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Of mice and men: Mutation linked to autism impairs oxytocin-mediated social behavior

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Mutations associated with autism can inhibit the release of the bonding hormone oxytocin and cause abnormal social behavior in mice

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 behavior. Prof. Furuichi and his colleagues have previously worked on developing mouse models of autism to unravel the condition’s neurochemical mechanisms, and 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 behavior. This finding promises to broaden our understanding of the neurobiology of social behavior.

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 center 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 behaviors, this could help to explain how mutations in the Caps2 gene could lead to atypical patterns of social behavior in persons with autism spectrum disorder. When asked about the social significance of his team’s work, Prof. 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 the society as a whole.

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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 Teiichi Furuichi from Tokyo University of Science

Teiichi Furuichi, PhD, has served as a Professor at the Tokyo University of Science since 2011. He has previously worked at the RIKEN Brain Science Institute, Saitama University, Hiroshima University, the University of Tokyo, Japan’s National Institute for Basic Biology, and the State University of New York at Stony Brook. His research interests include the molecular mechanisms of brain development and the transcriptomic basis of postnatal development of the mouse cerebellum. He has authored over 150 original articles.

Funding information

This work was supported by the Japan Society for the Promotion of Science; the Japanese Ministry of Education, Culture, Sports, Science and Technology; and the NOVARTIS Foundation (Japan) for the Promotion of Science.

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Source: https://bioengineer.org/of-mice-and-men-mutation-linked-to-autism-impairs-oxytocin-mediated-social-behavior/

Bioengineer

Researchers discover unique ‘spider web’ mechanism that traps, kills viruses

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Immunologists at McMaster University have discovered a previously unknown mechanism which acts like a spider web, trapping and killing pathogens such as influenza or SARS-CoV-2, the virus responsible for COVID-19.

The researchers have found that neutrophils, the most abundant white blood cells in the human body, explode when they bind to such pathogens coated in antibodies and release DNA outside of the cell, creating a sticky tangle which acts as a trap.

The findings, published online in the Proceedings of the National Academy of Science, are significant because little is understood about how antibodies neutralize viruses in the respiratory tract.

The discovery has implications for vaccine design and delivery, including aerosol and nasal spray technologies that could help the body head off infections before they have a chance to take hold.

“Vaccines can produce these antibodies that are present in our lungs, which are the first type of antibody to see viruses like flu or COVID-19, which infect our lungs and respiratory tracts,” says the study’s lead author Matthew Miller, an associate professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research and Canada’s Global Nexus for Pandemics and Biological Threats. “Mechanisms that can stop the infection at the site where it enters our body can prevent the spread and serious complications.”

By comparison, injectable vaccines are designed to bolster antibodies in the blood, but those antibodies are not as prevalent at the sites where infection begins.

“We should be thinking carefully about next generation COVID-19 vaccines that could be administered in the respiratory tract to stimulate antibodies. We don’t have many candidates right now that are focused on raising the mucosal response,” says Hannah Stacey, a graduate student in the Miller Lab and lead author of the paper, who recently won a major national scholarship from the Canadian Society for Virology for her work on COVID-19.

“If you want a lot of these antibodies that are really abundant in blood, then injections make the most sense, but if you want antibodies that are abundant in the respiratory tract, then a spray or an aerosol makes sense,” she says.

Researchers caution that while the body’s spider-web mechanism has the potential to be hugely beneficial, it can cause harm too, including inflammation and further illness when the web formation is uncontrollable.

They point to the early waves of the pandemic, prior to vaccinations, when these NETs, or neutrophil extracellular traps, were found in some patients’ lungs, and had made their breathing more difficult.

“An immune response that is meant to protect you can end up harming you if it’s not properly controlled,” says Miller. “It’s important to understand the balance of the immune system. If you have a lot of these antibodies before you get infected, they are likely going to protect you, but if the infection itself stimulates a lot of those antibodies it might be harmful.”

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Source: https://bioengineer.org/researchers-discover-unique-spider-web-mechanism-that-traps-kills-viruses/

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Making seawater drinkable in minutes

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According to the World Health Organization, about 785 million people around the world lack a clean source of drinking water. Despite the vast amount of water on Earth, most of it is seawater and freshwater accounts for only about 2.5% of the total. One of the ways to provide clean drinking water is to desalinate seawater. The Korea Institute of Civil Engineering and Building Technology (KICT) has announced the development of a stable performance electrospun nanofiber membrane to turn seawater into drinking water by membrane distillation process.

Membrane wetting is the most challenging issue in membrane distillation. If a membrane exhibits wetting during membrane distillation operation, the membrane must be replaced. Progressive membrane wetting has been especially observed for long-term operations. If a membrane gets fully wetted, the membrane leads to inefficient membrane distillation performance, as the feed flow through the membrane leading to low-quality permeate.

A research team in KICT, led by Dr. Yunchul Woo, has developed co-axial electrospun nanofiber membranes fabricated by an alternative nano-technology, which is electrospinning. This new desalination technology shows it has the potential to help solve the world’s freshwater shortage. The developed technology can prevent wetting issues and also improve the long-term stability in membrane distillation process. A three-dimensional hierarchical structure should be formed by the nanofibers in the membranes for higher surface roughness and hence better hydrophobicity.

The co-axial electrospinning technique is one of the most favorable and simple options to fabricate membranes with three-dimensional hierarchical structures. Dr. Woo’s research team used poly(vinylidene fluoride-co-hexafluoropropylene) as the core and silica aerogel mixed with a low concentration of the polymer as the sheath to produce a co-axial composite membrane and obtain a superhydrophobic membrane surface. In fact, silica aerogel exhibited a much lower thermal conductivity compared with that of conventional polymers, which led to increased water vapor flux during the membrane distillation process due to a reduction of conductive heat losses.

Most of the studies using electrospun nanofiber membranes in membrane distillation applications operated for less than 50 hours although they exhibited a high water vapor flux performance. On the contrary, Dr. Woo’s research team applied the membrane distillation process using the fabricated co-axial electrospun nanofiber membrane for 30 days, which is 1 month.

The co-axial electrospun nanofiber membrane performed a 99.99% salt rejection for 1 month. Based on the results, the membrane operated well without wetting and fouling issues, due to its low sliding angle and thermal conductivity properties. Temperature polarization is one of the significant drawbacks in membrane distillation. It can decrease water vapor flux performance during membrane distillation operation due to conductive heat losses. The membrane is suitable for long-term membrane distillation applications as it possesses several important characteristics such as, low sliding angle, low thermal conductivity, avoiding temperature polarization, and reduced wetting and fouling problems whilst maintaining super-saturated high water vapor flux performance.

Dr. Woo’s research team noted that it is more important to have a stable process than a high water vapor flux performance in a commercially available membrane distillation process. Dr. Woo said that “the co-axial electrospun nanofiber membrane have strong potential for the treatment of seawater solutions without suffering from wetting issues and may be the appropriate membrane for pilot-scale and real-scale membrane distillation applications.”

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The Korea Institute of Civil Engineering and Building Technology (KICT) is a government sponsored research institute established to contribute to the development of Korea’s construction industry and national economic growth by developing source and practical technology in the fields of construction and national land management.

This research was supported by an internal grant (20200543-001) from the KICT, Republic of Korea. The outcomes of this project were published in the international journal, Journal of Membrane Science, a renowned international journal in the polymer science field (IF: 7.183 and Rank #3 of the JCR category) in April 2021.

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Source: https://bioengineer.org/making-seawater-drinkable-in-minutes/

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McIndoe leading $6.2 million innovative research initiative

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Dr. Richard A. McIndoe, bioinformatics expert and associate director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia, is leading a dynamic, new $6.2 million federally funded initiative to support highly innovative research ideas in three areas with tremendous impact on health.

This Innovative Science Accelerator, or ISAC, program establishes an expedited but still extensive review process that will enable scientists to pursue some of their most innovative research ideas in diseases of the kidneys; the urinary tract in both sexes as well as the male reproductive organs; and the blood and bone marrow.

“The idea is that ISAC will provide seed funds to investigators who have high-risk, high-reward ideas, and they will get one year of money to try to figure out if their idea is going to work. If it works, they will be able to use the data they generate to apply for a larger grant,” says McIndoe, who wants the new program to be as innovative as the ideas scientists bring to it.

The five-year initiative is a new program of the Division of Kidney, Urologic and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

The goal is to move science forward that matters to people’s lives, and the opportunities include giving particularly new scientists experience writing grants, going through the review process and generating findings, McIndoe says.

ISAC will provide scientists an efficient path to secure a one-time $100,000 grant that should ease application for a larger, traditional NIH grant, the gold standard for biomedical research in the U.S., or conversely to acknowledge that their idea does not merit additional pursuit.

Another primary function of ISAC is to host an annual scientific meeting for scientists working in these areas where awardees can present their work, and that will help fuel discussion and collaboration, says McIndoe, Regents’ Professor and Georgia Research Alliance Distinguished Investigator.

High-risk research with high-reward potential often doesn’t get funded in the traditional, highly competitive process of seeking NIH funding, McIndoe says. For example, the 2019 payline for the NIDDK was 13%, which means only 13 of 100 submitted grants get funded.

About half of submitted grants, don’t even make it through the NIH study section manned by experts in the field who do the frontline review of grant proposals, says McIndoe, who at points in his career has sat on more than a half-dozen study sections annually.

As director of ISAC’s coordinating unit, McIndoe will also work with NIH program officers with expertise in the area of interest of an application to identify other experts across the country. He’ll then manage the review process from there, including assigning reviewers and making sure reviews are done on time.

He’ll ensure that the scores and critiques get back to the NIH program officers who also will rank the grant proposals, and that information along with what the ISAC office determines to be a fundable score range will then go to one more group of experts in the field, ISAC’s External Evaluation Committee, and if they agree with the determinations, the decision is made.

Although the review process is extensive, it’s about half of the standard process for submitting for scientists and reviewers alike, starting with a three-page research plan rather than up to a dozen pages for an RO1, the NIH’s oldest grant mechanism, and the application is easier for reviewers to digest, McIndoe says.

The ISAC Working Group recently opted to have three application review times annually to further expedite the process, and applications can be submitted at any time, McIndoe says. Scientists can begin submitting applications this fall, and the first annual meeting likely will be next Spring.

The local ISAC Working Group, which will advise McIndoe on kidney, urologic and hematology research, includes Dr. David Mattson, chair of the MCG Department of Physiology and an established hypertension researcher; Dr. Jennifer Sullivan, pharmacologist and physiologist in the Department of Physiology who is also interim dean of The Graduate School at AU and studies blood pressure regulation and kidney health, with a particular interest in gender differences; and Dr. Betty Pace, pediatric hematologist in the MCG Department of Pediatrics, an established sickle cell physician scientist who leads a federally funded national initiative to inspire the next generation of investigators.

ISAC’s target areas may change annually based on what’s happening in the scientific literature and what experts in respective fields identify as hot topics that need pursuing. The Working Group and the annual meetings will further enable those discussions and decisions.

McIndoe, an expert in managing and analyzing large amounts of data, has already managed two other innovative NIH funding approaches and consequently has a solid infrastructure in place to support this new initiative. For 20 years he has led the Coordinating and Bioinformatics Unit for the Diabetic Complications Consortium to fund shorter-term laboratory and human studies to better understand the complications of diabetes, like heart and kidney disease and vision problems. The consortium began as the Animal Models of Diabetes Complications, which specifically designed and shared good mouse models.

Fifteen years ago he began providing similar services for the Mouse Metabolic Phenotyping Centers, which make the specialized, expensive mouse-testing capabilities of a select number of universities available and affordable to researchers nationwide. Expertise includes things like characterizing mouse metabolism and analyzing blood composition.

Together those NIDDK initiatives, which also hold scientific meetings and support websites to support interested scientific communities, have resulted in thousands of publications that demonstrate new findings and helped scientists secure larger NIH grants. As an example, more than 60% of those receiving a $100,000 grant through the Diabetic Complications Consortium applied for an RO1 and about 25% were successful. “That’s higher than the normal percentage and a goal of these kinds of programs,” McIndoe says. Both those programs are scheduled to phase out next year.

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Source: https://bioengineer.org/mcindoe-leading-6-2-million-innovative-research-initiative/

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Oregon State graduate student sheds light on better way to study reputedly secretive toad

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CORVALLIS, Ore. – Research by a graduate student in Oregon State University’s College of Science has upended the conventional wisdom that for a century has incorrectly guided the study of a toad listed as endangered in part of its range.

Anne Devan-Song used spotlighting – shining a light in a dark spot and looking for eye reflections – to find large numbers of the eastern spadefoot toad. The study illustrates how confirmation bias – a tendency to interpret new information as ratification of existing theories – can hamper discovery and the development of better ones.

Her findings, which show that the toad spends much more time above ground than commonly believed, were published in the Journal of Herpetology.

Known for bright yellow eyes with elliptical pupils and, as the name suggests, a spade on each hind foot, the eastern spadefoot toad ranges from the southeast corner of the United States up the Atlantic Coast to New England. Known scientifically as Scaphiopus holbrooki, it is a species of conservation concern in the northern reaches of its territory.

Devan-Song, a Ph.D. student in integrative biology, grew up in Singapore, where she learned she could search for reptiles and amphibians by spotlighting. In Rhode Island, where she earned a master’s degree and then worked as a university research associate, the eastern spadefoot toad is endangered.

One rainless night while surveying for amphibians during a project in Virginia, Devan-Song’s spotlight detected one eastern spadefoot after another. That surprised her because the toads were thought to be detectable only on a few rainy nights every year, when they emerge from underground burrows to mate in wetlands.

She continued looking for eastern spadefoots and kept finding them on dry nights, including in upland forest locales not close to any damp areas. Spadefoots remain still when spotlighted so it was easy for Devan-Song to approach the eye-shines and positively identify the toads.

“They need to get above ground to hunt for insects and build up energy stores for mating,” she said. “That’s why we were finding them when and where conventional wisdom said we weren’t supposed to be finding them.”

Back in Rhode Island, she tried spotlighting for spadefoots; it took her just 15 minutes to find one. The success led to a 10-night survey in a pair of locations last summer that produced 42 sightings – nearly double the number of eastern spadefoot toad sightings in Rhode Island over the previous seven decades.

Devan-Song also learned that she wasn’t the first to question the notion that the eastern spadefoot was so “secretive” as to almost always avoid detection. As far back as 1944, Devan-Song said, it was suggested in scientific literature that the toad could be found outside of rain-induced migration and breeding aggregations. And in 1955, researchers used spotlighting to detect huge numbers of eastern spadefoots in Florida; the technique subsequently, inexplicably fell into disuse.

“Confirmation bias perpetuated the fallacy of when the eastern spadefoot could be found,” Devan-Song said. “No breeding events or migration occurred during our surveys and we detected thousands of toads in Virginia and dozens in Rhode Island. The majority of those were subadults, a demographic category mainly overlooked in the literature. Progress in learning about the toad, its ecology and its conservation has been greatly hindered by a misconception that persisted even when evidence to the contrary was presented.”

The ease with which many toads could be found during breeding, combined with a lack of data on toads in upland habitats, helped fuel confirmation bias in this case, she said.

“Everyone assumed they were underground most of the time so no one was really looking for them most of the time,” Devan-Song said. “Our research demonstrates that you can detect them year round, though they do remain rare in Rhode Island. But likely not as rare as the scientific community thought.”

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The National Park Service, through a cooperative agreement with the University of Rhode Island, supported this research.

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Source: https://bioengineer.org/oregon-state-graduate-student-sheds-light-on-better-way-to-study-reputedly-secretive-toad/

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