain. For these problems this paper proposes a Business to Business (B2B) collaboration system using homomorphic encryption and BC technique. Using the proposed system, each company on the supply chain can exchange confidential information on encrypted data and utilize the data for their own business. In addition, this paper considers a scenario focusing on quality data, which was difficult to collaborate because it is a top secret. In this scenario, we show a implementation scheme and a benefit of concrete data collaboration by proposing a comparison protocol that can grasp the change in quality while hiding the numerical value of quality data.

Keywords: business to business data collaboration, industrial supply chain, blockchain, homomorphic encryption

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Authors: Hiroaki Fukuda

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This paper shows a concurrent development process for modern web application, called Rich Internet Application (RIA), and describes its effect using a non-trivial application development. In the last years, RIAs such as Ajax and Flex have become popular based mainly on high-speed network. RIA provides sophisticated interfaces and user experiences, therefore, the development of RIA requires two kinds of engineer: a developer who implements business logic, and a designer who designs interface and experiences. Although collaborative works are becoming important for the development of RIAs, shared resources such as source code make it difficult. For example, if a design of interface is modified after developers have finished business logic implementations, they need to repeat the same implementations, and also tests to verify application’s behavior. MVC architecture and Object-oriented programming (OOP) enables to dividing an application into modules such as interfaces and logic, however, developers and/or designers have to write pieces of code (e.g., event handlers) that make these modules work as an application. On the other hand, Aspect-oriented programming (AOP) is ex- pected to solve complexity of application software development nowadays. AOP provides methods to separate crosscutting concerns that are scattered pieces of code from primary concerns. In this paper, we provide a concurrent development process for RIAs by introducing AOP concept. This process makes it possible to reduce shared resources between developers and designers, therefore they can perform their tasks concurrently. In addition, we describe experiences of development for a practical application using our proposed development process to show its availability.

Keywords: aspect-oriented programming, concurrent, development process, rich internet application

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Authors: Ratih Fitria Putri, Josaphat Tetuko Sri Sumantyo, Hiroaki Kuze

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Jakarta Metropolitan City is located on the northwest coast of West Java province with geographical location between 106º33’ 00”-107º00’00”E longitude and 5º48’30”-6º24’00”S latitude. Jakarta urban area has been suffered from land subsidence in several land use type as trading, industry and settlement area. Land subsidence hazard is one of the consequences of urban development in Jakarta. This hazard is caused by intensive human activities in groundwater extraction and land use mismanagement. Geologically, the Jakarta urban area is mostly dominated by alluvium fan sediment. The objectives of this research are to make an analysis of Jakarta urban land use type on land subsidence zone areas. The process of producing safer land use and settlements of the land subsidence areas are very important. Spatial distributions of land subsidence detection are necessary tool for land use management planning. For this purpose, Differential Synthetic Aperture Radar Interferometry (DInSAR) method is used. The DInSAR is complementary to ground-based methods such as leveling and global positioning system (GPS) measurements, yielding information in a wide coverage area even when the area is inaccessible. The data were fine tuned by using X-Band image satellite data from 2010 to 2013 and land use mapping data. Our analysis of land use type that land subsidence movement occurred on the northern part Jakarta Metropolitan City varying from 7.5 to 17.5 cm/year as industry and settlement land use type areas.

Keywords: land use analysis, land subsidence mapping, urban area, X-band satellite image

Procedia PDF Downloads 277

Authors: Shouta Sora, Shizuki Kuriu, Radhika Mishra, Ariunbuyan Sukhbaatar, Maya Sakamoto, Shiro Mori, Tetsuya Kodama

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Lymph node (LN) metastasis accounts for 20 - 30 % of all deaths in patients with head and neck cancer. Therefore, the control of metastatic lymph nodes (MLNs) is necessary to improve the life prognosis of patients with cancer. In a classical metastatic theory, tumor cells are thought to metastasize hematogenously through a bead-like network of lymph nodes. Recently, a lymph node-mediated hematogenous metastasis theory has been proposed, in which sentinel LNs are regarded as a source of distant metastasis. Therefore, the treatment of MLNs at the early stage is essential to prevent distant metastasis. Radiation therapy is one of the primary therapeutic modalities in cancer treatment. In addition, total body irradiation (TBI) has been reported to act as activation of natural killer cells and increase of infiltration of CD4+ T-cells to tumor tissues. However, the treatment effect of TBI for MLNs remains unclear. This study evaluated the possibilities of low-dose total body irradiation (L-TBI) and middle-dose total body irradiation (M-TBI) for the treatment of MLNs. Mouse breast cancer FM3A-Luc cells were injected into subiliac lymph node (SiLN) of MXH10/Mo/LPR mice to induce the metastasis to the proper axillary lymph node (PALN) and lung. Mice were irradiated for the whole body on 4 days after tumor injection. The L-TBI and M-TBI were defined as irradiations to the whole body at 0.2 Gy and 1.0 Gy, respectively. Tumor growth was evaluated by in vivo bioluminescence imaging system. In the non-irradiated group, tumor activities on SiLN and PALN significantly increased over time, and the metastasis to the lung from LNs was confirmed 28 days after tumor injection. The L-TBI led to a tumor growth delay in PALN but did not control tumor growth in SiLN and metastasis to the lung. In contrast, it was found that the M-TBI significantly delayed the tumor growth of both SiLN and PALN and controlled the distant metastasis to the lung compared with non-irradiated and L-TBI groups. These results suggest that the M-TBI is an effective treatment method for MLNs in the early stage and distant metastasis from lymph nodes via blood vessels connected with LNs.

Keywords: metastatic lymph node, lung metastasis, radiation therapy, total body irradiation, lymphatic system

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Authors: Takamitsu Kodama, Eiji Kawamoto

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Introduction: Ultrasound in emergency room has advantages of safer, faster, repeatable and noninvasive. Especially focused Point-Of-Care Ultrasound (POCUS) is used daily for prompt and accurate diagnoses, for quickly identifying critical and life-threatening conditions. That is why ultrasound has demonstrated its usefulness in emergency medicine. The true value of ultrasound has been once again recognized in recent years. It is thought that all resident physicians working at emergency room should perform an ultrasound scan to interpret signs and symptoms of deteriorating patients in the emergency room. However, a practical education on ultrasound is still in development. To resolve this issue, we established a new educational program using high-fidelity simulators and evaluated the efficacy of this course. Methods: Educational program includes didactic lectures and skill stations in half-day course. Instructor gives a lecture on POCUS such as Rapid Ultrasound in Shock (RUSH) and/or Focused Assessment Transthoracic Echo (FATE) protocol at the beginning of the course. Then, attendees are provided for training of scanning with cooperation of normal simulated patients. In the end, attendees learn how to apply focused POCUS skills at clinical situation using high-fidelity simulators such as SonoSim® (SonoSim, Inc) and SimMan® 3G (Laerdal Medical). Evaluation was conducted through surveillance questionnaires to 19 attendees after two pilot courses. The questionnaires were focused on understanding course concept and satisfaction. Results: All attendees answered the questionnaires. With respect to the degree of understanding, 12 attendees (number of valid responses: 13) scored four or more points out of five points. High-fidelity simulators, especially SonoSim® was highly appreciated to enhance learning how to handle ultrasound at an actual practice site by 11 attendees (number of valid responses: 12). All attendees encouraged colleagues to take this course because the high level of satisfaction was achieved. Discussion: Newly introduced educational course using high-fidelity simulators realizes the circle of learning to deepen the understanding on focused POCUS by gradual stages. SonoSim® can faithfully reproduce scan images with pathologic findings of ultrasound and provide experimental learning for a growth number of beginners such as resident physicians. In addition, valuable education can be provided if it is used combined with SimMan® 3G. Conclusions: Newly introduced educational course using high-fidelity simulators is supposed to be effective and helps in providing better education compared with conventional courses for emergency physicians.

Keywords: point-of-care ultrasound, high-fidelity simulators, education, circle of learning

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Authors: Siqing Guan, Fumiyo Oshima, Eiji Shimizu, Nozomi Tomita, Toru Takahashi, Hiroaki Kumano

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Risk factors for social anxiety in autism spectrum conditions involve executive attention, emotion regulation, and thought regulation as processes of cognitive dysregulation. Social camouflaging behaviors as strategies used to mask and/or compensate for autism characteristics during social interactions in autism spectrum conditions have also been emphasized. However, the role of cognitive dysregulation and social camouflaging related to social anxiety in autism spectrum conditions has not been clarified. Whether these factors are specific to social anxiety in autism spectrum conditions or common to social anxiety independent of autism spectrum conditions needs to be clarified. Here, we explored risk factors specific to social anxiety in autism spectrum conditions and general risk factors for social anxiety independent of autism spectrum conditions. From the Japanese participants in early adulthood (age=18~39) of the online survey in Japan, those who exceeded the Japanese version Autism-Spectrum Quotient cutoff (33 points or more )were divided into the autism spectrum conditions group (ASC; N=255, mean age=32.08, SD age=5.16)and those who did not exceed the cutoff were divided into the non-autism spectrum conditions group (Non-ASC; N=255, mean age=31.70, SD age=5.09). Using the Japanese versions of the Social Phobia Scale, the Social Interaction Anxiety Scale, and the Short Fear of Negative Evaluation Scale, a composite score for social anxiety was calculated using a method of principal. We also measured emotional control difficulties using the Difficulties in Emotion Regulation Scale, executive attention using the Effortful Control Scale for Adults, rumination using the Rumination-Reflection Questionnaire, and worry using the Penn State Worry Questionnaire. This study was passed through the review of the Ethics Committee. No conflicts of interest. Multiple regression analysis with forced entry method was used to predict social anxiety in the ASC and non-ASC groups separately, based on executive attention, emotion dysregulation, worry, rumination, and social camouflage. In the ASC group, emotion dysregulation (β=.277, p<.001), worry (β=.162, p<.05), assimilation (β=.308, p<.001) and masking (β=.275, p<.001) were significant predictors of social anxiety (F (7,247) = 45.791, p <.001, R2=.565). In the non-ASC groups,emotion dysregulation (β=.171, p<.05), worry (β=.344，p <.001), assimilation (β=.366,p <.001) and executive attention (β=-.132,p <.05) were significant predictors of social anxiety (F (7,207) =47.333, p <.001, R2=.615).The findings suggest that masking was shown to be a risk factor for social anxiety specific to autism spectrum conditions, while emotion dysregulation, worry, and assimilation were shown to be common risk factors for social anxiety, regardless of autism spectrum conditions. In addition, executive attention is a risk factor for social anxiety without autism spectrum conditions.

Keywords: autism spectrum, cognitive control, social anxiety, social camouflaging

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Authors: Sundaram Arulmozhiraja, Kanade Shimizu, Yuta Yamamoto, Satoshi Ichikawa, Maenaka Katsumi, Hiroaki Tokiwa

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Drug discovery is shifting from small molecule based drugs targeting local active site to middle molecules (MM) targeting large, flat, and groove-shaped binding sites, for example, protein-protein interface because at least half of all targets assumed to be involved in human disease have been classified as “difficult to drug” with traditional small molecules. Hence, MMs such as peptides, natural products, glycans, nucleic acids with various high potent bioactivities become important targets for drug discovery programs in the recent years as they could be used for ‘undruggable” intracellular targets. Cell membrane permeability is one of the key properties of pharmacodynamically active MM drug compounds and so evaluating this property for the potential MMs is crucial. Computational prediction for cell membrane permeability of molecules is very challenging; however, recent advancement in the molecular dynamics simulations help to solve this issue partially. It is expected that MMs with high membrane permeability will enable drug discovery research to expand its borders towards intracellular targets. Further to understand the chemistry behind the permeability of MMs, it is necessary to investigate their conformational changes during the permeation through membrane and for that their interactions with the membrane field should be studied reliably because these interactions involve various non-bonding interactions such as hydrogen bonding, -stacking, charge-transfer, polarization dispersion, and non-classical weak hydrogen bonding. Therefore, parameters-based classical mechanics calculations are hardly sufficient to investigate these interactions rather, quantum mechanical (QM) calculations are essential. Fragment molecular orbital (FMO) method could be used for such purpose as it performs ab initio QM calculations by dividing the system into fragments. The present work is aimed to study the cell permeability of middle molecules using molecular dynamics simulations and FMO-QM calculations. For this purpose, a natural compound syringolin and its analogues were considered in this study. Molecular simulations were performed using NAMD and Gromacs programs with CHARMM force field. FMO calculations were performed using the PAICS program at the correlated Resolution-of-Identity second-order Moller Plesset (RI-MP2) level with the cc-pVDZ basis set. The simulations clearly show that while syringolin could not permeate the membrane, its selected analogues go through the medium in nano second scale. These correlates well with the existing experimental evidences that these syringolin analogues are membrane-permeable compounds. Further analyses indicate that intramolecular -stacking interactions in the syringolin analogues influenced their permeability positively. These intramolecular interactions reduce the polarity of these analogues so that they could permeate the lipophilic cell membrane. Conclusively, the cell membrane permeability of various middle molecules with potent bioactivities is efficiently studied using molecular dynamics simulations. Insight of this behavior is thoroughly investigated using FMO-QM calculations. Results obtained in the present study indicate that non-bonding intramolecular interactions such as hydrogen-bonding and -stacking along with the conformational flexibility of MMs are essential for amicable membrane permeation. These results are interesting and are nice example for this theoretical calculation approach that could be used to study the permeability of other middle molecules. This work was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 18ae0101047.

Keywords: fragment molecular orbital theory, membrane permeability, middle molecules, molecular dynamics simulation

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