Tag: Japan

Dendritic structures that emerge during the growth of thin films are a major obstacle in large-area fabrication, a key step towards commercialization. However, current methods of studying dendrites involve crude visual inspection and subjective analysis. Moreover, growth optimization methods for controlling dendrite formation require extensive trial and error. Now, researchers have developed a new AI model that incorporates topology analysis and free energy to reveal the specific conditions and mechanisms that drive dendrite branching.

Thin film devices, composed of layers of materials a few nanometers thick, play an important role in various technologies, from semiconductors to communication technologies. For instance, graphene and hexagonal-boron nitride (h-BN) multilayer thin films, deposited on copper substrates, are promising materials for next-generation high-speed communications systems. Thin films are grown by depositing tiny layers of materials onto a substrate. The growth process conditions significantly influence the microstructure of these films, which in turn influences their function and performance.

Dendritic structures, or tree-like branching patterns that emerge during growth, pose a major challenge to large-area fabrication of thin-film devices, a key step toward commercial application. They are commonly observed in materials like copper, graphene, and borophene, particularly in the early growth stage and multilayer films. Since the microstructure directly impacts device performance, reducing dendritic formation is, therefore, critical. However, methods for studying dendrites have largely relied on crude visual analysis and subjective interpretation. Understanding the conditions that drive dendritic branching is essential for optimizing the thin-film growth process, but existing approaches often require considerable trial and error.

To address these challenges, a research team, led by Professor Masato Kotsugi from the Department of Material Science and Technology at Tokyo University of Science (TUS), Japan, developed an innovative explainable artificial intelligence (AI) model for analyzing dendritic structures. The team included Misato Tone, also from TUS, and Ippei Obayashi from Okayama University. The team developed a novel method that bridges structure and process in dendritic growth by integrating persistent homology and machine learning with energy analysis. “Our approach provides new insights into growth mechanisms and offers a powerful, data-driven pathway for optimizing thin-film fabrication,” explains Prof. Kotsugi. Their study was published online in Science and Technology of Advanced Materials: Methods on March 7, 2025.

To analyze the morphology of dendrite structures, the team used a cutting-edge topology method called persistent homology (PH). PH enables multiscale analysis of holes and connections within geometric structures, capturing the complex topological features of the tree-like dendrite microstructures that conventional image processing techniques often overlook.

The researchers combined PH with principal component analysis (PCA), a machine learning technique. Through PCA, the essential features of the dendrite morphology extracted via PH were reduced to a two-dimensional space. This enabled the team to quantify structural changes in dendrites and establish a relationship between these changes and Gibbs free energy, or the energy available in a material that influences how dendrites form during crystal growth. By analyzing this relationship, they uncovered the specific conditions and hidden growth mechanisms that influence dendritic branching. Prof. Kotsugi explains, “Our framework quantitatively maps dendritic morphology to Gibbs free energy variations, revealing energy gradients that drive branching behavior.”

To validate their approach, the researchers studied dendrite growth in a hexagonal copper substrate and compared their results with data from phase-field simulations.

“By integrating topology and free energy, our method offers a versatile approach to material analysis. Through this integration, we can establish a hierarchical connection between atomic-scale microstructures and macroscopic functionalities across a wide range of materials, paving the way for future advancements in material science,” remarks Prof. Kotsugi. “Importantly, our method could lead to the development of high-quality thin-film devices leading to high-speed communication beyond 5G.”

This study’s framework could pave the way for breakthroughs in sensor technology, nonequilibrium physics, and high-performance materials by uncovering hidden structure-function relationships and advancing complex system analysis.

Overuse of chemical pesticides has driven resistance in agricultural pests, including the adaptable two-spotted spider mite. Researchers from Japan have discovered novel elicitor proteins, Tet3 and Tet4, in mite saliva that could enhance sustainable pest control. They found that these proteins play a crucial role in modulating plant defense responses by acting as key players in the complex interactions between parasite and host, paving the way for new mite countermeasures.

As global food demand continues to increase, effective pest control remains one of agriculture’s most pressing challenges. Worldwide, farmers apply nearly 4 million tons of chemical pesticides annually to protect their crops, representing a $60 billion industry. While these compounds have significantly boosted agricultural productivity, their widespread use has raised concerns regarding environmental impact, health risks, and the long-term sustainability of modern farming.

The two-spotted spider mite, Tetranychus urticae, exemplifies the limitations of conventional pesticide-based pest management in agriculture and horticulture. These microscopic arachnids infest a wide range of crops and fruit trees and can reproduce extremely quickly. More importantly, unlike many other pests, they rapidly develop resistance to chemical pesticides, making control efforts increasingly challenging. With pesticide resistance on the rise, farmers worldwide are urgently seeking alternative, sustainable pest control strategies.

A research team led by Professor Gen-ichiro Arimura from the Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Japan, closely examined the fine molecular interplay that occurs between T. urticae mites and their host plants. Their study was published online in The Plant Journal on March 4, 2025. The team focused on specific substances called elicitors, secreted by T. urticae, and examined their biological effects on various crops.

“An elicitor is a molecule that plants or pests possess that can enhance the defense response of plants,” explains Prof. Arimura. “In our previous research, we identified two tetranins, labeled Tet1 and Tet2, as elicitors in the salivary glands of two-spotted spider mites; these substances induce defense responses in the common bean and other commercially important crops.”

The research team investigated the effects of an additional 18 salivary gland proteins on the resistance of common bean leaves to T. urticae. According to this initial screening, they identified two new tetranins—Tet3 and Tet4—that appear to reduce the reproduction of spider mites on the plants.

After a series of experiments involving genetic engineering and advanced molecular and biochemical methods, the team uncovered the roles of Tet3 and Tet4 in the complex interactions between T. urticae and its host plants. Interestingly, they found that the expression of Tet3 and Tet4 varies greatly depending on which plant the mites fed on. Mites feeding on common beans, their preferred host, had significantly higher levels of Tet3 and Tet4 expression than those on cucumbers, a less preferred option.

Notably, plants exposed to mites with higher expression of Tet3 and Tet4 exhibited stronger defense responses, including increased calcium-ion influx, higher generation of reactive oxygen species, and elevated expression of a defensive gene named PR1. The individual application of Tet3 and Tet4 to plants had different effects on plant defense responses, highlighting the specificity of each elicitor’s role. “Taken together, our findings show that these tetranins respond to variable host cues that may optimize herbivore fitness by altering the anti-mite response of the host plant,” remarks Prof. Arimura.

The implications of these findings are twofold. First, understanding the molecular mechanisms that underlie interactions between organisms leads to a better understanding of evolution, ecosystems, and biodiversity. Elicitors such as tetranins act as crucial links in these complex systems, making their detailed study essential for uncovering broader biological insights. From an agricultural perspective, tetranins and similar elicitors offer potential for crop improvement, as insights into the elicitor-sensing system can aid in breeding more sensitive and resilient crops. “Elicitors may be useful as biostimulants that can increase the potential pest resistance of plants,” highlights Prof. Arimura. “The development of such organic farming techniques is extremely meaningful in today’s world, as the environmental and ecological impact of heavy pesticide use grows more severe. Hopefully, identifying elicitors secreted by pests and elucidating their functions will lead to unprecedented spider mite countermeasures.”

With continued research, this fascinating topic could contribute to more sustainable agriculture and enhanced food safety.

Irritable bowel syndrome (IBS) is a common digestive disorder with unclear causes, affecting about 10% of the global population. Researchers from Japan have now discovered that opioid delta-receptor agonists may alleviate IBS symptoms by acting directly on the central nervous system. Using a novel stress-induced mouse model, they found these drugs reduce abdominal pain and regulate bowel movements. This research suggests a promising approach to treating IBS by targeting stress as a contributing factor.

Irritable bowel syndrome (IBS) is a common digestive disorder that affects the intestine, causing symptoms such as abdominal pain, bloating, gas, and changes in bowel habits, including diarrhea, constipation, or both. Although this condition affects about a tenth of the global population, the underlying causes and mechanisms of IBS remain unclear. Consequently, treatments for IBS primarily focus on managing symptoms rather than addressing the root cause of the disorder.

At Tokyo University of Science (TUS), Japan, Professor Akiyoshi Saitoh and his research group have spent the past decade exploring this topic. This study published online in the British Journal of Pharmacology on December 25, 2024, discovered that a class of drugs called opioid delta-receptor (DOP) agonists may help alleviate IBS symptoms by targeting the central nervous system rather than acting directly on the intestine. This study was co-authored by Toshinori Yoshioka, a third-year PhD student at TUS.

One of the main motivations for this study was the growing evidence linking IBS closely to psychological stress. Saitoh’s group aimed to address this potential root cause by focusing on finding a novel animal model for this condition. In a study published in 2022, they developed a mice model repeatedly exposed to psychological stress—using a method called chronic vicarious social defeat stress (cVSDS)—which developed symptoms similar to a type of IBS called IBS-D. These symptoms included overly active intestines and heightened sensitivity to abdominal pain, even though their organs showed no physical damage. The cVSDS animal model involved having the subject mouse repeatedly witness a territorial, aggressive mouse defeating a cage mate, inducing indirect chronic stress.

Using the cVSDS model, the researchers sought to determine whether DOP in the brain, which is closely linked to pain and mood regulation, could serve as promising drug targets for treating stress-induced IBS. To achieve this, they performed a series of detailed experiments to observe the effects of DOP agonists on IBS symptoms and chemical signaling in the brain. Some experiments involved measuring the speed of a charcoal meal through the intestine to assess gastrointestinal motility and evaluate the impact of stress or treatments on bowel movement speed, along with directly measuring neurotransmitter concentrations using in vivo brain microdialysis. This revealed that re-exposure to VSDS increased glutamate levels in the insular cortex, but these elevated levels were normalized with DOP agonists.

According to the results, the administration of DOP agonists helped relieve abdominal pain and regulated bowel movements in cVSDS mice. Interestingly, applying the DOP agonists directly to a specific brain region called the insular cortex had similar effects on IBS symptoms as systemic treatment. “Our findings demonstrated that DOP agonists acted directly on the central nervous system to improve diarrhea-predominant IBS symptoms in mice, and suggest that the mechanism of action involves the regulation of glutamate neurotransmission in the insular cortex,” highlights Saitoh.

Taken together, the continued research by Saitoh’s group on this topic could pave the way for effective treatments for IBS. “DOP agonists could represent a groundbreaking new IBS treatment that not only improves IBS-like symptoms but also provides anti-stress and emotional regulation effects. In the future, we would like to conduct clinical developments with the goal of expanding the indication of DOP agonists for IBS, in addition to depression,” remarks Saitoh.

Compared to currently available IBS treatments, such as laxatives, antidiarrheals, analgesics, and antispasmodics, targeting the underlying stress with DOP agonists may offer a more definitive solution with minimal adverse effects. Further clarification of the roles of stress and brain chemistry in the development of IBS will be essential in achieving this much-needed medical breakthrough. With promising prospects, future studies will translate Saitoh’s group’s findings to humans, bringing great relief to those affected by IBS.

Ising machines are specialized computing systems designed to solve complex optimization problems by arranging “spins” to minimize system energy. However, their fully connected architecture leads to a large circuit footprint, limiting scalability. In a recent study, researchers from Japan developed a method to halve the required spin–spin interactions using a novel matrix-folding technique. Their findings will pave the way for highly scalable Ising machines, making them more practical for real-world applications.

Computers are essential for solving complex problems in fields, like scheduling, logistics,
and route planning, but traditional computers struggle with large-scale combinatorial optimization, as they can’t efficiently process vast numbers of possibilities. To address this, researchers have explored specialized systems.

One such system is the Hopfield network, a significant artificial intelligence breakthrough from 1982, proven in 1985 to solve combinatorial optimization by representing solutions as energy levels and naturally finding the lowest energy, or optimal, solution. Building on similar ideas, Ising machines use the principles of magnetic spin to find efficient solutions by minimizing system energy through a process akin to annealing. However, a major challenge with Ising machines is their large circuit footprint, especially in fully connected
systems where every spin interacts with others, complicating their scalability.

Fortunately, a research team from the Tokyo University of Science, Japan, has been working towards finding solutions to this problem related to Ising machines. In a recent study led by Professor Takayuki Kawahara, they reported an innovative method that can halve the number of interactions that need to be physically implemented. Their findings were published in the journal IEEE Access on October 01, 2024.

The proposed method focuses on visualizing the interactions between spins as a two-dimensional matrix, where each element represents the interaction between two specific spins. Since these interactions are ‘symmetric’ (i.e., the interaction between Spin 1 and Spin 2 is the same as that between Spin 2 and Spin 1), half of the interaction matrix is redundant and can be omitted—this concept has been around for several years. In 2020, Prof. Kawahara and colleagues presented a method to fold and rearrange the remaining half of the interaction matrix into a rectangle shape to minimize the circuit footprint.
While this led to efficient parallel computations, the wiring required to read the interactions and update the spin values became more complex and harder to scale up.

In this study, the researchers proposed a different way of halving the interaction matrix that leads to better scalability in circuitry. They divided the matrix into four sections and halved each of these sections individually, alternatively preserving either the ‘top’ or ‘bottom’ halves of each submatrix. Then, they folded and rearranged the remaining elements into a rectangular shape, unlike the previous approach, which retained the regularity of its arrangement.

Leveraging this crucial detail, the researchers implemented a fully coupled Ising machine based on this technique on their previously developed custom circuit containing 16 field-programmable gate arrays (FPGAs). “Using the proposed approach, we were able to implement 384 spins on only eight FPGA chips. In other words, two independent and fully connected Ising machines could be implemented on the same board,” remarks Prof. Kawahara, “Using these machines, two classic combinatorial optimization problems were solved simultaneously—namely, the max-cut problem and four-color problem.” 

The performance of the circuit developed for this demo was astounding, especially when compared to how slow a conventional computer would be in the same situation. “We found that the performance ratio of two independent 384-spin fully coupled Ising machines was about 400 times better than simulating one Ising machine on a regular Core i7-4790 CPU to solve the two problems sequentially,” reports Kawahara, excited about the results.

In the future, these cutting-edge developments will pave the way to scalable Ising machines suitable for real-world applications such as faster molecular simulations to accelerate drug and materials discovery. Moreover, improving the efficiency of data centers and the electrical power grid is also feasible to use cases, which align well with global sustainability goals of reducing the carbon footprint of emerging technologies like electric vehicles and 5G/6G telecommunications. As innovations continue to unfold, scalable Ising
machines may soon become invaluable tools across industries, transforming how we tackle some of the world’s most complex optimization challenges.

Scientists from Tokyo University of Science uncover a pivotal enzyme, XccOpgD, and its critical role in synthesizing CβG16α, a key compound used by Xanthomonas pathogens to enhance their virulence against plants. This breakthrough opens new avenues for developing targeted pesticides that combat plant diseases without harming beneficial organisms. Insights into XccOpgD’s enzymatic mechanism and optimal conditions offer promising prospects for sustainable agriculture, bolstering crop resilience and global food security while minimizing environmental impact.

Plant diseases pose significant challenges to agricultural productivity, presenting formidable hurdles that require urgent attention. Left unchecked, these diseases can spread rapidly, inflicting widespread damage on crops and leading to reduced yields and substantial economic losses. Therefore, accurately identifying the pathogens responsible for these diseases is crucial. This identification allows for targeted interventions that minimize risks and effectively mitigate the agricultural impacts.

Xanthomonas species are notorious plant pathogens that affect a broad spectrum of hosts, including key crops like rice, wheat, and tomatoes. These pathogens augment their pathogenicity by utilizing α-1,6-cyclized β-1,2-glucohexadecaose (CβG16α) to suppress essential plant defense mechanisms, such as the expression of pathogenesis-related proteins and the accumulation of callose.

In a recent breakthrough published on June 19, 2024, in the Journal of the American Chemical Society, a team of researchers led by Associate Professor Masahiro Nakajima from Tokyo University of Science unveiled a significant discovery. They identified XccOpgD, a glycoside hydrolase (GH186) found in X. campestris pv campestris which plays a pivotal role in the biosynthesis of CβG16α. The research team also included Mr. Sei Motouchi from Tokyo University of Science, Principal Scientist Shiro Komba from the Institute of Food Research, NARO, and Hiroyuki Nakai from Niigata University.

“Glycan structures are intricate and multifaceted and fulfill diverse crucial roles in nature and organisms. Enzymes synthesize and degrade glycans, exhibiting diverse structures and functions that correspond to the glycan diversity. However, our understanding of these enzymes is still limited, which drives the search for new enzymes with varied new potentials,” explains Prof. Nakajima, elaborating on the study’s rationale.

The team conducted biochemical analysis to elucidate the role of XccOpgD in CβG16α biosynthesis. Advanced techniques such as X-ray crystallography were employed as structural analysis to unravel the enzyme’s catalytic mechanism and substrate specificity.

These efforts have yielded profound insights. XccOpgD belongs to the GH186 family, essential for regulating bacterial cell wall components. Unlike the first identified GH186 enzymes, XccOpgD exhibits an unprecedented enzymatic mechanism known as anomer-inverting transglycosylation.

“Reactions of typical GH enzymes are classified into four types by combination of retaining or inverting, and reaction with water (hydrolysis) or sugar (transglycosylation) theoretically. However, one classification is missing somehow in a long history of researches on carbohydrate associated enzymes and we discovered the missing classification. This breakthrough was made possible by unique structural environment, opening new possibilities for enzyme-based glycosylation,” explains Prof. Nakajima. Moreover, the sugar chains synthesized through this mechanism are not merely minor components but rather essential structures utilized by various Gram-negative bacteria in nature for pathogenic purposes.

Detailed studies revealed that linear β-1,2-glucan was converted to cyclic compound and the compound was identified as CβG16α using nuclear magnetic resonance. Structural analysis of the Michaelis complex identified crucial substrate binding residues, further elucidating specific interactions along the glucan chain. Notably, XccOpgD utilizes an anomer-inverting transglycosylation mechanism, with D379 and D291 playing pivotal roles as catalysts.

These findings deepen our understanding and open avenues for developing targeted strategies against Xanthomonas-induced plant diseases. “We are expecting a pesticide concept targeting this enzyme homolog in the future. Unlike fungicides that promote the emergence of drug-resistant bacteria in soil, targeting this enzyme could potentially inhibit pathogenicity without causing sterilization. Enzyme homologs identified in this study may serve as promising structure-based drug targets, offering a potential solution to the issue of drug-resistant bacteria,” says a hopeful Prof. Nakajima.

The discovery of XccOpgD and its role in CβG16α biosynthesis marks a major breakthrough in agriculture. It promises enhanced resilience and food security while mitigating environmental impacts linked to conventional pesticides. Overall, this advancement offers sustainable solutions to global agricultural challenges, promoting environmental stewardship and economic viability for farmers worldwide.

In a recent breakthrough, researchers at Tokyo University of Science have successfully developed an efficient method to synthesize eutyscoparol A and violaceoid C, two naturally occurring compounds with promising antimalarial and antibacterial properties. The new approach involves the synthesis of these compounds using readily available dinitriles. This method requires fewer steps and produces the bioactive compounds in higher yields compared to previous approaches, opening up new avenues for drug development.

The natural world is rich in chemical compounds with remarkable medicinal properties. A notable example is penicillin, discovered by chance from the Penicillium mold. This discovery revolutionized the treatment of bacterial infections and highlighted the potential of natural compounds in medicine. Since then, the identification, isolation, and synthesis of novel bioactive compounds from plants, fungi, and bacteria have become fundamental to drug development.

Recently, two groups of naturally occurring bioactive compounds have garnered significant attention: violaceoids A–F from the fungus Aspergillus violaceofuscus and eutyscoparols A-G from the fungus Eutypella scoparia. These compounds share similar structures, featuring a 2,3-alkylated quinol moiety and a hydroxymethyl group, and are believed to possess antimalarial and antibacterial properties. Following their initial discovery in 2014 and 2020, scientists have been working to produce these compounds in larger quantities for further study.

In a recent study, researchers from Tokyo University of Science (TUS), led by Associate Professor Takatsugu Murata and Professor Isamu Shiina from the Department of Applied Chemistry, Faculty of Science, have made significant progress by developing an efficient method to synthesize eutyscoparol A and violaceoid C. Their work, featured on the cover of Volume 13, Issue 7 of the Asian Journal of Organic Chemistry, and published on 25 April 2024, could lead to new treatments or drugs.

“Eutyscoparol is a group of compounds whose pharmacological activity had not been thoroughly explored. Our goal was to make this possible through artificial synthesis and support the development of new drugs,” says Dr. Murata.

The researchers used a retrosynthetic analysis to simplify the production process. This approach breaks down complex molecules into simpler, more accessible materials. They used this method to synthesize eutyscoparol A (4) and violaceoid C (3) starting from commercially available dinitriles (6) through violaceoid A (1) intermediates. Dinitriles were chosen because they are easy to obtain and can be converted into aldehydes (5), which are precursors to violaceoid A intermediates. To make the aldehyde (5), dinitrile (6) was first converted into diester. Then, the hydroxy groups in diester were protected with a tert-butyldiphenylsilyl (TBDPS) group to form protected ether. This ether was reduced to form a symmetric diol. One hydroxy group in diol was then selectively protected to create desymmetrized tetrahydropyranyl (THP)-ether, which was oxidized to produce the aldehyde.

With the aldehyde prepared, the researchers proceeded to synthesize violaceoid A (1) and rac-violaceoid B (2) intermediates through a series of reactions. To prepare violaceoid A (1), the aldehyde was first alkylated to form an intermediate, which was then converted to olefin using mesylation or the Julia–Kocienski reagent. The THP-protecting group in olefin was removed with isopropyl alcohol to produce alcohol. Finally, two TBDPS groups were removed from the alcohol to get violaceoid A (1). Rac-violaceoid B (2) was synthesized using similar methods.

These improvements made the process much more efficient. The researchers synthesized violaceoid A (1) in 8 steps with a 33% yield, compared to the previous 10-step process that had only an 11% yield. Similarly, they prepared rac-violaceoid B (rac-2) in 8 steps with a 35% yield, improving on the earlier 9-step process with a 15% yield.

After successfully synthesizing the intermediates, the researchers moved on to produce violaceoid C (3) and eutyscoparol A (4). The synthesis of violaceoid C (3) was relatively straightforward, involving the hydrogenation of the double bond in violaceoid A (1) to yield violaceoid C (3) with high efficiency. For eutyscoparol A (4), the researchers selectively methylated two of the three hydroxy groups in violaceoid A (1) by refluxing the reaction mixture with potassium carbonate and iodomethane. Overall, violaceoid C (3) was synthesized in nine steps with a 30% yield, and eutyscoparol A (4) in nine steps with a 28% yield.

With improved yields and simpler synthesis steps, the proposed approach makes it easier to produce these compounds on a larger scale and could lead to further research into their potential therapeutic properties. “The synthesis of violaceoid A and eutyscoparol C on a subgram scale will help us study their pharmacological effects, which we expect to include cytotoxic, antibacterial, and antimalarial activities,” concludes Prof. Shiina.