Tag: Japan

Colorectal tumors are a common adverse effect of chronic inflammation of the intestine. In a new study, researchers from Japan and China demonstrate that mice models with dendritic cell immunoreceptor (DCIR) protein deficiency are resistant to colonic tumors induced by dextran sodium sulfate and azoxymethane. Further, they identify an antibody that reduces colitis severity and colonic tumor growth, highlighting the potential of DCIR as a therapeutic target.

Inflammatory bowel disease (IBD) is an umbrella term for two diseases, Crohn’s disease and ulcerative colitis, that are characterized by the prolonged inflammation of the gastrointestinal tract. This condition often leads to the development of colorectal tumors. Understanding the pathogenesis of IBD is, therefore, crucial to mitigate the incidence of colonic tumors.

It turns out that innate immune receptors, particularly those expressed in the gut, such as C-type lectin receptors (CLRs), are responsible for the development of IBD. However, CLRs also play a vital role in the regulation of gut microbiota and defense against pathogens. As a result, a balance needs to be struck to maintain intestinal homeostasis.

Dendritic cell immunoreceptor (DCIR) is one such CLR that is responsible for maintaining homeostasis of the immune and skeletal systems. Previous studies have suggested that DCIR negatively regulates both innate and acquired immune responses. Blocking DCIR could, therefore, potentially boost immunity against colon tumor. However, its role in intestinal immunity has remained unclear.

Against this backdrop, a research group led by Professor Yoichiro Iwakura of Tokyo University of Science (TUS) in Japan has now shed light on this issue. In their study, to be published online on 02 August 2022 in the international journal Cell Reports, the group studied the development of colitis and colon tumor in mice models deficient in DCIR.

To this end, the group fed the mice with drinking water containing dextran sodium sulfate (DSS), a synthetic sulfated polysaccharide, and azoxymethane (AOM), a neurotoxic chemical, to induce colon tumors similar to that observed in humans with IBD.

To their surprise, they found that the mice lacking DCIR showed reduced colitis severity and AOM-DSS–induced colorectal tumor growth. Moreover, compared to the wild-type mice (control), the DCIR-deficient mice showed lower body weight loss as well as reduced proinflammatory cell infiltration in the colon.

What do these observations imply? Prof. Iwakura explains, “Our findings point to the fact that intestinal carcinogenesis and inflammation are facilitated by DCIR signalling, which points to the possibility that blocking DCIR might prevent ulcerative colitis and colon cancer.”

Corroborating this possibility, the study further revealed that the use of an antibody called “anti-NA2” against asialo-biantennary-N-glycans (NA2), a ligand (binding molecule) to DCIR, reduced DSS colitis symptoms and prevented colorectal tumor growth.

The researchers are excited by these findings. Speaking about the practical applications of their study, Prof. Iwakura says, “Our results suggest that therapeutics targeting DCIR and its ligands could be used to effectively treat autoimmune diseases, IBD, and cancer, which have been traditionally difficult to treat.”

Sure enough, this study could open doors to novel therapeutic strategies for treating colorectal tumors, improving not only the lives of patients with IBD but also our understanding of the pathogenesis of human diseases.

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Reference

Title of original paper: Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway

Journal: Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2022.111158

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Yoichiro Iwakura from Tokyo University of Science

Professor Yoichiro Iwakura has been the director of the Center for Animal Disease Models at the Tokyo University of Science (TUS) since 2013, and has published numerous papers since his graduation from Kyoto University in 1970. He started researching interferon proteins at the university’s Institute for Virus Research before moving to the Sloan-Kettering Cancer Institute in the United States to analyze the developmental mechanism of early mouse embryos. In 1985, he moved to the University of Tokyo where he generated more than 100 lines of gene-modified mice as the director of the Center for Experimental Medicine to analyze the pathogenesis of infectious and autoimmune diseases.

He retired from the University of Tokyo and became an Emeritus Professor in 2012. He then moved to TUS. He has been a visiting professor for many universities, including Dalian Medical University in China and Chiba University in Japan. His work involves the development and analysis of animal disease models and research on autoimmune diseases and infectious diseases. He won the Hideyo Noguchi Memorial Award for Medical Science in 2015 and was selected as a highly cited researcher (Thomson Reuters and Clarivate Analytics) for six consecutive years from 2014.

In 2017, the Japanese party system took a dramatic turn when the major opposition party split, turning the election into a three-way contest. Long-dormant policy disagreements prompted legislators to switch parties. To understand why, researchers from Japan have recently analyzed post-electoral expert survey data. Their findings reveal both the reasons for the separation and the basis for party cohesion, offering valuable insights into party unity and cohesion.

The transformation of party politics in Japan has been marked by an array of sensational events, from the dominance of the Liberal Democratic Party (LDP) to party fragmentation. Individual legislators switch parties for a number of reasons, including policy considerations. The payoffs from “party switching” are closely linked to electoral and party systems, leading to a shift in the dynamics of party competition.

In Japan, such a situation of party switching was witnessed before the 2017 election. The founding leader of a new party, “Hope,” aggressively politicized an inactive debate regarding defense policy. Several members were persuaded to join the Hope, resulting in the collapse of the largest opposition group, “Minshin,” into three parties. However, there remains a lack of explanation as to why the long-dormant disagreement culminated in such a severe rupture.

To uncover the underlying rationale, a Japanese research group consisting of Junior Associate Professor Tomoko Matsumoto of Tokyo University of Science, Associate Professor Hiroki Kubo of Meiji Gakuin University, and Professor Kentaro Yamamoto of Hokkai-Gakuen University, examined responses on “issue position” and the “salience of party policies” from an expert survey conducted shortly after the 2017 general elections. Speaking of the motivation of the study, Dr. Matsumoto says, “The frequent breakdowns of opposition parties have created uncertainty among voters. By analyzing the expert survey, we hope to understand the structure of oppositional party policies in Japan.” Their seminal study was recently published in Japanese Journal of Political Studies.

The researchers began by assessing the expert responses using the “differential-item functioning (DIF)” analysis of “Aldrich-McKelvey” scaling. They next employed “Blackbox transpose” scaling to examine the multidimensional nature of the issue stances. One important point raised by this study is that traditional DIF analysis assumes diversity in responses is due to perceptional limitations and biases. However, the diversity in this case meant that the parties were unable to discern and convey their policy positions. As a result, a corrected version of the DIF analysis is required. “When we performed the corrected DIF analysis, we realized that the corrected value differed from the average value of the raw data obtained from the responses. In other words, the importance of using responses after rectification was reaffirmed,” reveals Dr. Matsumoto. “This is a huge revelation since online surveys are increasingly being used for scientific research.”

The results revealed a strong discord among the splinter parties over defense policy. However, their opinions on the environment, decentralization, and other policies clearly coincided. This was most likely the foundation for the main opposition camp’s unity. Furthermore, DIF analysis revealed considerable differences in expert responses on the relevance of defense policy. As a result, the rapid politicization of defense policy may have contributed to its relevance, which in turn led to the split.

Although the study showed that the major opposition separated over defense policy disagreements, it also showed that splinter opposition parties agreed on environmental and decentralization policies. Dr. Matsumoto concludes, “Our findings suggest that party switching is triggered not just by policy disagreement, but also by the decision of which policy is politicized. This may help us comprehend the future dynamics between the ruling and opposition parties.”

Party competition and party systems are critical facets of parliamentary democracies. These findings go a long way towards improving our understanding of these political structures.

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Reference

Title of original paper: Party Switching and Policy Disagreement: Scaling Analysis of Experts’ Judgement

Journal: Japanese Journal of Political Studies

DOI: https://doi.org/10.1017/S1468109922000160

It is well known that whole-body exposure to high frequency ultrasound increases brain activity in humans. However, little is known about its impact and associated mechanisms on emotional states like depression. Now, a team of researchers at Tokyo University of Science have recently demonstrated the anti-depressant effects of ultrasound exposure in a rodent model of depression. Their findings shed light on the potential of ultrasound exposure as a non-invasive treatment for mental disorders.

The effect of ultrasound waves on the function of the human brain has been the key focus of recent research, which has indicated its potential as an effective, non-invasive approach for the modulation of brain activity. While the effects of ultrasound exposure on consciousness and cognition have been extensively explored, little is known about its impact on emotional states such as depression. To add to it, there are limitations in our understanding of neural and molecular mechanisms that underpin emotions.

Fortunately, rats experience pleasant emotions in response to high-frequency ultrasound vocalizations (USVs), making them ideal model organisms to study mechanisms underlying depression.

To this end, a team of researchers led by Professor Akiyoshi Saitoh, including Professor Satoru Miyazaki, Assistant Professor Daisuke Yamada and Ms. Tsugumi Yamauchi from Tokyo University of Science, and Mr. Shoichi Nishino from FUJIMIC, Inc., delved deeper into understanding the effects of ultrasound exposure on depression, by conducting experiments on rats lacking olfactory lobes—organs that regulate neurotransmission. These “olfactory bulbectomized (OB)” rats undergo changes in neurotransmitters, endocrine secretions, and behavior, which are similar to those observed in humans with depression.

Giving further insights into their study, Prof. Saitoh remarked, “Since studies on ultrasound exposure have been primarily conducted on human subjects, we needed to establish robust animal models to elucidate underlying mechanisms using invasive techniques. In our current study, we have used OB rats to study the effects of ultrasound on neural activity and behavior” Their study, published in Volume 33, Issue 10 of NeuroReport on July 6, 2022, is the first of its kind to demonstrate potential anti-depressant effects of ultrasound exposure in rats.

Initially, the team exposed wild type and OB rats to USV for 24 hours, following which they scored them for “hyperemotionality” (agitation and anxiety-like behavior) by studying their responses to getting attacked, getting startled, facing a struggle, and initiating a fight.

Next, they monitored plasma corticosterone (a hormone that is released in response to stress) levels in the blood samples of these rats. In addition, the team assessed anxiety-like behavior of the rodents using the elevated plus maze (EPM)—an approach which triggers behavioral anxiety in rats by exposing them to open spaces in a maze, and causes them to move to closed spaces.

Their findings revealed that OB rats exposed to USV had significantly lower hyperemotionality scores and lower plasma corticosterone levels than unexposed rats. Furthermore, in OB rats with a higher latency initially. i.e., higher inclination to reach the open areas of the maze, ultrasound exposure significantly decreased their latency. Similar effects were observed with a 50-kHz ultrasound frequency which was generated artificially.

This study provides novel evidence on the anti-depressant effects of ultrasound exposure in rodents. “Our findings suggest that OB rats may be a useful animal model for investigating the effects of ultrasound exposure and mechanisms of influence.”, exclaims Prof. Saitoh about the implications of the study.

He further adds, “Unlike drug therapy, ultrasound exposure is non-invasive and easy to use. An ultrasound based therapeutic device may therefore aid the treatment and prevention of mental disorders in patients while they go about their daily lives.”

Let’s hope that these results pave the way for developing ultrasound exposure therapy as a novel treatment to help patients cope with stress and psychiatric disorders.

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Reference

Title of original paper: High-frequency ultrasound exposure improves depressive-like behavior in an olfactory bulbectomized rat model of depression

Journal: NeuroReport

DOI: https://doi.org/10.1097/WNR.0000000000001804

Molecular 2D materials find immense applications in materials science, owing to their wide structural variety and easy controllability. Establishing a simple and efficient method for their synthesis is, therefore, important. Now, scientists from Japan present a simple method for synthesizing heterolayer coordination nanosheets, a promising 2D material, shedding light on how certain chemical coordination reactions occur at liquid–liquid interfaces. Their method could help develop novel 2D materials with applications in optoelectronic devices.

The past few decades have witnessed a great amount of research in the field of two-dimensional (2D) materials. As the name implies, these thin film-like materials are composed of layers that are only a few atoms thick. Many of the chemical and physical properties of 2D materials can be fine-tuned, leading to promising applications in many fields, including optoelectronics, catalysis, renewable energy, and more.

Coordination nanosheets are one particularly interesting type of 2D material. The “coordination” refers to the effect of metallic ions in these molecules, which act as coordination centers. These centers can spontaneously create organized molecular dispositions that span multiple layers in 2D materials. This has attracted the attention of materials scientists due to their favorable properties. In fact, we have only begun to scratch the surface regarding what heterolayer coordination nanosheets – coordination nanosheets whose layers have different atomic composition – can offer.

In a recent study published first on June 13, 2022, and featured on the front cover of Chemistry—A European Journal, a team of scientists from Tokyo University of Science (TUS) and The University of Tokyo in Japan reported a remarkably simple way to synthesize heterolayer coordination nanosheets. Composed of the organic ligand, terpyridine, coordinating iron and cobalt, these nanosheets assemble themselves at the interface between two immiscible liquids in a peculiar way. The study, led by Prof. Hiroshi Nishihara from TUS, also included contributions from Mr. Joe Komeda, Dr. Kenji Takada, Dr. Hiroaki Maeda, and Dr. Naoya Fukui from TUS.

To synthesize the heterolayer coordination nanosheets, the team first created the liquid–liquid interface to enable their assembly. They dissolved tris(terpyridine) ligand in dichloromethane (CH2Cl2), an organic liquid that does not mix with water. They then poured a solution of water and ferrous tetrafluoroborate, an iron-containing chemical, on top of the CH2Cl2. After 24 hours, the first layer of the coordination nanosheet, bis(terpyridine)iron (or “Fe-tpy”), formed at the interface between both liquids.

Following this, they removed the iron-containing water and replaced it with cobalt-containing water. In the next few days, a bis(terpyridine)cobalt (or “Co-tpy”) layer formed right below the iron-containing one at the liquid–liquid interface.

The team made detailed observations of the heterolayer using various advanced techniques, such as scanning electron microscopy, X-ray photoelectron spectroscopy, atomic force microscopy, and scanning transmission electron microscopy. They found that the Co-tpy layer formed neatly below the Fe-tpy layer at the liquid–liquid interface. Moreover, they could control the thickness of the second layer depending on how long they left the synthesis process run its course.

Interestingly, the team also found that the ordering of the layers could be swapped by simply changing the order of the synthesis steps. In other words, if they first added a cobalt-containing solution and then replaced it with an iron-containing solution, the synthesized heterolayer would have cobalt coordination centers on the top layer and iron coordination centers on the bottom layer. “Our findings indicate that metal ions can go through the first layer from the aqueous phase to the CH2Cl2 phase to react with terpyridine ligands right at the boundary between the nanosheet and the CH2Cl2 phase,” explains Prof. Nishihara. “This is the first ever clarification of the growth direction of coordination nanosheets at a liquid/liquid interface.”

Additionally, the team investigated the reduction–oxidation properties of their coordination nanosheets as well as their electrical rectification characteristics. They found that the heterolayers behaved much like a diode in a way that is consistent with the electronic energy levels of Co-tpy and Fe-tpy. These insights, coupled with the easy synthesis procedure developed by the team, could help in the design of heterolayer nanosheets made of other materials and tailored for specific electronics applications. “Our synthetic method could be applicable to other coordination polymers synthesized at liquid–liquid interfaces,” highlights Prof. Nishihara. “Therefore, the results of this study will expand the structural and functional diversity of molecular 2D materials.”

With eyes set on the future, the team will keep investigating chemical phenomena occurring at liquid–liquid interfaces, elucidating the mechanisms of mass transport and chemical reactions. Their findings can help expand the design of 2D materials and, hopefully, lead to better performance of optoelectronic devices, such as solar cells.

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Reference

Title of original paper: Chemically Laminated 2D Bis(terpyridine)metal Polymer Films: Formation Mechanism at the Liquid–Liquid Interface and Redox Rectification

Journal: Chemistry—A European Journal

DOI: https://doi.org/10.1002/chem.202201316

Fearful events negatively impact the brain.

For instance, war veterans often go through post-traumatic stress disorder months after the cessation of the triggering event. Now, in a study led by Tokyo University of Science researchers, the precise mechanism of suppression of such fearful memories has been uncovered. Using a mouse model, the researchers identified the associated biochemical pathways, thus paving the way for the development and clinical evaluation of therapeutic compounds such as KNT-127.

Tragic events like wars, famines, earthquakes, and accidents create fearful memories in our brain. These memories continue to haunt us even after the actual event has passed. Luckily, researchers from Tokyo University of Science (TUS) have recently been able to understand the hidden biochemical mechanisms involved in the selective suppression of fearful memories, which is called fear extinction.

The researchers, who had previously demonstrated fear extinction in mice using the chemically synthesized compound “KNT-127,” have now identified the underlying mechanism of this compound’s action. Their findings have been published recently in Frontiers in Behavioral Neuroscience.

Prof. Akiyoshi Saitoh, lead author of the study, and Professor at TUS, muses, “Drugs that treat fear-related diseases like anxiety and posttraumatic stress disorder must be able to help extinguish fear. We previously reported that KNT-127, a selective agonist of the d-opioid receptor or DOP, facilitates contextual fear extinction in mice. However, its site of action in the brain and the underlying molecular mechanism remained elusive. We therefore investigated brain regions and cellular signaling pathways that we assumed would mediate the action of KNT-127 on fear extinction.”

“We investigated the molecular mechanism of KNT-127-mediated suppression of fearful memories. We administered KNT-127 to specific brain regions and identified the brain regions involved in promoting fear extinction via delta receptor activation,” elaborates Dr. Daisuke Yamada, co-author of the study, and Assistant Professor at TUS.

Using a mouse model, the research team performed fear conditioning test on laboratory mice. During fear conditioning, mice learn to associate a particular neutral conditioned stimulus with an aversive unconditioned stimulus (e.g., a mild electrical shock to the foot) and show a conditioned fear response (e.g., freezing).

After the initial fear conditioning, the mice were re-exposed to the conditioning chamber for six minutes as part of the extinction training. Meanwhile, the fear-suppressing therapeutic “KNT-127” was microinjected into various regions of the brain, 30 minutes prior to re-exposure. The treated brain regions included the basolateral nucleus of the amygdala (BLA), the hippocampus (HPC), and the prelimbic (PL) or infralimbic subregions (IL) of the medial prefrontal cortex. The following day, the treated mice were re-exposed to the chamber for six minutes for memory testing.

The fear-suppressing “KNT-127” that infused into the BLA and IL, but not HPC or PL, significantly reduced the freezing response during re-exposure. Such an effect was not observed in mice that did not receive the KNT-127 treatment, thus confirming the fear-suppressing potential of this novel compound.

Chemical compounds known to inhibit the actions of key intracellular signaling pathways like PI3K/Akt and MEK/ERK pathways reversed the therapeutic effect, thereby suggesting the key roles of these two pathways in influencing KNT-127-mediated fear extinction.

The first author of the study, Ayako Kawaminami, who is currently pursuing research at TUS, says, “The selective DOP antagonist that we used for pretreatment antagonized the effect of KNT-127 administered into the BLA and IL. Further, local administration of MEK/ERK inhibitor into the BLA and of PI3K/Akt inhibitor into the IL abolished the effect of KNT-127. These findings strongly indicated that the effect of KNT-127 is mediated by MEK/ERK signaling in the BLA, by PI3K/Akt signaling in the IL, and by DOPs in both brain regions. We have managed to show that DOPs play a role in fear extinction via distinct signaling pathways in the BLA and IL.”

PTSD and phobias are thought to be caused by the inappropriate or inadequate control of fear memories. Currently, serotonin reuptake inhibitors and benzodiazepines are prescribed during therapy. However, many patients do not derive significant therapeutic benefits from these drugs. Therefore, there is an urgent need for the development of new therapeutic agents that have a different mechanism of action from existing drugs.

Dr. Hiroshi Nagase, a Professor at University of Tsukuba and a coauthor of the study, concludes, “We have succeeded in creating KNT-127 by successfully separating convulsion- and catalepsy-inducing actions, which has so far been extremely difficult. Our findings will provide useful and important information for the development of evidence-based therapeutics with a new mechanism of action, that is targeting DOP.”

Fighting fear with the right therapeutic is the need of the hour, as anxiety and stress increase globally, and the findings of this study could help us achieve this objective. We have our fingers crossed.

***

Reference

Title of original paper: Selective δ-Opioid Receptor Agonist, KNT-127, Facilitates Contextual Fear Extinction via Infralimbic Cortex and Amygdala in Mice

Journal: Frontiers in Behavioral Neuroscience

DOI: https://doi.org/10.3389/fnbeh.2022.808232

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Akiyoshi Saitoh from Tokyo University of Science

Dr. Akiyoshi Saitoh is serving as a Professor in the Department of Pharmacy, at the Tokyo University of Science, Japan. His research work primarily focuses on the role of the amygdala in the rodent fear extinction memory as well as on the development of novel opioid delta receptor agonists for combating depression and anxiety. Prof. Saitoh has published over 100 refereed papers so far. He also has a patent to his credit.

In materials science, candidates for novel functional materials are usually explored in a trial-and-error fashion through calculations, synthetic methods, and material analysis. However, the approach is time-consuming and requires expertise. Now, researchers from Japan have used a data-driven approach to automate the process of predicting new magnetic materials. By combining first-principles calculations, Bayesian optimization, and monoatomic alternating deposition, the proposed method can enable a faster development of next-generation electronic devices.

Materials scientists are constantly on the lookout for new “functional materials” with favorable properties directed towards some application. For instance, finding novel functional magnetic materials could open doors to energy-efficient spintronic devices. In recent years, the development of spintronics devices like magnetoresistive random access memory—an electronic device in which a single magnetoresistive element is integrated as one bit of information—has been progressing rapidly, for which magnetic materials with high magnetocrystalline anisotropy (MCA) are required. Ferromagnetic materials, which retain their magnetization without an external magnetic field, are of particular interest as data storage systems, therefore. For instance, L10-type ordered alloys consisting of two elements and two periods, such as L10-FeCo and L10-FeNi, have been studied actively as promising candidates for next-generation functional magnetic materials. However, the combination of constituent elements is extremely limited, and materials with extended element type, number, and periodicity have rarely been explored.

What impedes this exploration? Scientists point at combinatorial explosions that can occur easily in multilayered films, requiring a great deal of time and effort in the selection of the constituent elements and material fabrication, as the major reason. Besides, it is extremely difficult to predict the function of MCA because of the complex interplay of various parameters including crystal structure, magnetic moment, and electronic state, and the conventional protocol relies largely on trial and error. Thus, there is much scope and need for developing an efficient route to discovering new high-performance magnetic materials.

On this front, a team of researchers from Japan including Prof. Masato Kotsugi, Mr. Daigo Furuya, and Mr. Takuya Miyashita from Tokyo University of Science (TUS), along with Dr. Yoshio Miura from the National Institute for Materials Science (NIMS), has now turned to a data-driven approach for automating the prediction and synthesis of new magnetic materials. In a new study, which was made available online on June 30, 2022 and published in Science and Technology of Advanced Materials: Methods on July 1, 2022, the team reported their success in the development of material exploration system by integrating computational, information, and experimental sciences for high MCA magnetic materials. Prof. Kotsugi explains, “We have focused on artificial intelligence and have combined it with computational and experimental science to develop an efficient material synthesis method. Promising materials beyond human expectation have been discovered in terms of electronic structure. Thus, it will change the nature of materials engineering!”

In their study, which was the result of joint research by TUS and NIMS and supported by JST-CREST, the team calculated MCA energy through first-principles calculations (a method used to calculate electronic states and physical properties in materials based on the laws of quantum mechanics) and performed Bayesian optimization to search for materials with high MCA energy. After examining the algorithm for Bayesian optimization, they found promising materials five times more efficiently than through the conventional trial-and-error approach. This robust material search method was less susceptible to influences from irregular factors like outliers and noise and allowed the team to select the top three candidate materials—(Fe/Cu/Fe/Cu), (Fe/Cu/Co/Cu), and (Fe/Co/Fe/Ni)—comprising iron (Fe), cobalt (Co), nickel (Ni), and copper (Cu).

The top three predicted materials with the largest MCA energy values were then fabricated via the monoatomic alternating stacking method using the laser-driven pulsed deposition technique to create multilayered magnetic materials consisting of 52 layers, namely [Fe/Cu/Fe/Cu]13, [Fe/Cu/Co/Cu]13, and [Fe/Co/Fe/Ni]13. Among the three structures, [Fe/Co/Fe/Ni]1 showed an MCA value (3.74 × 106 erg/cc) much above that of L10-FeNi (1.30 × 106 erg/cc).

Furthermore, using the second-order perturbation method, the team found that MCA is generated in the electronic state, which has not been realized in previously reported materials. This attests to the suitability of employing Bayesian optimization to identify electronic states that are likely impossible to envision through human experience and intuition alone. Thus, the developed method can autonomously search for suitable elements to design functional magnetic materials. “This technique is extendable to advanced magnetic materials with more complicated electronic correlations, such as Heusler alloys and spin-thermoelectric materials,” observes Prof. Kotsugi.

With these findings, the study sets the groundwork for automating the synthesis of hitherto-unexplored high-performance functional materials, which could enable the production of high-speed, energy-saving electronic devices and even pave the way for a carbon-neutral society!

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Reference

Title of original paper: Autonomous synthesis system integrating theoretical, informatics, and experimental approaches for large-magnetic-anisotropy materials

Journal: Science and Technology of Advanced Materials: Methods

DOI: https://doi.org/10.1080/27660400.2022.2094698

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Masato Kotsugi from Tokyo University of Science

Professor Masato Kotsugi graduated from Sophia University, Japan, in 1996 and then received a PhD from the Graduate School of Engineering Science at Osaka University in 2001. He joined the Tokyo University of Science in 2015 as a lecturer and is currently a Professor at the Faculty of Advanced Engineering, Department of Materials Science and Technology. Prof. Kotsugi and students at his laboratory conduct cutting edge research on high-performance materials with the aim of creating a green energy society. He has published over 118 refereed papers and is currently interested in solid-state physics, magnetism, synchrotron radiation, and materials informatics.

He can be reached at [email protected]

Funding information

This work was partially supported by the Japan Society for the Promotion of Science (KAKENHI) Grant-in-Aid for Scientific Research (A) (21H04656) and (B) (20H02190), and the Japan Science and Technology Agency (JST) CREST (Grant No. JPMJCR21O1).

Researchers from Japan have developed novel complex-peptide hybrids, which can induce programmed cell death in apoptosis-resistant cancer cells

Inducing programmed cell death (PCD), such as apoptosis, is a widely used therapeutic option for the treatment of cancer. Unfortunately, many cancer cells become resistant to PCDs, and continue multiplying. In a new study, researchers from Tokyo University of Science synthesized new complex-hybrid compounds named triptycene-peptide hybrids (TPHs), which successfully induced a kind of PCD known as paraptosis in Jurkat cells—a type of lymphocytes. These paraptosis-inducing compounds can revolutionize cancer therapy in the future.

Apoptosis, a type of programmed cell death (PCD), is a biological process through which unwanted cells are eliminated in multicellular organisms. In most cells, certain proteins known as “caspases” trigger apoptosis. This process is especially important for the treatment of cancer, since inducing cell death in cancer cells can help in their elimination.

Other than apoptosis, several types of PCDs occur in cells, including paraptosis, necroptosis, and autophagy. Of these, paraptosis is the most recently identified type of PCD, which is caused by the influx of excess calcium in the cells, leading to cell death.

Cancer cells often become resistant to drugs that induce apoptosis and other types of PCDs. In such cases, inducing paraptosis, which is not dependent on caspases, could act as a promising anti-cancer treatment. Hence, the development of compounds that can induce paraptosis in cancer cells is crucial.

To this end, a team of researchers from the Tokyo University of Science, led by Prof. Shin Aoki in collaboration with Mr. Kohei Yamaguchi and Dr. Kenta Yokoi, conducted a study to develop novel complex-peptide hybrids with paraptosis-inducing potential. This study was made available online on 11 April 2022, and subsequently published in Volume 33 of the journal Bioconjugate Chemistry, on 20 April 2022.

“Previously, we synthesized an iridium complex-peptide hybrid compound and observed that it induced cell death in cancer cells, which was different from apoptosis. Since this compound was unlike other paraptosis-inducing compounds, we wanted to understand its mechanism of paraptosis induction. Our goal now is to synthesize new compounds and elucidate how they induce paraptosis in cells, before we share this crucial information with the public,” explains Prof. Aoki while discussing the team’s motivation behind this study.

The newly synthesized compounds were composed of a triptycene core—an aromatic hydrocarbon—with two or three cationic peptides made of the amino acids lysine and glycine (represented as KKKGG) through a C8 alkyl linker chain, at different positions of the triptycene units. As a result, three triptycene core hybrids (TPHs) were produced, namely, 5, syn-6, and anti-6.

The team subsequently performed experiments on Jurkat cells, a type of immortalized human lymphocytes used in research, to understand the type of PCD that occurred in these cells on treatment with syn-6 and anti-6. They found that death in these cells was inhibited by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) which is an uncoupling reagent and an inhibitor of mitochondrial calcium uptake, RuRed, which is an inhibitor of the mitochondrial calcium channel), and 2-aminoethoxydiphenyl borate (2-APB), which is an inhibitor of D-inositol-1,4,5-trisphosphate receptor. However, cell death was not inhibited by inhibitors of the other types of PCDs.

Hence, they ruled out autophagy, necroptosis, and apoptosis, confirming that paraptosis is a major PCD pathway induced by syn-6 and anti-6 in Jurkat cells.

“Studies have indicated that the TPHs syn-6 and anti-6 induce the transfer of excess calcium from the endoplasmic reticulum (ER) to mitochondria, resulting in a loss of mitochondrial membrane potential. It is very likely that these phenomena are strongly related with the fusion of the ER with the mitochondria, followed by cytoplasmic vacuolization, resulting in cell death,” said Prof. Aoki, when asked why these two TPHs were selected for the study. The TPHs syn-6, and anti-6 are more hydrophilic than other TPHs, which could also be a reason for their high paraptosis-inducing anti-cancer potential.

Through additional imaging experiments, the team detected the presence of cytoplasmic vacuolization, elevated mitochondrial calcium concentrations, and the degradation of the ER in Jurkat cells treated with syn-6 and anti-6.
Based on previous findings, the team hypothesized that in Jurkat cells as well, the influx of calcium in the mitochondria might be facilitated by the close proximity of the ER and the mitochondria. As expected, they found that the ER and mitochondrial membranes were attached to one another, facilitating direct transfer of calcium.

These findings confirmed that Jurkat cells treated with syn-6 and anti-6 had undergone programmed cell death, owing to paraptosis. They also provide crucial information for the design of compounds that can be used as therapeutic agents against cancer and other diseases.

Here’s hoping that these promising findings contribute to the development of effective therapy against the ever-evolving cancer cells.

***

Reference

Title of original paper: Design, Synthesis, and Anticancer Activity of Triptycene–Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells

Journal: Bioconjugate Chemistry

DOI: https://doi.org/10.1021/acs.bioconjchem.2c00076

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Shin Aoki from Tokyo University of Science

Professor Shin Aoki is a professor of cancer biology & research at the Faculty of Pharmaceutical Sciences, Tokyo University of Science. He is engaged in the study of medicinal chemistry, pharmacology, bioinorganic chemistry, and supramolecular chemistry. He is a recipient of the Award of Japan Society of Coordination Chemistry for Young Scientists (1999); the AJINOMOTO Award in Synthetic Organic Chemistry, Japan (2001); and the Pharmaceutical Society of Japan Award for Young Scientists (2002). He is a graduate from the University of Tokyo with B. S. (1986), M.S. (1988), and Ph.D. (1992) degrees in pharmaceutical sciences. He holds a post doctorate degree from the Department of Chemistry, the Scripps Research Institute, USA.

Schiff base-metal complexes exhibit promising antibacterial and antioxidant properties. However, conventional methods for their preparation can be time-consuming. To reduce the reaction time and improve the quality and quantity of the products, researchers designed a new synthesis technique that uses microwave irradiation and methanol for the preparation of amino acid Schiff base copper complexes in just 10 minutes. The resulting products exhibit desirable properties, such as mild antioxidant activity and antibacterial activity against Escherichia coli.

Ever since their development in the late 19th century, Schiff bases have been a popular group of organic compounds, owing to their wide variety of desirable properties. The presence of both nitrogen and oxygen in their structure makes them versatile molecules with an array of applications, ranging from dyes and catalysts to environmental sensors and raw materials for chemical synthesis.

Recently, there has been growing interest in the biological activity of Schiff bases, as researchers have discovered that metal complex derivatives of Schiff bases can serve as antioxidant, antimicrobial, and anticancer agents. Among these compounds, studies have shown that amino acid Schiff base copper (Cu) complexes have the most promising antimicrobial properties; however, the reaction time taken to create these compounds can range from hours to days.

In a recent breakthrough published on 18 June 2022 in Applied Microbiology, a team of researchers led by Professor Takashiro Akitsu from the Tokyo University of Science reported a two-step synthesis procedure that produced amino acid Schiff base Cu (II) complexes within a mere 10 minutes! The team included Dr. Estelle Léonard and Dr. Antoine Fayeulle from ESCOM, TIMR (Integrated Transformations of Renewable Matter), Centre de Recherche Royallieu, University of Technology of Compiègne, France.

“Amino acid Schiff base Cu (II) complexes have the potential to be used as antimicrobial agents but their wider applications are being limited by conventional methods for synthesis that often takes several hours and sometimes days. With our research, we aim to overcome this challenge by making the synthesis process more facile,” comments Prof. Akitsu on the rationale behind their study.

The team used microwave irradiation to prepare these compounds, owing to its ability to greatly accelerate the reaction while providing controlled heating. This method also ensures higher yields, better purity, and fewer by-products. Additionally, they chose methanol as the solvent for the reactions. With a high loss tangent of 0.659, which determines the ability to convert microwave energy into heat, and a high microwave absorption rate, methanol was ideal for accelerating the reactions and lowered the global reaction time to 10 minutes.

To gauge the antibacterial properties of the compounds, the researchers tested them against various bacteria. They found that the one- and two-chlorine substituted complexes showed better action against bacteria, with remarkable activity against E. coli, than the molecules with no chlorine groups. The team also noted the presence of light antioxidant properties in the one- and two-chlorinated complexes. In the future, the team aims to check for the toxicity of these compounds toward kidney, liver, and skin cells.

This new synthesis technique minimizes the global reaction time, maximizes the reaction conditions, and produces high purity products with promising antibacterial activity. The insights from this study can be used as a framework for the development of fast and facile synthesis techniques for biologically active amino acid derivatives of Schiff base metal complexes. “Bacterial infectious diseases are a major threat to public health. Our study aims to contribute towards the improvement of health care systems in developing nations that are often affected by infectious epidemics,” concludes Prof Akitsu.

***

Reference

Title of original paper: Synthesis, Identification and Antibacterial Activities of Amino Acid Schiff Base Cu(II) Complexes with Chlorinated Aromatic Moieties

Journal: Applied Microbiology

DOI: https://doi.org/10.3390/applmicrobiol2020032

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science by inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Takashiro Akitsu from Tokyo University of Science

Prof. Takashiro Akitsu is a professor in the Department of Chemistry, Faculty of Science, Tokyo University of Science (TUS), Japan. He graduated from Osaka University and obtained his Ph.D. in Physical and Inorganic Chemistry in 2000 and went on to study physical and bioinorganic chemistry at Stanford before moving to TUS. He joined the TUS as a Junior Associate Professor in 2008 and became a Professor in 2016. He has published 220 articles and book chapters and served as an editorial board member in many international peer-reviewed journals. His current research areas involve the study of imines, Schiff bases, coordination chemistry, and crystal structures.

Funding information

This research was funded by TIMR UTC‐ESCOM, and this work was supported by a

Grant‐in‐Aid for Scientific Research (A) KAKENHI (20H00336).

The novel terminator-assisted solid-phase complementary DNA amplification and sequencing (TAS-Seq) method provides high-precision data on gene expression

Single-cell RNA sequencing (scRNA-seq) is one of the most important methods to study biological function in cells, but it is limited by potential inaccuracies in the data it generates. Now, a research team from Japan has developed a new method called terminator-assisted solid-phase complementary DNA amplification and sequencing (TAS-Seq), which overcomes these limitations and provides higher-precision data than existing scRNA-seq platforms.

The advent of single-cell RNA sequencing (scRNA-seq) has revolutionized the fields of medicine and biology by providing the ability to study the inner workings of thousands of cells at one go. But scRNA-seq methods are limited by potential inaccuracies in determining cell composition and inefficient complementary DNA (cDNA) amplification—a process by which a double-stranded DNA that ‘complements’ the single-stranded RNA is generated and replicated millions of times—by the commonly-used template-switching reaction.

Recently, a research team from Japan, led by Assistant Prof. Shigeyuki Shichino and Prof. Kouji Matsushima of Tokyo University of Science, has developed a new and improved technique for scRNA-seq. The new method, terminator-assisted solid-phase cDNA amplification and sequencing (TAS-Seq), uses simple materials and equipment to provide higher-precision scRNA-seq data than current, widely-used technologies. “Our technique, TAS-Seq, combines genetic detection sensitivity, robustness of reaction efficiency, and accuracy of cellular composition to enable us to capture important cellular information,” reveals Assistant Prof. Shichino. The study was published in Communications Biology on June 27, 2022. The research team also included Associate Prof. Satoshi Ueha of Tokyo University of Science, Prof. Taka-aki Sato of the University of Tsukuba, and Prof. Shinichi Hashimoto of Wakayama Medical University.

TAS-Seq uses a template independent enzyme for cDNA amplification called terminal transferase (TdT). But TdT is difficult to handle. To surmount this challenge, the research team included dideoxynucleotide phosphate (ddNTP) as a ‘terminator’ for the cDNA amplification reaction. “ddNTP spike-in, specifically dideoxycytidine phosphate (ddCTP), stops the excessive extension of polyN-tail by TdT in a stochastic manner, and greatly reduces the technical difficulties of the TdT reaction,” explains Assistant Prof. Shichino. TAS-Seq also uses a nanowell/bead-based scRNA-seq platform, which allows the isolation of single cells in tissue samples, thereby decreasing cell sampling bias and improving the accuracy of cell composition data.

The research team then verified the efficiency of TAS-Seq and compared it to the current, widely used scRNA-seq techniques, 10X Chromium V2 and Smart-seq2, using murine and human lung tissue samples. They found that TAS-Seq could not only detect more genes overall, but also identify more highly variable genes, when compared to major scRNA-seq platforms. Assistant Prof. Shichino says, “We found that TAS-Seq may outperform 10X Chromium V2 and Smart-seq2 in terms of gene detection sensitivity and gene drop-out rates, indicating that TAS-Seq might be one of the most sensitive high-throughput scRNA methods. We can detect genes across a wide range of expression levels more uniformly and also detect growth factor and interleukin genes more robustly.”

An added advantage of the new method is that TAS-Seq is less susceptible to batch effects. TAS-Seq data was also highly correlated with flow-cytometric data on the tissue samples, indicating that it can generate highly accurate cell composition data.

Speaking on the future, Assistant Prof. Shichino reveals, “We have already completed development of TAS-Seq2, an improved, extensively-optimized version of TAS-Seq. TAS-Seq2 has 1.5 to 2 times more sensitive gene detection in mouse spleen cells.” The research team has also established ImmunoGenetics, a venture company from Tokyo University of Science, to provide scRNA-seq services using TAS-Seq and TAS-Seq2.

scRNA-seq is an important tool for medical and biology researchers. The development of TAS-Seq and TAS-Seq2 will lead to the discovery of new therapeutic targets for diseases and advancements in the field of ‘spatial transcriptomics,’ which also relies on solid-phase cDNA synthesis. It will also accelerate the development of single-cell omics technology, thereby promoting our understanding of the principles of biology and disease development and progression.

***

Reference

Title of original paper: TAS-Seq is a robust and sensitive amplification method for bead-based scRNA-seq

Journal: Communications Biology

DOI: https://doi.org/10.1038/s42003-022-03536-0

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Assistant Professor Shigeyuki Shichino and Professor Kouji Matsushima from Tokyo University of Science

Assistant Prof. Shigeyuki Shichino is part of the Research Institute for Biomedical Sciences, Tokyo University of Science. His research focuses on system genome science, including transcriptome, single-cell, and interactome network, and experimental pathology, including lung fibrosis, macrophage/fibroblast biology, and single-cell RNA sequencing. He has published 21 papers.

Prof. Kouji Matsushima is part of the Research Institute for Biomedical Sciences, Tokyo University of Science. His research focuses on inflammation, immunology, and cancer immunotherapy. He was conferred a Lifetime Honorary Membership Award by the International Cytokine and Interferon Society in 2019. In 2021, he won the Takeda Prize for Medical Science.