A gene-encoded blueprint tells growing neurons which brain regions to connect with ? 

How complex neural circuits are genetically designed and wired is a fundamental question in neuroscience. Scientists have shown for the first time that genes encode a ¡°wiring map¡± that guides neurons to connect with the correct brain regions. The findings, based on machine learning analysis of mouse brain data, were published in , and offer new avenues for research into brain development and disease.

Mapping connections between brain regions with data

The research team, led by scientists from ÐßÐßÊÓƵ in Japan, aimed to understand the wiring rules that guide nerve fibers during brain development. These long, thin fibers, called axons, extend from neurons and send signals to other neurons.?
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The researchers developed an analysis method called SPERRFY that combines two datasets. One dataset maps which brain regions are connected to each other, and the other tracks the activity levels of 763 genes in all 213 brain regions in mice.?
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¡°Some genes are highly active in certain brain regions and less active in others. These differences create distinct patterns of gene activity throughout the brain,¡± said Naoki Honda, senior author and professor from ÐßÐßÊÓƵ’s . ¡°When hundreds of patterns overlap, they give each brain region a unique molecular identity. These identities are what SPERRFY was designed to decode.¡±?
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By feeding both datasets into a machine learning algorithm, SPERRFY identified these patterns of gene activity, called gene expression gradients, that predict which brain regions are likely to connect. For each pair of connected brain regions, SPERRFY paired the gene activity profile of the source region (where the nerve fiber originates) with the profile of the target region it connects to.???
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From these gene expression gradients, the researchers produced a brain wiring map that tells each brain region where it is relative to every other region. Overlapping patterns of gene activity reconstructed the brain’s connection patterns with a prediction-performance score of 0.88 on a 0-to-1 scale, where 1.0 indicates perfect prediction. By comparison, predictions based only on the physical distance between brain regions scored about 0.70.

Additionally, the researchers discovered that the brain’s wiring map operates on two levels. Broad gene activity patterns determine the overall organization between brain regions, while more detailed patterns regulate the specific connections within them.

Testing a 60-year-old theory on the whole brain 

The findings build on the chemoaffinity theory proposed by Nobel laureate Roger Sperry in 1963. He suggested that neurons find their connection partners by following molecular concentration gradients ¡ª chemical signals that vary in strength throughout the brain. These gradients act like a GPS system for growing nerve fibers.??
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¡°The chemoaffinity theory was well established for simple circuits such as the visual and olfactory systems. But until now, the complexity of whole-brain connectivity made it difficult to test whether the same principle operates across the brain,¡± said Jigen Koike, first author and former PhD student at Hiroshima University, who also conducted research as a special research student at ÐßÐßÊÓƵ’s Graduate School of Medicine.?
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This complexity made it extremely difficult to test Sperry¡¯s theory across the entire brain without computational tools. Using machine learning, the researchers developed the tools to do this for the first time. Their findings support the idea that this long-standing principle is not limited to simple sensory circuits, but also helps explain how connections are organized across the whole brain.??

Future research 

By comparing the activity of 763 genes against the wiring map, SPERRFY also identified specific genes with activity patterns that closely matched, including genes known to guide nerve growth. This supports the validity of the method and provides a starting point for research on the molecular mechanisms of brain wiring. 
 
The researchers note that their method can be applied to any species for which maps of the brain¡¯s neural circuits and gene expression data are available, such as humans, marmosets, and fruit flies. As these datasets expand, the method could help determine if the same molecular wiring principles are shared across species and how they have evolved. SPERRFY could also assist scientists in understanding how disruptions in brain wiring contribute to neurodevelopmental disorders.   

Paper information:

Jigen Koike, Ken Nakae, Riichiro Hira, Yuichiro Yada, Naoki Honda, 2026. A data-driven framework linking the connectome to spatial gene expression gradients inspired by chemoaffinity theory. Proceedings of the National Academy of Sciences, 123(10). DOI:

Funding information: 

This work was supported by JST, the establishment of university fellowships toward the creation of science technology innovation (grant number JPMJFS2129), JST SPRING (grant number JPMJSP2132), JSPS KAKENHI (grant number JP22H05163), Moonshot R&D¨CMILLENNIA Program (grant number JPMJMS2024-9), Agency for Medical Research and Development (AMED) Multidisciplinary Frontier Brain and Neuroscience Discoveries (Brain/MINDS 2.0) (grant number JP25wm0625322 and JP25wm0625210), and the Cooperative Study Program of Exploratory Research Center on Life and Living Systems (ExCELLS: program number 19¨C102).  

Expert contact: 

Honda Naoki   
Graduate School of Medicine   
ÐßÐßÊÓƵ   
Email: honda.naoki.t1@f.mail.nagoya-u.ac.jp 

Media contact:  

Merle Naidoo   
International Communications Office   
ÐßÐßÊÓƵ   
Email: icomm_research@t.mail.nagoya-u.ac.jp  

Top image:

A 3D visualization of the 13 major regions in the mouse brain. Black dots mark the centers of the 213 subdivisions used by SPERRFY to analyze relationships between brain connectivity and gene activity patterns. Credit: Koike et al., PNAS, 2026. CC BY 4.0 

By targeting a schizophrenia-associated brain protein, KD025 restored neural connections and reduced schizophrenia symptoms in mice with fewer side effects

Schizophrenia is a serious brain disorder that causes confused thinking, severe memory problems, and hallucinations. It affects about 23 million people worldwide, with cognitive dysfunction present in over 80% of patients. A research group led by scientists from ÐßÐßÊÓƵ in Japan tested a drug used to treat an immune disease to see if it could reduce schizophrenia-related symptoms in mice. The findings, published in , show that KD025 restored connections between neurons and significantly improved memory and visual recognition in mice, without causing the serious side effects common to current schizophrenia medications.  

Need for safer treatments for schizophrenia

Current medications help with some symptoms, but they often do not improve cognitive function. They also cause serious side effects such as hormonal disruptions, involuntary muscle movements, and weight gain, which leads to many patients stopping treatment. Therefore, better options are urgently needed. 

Researchers focused on a gene called ARHGAP10. Variants of this gene (small changes in the gene¡¯s DNA sequence) are much more common in people with schizophrenia than in the general population.  

¡°ARHGAP10 controls the activity of a brain protein called ROCK2. In mice with these genetic variants, ROCK2 becomes overactive. In a previous study, we found that this overactivity appears to damage connections between neurons and impair cognition,¡± said Rinako Tanaka, co-lead author and former project assistant professor at ÐßÐßÊÓƵ¡¯s .

Repurposing drugs to achieve better treatment

The team tested KD025, approved in the United States to treat an immune disease called chronic graft-versus-host disease, which can occur after bone marrow transplants. In mice engineered to carry schizophrenia-associated gene variants, the drug decreased the overactivity of ROCK2.  

Furthermore, KD025 restored the density of tiny structures on neurons called dendritic spines, which are critical for memory. These had been reduced in mice carrying schizophrenia-associated gene variants. The drug had no effect on healthy mice. 

¡°Importantly, KD025 did not cause the side effects typical of current antipsychotic drugs. At effective doses, it caused no involuntary movements, hormonal abnormalities, or significant changes in blood pressure or blood sugar. This safety profile sets it apart from older antipsychotics like haloperidol and newer drugs like clozapine,¡± said Hiroyuki Mizoguchi, coauthor and associate professor from the Department of Neuropsychopharmacology and Hospital Pharmacy at ÐßÐßÊÓƵ. 

Because KD025 has already been through clinical safety trials for another condition, human trials for schizophrenia could start sooner than for a new drug. While the researchers caution that all experiments were in mice, and human studies are needed, the findings point to a promising target for treatments that are more effective and better tolerated by patients. 

Future studies will investigate how KD025 improves brain cell connections and function, and further evaluate its safety and efficacy to support human trials.?

Paper information:

Rinako Tanaka, Jingzhu Liao, Yue Liu, Wenjun Zhu, Kisa Fukuzawa, Masamichi Kondo, Masahito Sawahata, Daisuke Mori, Akihiro Mouri, Hisayoshi Kubota, Daiki Tachibana, Yohei Kobayashi, Tetsuo Matsuzaki, Taku Nagai, Toshitaka Nabeshima, Kozo Kaibuchi, Norio Ozaki, Hiroyuki Mizoguchi & Kiyofumi Yamada (2026). Antipsychotic-like effects of the selective Rho-kinase 2 inhibitor KD025 in genetic and pharmacological mouse models of schizophrenia, Molecular Psychiatry. DOI:  

Funding information:

This study was supported by the Japan Agency for Medical Research and Development (AMED) (Grant numbers: JP21wm0425007, JP21wm0425017, JP25wm0625518, JP23ak0101215, JP24ak0101221, JP22gm1410011, JP24zf0127011, JP23gm1910005); Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant numbers: JP23H02669, JP23K19425, JP24K18365); Japanese SRF Grant for Biomedical Research, Takeda Science Foundation, and Toyoaki Scholarship Foundation. ?

Expert contact:

Hiroyuki Mizoguchi    
Graduate School of Medicine  
ÐßÐßÊÓƵ   
E-mail: mizoguchi.hiroyuki.d5@f.mail.nagoya-u.ac.jp 

Media contact:  

Merle Naidoo   
International Communications Office   
ÐßÐßÊÓƵ   
Email: icomm_research@t.mail.nagoya-u.ac.jp 

Top image:

Microscopy images showing dendrites, the rod-like branches of brain cells, with tiny protrusions called dendritic spines that are critical for memory and learning. Normal mice show similar spine density with (bottom left) and without KD025 treatment (top left). In mice carrying schizophrenia-associated gene variants, the tiny protrusions are visibly reduced without treatment (top right) but restored after KD025 treatment (bottom right). Scale bar: 5 ¦Ìm. Credit: Tanaka et al., 2026 
 

Offering someone the right words for what they feel could play a role in how people manage their anxiety, with potential implications for classrooms, counseling, and home environments

We feel more anxious when facing uncertain or unpredictable situations, but for those who score higher on autistic traits, this anxiety tends to be stronger. Published in , a new study suggests uncertainty-driven anxiety plays a role in how people manage their emotions. Researchers at ÐßÐßÊÓƵ in Japan found evidence that people with higher autistic traits may try to cope with uncertainty by labeling their feelings. Offering support, such as the right words for what they feel, could play a role in managing anxiety. 

Putting a name to a feeling could reduce emotional stress 

Previous research has suggested that labeling an emotion, whether by writing it down or saying it out loud, can help us calm down. While the anxiety does not disappear, it becomes less overwhelming when the emotion has a name.?
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Autistic traits refer to characteristics associated with autism spectrum disorder, such as differences in social communication and a preference for routine and predictability. These traits vary in degree across the general population.?
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A total of 505 Japanese adults aged 20 to 39 completed an online survey measuring autistic traits, discomfort with uncertainty, the tendency to put feelings into words, and anxiety levels.??
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¡°We measured autistic traits using a 50-item questionnaire called the Autism-Spectrum Quotient which covers five areas: social skills, the ability to shift attention, communication, imagination, and attention to detail,¡± said first author and doctoral student Akitaka Fujii from the at ÐßÐßÊÓƵ.?
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The researchers found that people who scored higher on autistic traits also experience stronger anxiety in uncertain situations. This is known as intolerance of uncertainty, a tendency to react negatively when situations feel ambiguous or beyond one’s control.???

¡°Our findings suggest that discomfort with uncertainty is associated with a greater tendency to put feelings into words, and this is linked to lower anxiety levels,¡± said Masahiro Hirai, coauthor and associate professor from the Graduate School of Informatics. ?
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Offering someone the right words to describe how they feel may help them manage their anxiety. For example, a teacher or family member might say “I think you might be feeling anxious about that” when someone struggles to express distress. This perspective could inform future approaches in classroom and counseling settings.?

Limitations and next steps 

The researchers caution that these are early findings and more research is needed to confirm their theory. Because the study did not involve people with a clinical diagnosis of autism, the findings cannot be directly applied to autistic people. 
 
The Hirai Lab is currently conducting a follow-up study with adults who have a clinical diagnosis of autism to test whether similar patterns are observed. The authors highlight the need for further studies that track participants over time to determine if these patterns reflect cause and effect.  

Paper information: 

Akitaka Fujii and Masahiro Hirai, 2026. Autism related traits and anxiety in the general population are linked through intolerance of uncertainty and affect labeling. Scientific Reports, 16(13149). DOI:  

Funding information: 

This work was supported by JST SPRING (Grant Number JPMJSP2125). 

Expert contact: 

Masahiro Hirai   
Graduate School of Informatics   
ÐßÐßÊÓƵ   
Email: hirai@i.nagoya-u.ac.jp

Media contact: 

Merle Naidoo   
International Communications Office   
ÐßÐßÊÓƵ   
Email: icomm_research@t.mail.nagoya-u.ac.jp 

Top image:

In their paper published in Scientific Reports, Masahiro Hirai (L) and Akitaka Fujii (R) from ÐßÐßÊÓƵ’s Graduate School of Informatics found evidence suggesting that people with higher autistic traits may try to cope with uncertainty by labeling their feelings. Credit: Merle Naidoo, ÐßÐßÊÓƵ

Their SMART method accelerates enzyme evolution by reducing the selection period for superior variants from several weeks to a few days, and decreases overall enzyme engineering campaign costs by eliminating the need for specialized equipment.

Enzymes are proteins that catalyze chemical reactions in living organisms. They are widely applied in industries such as food production, detergents, pharmaceuticals, and chemicals. However, for commercial use, natural enzymes often need improved stability, substrate specificity, or catalytic efficiency.

Directed evolution is a Nobel Prize-winning strategy for improving proteins. It introduces artificial mutations into their genes and then selects superior variants. This approach mimics natural evolution over several weeks instead of millions of years.

A significant challenge of this approach is that artificially induced mutations can generate up to 100 trillion candidate variants, which renders the screening process extremely time-consuming and expensive.

To address this challenge, researchers at ÐßÐßÊÓƵ and their colleagues have developed SMART (Single-Molecule Assay on Ribonucleic acid by Translated product), an in vitro selection platform.

Their study demonstrated that SMART identifies improved enzyme variants much more rapidly and cost-effectively than conventional methods. The findings were published in the journal .

The SMART system was developed by a research group led by Associate Professor and Professor of the , in collaboration with researchers from the Institute of Science Tokyo and Saitama University. This approach successfully combines mRNA display, next-generation sequencing, and bioinformatics.

Key features of the SMART system

Typically, proteins and genes are physically separate, making it difficult and time-consuming to identify which gene encodes a discovered enzyme.

In the SMART system, puromycin acts as a chemical bridge, linking the enzyme protein to its corresponding blueprint, messenger RNA (mRNA). This mRNA display technique enables precise tracking of the relationship between individual proteins and their encoding genes at the single-molecule level.

Nakano emphasized, “In principle, there is no method for enzyme screening that is more efficient than this system. Screening enzymes at the single-molecule level has rarely been attempted before.”

SMART also incorporates an auxiliary unit for detecting enzyme activity. This study used engineered ascorbate peroxidase 2 (APEX2) as the auxiliary enzyme for oxidase screening. When the target oxidase is active and releases hydrogen peroxide (H?O?), APEX2 attaches a biotin marker to nearby molecules, enabling their isolation and capture.

Enzyme screening experiments using SMART

The researchers chose a yeast oxidase, SpDAAO, as a model enzyme because it has great potential for drug synthesis and diagnostics. The selection prioritized D-amino acids as enzyme substrates due to their growing relevance in medical applications.

The SMART method consists of several steps¡ªcreating a DNA library of enzyme variants, synthesizing enzymes in vitro, forming an mRNA display library, labeling catalytically active enzymes, isolating them with magnetic beads, and using sequencing data to guide subsequent rounds.

To assess the method, the team tested it on a simulated library with different ratios of active and inactive variants. After a single selection round, active variants were highly enriched, confirming SMART’s effectiveness.

In practical experiments, the team generated a mutant library by substituting the essential 232nd amino acid with each of the 20 other amino acids. Next-generation sequencing analysis showed that the wild-type (original form) Y232 was clearly selected (p < 0.001), reinforcing the method’s selectivity.

Initially, genetic analysis indicated selection of several variants, in addition to the original form. However, further statistical analysis identified these as experimental noise with minimal practical significance, supporting the method’s specificity.

Conclusion and future perspectives

The experiments showed that SMART selection is highly effective. At the same time, the team recognized the need for rigorous statistical analysis and careful experimentation, rather than relying solely on initial results.

The researchers expect SMART to be applicable beyond oxidases. They aim to facilitate the integration of novel enzymes into industry, establishing the system as a foundation for future enzyme development and practical biocatalytic solutions.

Publication

Kalhari Munaweera, Nana Odake, Hannah Patricia Halim, Kakeru Ikeda, Bo Zhu, Maurizio Camagna, Tomokazu Ito, Tetsuya Kitaguchi, Naoto Nemoto, Hideo Nakano, and Jasmina Damnjanovi? (2026). Harnessing the Power of SMART Single-Molecule Display for Enzyme Evolution: A Focus on Oxidase, ACS Synthetic Biology. DOI:

Funding

This work was supported by Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Early-Career scientists [grant number JP18K14387 and JP22K14828] and Grant-in-Aid for Transformative Research Areas (A) (Publicly Offered Research) [grant number JP25H02263], the Collaborative Research Program by Network Joint Research Center for Materials and Devices (Ministry of Education, Culture, Sports, Science and Technology -Japan: MEXT), and Retention, Development, and Promotion Program Program Aiming at Maximizing the Career Potential of Female Researchers, ÐßÐßÊÓƵ, (MEXT’s Initiative for Realizing Diversity in the Research Environment, Leadership training type for women) awarded to Jasmina Damnjanovi?, and in part by Pre-Research Unit System of the Institute of Integrated Research, Institute of Science Tokyo and JSPS Grant-in-Aid for Transformative Research Areas (A) (Publicly Offered Research) [grant number JP24H01123] awarded to Bo Zhu.

Expert contact

Jasmina Damnjanovi?
Graduate School of Bioagricultural Sciences, ÐßÐßÊÓƵ
Email: jasmina@agr.nagoya-u.ac.jp

Media contact

Naomi Inoue
International Communications Office, ÐßÐßÊÓƵ
Email: icomm_research@t.mail.nagoya-u.ac.jp

Top image

The SMART single-molecule display model, predicted by Alphafold3, shows SpDAAO (red) linked to a puromycin linker (magenta) through puromycin incorporation into the growing polypeptide. The mRNA (gray) is hybridized and chemically joined to the linker, connecting it to its protein, SpDAAO. An auxiliary unit is added using ORC hairpin DNA (blue) with APEX2-scCro fusion protein (green).
Credit: Hideo Nakano and Jasmina Damnjanovi?

Hiroyoshi Nishikawa

Professor of the Department of Immunology, ÐßÐßÊÓƵ Graduate School of Medicine, and also Chief of the Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center

In 2022, Dr. Nishikawa was honored as one of the Highly Cited Researchers 2022 by Clarivate Analytics for a third consecutive year, following his recognition in 2020 and 2021. He continues to be a leader in the field of cancer immunology.

Don¡¯t pretend to understand what you don¡¯t understand.

Dr. Nishikawa said that his early work, conducted more than 20 years ago, still serves as the cornerstones of his current research.

¡°I was lucky to have experienced that work at the beginning. When something happens that I never expected, I can think that there¡¯s only so much wisdom I can have, and there¡¯s still so much I have yet to learn,¡± he said.

Our body¡¯s immune system plays a crucial role in not only fighting against bacteria and viruses but also eliminating cancer. Dr. Nishikawa started his research in the field of cancer immunology in the late 1990s, when the focus was mainly on the study of killer T cells, which directly attack cancer cells.

At that time, he thought that immunity was not so simple and decided to focus his research on helper T cells, which were recognized as coordinating the immune response. However, at the time, it was believed that helper T cells only assisted killer T cells in their fight against cancer, although much remained to be understood. He divided mice with cancer into several groups and treated them in different ways:

1. Activation of killer T cells only
2. Activation of helper T cells only
3. Activation of both killer and helper T cells
4. No treatment

He expected that mice with activated killer T cells and/or helper T cells would have better prognoses although to varying degrees; but unexpectedly, mice with only activated helper T cells showed cancer progression.

Why? Though he later noticed the fact during the days of research, CD4-positive T cells, to which helper T cells belong, can actually be further classified. In reality, in addition to helper T cells supporting killer T cells in fighting cancer, another subset of CD4-positive T cells called ¡°regulatory T cells¡± also exist. They play a different role by putting the brakes on killer T cells¡¯ attacks. Immunity is such a powerful mechanism that once it gets out of control, it may cause excessive immune responses in the body. Regulatory T cells constantly monitor and control the immune system to prevent immune responses from getting out of hand.

Cancer can manipulate and exploit immune suppressive cells including regulatory T cells as a clever mechanism to evade attacks by the immune system. This mechanism may explain the results of his early research described above, in which treatment intended to activate helper T cells also activated regulatory T cells, unexpectedly leading to the protection of cancer cells. In fact, the two types of T cells work in balance with each other. CD4-positive T cells should not be lumped together as helper T cells only. The expected outcome would not be seen unless the two subsets of CD4-positive T cells are activated differently.

Dr. Shimon Sakaguchi, specially-appointed professor of the University of Osaka, discovered regulatory T cells in 1995. At the time, Dr. Nishikawa struggled with mysterious results, turned to Dr. Sakaguchi¡¯s research on regulatory T cells, thinking that it could be the key. Thus, he found the key to the solution and eventually paved the way for cancer immunology research.

He said, ¡°Actually, immunology was my least favorite subject as a medical student. The theory at that time seemed like a patchwork of disconnected information that was being forced together. I couldn¡¯t understand it very well.¡±

There are significant factors, such as one¡¯s position as a researcher and research trends at the time, that determine one¡¯s research theme. At the time, it must have taken courage for Dr. Nishikawa to focus on studying helper T cells.

¡°It is important for researchers to sincerely face the occurring phenomena. We should not pretend to understand what we don¡¯t understand,¡± he said.

When you cannot explain well a phenomenon you are seeing or when you do not feel fully convinced, there is surely something wrong. An attitude of not running away from such dissatisfaction can lead to new findings.

A saying of his boss serves as his driving force: ¡°If you see one phenomenon, continue to sit in front of it until you have written five papers on it.¡±

The research of Dr. Tasuku Honjo, who is the Nobel Prize laureate in Physiology or Medicine 2018, has opened up a new field of cancer treatment known as ¡°cancer immunotherapy,¡±  particularly, ¡°PD-1 blockade therapy¡±. One drug used in this therapy is nivolumab (Opdivo).

Killer T cells typically do not attack unless they can recognize and identify other cells as their attack targets. This is another mechanism that prevents excessive immune response, and cancer cells can also take advantage of this mechanism to suppress the attackers. Cancer cells provide a ¡°certificate¡± that they are not the attack targets as another means of escape. Killer T cells are slowed down and cannot show their ability to attack in the presence of this certificate. PD-1 blockade therapy including Opdivo has the function of nullifying this certificate, allowing killer T cells to attack cancer cells.

Cancer immunotherapy is a relatively new field of medicine. Unfortunately, PD-1 blockade therapy is only effective in 20% to 30% of eligible cancer cases, for some reasons not entirely explained. Dr. Nishikawa has proven one of the reasons.

¡°The immune system works properly in a positive and negative balance. I realized the phenomenon I encountered 20 years ago commonly underlied the results of my current work,¡± he said.

It has been shown that PD-1 blockade therapy activates not only killer T cells but also regulatory T cells surrounding cancer. Therefore, the key to the efficacy of the drug is the balance between the two types of T cells. If regulatory T cells in the periphery of cancer are strong, the killer T cells will eventually be outcompeted by them.

Dr. Nishikawa¡¯s research progressed further, and the next step was to demonstrate exactly what determines the balance between killer and regulatory T cells. He turned his attention to cancer metastases in the liver, which are particularly resistant to PD-1 blockade therapy.

The liver is a metabolically active organ that receives abundant nutrients supplied from the digestive system such as the large and small intestines. The liver consumes a large amount of glucose to generate energy for metabolism, which results in the release of lactic acid. Cancer cells also consume high amounts of glucose to grow and divide. Metastatic cancer tissues in the liver are richer in lactic acid than other tissues.

¡°What I keep in my mind during my research on cancer immunology is to have both the viewpoints of cancer and immunity. I¡¯ve noticed that regulatory T cells can utilize lactic acid, which hasn¡¯t received attention in previous studies,¡± said Dr. Nishikawa.

Killer T cells and most other types of immune cells use glucose as an energy source for their activities, but they cannot use lactic acid. In an area where a large number of immune cells are accumulating and actively working, glucose levels decrease while lactic acid levels increase. In such an environment, regulatory T cells, which can utilize lactic acid, would not have any trouble obtaining an energy source, allowing them to constantly monitor and control immune responses.

Furthermore, Dr. Nishikawa has demonstrated that high levels of lactic acid slow down the activity of killer T cells; this suggests that metastatic cancer in the liver may be a more favorable environment for regulatory T cells than for other immune cells.

This series of discoveries has provided new insights into the study of cancer immunology, and has significantly impacted clinical practice. It is a great advance to identify patients who are not expected to respond to PD-1 blockade therapy, considering their cost and potential side effects.

Dr. Nishikawa has accomplished many studies, and describes himself as ¡°being persistent¡± when it comes to his research, while attributing much of his success to advances in science and technology and to superior researchers who have supported him. His research attitude can be traced back to the time when he was a researcher at the Memorial Sloan-Kettering Cancer Center in New York, U.S., from 2003 to 2006. His boss at the time, Dr. Lloyd J. Old, was a renowned leader in the field of cancer immunology.

¡°He told me that when you see one phenomenon, continue to sit in front of it until you have written five papers on it. It¡¯s pretty hard to write five papers, but I learned from him the attitude of doing as much as I can to solve a series of things,¡± said Dr. Nishikawa.

The immune system is purposeful, interesting, and beautiful.

When and how does the immune system find and recognize cancer cells? Does the judgment of whether or not something is foreign depending on the situation? Can we create killer T cells that can utilize lactic acid?

Questions arise in his mind one after another. The immune system is very complex, and much of it is still a mystery. Therefore, efforts may not yield fruitful results. ¡°It¡¯s daunting, and there¡¯s so much I don¡¯t understand yet, but that¡¯s what makes it exciting,¡± Dr. Nishikawa stated. Each of his words sounds as if it conveys a spark of curiosity.

¡°While study immunology, I sometimes feel thrilled at such a complex but sophisticated mechanism present in our bodies, and the more I study, the more I am amazed and can only stand in awe of it. When I think something is wrong and research it again, I get exactly the results I was looking for. The immune system is so amazing that it makes me realize that human understanding is so far behind,¡± he said.

Aortic aneurysms are characterized by abnormal enlargement of the aorta, the primary artery responsible for carrying blood from the heart. Rupture often leads to sudden death, and currently, no effective drug therapies are available to halt disease progression.

Researchers at ÐßÐßÊÓƵ in Japan found that aortic aneurysms are associated with clonal hematopoiesis, an age-related process in which blood-forming stem cells acquire genetic mutations. Their findings, published in the , suggest that commonly used osteoporosis drugs could slow or halt aneurysm progression.

Currently, surgery is the only definitive treatment for aortic aneurysms. Surgical decisions are guided by the risk of rupture, which is assessed through imaging of aneurysm diameter, morphological features, and expansion rate.

It remains difficult to predict which patients will experience progressive aneurysm enlargement, highlighting the need for additional indicators to better stratify disease progression risk. Furthermore, developing drugs that slow disease progression is crucial for reducing mortality. Achieving both goals requires a clear understanding of the underlying mechanisms.

To address this challenge, Assistant Professor and graduate student Jun Yonekawa of the , along with their colleagues, conducted a comprehensive study.

The research team hypothesized that macrophages derived from clonal hematopoiesis accelerate the progression of aortic aneurysms. Although clonal hematopoiesis is recognized as a contributor to several age-related diseases, such as cardiovascular diseases and osteoporosis, its association with aortic aneurysms remains unclear.

Analysis of patient data

Researchers first conducted a clinical study to examine the relationship between clonal hematopoiesis and abdominal aortic aneurysms in 44 patients scheduled for aneurysm surgery.

Genetic analysis and retrospective clinical data showed that approximately 60% of patients had clonal hematopoiesis. These patients had a significantly faster aneurysm expansion rate compared to those without clonal hematopoiesis.

These results suggest that clonal hematopoiesis, which is detectable through routine blood sampling, may serve as a novel biological marker alongside conventional indicators.

Investigation of causal mechanisms in animal models

Researchers then used a mouse model of clonal hematopoiesis driven by Tet2 mutations. These mice exhibited more rapid aneurysm progression and greater increases in aortic diameter than control mice.

Histological analysis showed thinning and fragmentation of elastin fibers in the aortic wall, substantial macrophage infiltration, and degeneration of adjacent vascular smooth muscle cells.

Further analyses suggested that Tet2-mutant macrophages in affected mice exhibited increased expression of osteoclast-related markers, including TRAP. In vitro, these macrophages showed an enhanced propensity to differentiate into osteoclast-like cells and upregulated MMP-9 expression. These findings suggest a potential mechanism by which Tet2-mutant macrophages may contribute to extracellular matrix degradation and aneurysm progression.

The study also identified the RANK/RANKL signaling axis as a key driver of cellular differentiation. This axis is also involved in the pathogenesis of osteoporosis. Researchers found that inactivating the RANK gene in macrophages suppressed cellular transformation and abnormal aortic expansion.

Potential non-surgical approach

To assess clinical relevance, researchers treated affected mice with osteoporosis drugs¡ªanti-RANKL antibodies and alendronate. This intervention significantly reduced aneurysm progression.

“These drugs could potentially be repurposed for clinical use, as they are already FDA-approved and have established safety profiles,” said Yonekawa, the study’s first author. “Our findings provide a rationale for exploring drug-based therapeutic strategies for aortic aneurysms.”

Yura, the study’s corresponding author, concluded: “Our hypothesis that vascular diseases may result from blood aging enabled us to identify a mechanism underlying aortic aneurysms. We hope these results will improve the prediction of the disease and support the development of treatments to halt progression.”

Paper information:

Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara (2026). Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast-like differentiation, The Journal of Clinical Investigation.

DOI:

Expert contact:

Yoshimitsu Yura
ÐßÐßÊÓƵ Graduate School of Medicine
Email: yura.yoshimitsu.z6@f.mail.nagoya-u.ac.jp

Medica contact:

Naomi Inoue
ÐßÐßÊÓƵ International Communications Office
Email: icomm_research@t.mail.nagoya-u.ac.jp

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Graphical abstract of the study showing that Tet2-driven clonal hematopoiesis promotes aortic aneurysm progression through macrophage-to-osteoclast-like differentiation.

(Credit: ÐßÐßÊÓƵ / Jun Yonekawa and Yoshimitsu Yura)

Nearly two thirds of participants held positive attitudes toward sexual and gender minorities, but most assumed others were less accepting

 
Coming out is known to have clear benefits for mental health and wellbeing, yet for many LGBTQ+ individuals in Japan, doing so remains a significant challenge. Researchers at ÐßÐßÊÓƵ surveyed cisgender, heterosexual Japanese adults on their attitudes toward sexual and gender minorities and coming out. Their findings, published in , show that while most participants had positive attitudes toward LGBTQ+ people, they assumed the public was more negative than themselves¡ªa misperception that may be stopping people from showing their support.  
 
¡°For sexual and gender minority individuals, concealing their gender identity or sexual orientation can have a serious impact on their mental health, while being accepted after coming out is associated with improved quality of life,¡± Xianwei Meng, associate professor at ÐßÐßÊÓƵ¡¯s , said.  
 
¡°In Japan, many sexual and gender minority individuals report feeling unable to come out. Much of the existing research has focused on the fear of discrimination and stigma, while the role of support from others has been overlooked, even though it¡¯s critical to whether someone feels safe enough to openly share their identity.¡± 

Measuring the gap between personal and estimated societal attitudes 

The online survey collected 370 responses and measured three things: participants¡¯ own attitudes toward sexual and gender minorities, their estimates of how accepting the Japanese public is toward them, and their willingness to support a friend who wished to come out. These were measured using numerical rating scales.  
 
The average personal attitude score toward sexual and gender minorities was 4.24 (on a 6-point scale), while the average estimated public attitude score was 3.83. This statistically significant gap shows that participants underestimated how accepting others were. ? 

Based on their responses, participants were divided into three main groups: those who were positive toward sexual and gender minorities and estimated others as positive (62%), those who were positive but estimated others as negative (17%), and those who held negative attitudes and estimated others as also negative (16%).  
 
These group differences had a notable impact on participants’ willingness to support coming out. The study found that participants who held positive attitudes but assumed others were negative scored significantly lower on willingness to support a friend coming out than those who held positive attitudes and believed others shared their views (3.93 vs. 4.43 out of 7). Their support level was closer to neutral, neither actively helping nor refusing. 

Impact on support for those who want to come out 

¡°Our findings suggest that attitudes toward sexual and gender minorities in Japan are more positive than commonly assumed. However, the misperception that others hold more negative views may discourage people from expressing support, making society appear less accepting than it actually is. Sharing the reality that many people are accepting could help create a more inclusive society,¡± said coauthor Yuka Mizuno, a master¡¯s student at ÐßÐßÊÓƵ who specializes in social psychology. 
 
The findings carry important implications beyond individual attitudes. In workplaces and schools, raising awareness that acceptance is more widespread than people assume could help build more supportive environments. Media coverage also has a role to play, as reporting that focuses heavily on discrimination and exclusion may inadvertently reinforce a misperception that negative attitudes are the norm. ? ?

Paper information:

Yuka Mizuno and Xianwei Meng (2026). Misperceived Public Attitudes Undermine Support for Sexual and Gender Identity Disclosure in Japan, Psychology of Sexual Orientation and Gender Diversity. DOI: .  

Expert contact:  

Xianwei Meng  
Graduate School of Informatics   
ÐßÐßÊÓƵ   
E-mail: meng@i.nagoya-u.ac.jp ? ? 

Media contact:  

Merle Naidoo   
International Communications Office   
ÐßÐßÊÓƵ   
Email: icomm_research@t.mail.nagoya-u.ac.jp   

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How mistaken beliefs about society can silence support for coming out: A person who personally holds positive attitudes toward LGBTQ+ individuals but assumes society is negative may hesitate to encourage a friend to come out. Yuka Mizuno, ÐßÐßÊÓƵ 

The origins of a debilitating muscle-wasting disease begin at birth, not in adulthood, ÐßÐßÊÓƵ researchers have shown. A single treatment at this early stage significantly reduced nerve cell breakdown in adult mice. ? 

Spinal and Bulbar Muscular Atrophy (SBMA) is a rare inherited disease that causes progressive muscle weakness and wasting in men. Patients typically develop early symptoms such as hand tremors in their thirties, but diagnosis usually occurs around age 40 when muscle weakness becomes more evident. Because the disease is triggered by high levels of testosterone, only males are affected.  
 
Researchers at ÐßÐßÊÓƵ have found that a natural burst of testosterone right after birth causes a mutant protein to overactivate the nerve cells that control muscles (motor neurons) in newborn mice carrying the SBMA mutation. This ongoing overactivation eventually causes those nerve cells to break down in adulthood. The findings, published in , showed that treatment given at birth significantly reduced this breakdown. 

While it is well established that abnormal protein accumulation in neurodegenerative diseases begins years or decades before symptoms appear, what actually happens in the body during this period remains poorly understood. This study focused on the earliest stage of SBMA, the first days after birth.  
 
A brief natural spike in testosterone known as the neonatal testosterone surge or ¡°mini-puberty¡± occurs in all newborn males and lasts approximately 10 days in mice and around 6 months in humans. Because the defective protein produced by the SBMA mutation¡ªmutant androgen receptor protein¡ªrequires testosterone to move into the nucleus of motor neurons and cause damage, the team suspected that this surge represented the earliest moment at which the disease could be triggered. 
 
¡°We confirmed that mutant protein accumulates in the nuclei of motor neurons in male SBMA mice within the first day of life, driven by the neonatal testosterone surge. Female mice with the same mutation showed no such effects, confirming that testosterone is the key trigger,¡± said lead author and assistant professor Tomoki Hirunagi from ÐßÐßÊÓƵ¡¯s .

Additionally, genes responsible for activating nerve cells, especially glutamate receptors, were abnormally overactive in SBMA mice in the first week of life and caused motor neurons to become overactive. Importantly, the same abnormal overactivity was also observed in motor neurons grown in the laboratory from the cells of actual SBMA patients. This suggests that the disease process in humans may follow the same pattern.

?To test whether treating the disease at birth could help, the researchers administered two gene-silencing drugs to newborn mice with the SBMA mutation, one targeting the mutant protein directly, and one targeting REST4, a protein found to drive the abnormal nerve cell overactivity.  
 
The drug targeting the mutant protein temporarily reduced mutant protein levels and the drug targeting REST4 corrected abnormal gene activity in motor neurons. Both treatments improved survival and motor performance, and decreased motor neuron degeneration in mice assessed at 13 weeks of age.  

¡°Perhaps the most remarkable finding was that a drug given at birth to target the mutant protein continued to protect motor neurons months later, even though the drug effects  had worn off within two weeks. This suggests that intervening at the right moment early in life can have lasting consequences, long after the treatment is gone,¡± Dr. Hirunagi said. 
 
REST4, the protein found to drive the abnormal nerve cell overactivity in SBMA, represents a potential new target for future therapies. 

ÐßÐßÊÓƵ has previously developed leuprorelin acetate, the only drug approved in Japan for SBMA treatment, making these discoveries part of a broader research legacy in tackling the disease. 
 
The research team identified the next priority as determining whether the same abnormal nerve cell overactivity occurs in human SBMA patients. ¡°This is currently very difficult to study directly, because examining newborn nervous system activity in living patients is not feasible. Our goal is to translate these findings into patient care,¡± Dr. Hirunagi said. The team also intends to evaluate the safety of gene-silencing drugs and the efficacy of repeated treatment. 

Paper information:  

Tomoki Hirunagi, Kentaro Sahashi, Madoka Iida, Kazunari Onodera, Satoshi Yokoi, Yosuke Ogura, Genki Tohnai, Kenji Sakakibara, Kentaro Maeda, C. Frank Bennett, Yohei Okada, Masahisa Katsuno (2026). Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy, Nature Communications, 17: 2412. DOI: .??

Funding information: 

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant numbers: JP20H00527, JP23H00420, JP24K18683, JP23K24249, JP24K18712, JP25K02585) and the Japan Agency for Medical Research and Development (AMED) (Grant numbers: JP22nk0101575, JP22am0401007, JP22bm0804020, JP25bm1423003).

Expert contact:  

Tomoki Hirunagi   
Graduate School of Medicine  
ÐßÐßÊÓƵ  
E-mail: hirunagi.tomoki.k3@f.mail.nagoya-u.ac.jp 

Masahisa Katsuno 
Graduate School of Medicine  
ÐßÐßÊÓƵ 
E-mail: katsuno.masahisa.i1@f.mail.nagoya-u.ac.jp

Media contact:  

Merle Naidoo?
International Communications Office?
ÐßÐßÊÓƵ?
Email: icomm_research@t.mail.nagoya-u.ac.jp

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Microscopy images of spinal cord tissue from male (left) and female (right) SBMA model mice on the first day after birth. Brown staining indicates accumulation of the mutant androgen receptor protein in motor neuron nuclei. The protein accumulates extensively in male mice but shows little to no accumulation in female mice, confirming that testosterone drives the early accumulation of the mutant protein in motor neurons. Credit: Hirunagi et al., 2026 

Fumagillin has been investigated as a drug lead for more than 70 years, but its more potent relative ovalicin was never developed. Now, scientists have identified metabolic instability as the key barrier and have overcome it through chem-bio hybrid synthesis, yielding drug candidates for amebiasis, a parasitic infection affecting 50 million people annually. 

Amebiasis is a parasitic disease caused by the microscopic protozoan Entamoeba histolytica. Infection occurs through the ingestion of cysts from contaminated water or food. Worldwide, approximately 50 million symptomatic cases are estimated annually, mainly in tropical and subtropical regions.??
?
Fumagillin, a fungal natural product, has been studied for decades as a potential antiparasitic drug, but its more potent relative ovalicin was never developed. Now, a study published in the reveals why: although ovalicin is highly active against amebiasis, liver enzymes rapidly break it down in the body. Researchers ?used a chem-bio hybrid approach to turn that insight into metabolically stable drug candidates that worked in animal models of amebiasis, including liver infection with abscess formation.?
?
The research team, led by scientists from the at ÐßÐßÊÓƵ, ?identified the liver cytochrome P450 enzymes responsible for ovalicin breakdown, with CYP 2B1 and CYP 2C6 emerging as the main drivers. Blocking these enzymes with a chemical inhibitor significantly prolonged ovalicin survival, providing strong evidence that rapid liver metabolism limits its effectiveness.?

Successfully curing infections in animals 

¡°We engineered fungi to build modified ovalicin molecules with a special attachment point that we could customize. We then clipped different molecular groups onto that point to create versions that the liver could not destroy,¡± explained senior author and associate professor Yuta Tsunematsu.  
 
Using genetically engineered filamentous fungi, the team produced gram-scale quantities of a non-natural ovalicin molecule. They then created about 30 derivatives and tested each one to find versions that killed parasites, survived liver breakdown, and were not toxic. 
 
The protozoan parasite depends on an enzyme called MetAP2 for its proteins to work properly and survive. Blocking MetAP2 kills it but does not harm humans because we have a backup enzyme that can perform the same function. 
 
Two of the new compounds, YOK24 and NS-181, blocked the parasite¡¯s MetAP2 enzyme and eliminated the parasitic infection in hamsters, causing liver abscesses to disappear entirely. 
 
These results are an important step toward testing these drug candidates in humans. Importantly, the compounds were effective after both injection and oral administration. Oral treatment would be especially valuable in low-resource settings, where amebiasis is most prevalent. 

A new drug development method 

Current amebiasis treatments, such as metronidazole, can cause side effects and face growing concerns about drug resistance. 
 
This study introduces Chem-Bio Hybrid Synthesis, a new method that combines genetic engineering of microbes and chemistry to transform natural compounds that worked in lab tests but failed in patients due to rapid breakdown or toxicity. The approach could address these challenges for amebiasis and be applied to develop treatments for other parasitic diseases, cancer, and obesity. 

Paper information:  

Yuki Okura, Yumiko Saito-Nakano, Andrii Balia, Nurul Syahmin Binti Suhaimi, Chika Ando, Namiko Ogata, Tomona Ikeda, Takumi Sato, Keiko Kano, Emi Mishiro-Sato, Masaki Kita, Noriyuki Miyoshi, Kenji Watanabe, Kouichi Yoshinari, Norio Shibata, Mihoko Mori, Seiki Kobayashi, Yuji Sumii, Ryota Shizu, Tomoyoshi Nozaki, Yuta Tsunematsu (2026). Chem¨CBio Hybrid Synthesis Enables Reengineering of Natural Product-Based Methionine Aminopeptidase 2 Inhibitors for Treating Amebiasis, Journal of the American Chemical Society, 148(7), 7189¨C7201. DOI: . 

Funding information:

This work was financially supported by the Japan Agency for Medical Research and Development (AMED) (Grant numbers: JP22wm0325020, JP23wm0325070, JP25jm0110022) and the Japan Society for the Promotion of Science (JSPS) (Grant number 24K02190). 

Expert contact: 

Yuta Tsunematsu 
Graduate School of Bioagricultural Sciences 
ÐßÐßÊÓƵ 
E-mail: tsunematsu.yuta.p4@f.mail.nagoya-u.ac.jp 

Media contact:

Merle Naidoo?
International Communications Office?
ÐßÐßÊÓƵ?
Email: icomm_research@t.mail.nagoya-u.ac.jp 

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Scientists genetically engineered the fungus Aspergillus nidulans to produce a modified ovalicin molecule. Although this molecule itself was still susceptible to liver breakdown, it provided a chemical handle that enabled the synthesis of metabolically stable drug candidates for amebiasis. Credit: Yuta Tsunematu, ÐßÐßÊÓƵ?

Professor Hiroyoshi Nishikawa (Graduate School of Medicine) has been awarded the Japan Academy Prize.

This prize is awarded by for particularly outstanding academic papers, books, and other research achievements.

The research topic recognized under the award was ¡°Establishment of the Immuno-Genomic Cancer Evolution Hypothesis and its Application to Precision Medicine for Cancer Immunotherapy.¡±

Nishikawa developed a method for the precise analysis of live human cancer tissue. He demonstrated that genomic mutations in cancer cells both promote their own proliferation and induce an immunosuppressive environment, thereby causing tumor initiation and progression. Nishikawa named this mechanism the ¡°Immuno-Genomic Cancer Evolution Hypothesis.¡±

This concept is believed to have brought significant advancements to cancer immunology, as well as having opened up a new field in tumor biology. With this research, Nishikawa also established a new technical foundation that integrates molecular targeted therapies aimed at genomic mutations with cancer immunotherapy (immuno-genomic precision medicine), and he is currently pursuing its clinical application.