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Producing a gaseous messenger molecule inside the body, on demand

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Nitric oxide is an important signaling molecule in the body, with a role in building nervous system connections that contribute to learning and memory. It also functions as a messenger in the cardiovascular and immune systems.

But it has been difficult for researchers to study exactly what its role is in these systems and how it functions. Because it is a gas, there has been no practical way to direct it to specific individual cells in order to observe its effects. Now, a team of scientists and engineers at MIT and elsewhere has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new lines of research on this essential molecule’s effects.

The findings are reported today in the journal Nature Nanotechnology, in a paper by MIT professors Polina Anikeeva, Karthish Manthiram, and Yoel Fink; graduate student Jimin Park; postdoc Kyoungsuk Jin; and 10 others at MIT and in Taiwan, Japan, and Israel.

“It’s a very important compound,” Anikeeva says. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process has been difficult. So far, most studies have resorted to looking at systemic effects, by knocking out genes responsible for the production of enzymes the body uses to produce nitric oxide where it’s needed as a messenger.

But that approach, she says, is “very brute force. This is a hammer to the system because you’re knocking it out not just from one specific region, let’s say in the brain, but you essentially knock it out from the entire organism, and this can have other side effects.”

Others have tried introducing compounds into the body that release nitric oxide as they decompose, which can produce somewhat more localized effects, but these still spread out, and it is a very slow and uncontrolled process.

The team’s solution uses an electric voltage to drive the reaction that produces nitric oxide. This is similar to what is happening on a much larger scale with some industrial electrochemical production processes, which are relatively modular and controllable, enabling local and on-demand chemical synthesis. “We’ve taken that concept and said, you know what? You can be so local and so modular with an electrochemical process that you can even do this at the level of the cell,” Manthiram says. “And I think what’s even more exciting about this is that if you use electric potential, you have the ability to start production and stop production in a heartbeat.”

The team’s key achievement was finding a way for this kind of electrochemically controlled reaction to be operated efficiently and selectively at the nanoscale. That required finding a suitable catalyst material that could generate nitric oxide from a benign precursor material. They found that nitrite offered a promising precursor for electrochemical nitric oxide generation.

“We came up with the idea of making a tailored nanoparticle to catalyze the reaction,” Jin says. They found that the enzymes that catalyze nitric oxide generation in nature contain iron-sulfur centers. Drawing inspiration from these enzymes, they devised a catalyst that consisted of nanoparticles of iron sulfide, which activates the nitric oxide-producing reaction in the presence of an electric field and nitrite. By further doping these nanoparticles with platinum, the team was able to enhance their electrocatalytic efficiency.

To miniaturize the electrocatalytic cell to the scale of biological cells, the team has created custom fibers containing the positive and negative microelectrodes, which are coated with the iron sulfide nanoparticles, and a microfluidic channel for the delivery of sodium nitrite, the precursor material. When implanted in the brain, these fibers direct the precursor to the specific neurons. Then the reaction can be activated at will electrochemically, through the electrodes in the same fiber, producing an instant burst of nitric oxide right at that spot so that its effects can be recorded in real-time.

As a test, they used the system in a rodent model to activate a brain region that is known to be a reward center for motivation and social interaction, and that plays a role in addiction. They showed that it did indeed provoke the expected signaling responses, demonstrating its effectiveness.

Anikeeva says this “would be a very useful biological research platform, because finally, people will have a way to study the role of nitric oxide at the level of single cells, in whole organisms that are performing tasks.” She points out that there are certain disorders that are associated with disruptions of the nitric oxide signaling pathway, so more detailed studies of how this pathway operates could help lead to treatments.

The method could be generalizable, Park says, as a way of producing other molecules of biological interest within an organism. “Essentially we can now have this really scalable and miniaturized way to generate many molecules, as long as we find the appropriate catalyst, and as long as we find an appropriate starting compound that is also safe.” This approach to generating signaling molecules in situ could have wide applications in biomedicine, he says.

“One of our reviewers for this manuscript pointed out that this has never been done — electrolysis in a biological system has never been leveraged to control biological function,” Anikeeva says. “So, this is essentially the beginning of a field that could potentially be very useful” to study molecules that can be delivered at precise locations and times, for studies in neurobiology or any other biological functions. That ability to make molecules on demand inside the body could be useful in fields such as immunology or cancer research, she says.

The project got started as a result of a chance conversation between Park and Jin, who were friends working in different fields — neurobiology and electrochemistry. Their initial casual discussions ended up leading to a full-blown collaboration between several departments. But in today’s locked-down world, Jin says, such chance encounters and conversations have become less likely. “In the context of how much the world has changed, if this were in this era in which we’re all apart from each other, and not in 2018, there is some chance that this collaboration may just not ever have happened.”

“This work is a milestone in bioelectronics,” says Bozhi Tian, an associate professor of chemistry at the University of Chicago, who was not connected to this work. “It integrates nanoenabled catalysis, microfluidics, and traditional bioelectronics … and it solves a longstanding challenge of precise neuromodulation in the brain, by in situ generation of signaling molecules. This approach can be widely adopted by the neuroscience community and can be generalized to other signaling systems, too.”

Besides MIT, the team included researchers at National Chiao Tung University in Taiwan, NEC Corporation in Japan, and the Weizman Institute of Science in Israel. The work was supported by the National Institute for Neurological Disorders and Stroke, the National Institutes of Health, the National Science Foundation, and MIT’s Department of Chemical Engineering.


Topics: Research, Materials Science and Engineering, DMSE, McGovern Institute, Research Laboratory of Electronics, School of Science, School of Engineering, Nanoscience and nanotechnology, Chemical engineering, Brain and cognitive sciences, Neuroscience

Source: http://news.mit.edu/2020/nitric-oxide-messenger-molecule-inside-body-demand-0629

Biotechnology

Getting a grasp on India’s malaria burden

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A method that involves infecting liver cells with mosquito-bred parasites could improve the study of malaria in India

A new approach could illuminate a critical stage in the life cycle of one of the most common malaria parasites. The approach was developed by scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) in Japan and published in the Malaria Journal.

“The Plasmodium vivax malaria parasite can stay dormant in a person’s liver cells up to years following infection, leading to clinical relapses once the parasite is reactivated,” says Kouichi Hasegawa, an iCeMS stem cell biologist and one of the study’s corresponding authors.

P. vivax is responsible for around 7.5 million malaria cases worldwide, about half of which are in India. Currently, there is only one licensed drug to treat the liver stage of the parasite’s life cycle, but it has many side effects and cannot be used in pregnant women and infants. The liver stage is also difficult to study in the lab. For example, scientists have struggled to recreate high infection rates in cultured liver cells.

Hasegawa and his colleagues in Japan, India and Switzerland developed a successful system for breeding mature malaria parasites, culturing human liver cells, and infecting the cells with P. vivax. While it doesn’t solve the high infection rate problem, the system is providing new, localized insight into the parasite’s liver stage.

“Our study provides a proof-of-concept for detecting P. vivax infection in liver cells and provides the first characterization of this infectious stage that we know of in an endemic region in India, home to the highest burden of vivax malaria worldwide,” says Hasegawa.

The researchers bred Anopheles stephensi mosquitos in an insectarium in India. Female mosquitos were fed with blood specifically from Indian patients with P. vivax infection.

Two weeks later, mature sporozoites, the infective stage of the malaria parasite, were extracted from the mosquitos’ salivary glands and added to liver cells cultured in a petri dish.

The scientists tested different types of cultured liver cells to try to find cells that would be infected by lots of parasites like in the human body. Researchers have already tried using cells taken liver biopsies and of various liver cancer cell lines. So far, none have led to large infections.

Hasegawa and his colleagues tried using three types of stem cells that were turned into liver cells in the lab. Notably, they took blood cells from malaria-infected patients, coaxed them into pluripotent stem cells, and then guided those to become liver cells. The researchers wondered if these cells would be genetically more susceptible to malaria infection. However, the cells were only mildly infected when exposed to the parasite sporozoites.

A low infection rate means the liver cells cannot be used for testing many different anti-malaria compounds at once. But the researchers found the cells could test if a specific anti-malaria compound would work for a specific patient’s infection. This could improve individualized treatment for patients.

The scientists were also able to study one of the many aspects of parasite liver infection. They observed the malaria protein UIS4 interacting with the human protein LC3, which protected the parasite from destruction. This demonstrates their approach can be used to further investigate this important stage in the P. vivax life cycle.

###

DOI: 10.1186/s12936-020-03284-8

About Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS):

At iCeMS, our mission is to explore the secrets of life by creating compounds to control cells, and further down the road to create life-inspired materials.
https://www.icems.kyoto-u.ac.jp/

For more information, contact:

I. Mindy Takamiya/Mari Toyama

[email protected]

Source: https://bioengineer.org/getting-a-grasp-on-indias-malaria-burden/

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Biotechnology

More ecosystem engineers create stability, preventing extinctions

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When we think of engineering in nature, we tend to think of beavers — the tree-felling, dam-building rodents whose machinations can shape the landscape by creating lakes and changing the path of rivers. But beavers are far from the only organisms to reshape their environment. A squirrel who inadvertently plants oak trees is also an “ecosystem engineer” — roughly speaking, any organism whose impact on the environment outlasts its own lifetime. The coolest of these biological builders, according to Justin Yeakel, might be the shipworm, which eats through rocks in streams, creating cozy abodes for future invertebrate inhabitants.

Yeakel, an ecologist at the University of California, Merced, and a former Santa Fe Institute Omidyar Fellow is the lead author of a new paper that models the long term impact of ecosystem engineers. Researchers have long considered the role of ecosystem engineers in natural histories, but this study is among the first to quantitatively assess them in an ecological network model.

“We wanted to understand how food webs and interaction networks were established from a mechanistic perspective,” he says. “To do that, you have to include things like engineering because species influence their environment and there’s this feedback between the environment to the species.”

In particular, the model uses simple rules to show how food webs can be assembled, how species interactions can change over time, and when species go extinct. One striking result: Few ecosystem engineers led to many extinctions and instability while many ecosystem engineers led to stability and few extinctions.

“As you increase the number of engineers, that also increases the redundancy of the engineers and this tends to stabilize the system,” Yeakel says.

So, how do you create an ecological network model? It’s highly abstracted — there are no specific species like beavers or concrete environmental features like rivers. Everything is reduced to interactions: species can eat, need, or make. In this sense, nature becomes a network of interactions. For example, bees eat nectar from flowers; flowers need bees to be pollinated; trees make shade which flowers need.

The researchers gave the model a small number of rules, the main one being: Species have to eat only one thing to survive but they have to obtain all of the things they need. In less abstract terms, even if one flower species goes extinct, bees could survive on nectar from other flowers. But if either bees or trees fail to provide pollination or shade, which flowers need, then the flowers will go extinct.

Using these rules, the models were able to produce ecological networks similar to those in the real world, with a characteristic hourglass shape in species diversity — more diversity at the top and the bottom of the web, less in the middle. To expand the model for future research, Yeakel plans on incorporating evolutionary dynamics so that species can change what they eat and need and make.

Two and a half billion years before humans showed up, cyanobacteria were a planetary-scale engineer that slowly changed the composition of the entire atmosphere by oxygenating it. But unlike our photosynthetic predecessors, “we’re making changes on ecological timescales rather than evolutionary timescales,” Yeakel says. “Is an organism that becomes a planetary-scale engineer doomed to extinction if it changes the environment too quickly?”

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Source: https://bioengineer.org/more-ecosystem-engineers-create-stability-preventing-extinctions/

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Biotechnology

Lab-Grown ‘Mini-Brains’ Suggest COVID-19 Virus Can Infect Brain

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How coronavirus infects brain cells?
–Sharing is Caring–

   Mini-brain study: How coronavirus can infect human brain cells?

A study revealed that the SARS-CoV-2 can infect the organoids – tiny tissue cultures made from human cells that replicate entire body organs known as “mini-brains”. The study was carried out by a team from two Johns Hopkins University institutions, consisting of infectious disease specialists from the school of medicine, and neurotoxicologists and virologists from the Bloomberg School of Public Health.

The outcomes of the study titled “Infectability of human BrainSphere neurons suggest neurotropism of SARS-CoV-2” were posted in the journal ALTEX: Alternatives to Animal Experimentation.

According to the early reports from Wuhan, 36% of patients with the COVID-19 show neurological signs and symptoms, however, whether or not the coronavirus infects human brain cells is not clear yet. The research showed the ACE2 receptor that the SARS-CoV-2 virus uses to enter the lungs is also present in the human neurons. So, they theorized, ACE2 may also offer access to the brain.

The study found – evidence of infection and replication of the pathogen when SARS-CoV-2 virus particles were introduced into a human mini-brain model – what is thought to be the first time.

Naturally, the blood-brain barrier protects the human brain from numerous viruses, bacteria, and chemical agents, it often protects against brain infections. Thomas Hartung, M.D., Ph.D., chair for evidence-based toxicology, the Bloomberg School of Public Health said, whether the SARS-CoV-2 virus passes this barrier or not is yet to be shown. But, it is understood that the blood barrier disintegrates during severe inflammations, such as those observed in COVID-19 individuals.

He added the impermeability of the blood-brain barrier can also offer a problem for drug designers targeting the brain.

The impact of SARS-CoV-2 on the developing brain is an additional issue elevated by the research. Prior research from Paris-Saclay University has shown that the virus crosses the placenta, and most notably during the early development, the embryos lack the blood-brain barrier – this can increase the risk of brain infections. Hartung said we have no proof that the developmental disorders can be caused by the viruses.

But, the ACE2 receptor is present in the “mini-brains” from their earliest stages of development. Hartung claims that the outcomes of the study suggest that during pregnancy extra care needs to be taken.

William Bishai, M.D., Ph.D., professor of medicine, the Johns Hopkins University School of Medicine, and leader of the infectious disease team for the study said this study is an additional crucial step in our understanding of how infection results to symptoms, and where we might treat COVID-19 with drugs.

The mini-brain models known as BrainSpheres were derived from human stem cells and developed at the Bloomberg School of Public Health 4 years ago. These BrainSpheres were the first mass-produced, highly standardized organoids of their kind, and have actually been utilized to model a number of diseases, consisting of infections by viruses such as HIV, dengue, and Zika.

Source

Author: Sruthi S

Source: https://www.biotecnika.org/2020/07/how-coronavirus-infects-brain-cells-mini-brain-study-reveals-the-secret/

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