Tag: Tokyo University of Science

In the fight against COVID-19, scientists have been scanning their arsenals of previously used drugs in hopes of finding any that can be used to treat the disease. One of the contenders under scrutiny, an anti-malarial drug called mefloquine shows great promise, according to a new breakthrough study by a team of Japanese scientists, perhaps giving us a better fighting chance.

In a breakthrough study, a team of scientists—comprising Dr. Koichi Watashi, Kaho Shionoya, Masako Yamasaki, Dr. Hirofumi Ohashi, Dr. Shin Aoki, Dr. Kouji Kuramochi, and Dr. Tomohiro Tanaka from Tokyo University of Science (along with scientists from the National Institute of Infectious Diseases, Kyushu University, The University of Tokyo, Kyoto University, Japanese Foundation for Cancer Research, and Science Groove Inc.)—have identified an anti-malarial drug, mefloquine (which is incidentally a derivative of hydrochloroquine), that is effective against SARS-CoV-2. Their findings are published
in Frontiers in Microbiology.

Detailing their modus operandi, lead scientist in the team Dr. Watashi says, “To identify drugs with higher antiviral potency than existing antivirals, we first screened approved
anti-parasitic/anti-protozoal drugs. We found that mefloquine had the highest anti-SARS-CoV-2 activity among the tested compounds. Upon testing it against other quinoline derivatives, such as hydrochloroquine, in a cell line mimicking the cell-based environments of human lung cells, we found it to be better.”

The team further explored mefloquine’s mechanism of action. Dr. Watashi explains the process, “In our cell assays, mefloquine readily reduced the viral RNA levels when applied at the viral entry phase but showed no activity during virus-cell attachment. This shows that mefloquine is effective on SARS-COV-2 entry into cells after attachment on cell
surface.”

Thus, to bolster mefloquine’s anti-viral activity, the scientists looked into the possibility of combining it with a drug that inhibits the replication step of SARS-CoV-2: Nelfinavir. Interestingly, they observed that the two drugs acted in “synergy” and the drug combination showed greater anti-viral activity than either showed alone, without being toxic to the cells in the cell lines themselves.

The scientists also mathematically modelled the effectiveness of mefloquine to predict its potential real-world impact if applied to treat COVID-19. What they predicted was that mefloquine could reduce the overall viral load in affected patients to under 7% and shorten the ‘time-till-virus-elimination’ by 6.1 days.

This study must of course be succeeded by clinical trials, but the world can hope that mefloquine becomes a drug used to effectively treat patients with COVID-19.

Acrylamide, which is extensively used in industries, causes peripheral neuropathy or encephalopathy. Now, scientists from Japan examined the response against oxidative stress in acrylamide-induced neurotoxicity and found that nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the immune system and response to oxidative stress, was at the centre of this toxicity. They found that Nrf2 plays a protective role by increasing the expression of protective genes and decreasing that of pro-inflammatory genes.

In a recent study, a team of scientists, led by Prof. Gaku Ichihara from Tokyo University of Science, reported the role of Nrf2 in acrylamide-induced neurotoxicity. Prof. Ichihara
states, “Our study showed that Nrf2 has a protective role against neurologic damage and suggests it is through activation of antioxidant stress genes and suppression of proinflammatory cytokine genes.”

In their study published in the journal Toxicology, Prof. Gaku Ichihara, along with his colleagues Prof. Masayuki Yamamoto from Tohoku University, Prof. Ken Itoh from Hirosaki University, Associate Prof. Seiichiroh Ohsako from The University of Tokyo, and Prof. Sahoko Ichihara from Jichi Medical University, used mice models to study the role of Nrf2 in acrylamide-induced neurotoxicity.

They tested their hypothesis that when Nrf2 gene is removed, the neurotoxic effects of acrylamide will be amplified. For this, they developed “knockout” mice that could not produce Nrf2, and gave the Nrf2-knockout mice and a set of counterpart “wild-type” mice that could produce Nrf2 different concentrations of acrylamide for 4 weeks. Then, they compared the neurotoxicity between both groups of mice using various sensory and motor tests, immunohistochemistry, and protein and gene expression analyses.

The scientists found that the Nrf2-knockout mice had severe neurotoxic effects such as sensory and motor system dysfunction and axonal damage. While these mice produced fewer antioxidants and protective factors in response to acrylamide, they also showed enhanced release of pro-inflammatory chemicals, called “cytokines,” in the brain, which can potentially cause additional damage. Additionally, as different doses were given to the mice, the scientists also determined that the neurotoxicity was dose-dependent.

Previous studies have established the role of Nrf2 as a master regulator of protective genes but this study explained the specific mechanisms of immune response to acrylamide-induced toxicity, with Nrf2 at the center of it all. As Prof. Ichihara states, “The results document the first known morphological and neuro-functional evidence of the regulatory role of Nrf2 in acrylamide-induced neurotoxic effects in mice.”

The findings of this study are also immensely valuable in the field of disease biology, as recent studies have shown a link between air pollution and Alzheimer’s disease. Since the air contains other acrylamide-like chemical pollutants with similar neurotoxic effects, the study’s findings could prove useful in the prevention of Alzheimer’s disease.

Prof. Ichihara and his team’s study is certainly a timely one, as reports of acrylamide intoxication are on the rise and further research is required to better understand the specific mechanisms by which the body protects itself from harm.

Some nonpathogenic microorganisms can stimulate plant immune responses without
damaging the plants, which allows them to act like plant vaccines, but screening microorganisms for such properties has traditionally been time-consuming and expensive.

Associate Professor Toshiki Furuya and Professor Kazuyuki Kuchitsu of Tokyo University of Science and their colleagues decided to develop a screening strategy involving cultured
plant cells. A description of their method appears in a paper recently published in Scientific Reports.

The first step in this screening strategy involves incubating the candidate microorganism together with BY-2 cells, which are tobacco plant cells known for their rapid and stable growth rates. The next step is to treat the BY-2 cells with cryptogein, which is a protein secreted by fungus-like pathogenic microorganisms that can elicit immune responses from tobacco plants.

A key part of the cryptogein-induced immune responses is the production of a class of chemicals called reactive oxygen species (ROS), and scientists can easily measure cryptogein-induced ROS production and use it as a metric for evaluating the effects of the nonpathogenic microorganisms.

To put it simply, an effective pretreatment agent will increase the BY-2 cells’ ROS production levels (i.e., cause the cells to exhibit stronger immune system activation) in response to cryptogein exposure.

To test the practicability of their screening strategy, Dr. Furuya and his colleagues used the strategy on 29 bacterial strains isolated from the interior of the Japanese mustard spinach plant (Brassica rapa var. perviridis), and they found that 8 strains boosted cryptogein-induced ROS production.

They then further tested those 8 strains by applying them to the root tips of seedlings from the Arabidopsis genus, which contains species commonly used as model organisms for studies of plant biology. Interestingly, 2 of the 8 tested strains induced whole-plant resistance to bacterial pathogens.

Based on the proof-of-concept findings concerning those 2 bacterial strains, Dr Furuya proudly notes that his team’s screening method “can streamline the acquisition of microorganisms that activate the immune system of plants.”

When asked how he envisions the screening method affecting agricultural practices, he explains that he expects his team’s screening system “to be a technology that contributes to the practical application and spread of microbial alternatives to chemical pesticides.”

In time, the novel screening method developed by Dr Furuya and team may make it significantly easier for crop scientists to create greener agricultural methods that rely on the defence mechanisms that plants themselves have evolved over millions of years.

With increasing public awareness of crises associated with degraded environments and mounting pressure to act, governments worldwide have begun to examine environmentally sustainable policies. However, there are many questions about whether enacting these policies will negatively affect economic growth. Now, a modelling study conducted by researchers from Tokyo University of Science and The Shoko Chukin Bank, Japan, published in the Journal of Cleaner Production, shows that it is possible to achieve economic growth
simultaneously with environmental preservation.

“There are existing models that look at how economies fluctuate under various conditions, such as differing environmental quality or tax rates, but these models haven’t examined the effects of implementing the kindergarten rule,” Prof. Hideo Noda, the study’s lead author, explained.

“So we thought it was important to extend the model and include a condition where the hypothetical society spends a part of its GDP to achieve zero emissions. Looking at emissions is also more tangible and easier to grasp than a vaguer concept of ‘environmental quality.”

The researchers used an economic model that allows for movement back and forth between two stages: a no-innovation phase and an innovation phase. The key to this model is the importance of innovation; previous models that focus on the environment and the economy did not account for innovation (e.g., research and development) as a major driver of economic growth in most developed nations. Acknowledging this connection is essential for improving our knowledge regarding how environmental problems and economic growth are linked.

When researchers included rules for the zero-emission society, the model indicated that it was compatible with economic growth (i.e., a sustained GDP growth), despite a portion of the GDP being dedicated to reducing pollution. For this to work, however, the model says that the GDP needs to be above a certain level.

Additionally, the amount of GDP allocated to lowering pollution must be flexible. Researchers also observed that under the no innovation phase, GDP growth is higher and the amount spent on pollution reduction decreases faster. In contrast, under the innovation phase, GDP growth is lower and the decrease in the amount spent combating pollution is also slower.

According to Prof. Noda, this work provides the important theoretical groundwork for policy, because currently, the relationship between zero emissions and economic growth isn’t well understood. “Yet, this topic is extremely relevant to any policy push for sustainability—for example, one section of the UN’s Sustainable Development Goals explicitly focuses on economic growth,” he explains.

“Our model should help persuade the leaders of some countries that it is feasible to reduce emissions without tanking the economy.”

That, Prof. Noda hopes, may in turn make leaders more eager to implement the changes that are urgently needed to address global environmental crises like climate change.

A rare mutation in the Caps2 gene, which encodes a protein that regulates the release of brain chemicals called neurotransmitters, has also been linked with autism spectrum disorders. Now, researchers at the Tokyo University of Science report that Caps2 mutations in mice limit the release of oxytocin (a hormone that regulates social behaviour), causing diminished sociality in these animals. These findings may help researchers understand the neurobiology of autism and develop effective treatments for it.

Autism spectrum disorder is a neurodevelopmental condition involving impaired social abilities, and this makes it a fascinating subject for neuroscientists like Prof. Teiichi Furuichi of the Tokyo University of Science who study the neuroscience of social behaviour. Professor Furuichi and his colleagues have previously worked on developing mouse models of autism to unravel the condition’s neurochemical mechanisms.

In a paper recently published in the prestigious Journal of Neuroscience, they provide evidence that a genetic mutation associated with autism can impair the release of a peptide called oxytocin that plays an important role in regulating social behaviour. This finding promises to broaden our understanding of the neurobiology of social behaviour.

The gene that Prof. Furuichi’s team chose to study is Caps2, which encodes a protein called Ca2+-dependent activator protein for secretion 2 (CAPS2) that regulates the release of brain chemicals (or “neurotransmitters”). Previous studies have shown that CAPS2 deficiencies in mice cause behavioral impairments such as reduced sociality, increased anxiety, and disrupted circadian rhythms.

Furthermore, a study of Japanese patients with autism spectrum disorder revealed that some of them had Caps2 mutations that adversely affect the CAPS2 protein’s functions. Prof. Furuichi and his colleagues had previously discovered that the CAPS2 protein is expressed in neurons in the hypothalamus and pituitary gland that release the neuropeptide oxytocin. This information formed the basis of their recent study.

As Prof. Furuichi explains, “We hypothesized that CAPS2 deficiencies in mice should alter oxytocin release, which should in turn result in impaired social behavior.”

To test this hypothesis, researchers Shuhei Fujima, Graduate Student at Tokyo University of Science; Yoshitake Sano, Junior Associate Professor at Tokyo University of Science; Yo Shinoda, Associate Professor at Tokyo University of Pharmacy and Life Sciences; Tetsushi Sadakata, Associate Professor in Gunma University; Manabu Abe, Associate Professor at Niigata University; and Kenji Sakimura, a Fellow of Niigata University, among others, led by Prof. Furuichi conducted a series of experiments involving mice that carried genetic alterations that prevented them from expressing the CAPS2 protein.

These mice had lower-than-normal oxytocin levels in their blood but higher-than-normal oxytocin levels in the hypothalamus and pituitary gland. The researchers interpreted this finding as evidence that CAPS2 deficiencies impede the normal release of oxytocin from these brain regions into the bloodstream.

Unsurprisingly, the reduced bloodstream levels of oxytocin had clear behavioral effects. When placed inside a rectangular box, the oxytocin neuron-specific CAPS2-deficient mice were unwilling to spend much time in the centre of the box, and the researchers interpreted this as evidence of increased anxiety about the risk of a predator attacking them.

The CAPS2-deficient mice also exhibited diminished willingness to engage in social
interactions when introduced to unfamiliar mice. Interestingly, spraying an oxytocin solution into the noses of the CAPS2-deficient mice acted to restore their willingness to socially interact with unfamiliar mice.

Based on these findings, Prof. Furuichi and his colleagues conclude that the CAPS2 protein plays a critical role in facilitating the release of peripheral oxytocin into the bloodstream. They similarly suggest that CAPS2 is also involved in the release of central oxytocin into the brain regions relating to the control of sociality. Given the key role that oxytocin plays in regulating social behaviours, this could help to explain how mutations in the Caps2 gene
could lead to atypical patterns of social behaviour in persons with an autism spectrum disorder.

When asked about the social significance of his team’s work, Professor Furuichi remarks, “We believe that this research, although basic, is an important achievement that will contribute to the development of tools for the early molecular diagnosis and effective treatment of autism spectrum disorder.”

Given the relatively high prevalence of autism and how extremely disabling severe cases can be, the development of effective treatments would have major benefits for people with autism and society as a whole.

At Tokyo University of Science, Japan, Professor Takayuki Hamamoto has been leading a research team focused on taking the capabilities of single-photon imaging further. In the latest study by Professor Hamamoto and his team, which was published in IEEE Access, they developed a highly effective algorithm to fix the blurring caused by motion in the imaged objects, as well as the common blurring of the entire image such as that caused by the shaking of the camera.

Their approach addresses many limitations of existing deblurring techniques for single-photon imaging, which produce low-quality pictures when multiple objects in the scene
are moving at different speeds and dynamically overlapping each other.

Instead of adjusting the entire image according to the estimated motion of a single object or on the basis of spatial regions where the object is considered to be moving, the proposed method employs a more versatile strategy.

First, a motion estimation algorithm tracks the movement of individual pixels through statistical evaluations on how bit values change over time (over different bit planes). In this way, as demonstrated experimentally by the researchers, the motion of individual objects can be accurately estimated.

“Our tests show that the proposed motion estimation technique produced results with errors of less than one pixel, even in dark conditions with few incident photons,” remarks Prof. Hamamoto.

The team then developed a deblurring algorithm that uses the results of the motion estimation step. This second algorithm groups pixels with a similar motion together, thereby identifying in each bit plane separate objects moving at different speeds.

This allows for deblurring each region of the image independently according to the motions of objects that pass through it. Using simulations, the researchers showed that their strategy produced very crisp and high-quality images, even in low-light dynamic scenes crowded with objects coursing at disparate velocities.

Overall, the results of this study aptly showcase how greatly single-photon imaging can be improved if one gets down to developing effective image processing techniques.

“Methods for obtaining crisp images in photon-limited situations would be useful in several fields, including medicine, security, and science. Our approach will hopefully lead to new technology for high-quality imaging in dark environments, like outer space, and super-slow recording that will far exceed the capabilities of today’s fastest cameras,” says Prof. Hamamoto. He also states that even consumer-level cameras might timely benefit from progress in single-photon imaging.