Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 18

Search results for: Katsumi Yoshida

18 X-Ray Diffraction and Precision Dilatometer Study of Neutron-Irradiated Nuclear Graphite Recovery Process up to 1673K

Authors: Yuhao Jin, Zhou Zhou, Katsumi Yoshida, Zhengcao Li, Tadashi Maruyama, Toyohiko Yano


Four kinds of nuclear graphite, IG-110U, ETP-10, CX-2002U and IG-430U were neutron-irradiated at different fluences and temperatures, ranged from 1.38 x 1024 to 7.4 x 1025 n/m2 (E > 1.0 MeV) at 473K, 573K and 673K. To take into account the disorder in the microstructure, such as stacking faults and anisotropic coherent lengths, the X-ray diffraction patterns were interpreted using a comprehensive structural model and a refinement program CARBONXS. The deduced structural parameters show the changes of lattice parameters, coherent lengths along the c-axis and the basal plane, and the degree of turbostratic disorder as a function of the irradiation dose. Our results reveal neutron irradiation effects on the microstructure and macroscopic dimension, which are consistent with previous work. The methodology used in this work enables the quantification of the damage on the microstructure of nuclear graphite induced by neutron irradiation.

Keywords: nuclear graphite, neutron irradiation, thermal annealing, recovery behavior, dimensional change, CARBONX, XRD analysis

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17 Co-Liquefaction of Cellulosic Biomass and Waste Plastics

Authors: Katsumi Hirano, Yusuke Kakuta, Koji Yoshida, Shozo Itagaki, Masahiko Kajioka, Toshihiko Okada


A conversion technology of cellulosic biomass and waste plastics to liquid fuel at low pressure and low temperature has been investigated. This study aims at the production of the liquefied fuel (CPLF) of substituting diesel oil by mixing cellulosic biomass and waste plastics in the presence of solvent. Co-liquefaction of cellulosic biomass (Japan cedar) and polypropylene (PP) using wood tar or mineral oil as solvent at 673K with an autoclave was carried out. It was confirmed that the co-liquefaction gave CPLF in a high yield among the cases of wood or of polypropylene Which was ascribed the acceleration of decomposition of plastics by radicals derived from the decomposition of wood. The co-liquefaction was also conducted by a small twin screw extruder. It was found that CPLF was obtained in the co-liquefaction, And the acceleration of decomposition of plastics in the presence of cellulosic biomass. The engine test of CPLF showed that the engine performances, Compression ignition and combustion characteristics were almost similar to those of diesel fuel at any mixing ratio of CPLF and any load, Therefore, CPLF could be practically used as alternative fuel for diesel engines.

Keywords: Cellulosic Biomass, Co-liquefaction, Solvent, Waste Plastics

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16 Carbothermic Reduction of Phosphoric Acid Extracted from Dephosphorization Slags to Produce Yellow Phosphorus

Authors: Ryoko Yoshida, Jyunpei Yoshida, Hua Fang Yu, Yasushi Sasaki, Tetsuya Nagasaka


Phosphorous is an important element for agriculture and industry and is a non-renewable resource. Especially, yellow phosphorus is an essential material in advanced industrial technology, but phosphorus resources were not produced in Japan at all, and all depend on imports. It has been suggested, however, that the remaining accessible reserves of phosphate ore will be depleted within 50 years. Therefore, alternative resources for phosphate ore must be found. In this research, we have developed a process that enables the production of high-purity yellow phosphorus from domestic unused phosphorus resources such as steelmaking slags. The process consists of two parts: (1) the production of crude phosphoric acid from wastes such as steelmaking slag; (2) producing high-purity yellow phosphorus by low-temperature carbothermic reduction of phosphoric acid (H3PO4). The details of the carbothermic reduction of phosphoric acid are presented in this paper. Yellow phosphorus is commercially produced by carbothermic reduction of phosphate ore in an electric arc furnace at more than 1673K. In the newly developed system, gaseous P4O10 evaporated from H3PO4 is successfully reduced to yellow phosphorus by using carbon packed bed at less than 1273K. To meet the depletion of phosphate ore, the proposed process in this study to produce yellow phosphorus by carbothermic reduction of H3PO4 that are extracted from dephosphorization slags will be one of the effective and economical solutions.

Keywords: carbothermic reduction, phosphoric acid, dephosphorization slags, yellow phosphorus

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15 Slice Bispectrogram Analysis-Based Classification of Environmental Sounds Using Convolutional Neural Network

Authors: Katsumi Hirata


Certain systems can function well only if they recognize the sound environment as humans do. In this research, we focus on sound classification by adopting a convolutional neural network and aim to develop a method that automatically classifies various environmental sounds. Although the neural network is a powerful technique, the performance depends on the type of input data. Therefore, we propose an approach via a slice bispectrogram, which is a third-order spectrogram and is a slice version of the amplitude for the short-time bispectrum. This paper explains the slice bispectrogram and discusses the effectiveness of the derived method by evaluating the experimental results using the ESC‑50 sound dataset. As a result, the proposed scheme gives high accuracy and stability. Furthermore, some relationship between the accuracy and non-Gaussianity of sound signals was confirmed.

Keywords: environmental sound, bispectrum, spectrogram, slice bispectrogram, convolutional neural network

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14 Estimating 3D-Position of a Stationary Random Acoustic Source Using Bispectral Analysis of 4-Point Detected Signals

Authors: Katsumi Hirata


To develop the useful acoustic environmental recognition system, the method of estimating 3D-position of a stationary random acoustic source using bispectral analysis of 4-point detected signals is proposed. The method uses information about amplitude attenuation and propagation delay extracted from amplitude ratios and angles of auto- and cross-bispectra of the detected signals. It is expected that using bispectral analysis affects less influence of Gaussian noises than using conventional power spectral one. In this paper, the basic principle of the method is mentioned first, and its validity and features are considered from results of the fundamental experiments assumed ideal circumstances.

Keywords: 4-point detection, a stationary random acoustic source, auto- and cross-bispectra, estimation of 3D-position

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13 Incremental Learning of Independent Topic Analysis

Authors: Takahiro Nishigaki, Katsumi Nitta, Takashi Onoda


In this paper, we present a method of applying Independent Topic Analysis (ITA) to increasing the number of document data. The number of document data has been increasing since the spread of the Internet. ITA was presented as one method to analyze the document data. ITA is a method for extracting the independent topics from the document data by using the Independent Component Analysis (ICA). ICA is a technique in the signal processing; however, it is difficult to apply the ITA to increasing number of document data. Because ITA must use the all document data so temporal and spatial cost is very high. Therefore, we present Incremental ITA which extracts the independent topics from increasing number of document data. Incremental ITA is a method of updating the independent topics when the document data is added after extracted the independent topics from a just previous the data. In addition, Incremental ITA updates the independent topics when the document data is added. And we show the result applied Incremental ITA to benchmark datasets.

Keywords: text mining, topic extraction, independent, incremental, independent component analysis

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12 BECOME: Body Experience-Based Co-Operation between Juveniles through Mutually Excited Team Gameplay

Authors: Tsugunosuke Sakai, Haruya Tamaki, Ryuichi Yoshida, Ryohei Egusa, Etsuji Yamaguchi, Shigenori Inagaki, Fusako Kusunoki, Miki Namatame, Masanori Sugimoto, Hiroshi Mizoguchi


We aim to develop a full-body interaction game that could let children cooperate and interact with other children in small groups. As the first step for our aim, the objective of the full-body interaction game developed in this study is to make interaction between children. The game requires two children to jump together with the same timing. We let children experience the game and answer the questionnaires. The children using several strategies to coordinate the timing of their jumps were observed. These included shouting time, watching each other, and jumping in a constant rhythm as if they were skipping rope. In this manner, we observed the children playing the game while cooperating with each other. The results of a questionnaire to evaluate the proposed interactive game indicate that the jumping game was a very enjoyable experience in which the participants could immerse themselves. Therefore, the game enabled children to experience cooperation with others by using body movements.

Keywords: children, cooperation, full-body interaction game, kinect sensor

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11 The Potential of Hydrophobically Modified Chitosan Cryogels to Be Used as Drug Delivery Systems

Authors: Courtney Evans, Yuto Morimitsu, Tsubasa Hisadome, Futo Inomoto, Masahiro Yoshida, Takayuki Takei


Hydrogels are useful biomaterials due to their highly biocompatible nature and their ability to absorb large quantities of liquid and mimic soft tissue. They are often used as therapeutic drug delivery systems. However, it is sometimes difficult to sustain controlled release when using hydrophobic medicines, as hydrogels are frequently hydrophilic. As such, this research shows the success of chitosan hydrogels modified through hydrophobic interaction. This was done through the imide bonding of the alkyl groups in fatty aldehydes and the amino groups in chitosan, followed by reductive animation. The resulting cryogels could be optimized for strength as well as sorption and desorption (of a hydrophobic dye used to mimic hydrophobic medicine) by varying the alkyl chain length and the substitution degree of the fatty aldehyde. Optimized cryogels showed potential as biomedical materials, particularly as drug delivery systems.

Keywords: biomedical materials, chitosan, drug carriers, hydrophobic modification

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10 Sunshine Hour as a Factor to Maintain the Circadian Rhythm of Heart Rate: Analysis of Ambulatory ECG and Weather Big Data

Authors: Emi Yuda, Yutaka Yoshida, Junichiro Hayano


Distinct circadian rhythm of activity, i.e., high activity during the day and deep rest at night are a typical feature of a healthy lifestyle. Exposure to the skylight is thought to be an important factor to increase arousal level and maintain normal circadian rhythm. To examine whether sunshine hours influence the day-night contract of activity, we analyzed the relationship between 24-hour heart rate (HR) and weather data of the recording day. We analyzed data in 36,500 males and 49,854 females of Allostatic State Mapping by Ambulatory ECG Repository (ALLSTAR) database in Japan. Median (IQR) sunshine duration was 5.3 (2.8-7.9) hr. While sunshine hours had only modest effects of increasing 24-hour average HR in either gender (P=0.0282 and 0.0248 for male and female) and no significant effects on nighttime HR in either gender, it increased daytime HR (P = 0.0007 and 0.0015) and day-night HF difference in both genders (P < 0.0001 for both) even after adjusting for the effects of average temperature, atmospheric pressure, and humidity. Our observations support for the hypothesis that longer sunshine hours enhance circadian rhythm of activity.

Keywords: big data, circadian rhythm, heart rate, sunshine

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9 Effects of a Bacteria-Based Probiotic on Subpopulations of Peripheral Leukocytes and Their Interleukin mRNA Expression in Calves

Authors: Abdul Qadir Qadis, Satoru Goya, Minoru Yatsu, Yu-uki Yoshida, Toshihiro Ichijo, Shigeru Sato


Bacterial probiotics are known to modulate the gut-associated lymphoid and epithelial tissue response to enhance the activities of intestinal and systemic immune system in human and animals. In cattle, the immune-stimulatory effects of probiotics have been evaluated during intestinal disorders. To investigate the effects of probiotic on the function of peripheral blood mononuclear cells, eight healthy Holstein calves (10 ± 3 weeks) were assigned to a 4 × 2 experimental design. The probiotic, consisting of Lactobacillus plantarum, Enterococcus faecium and Clostridium butyricum, was administered orally at 3.0 g/100 kg body weight to calves once daily for 5 consecutive days. Calves given no probiotic served as the control. In the treatment group, increases in numbers of CD282+ monocytes, CD3+ T-cells and CD4+, CD8+ and WC1+ γδ T- cell subsets were noted on day 7 post-placement compared to pre-dose day and the control group. Expression of interleukin-6, interferon-gamma and tumor necrosis factor-alpha was elevated in peripheral leukocytes on days 7 and 14. These results suggest that peripheral blood leukocytes in healthy calves may be stimulated via the gastrointestinal microbiota, which was increased by the oral probiotic treatment. The 5-day repeated administration of a bacterial probiotic may enhance cellular immune function in weaned calves.

Keywords: bacterial-probiotic, calf, interleukin, leukocyte

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8 Mercury Contamination of Wetland Caused by Wastewater from Chlor-Alkali Industry

Authors: Mitsuo Yoshida


A significant mercury contamination of soil/sediment was unveiled by an environmental monitoring program in a wetland along La Plata River, west to Montevideo City, Uruguay. The mercury contamination was caused by industrial wastewater discharged from a chlor-alkali plant using a mercury-cell process. The contamination level is above 60 mg/kg in soil/sediment. Most of mercury (Hg) in the environment is inorganic, but some fractions are converted by bacteria to methylmercury (MeHg), a toxic organic compound. MeHg biologically accumulates through a food-chain and become serious public health risk. In order to clarify the contaminated part for countermeasure operation, an intervention value of mercury contamination of sediment/soil was defined as 15 mg/kg (total Hg) by the authority. According to the intervention value, mercury contaminated area in the La Plata site is approximately 48,280 m² and estimated total volume of contaminated sediments/soils was around 18,750 m³. The countermeasures to contaminated zone were proposed in two stages; (i) mitigation of risks for public health and (ii) site remediation. The first stage is an installation of fens and net around the contamination zone, for mitigating risks of exposure, inhalation, and intake. The food chain among wetland-river ecosystem was also interrupted by the installation of net and fens. The state of mercury contamination in La Plata site and plan of countermeasure was disclosed to local people and the public, and consensus on setting off-limit area was successfully achieved. Mass media also contribute to share the information on the contamination site. The cost for countermeasures was borne by the industry under the polluter-pay-principle.

Keywords: chlor-alkali plant, mercury contamination, polluter pay principle, Uruguay, wetland

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7 Quality Control of 99mTc-Labeled Radiopharmaceuticals Using the Chromatography Strips

Authors: Yasuyuki Takahashi, Akemi Yoshida, Hirotaka Shimada


99mTc-2-methoxy-isobutyl-isonitrile (MIBI) and 99mTcmercaptoacetylgylcylglycyl-glycine (MAG3 ) are heat to 368-372K and are labeled with 99mTc-pertechnetate. Quality control (QC) of 99mTc-labeled radiopharmaceuticals is performed at hospitals, using liquid chromatography, which is difficult to perform in general hospitals. We used chromatography strips to simplify QC and investigated the effects of the test procedures on quality control. In this study is 99mTc- MAG3. Solvent using chloroform + acetone + tetrahydrofuran, and the gamma counter was ARC-380CL. The changed conditions are as follows; heating temperature, resting time after labeled, and expiration year for use: which were 293, 313, 333, 353 and 372K; 15 min (293K and 372K) and 1 hour (293K); and 2011, 2012, 2013, 2014 and 2015 respectively were tested. Measurement time using the gamma counter was one minute. A nuclear medical clinician decided the quality of the preparation in judging the usability of the retest agent. Two people conducted the test procedure twice, in order to compare reproducibility. The percentage of radiochemical purity (% RCP) was approximately 50% under insufficient heat treatment, which improved as the temperature and heating time increased. Moreover, the % RCP improved with time even under low temperatures. Furthermore, there was no deterioration with time after the expiration date. The objective of these tests was to determine soluble 99mTc impurities, including 99mTc-pertechnetate and the hydrolyzed-reduced 99mTc. Therefore, we assumed that insufficient heating and heating to operational errors in the labeling. It is concluded that quality control is a necessary procedure in nuclear medicine to ensure safe scanning. It is suggested that labeling is necessary to identify specifications.

Keywords: quality control, tc-99m labeled radio-pharmaceutical, chromatography strip, nuclear medicine

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6 Dermatological Study on Risk Factors for Pruritic Skin: Skin Properties of Elderly

Authors: Dianis Wulan Sari, Takeo Minematsu, Mikako Yoshida, Hiromi Sanada


Introduction: Pruritus is diagnosed as itching without macroscopic abnormalities on skin. It is the most skin complaint of elderly people. In the present study, we conducted a dermatological study to examine the risk factors of pruritic skin and predicted how to prevent pruritus especially in the elderly population. Pruritus is caused several types of inflammation, including epidermal innate immunity based on keratinocyte responses and acquired immunity regulated by type 1 or 2 helper T (Th) cells. The triggers of pruritus differ among inflammation types, therefore we did separately assess the pruritus-associated factors of each inflammation type in an effort to contribute to the identification of intervention targets for preventing pruritus. Therefore, this study aimed to investigate the factors related with actual condition of pruritic skin by examine the skin properties. Method: This study was conducted in elderly population of Indonesian nursing home. Basic characteristics and behaviors were obtained by interview. The properties of pruritic skin were collected by examination of skin biomarker using skin blotting as novel method of non-invasive skin assessment method and examination of skin barrier function using stratum corneum hydration and skin pH. Result: The average age of participants was 74 years with independent status was 66.8%. Age (β = -0.130, p = 0.044), cumulative lifetime sun exposure (β = 0.145, p = 0.026), bathing duration (β = 0.151, p = 0.022), clothing change frequency (β = 0.135, p = 0.029), and clothing type (β = -0.139, p = 0.021) were risk factors of pruritic skin in multivariate analysis. Conclusion: Risk factors of pruritic skin in elderly population were caused by internal factors such as skin senescence and external factors such as sun exposure, hygiene care and skin care behavior.

Keywords: aging, hygiene care, pruritus, skin care, sun exposure

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5 Feasibility Study on the Use of HEMS for Thermal Comfort and Energy Saving in Japanese Residential Buildings

Authors: K. C. Rajan, H. B. Rijal, Kazui Yoshida, Masanori Shukuya


The electricity consumption in the Japanese household sector has increased with higher rate than that of other sectors. This may be because of aging and information oriented society that requires more electrical appliances to make the life better and easier, under this circumstances, energy saving is one of the essential necessity in Japanese society. To understand the way of energy use and demand response of the residential occupants, it is important to understand the structure of energy used. Home Energy Management System (HEMS) may be used for understanding the pattern and the structure of energy used. HEMS is a visualization system of the energy usage by connecting the electrical equipment in the home and thereby automatically control the energy use in each device, so that the energy saving is achieved. Therefore, the HEMS can provide with the easiest way to understand the structure of energy use. The HEMS has entered the mainstream of the Japanese market. The objective of this study is to understand the pattern of energy saving and cost saving in different regions including Japan during HEMS use. To observe thermal comfort level of HEMS managed residential buildings in Japan, the field survey was made and altogether, 1534 votes from 37 occupants related to thermal comfort, occupants’ behaviors and clothing insulation were collected and analyzed. According to the result obtained, approximately 17.9% energy saving and 8.9% cost saving is possible if HEMS is applied effectively. We found the thermal sensation and overall comfort level of the occupants is high in the studied buildings. The occupants residing in those HEMS buildings are satisfied with the thermal environment and they have accepted it. Our study concluded that the significant reduction in Japanese residential energy use can be achieved by the proper utilization of the HEMS. Better thermal comfort is also possible with the use of HEMS if energy use is managed in a rationally effective manner.

Keywords: energy reduction, thermal comfort, HEMS utility, thermal environment

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4 Creating Complementary Bi-Modal Learning Environments: An Exploratory Study Combining Online and Classroom Techniques

Authors: Justin P. Pool, Haruyo Yoshida


This research focuses on the effects of creating an English as a foreign language curriculum that combines online learning and classroom teaching in a complementary manner. Through pre- and post-test results, teacher observation, and learner reflection, it will be shown that learners can benefit from online programs focusing on receptive skills if combined with a communicative classroom environment that encourages learners to develop their productive skills. Much research has lamented the fact that many modern mobile assisted language learning apps do not take advantage of the affordances of modern technology by focusing only on receptive skills rather than inviting learners to interact with one another and develop communities of practice. This research takes into account the realities of the state of such apps and focuses on how to best create a curriculum that complements apps which focus on receptive skills. The research involved 15 adult learners working for a business in Japan simultaneously engaging in 1) a commercial online English language learning application that focused on reading, listening, grammar, and vocabulary and 2) a 15-week class focused on communicative language teaching, presentation skills, and mitigation of error aversion tendencies. Participants of the study experienced large gains on a standardized test, increased motivation and willingness to communicate, and asserted that they felt more confident regarding English communication. Moreover, learners continued to study independently at higher rates after the study than they had before the onset of the program. This paper will include the details of the program, reveal the improvement in test scores, share learner reflections, and critically view current evaluation models for mobile assisted language learning applications.

Keywords: adult learners, communicative language teaching, mobile assisted language learning, motivation

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3 UKIYO-E: User Knowledge Improvement Based on Youth Oriented Entertainment, Art Appreciation Support by Interacting with Picture

Authors: Haruya Tamaki, Tsugunosuke Sakai, Ryuichi Yoshida, Ryohei Egusa, Shigenori Inagaki, Etsuji Yamaguchi, Fusako Kusunoki, Miki Namatame, Masanori Sugimoto, Hiroshi Mizoguchi


Art appreciation is important as part of children education. Art appreciation can enrich sensibility and creativity. To enrich sensibility and creativity, the children have to learning knowledge of picture such as social and historical backgrounds and author intention. High learning effect can acquire by actively learning. In short, it is important that encourage learning of the knowledge about pictures actively. It is necessary that children feel like interest to encourage learning of the knowledge about pictures actively. In a general art museum, comments on pictures are done through writing. Thus, we expect that this method cannot arouse the interest of the children in pictures, because children feel like boring. In brief, learning about the picture information is difficult. Therefore, we are developing an art-appreciation support system that will encourage learning of the knowledge about pictures actively by children feel like interest. This system uses that Interacting with Pictures to learning of the knowledge about pictures. To Interacting with Pictures, children have to utterance by themselves. We expect that will encourage learning of the knowledge about pictures actively by Interacting with Pictures. To more actively learning, children can choose who talking with by information that location and movement of the children. This system must be able to acquire real-time knowledge of the location, movement, and voice of the children. We utilize the Microsoft’s Kinect v2 sensor and its library, namely, Kinect for Windows SDK and Speech Platform SDK v11 for this purpose. By using these sensor and library, we can determine the location, movement, and voice of the children. As the first step of this system, we developed ukiyo-e game that use ukiyo-e to appreciation object. Ukiyo-e is a traditional Japanese graphic art that has influenced the western society. Therefore, we believe that the ukiyo-e game will be appreciated. In this study, we applied talking to pictures to learn information about the pictures because we believe that learning information about the pictures by talking to the pictures is more interesting than commenting on the pictures using only texts. However, we cannot confirm if talking to the pictures is more interesting than commenting using texts only. Thus, we evaluated through EDA measurement whether the user develops an interest in the pictures while talking to them using voice recognition or by commenting on the pictures using texts only. Hence, we evaluated that children have interest to picture while talking to them using voice recognition through EDA measurement. In addition, we quantitatively evaluate that enjoyed this game or not and learning information about the pictures for primary schoolchildren. In this paper, we summarize these two evaluation results.

Keywords: actively learning, art appreciation, EDA, Kinect V2

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2 Time Lag Analysis for Readiness Potential by a Firing Pattern Controller Model of a Motor Nerve System Considered Innervation and Jitter

Authors: Yuko Ishiwaka, Tomohiro Yoshida, Tadateru Itoh


Human makes preparation called readiness potential unconsciously (RP) before awareness of their own decision. For example, when recognizing a button and pressing the button, the RP peaks are observed 200 ms before the initiation of the movement. It has been known that the preparatory movements are acquired before actual movements, but it has not been still well understood how humans can obtain the RP during their growth. On the proposition of why the brain must respond earlier, we assume that humans have to adopt the dangerous environment to survive and then obtain the behavior to cover the various time lags distributed in the body. Without RP, humans cannot take action quickly to avoid dangerous situations. In taking action, the brain makes decisions, and signals are transmitted through the Spinal Cord to the muscles to the body moves according to the laws of physics. Our research focuses on the time lag of the neuron signal transmitting from a brain to muscle via a spinal cord. This time lag is one of the essential factors for readiness potential. We propose a firing pattern controller model of a motor nerve system considered innervation and jitter, which produces time lag. In our simulation, we adopt innervation and jitter in our proposed muscle-skeleton model, because these two factors can create infinitesimal time lag. Q10 Hodgkin Huxley model to calculate action potentials is also adopted because the refractory period produces a more significant time lag for continuous firing. Keeping constant power of muscle requires cooperation firing of motor neurons because a refractory period stifles the continuous firing of a neuron. One more factor in producing time lag is slow or fast-twitch. The Expanded Hill Type model is adopted to calculate power and time lag. We will simulate our model of muscle skeleton model by controlling the firing pattern and discuss the relationship between the time lag of physics and neurons. For our discussion, we analyze the time lag with our simulation for knee bending. The law of inertia caused the most influential time lag. The next most crucial time lag was the time to generate the action potential induced by innervation and jitter. In our simulation, the time lag at the beginning of the knee movement is 202ms to 203.5ms. It means that readiness potential should be prepared more than 200ms before decision making.

Keywords: firing patterns, innervation, jitter, motor nerve system, readiness potential

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1 Membrane Permeability of Middle Molecules: A Computational Chemistry Approach

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


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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