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Modifying the Body’s Immune System to Help Treat Type 1 Diabetes

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In a new study, a team of researchers from the University of Missouri, Georgia Tech and Harvard University has demonstrated the successful use of a novel Type 1 diabetes treatment in a large animal model. Their approach involves transplanting insulin-producing pancreas cells — called pancreatic islets — from a donor to a recipient, without the need of long-term immunosuppressive drugs.

Credit: University of Missouri

In a new study, a team of researchers from the University of Missouri, Georgia Tech and Harvard University has demonstrated the successful use of a novel Type 1 diabetes treatment in a large animal model. Their approach involves transplanting insulin-producing pancreas cells — called pancreatic islets — from a donor to a recipient, without the need of long-term immunosuppressive drugs.

In people living with Type 1 diabetes, their immune system can malfunction, causing it to attack itself, said Haval Shirwan, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, and one of the study’s lead authors.

“The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections,” Shirwan said. “Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is eliminated, the immune system’s command-and-control mechanism kicks in to eliminate any rogue cells. However, if this mechanism fails, diseases such as Type 1 diabetes can manifest.”

Diabetes affects the body’s ability to produce or use insulin, a hormone which helps regulate how blood sugar is used in the body. People living with Type 1 diabetes do not make insulin, and therefore are unable to control their blood sugar levels. That loss of control can lead to life-threatening complications such as heart disease, kidney damage and eye damage.

Over the last two decades, Shirwan and Esma Yolcu, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys “rogue” immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the surface of the islets.

“A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die,” said Yolcu, one of the study’s first authors. “Therefore, our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells. Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.”

One advantage of this new method is the opportunity to potentially forgo a lifetime of taking immunosuppressive drugs, which counteract the immune system’s ability to seek and destroy a foreign object when introduced into the body, such as an organ, or in this case, cell, transplant.

“The major problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as high instances of developing cancer,” Shirwan said. “So, using our technology, we found a way that we can modulate or train the immune system to accept, and not reject, these transplanted cells.”

Their method utilizes technology included in a U.S. patent filed by the University of Louisville and Georgia Tech, and has since been licensed by a commercial company with plans to pursue FDA approval for human testing. To develop the commercial product, the MU researchers collaborated with Andres García and the team at Georgia Tech to attach FasL to the surface of microgels with a proof-of-efficacy in a small animal model. Then, they joined with Jim Markmann and Ji Lei from Harvard to assess the efficacy of the FasL-microgel technology in a large animal model, which is published in this study.

Incorporating the power of NextGen

This study represents a significant milestone in the process of bench-to-bedside research, or how laboratory results are directly incorporated into use by patients in order to help treat different diseases and disorders, a hallmark of MU’s most ambitious research initiative, the NextGen Precision Health initiative.

Highlighting the promise of personalized health care and the impact of large-scale interdisciplinary collaboration, the NextGen Precision Health initiative is bringing together innovators like Shirwan and Yolcu from across MU and the UM System’s three other research universities in pursuit of life-changing precision health advancements. It’s a collaborative effort to leverage the research strengths of MU toward a better future for the health of Missourians and beyond. The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in the state-of-the-art research facility.

“I think by being at the right institution with access to a great facility like the Roy Blunt NextGen Precision Health building, will allow us to build on our existing findings and take the necessary steps to further our research, and make the necessary improvements, faster,” Yolcu said.

Shirwan and Yolcu, who joined the faculty at MU in spring 2020, are part of the first group of researchers to begin working in the NextGen Precision Health building, and after working at MU for nearly two years they are now among the first researchers from NextGen to have a research paper accepted and published in a high-impact, peer-reviewed academic journal.

“FasL microgels induce immune acceptance of islet allografts in nonhuman primates,” was published in Science Advances, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided by grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-S-B) and the National Institutes of Health (U01 AI132817) as well as a Juvenile Diabetes Research Foundation Post-Doctoral Fellowship and a National Science Foundation Graduate Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Other authors on the study include Ji Lei, Hongping Deng, Zhihong Yang, Kang Lee, Alexander Zhang, Cole Peters, Zhongliang Zou, Zhenjuan Wang, Ivy Rosales and James Markmann at Harvard; Michael Hunckler, and Andrés J. García at Georgia Institute of Technology (Georgia Tech); Hao Luo at the General Hospital of Western Theater Command in Chengdu, China; Tao Chen at Xiamen University Medical School in Xiamen, China; and Colleen McCoy at Massachusetts Institute of Technology. The study’s authors would also like to acknowledge Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Deng, Rudy Matheson and Nikolaos Serifis for their technical contributions.

Potential conflicts of interest are also noted. Three of the study’s authors, García, Shirwan and Yolcu, are inventors on a U.S. patent application filed by the University of Louisville and the Georgia Tech Research Corporation (16/492441, filed Feb. 13, 2020). In addition, García and Shirwan are co-founders of iTolerance, and García, Shirwan and Markmann serve on the scientific advisory board for iTolerance.

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Original Article: bioengineer.org

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Gene Linked to Severe Learning Disabilities Governs Cell Stress Response

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DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

Cells are stressed by factors  that may damage them, such as extreme temperatures, toxic substances, or mechanical shocks. When this happens, they undergo a range of molecular changes called the cellular stress response.

“Every cell, no matter from which organism, is always exposed to harmful substances in their environment that they have to deal with all the time,” said Gustavo Silva, assistant professor of biology at Duke and senior author on the paper. “Many human diseases are caused by cells not being able to cope with these aggressions.”

During the stress response, cells press pause the genes related to their normal housekeeping activities, and turn on genes related to crisis mode. Just like in a house being flooded, they put down the window cleaner, turn off the TV, and run to close the windows, then they patch holes, turn on the sump pump, and if needed, rip up carpet and throw away irreparably damaged furniture.

While studying mechanisms related to the cells’ health and their response to stress, the team saw that, under stress, a group of proteins was being modified inside the cells. They dug into it and found that the master regulator of this process is a gene called Rad6.

“When there is a stressor, cells need to change what proteins are produced,” said Vanessa Simões, associate in research in the Silva lab and lead author of the paper. “Rad6 goes in and gets the (protein-building) ribosomes to change their program and adapt what they are producing for the new stressful circumstances.”

Rad6 isn’t just any random gene. It can be found, sometimes under a different name, in almost all multicellular organisms. In humans, it is known for its association with a set of symptoms called “Nascimento Syndrome,” that include severe learning disabilities.

Nascimento Syndrome, also called X-linked intellectual disability type Nascimento, is still a poorly understood disease. It was officially described in 2006, and tends to run in families, giving scientists an early clue to its genetic causes. Affected individuals have severe learning disabilities, characteristic facial traits, with wide-set eyes and a depressed nose bridge, and a range of other debilitating symptoms.

Like many other genes, Rad6 doesn’t just do one thing. It’s a multiuse tool. By discovering an additional function, and one so tightly related to the cell’s health, Silva and his team get to add a new piece to the puzzle of Nascimento Syndrome.

“It’s still a big question or how exactly can a mutation to this gene lead to such a drastic syndrome in humans,” said Silva. “Our findings are exciting because Rad6 can be a model on which we can do genetic manipulations to try to understand how problems in coping with harmful conditions can be connected to how this disease progresses.”

“If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have a better outcome.” he said.

But how does one actually “look” at what is happening with an infinitesimally small protein when a cell is stressed? With a fair amount of teamwork. Simões and Silva paired up with researchers from the Duke Biochemistry department and the Pratt School of engineering to gather all the help they needed.  

“We used biochemistry analyses, cellular assays, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques,” said Silva.

“It’s the cool thing about being in a place like Duke,” he said. “We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do a more complete work.”

Funding for this study was provided by US National Institutes of Health R00 Award ES025835 and R35 Award GM137954 to Gustavo Silva. This work was also supported in part by R01 Award GM141223 to Alberto Bartesaghi and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Grant ZIC ES103326 to Mario J. Borgnia. Cryo- EM work was performed at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (grant ECCS- 1542015) as part of the National Nanotechnology Coordinated Infrastructure (NNCI). Funding was also provided from the UNC Lineberger Comprehensive Cancer Center through the University of California, Riverside Fund and the Cancer Center Support Grant P30CA016086. 

CITATION: “Redox-Sensitive E2 1 Rad6 Controls Cellular Response to Oxidative Stress Via K63-Linked Ubiquitination of Ribosomes,” Vanessa Simões, Blanche K. Cizubu, Lana Harley, Ye Zhou, Joshua Pajak, Nathan A Snyder, Jonathan Bouvette, Mario J. Borgnia, Gaurav Arya, Alberto Bartesaghi, and Gustavo M. Silva. Cell Reports, May 24 2022. DOI: 10.1016/j.celrep.2022.110860

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New Light-powered Catalysts Could Aid in Manufacturing

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CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

MIT chemists have now designed a new type of photoredox catalyst that could make it easier to incorporate light-driven reactions into manufacturing processes. Unlike most existing photoredox catalysts, the new class of materials is insoluble, so it can be used over and over again. Such catalysts could be used to coat tubing and perform chemical transformations on reactants as they flow through the tube.

“Being able to recycle the catalyst is one of the biggest challenges to overcome in terms of being able to use photoredox catalysis in manufacturing. We hope that by being able to do flow chemistry with an immobilized catalyst, we can provide a new way to do photoredox catalysis on larger scales,” says Richard Liu, an MIT postdoc and the joint lead author of the new study.

The new catalysts, which can be tuned to perform many different types of reactions, could also be incorporated into other materials including textiles or particles.

Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT, is the senior author of the paper, which appears today in Nature Communications. Sheng Guo, an MIT research scientist, and Shao-Xiong Lennon Luo, an MIT graduate student, are also authors of the paper.

Hybrid materials

Photoredox catalysts work by absorbing photons and then using that light energy to power a chemical reaction, analogous to how chlorophyll in plant cells absorbs energy from the sun and uses it to build sugar molecules.

Chemists have developed two main classes of photoredox catalysts, which are known as homogenous and heterogenous catalysts. Homogenous catalysts usually consist of organic dyes or light-absorbing metal complexes. These catalysts are easy to tune to perform a specific reaction, but the downside is that they dissolve in the solution where the reaction takes place. This means they can’t be easily removed and used again.

Heterogenous catalysts, on the other hand, are solid minerals or crystalline materials that form sheets or 3D structures. These materials do not dissolve, so they can be used more than once. However, these catalysts are more difficult to tune to achieve a desired reaction.

To combine the benefits of both of these types of catalysts, the researchers decided to embed the dyes that make up homogenous catalysts into a solid polymer. For this application, the researchers adapted a plastic-like polymer with tiny pores that they had previously developed for performing gas separations. In this study, the researchers demonstrated that they could incorporate about a dozen different homogenous catalysts into their new hybrid material, but they believe it could work more many more.

“These hybrid catalysts have the recyclability and durability of heterogeneous catalysts, but also the precise tunability of homogeneous catalysts,” Liu says. “You can incorporate the dye without losing its chemical activity, so, you can more or less pick from the tens of thousands of photoredox reactions that are already known and get an insoluble equivalent of the catalyst you need.”

The researchers found that incorporating the catalysts into polymers also helped them to become more efficient. One reason is that reactant molecules can be held in the polymer’s pores, ready to react. Additionally, light energy can easily travel along the polymer to find the waiting reactants.

“The new polymers bind molecules from solution and effectively preconcentrate them for reaction,” Swager says. “Also, the excited states can rapidly migrate throughout the polymer. The combined mobility of the excited state and partitioning of the reactants in the polymer make for faster and more efficient reactions than are possible in pure solution processes.”

Higher efficiency

The researchers also showed that they could tune the physical properties of the polymer backbone, including its thickness and porosity, based on what application they want to use the catalyst for.

As one example, they showed that they could make fluorinated polymers that would stick to fluorinated tubing, which is often used for continuous flow manufacturing. During this type of manufacturing, chemical reactants flow through a series of tubes while new ingredients are added, or other steps such as purification or separation are performed.

Currently, it is challenging to incorporate photoredox reactions into continuous flow processes because the catalysts are used up quickly, so they have to be continuously added to the solution. Incorporating the new MIT-designed catalysts into the tubing used for this kind of manufacturing could allow photoredox reactions to be performed during continuous flow. The tubing is clear, allowing light from an LED to reach the catalysts and activate them.

“The idea is to have the catalyst coating a tube, so you can flow your reaction through the tube while the catalyst stays put. In that way, you never get the catalyst ending up in the product, and you can also get a lot higher efficiency,” Liu says.

The catalysts could also be used to coat magnetic beads, making them easier to pull out of a solution once the reaction is finished, or to coat reaction vials or textiles. The researchers are now working on incorporating a wider variety of catalysts into their polymers, and on engineering the polymers to optimize them for different possible applications.

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The research was funded by the National Science Foundation and the KAUST Sensor Initiative.

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Watching Video Feed of Hospitalized Baby Improves Pumping Experience

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Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

“Breast milk feeding is an essential component of care for the hospitalized premature infant, but it can be challenging due to factors including low milk supply, the need to express milk instead of feeding directly from the breast, as well as the stress and anxiety for new parents who are physically separated from their premature infants in the hospital environment,” said study lead author Adrienne Hoyt-Austin. “Our study explored the experience of pumping milk while watching one’s hospitalized baby with videoconferencing.”

The UC Davis Health study enrolled parents who used FamilyLink when they are not at the bedside in the UC Davis NICU. FamilyLink is a videoconferencing program which gives families the option to see their baby through a secure connection from a home computer, tablet or cellphone 24/7.

The team interviewed participants who pumped breastmilk while using FamilyLink to view their infant and those who pumped without videoconferencing.

Participants had given birth to an infant who was less than 34 weeks gestational age and was admitted to the UC Davis NICU.

In a one-on-one interview, participants were asked 14 open-ended questions regarding their breast milk pumping experience. The qualitative analysis identified four common themes. It showed that videoconferencing:

Provided bonding and connection. Participants felt “more of a connection” and “more of a bond” when seeing their hospitalized infant on video.
Provided motivation to pump. One participant said that seeing their baby is a “visual reminder that this is what I’m doing this for.”
Reminded participants that they were separated from their baby. One participant said, “I became just kind of guilty watching, feeling like I should be there instead of away.”
 Connected the whole family to their baby. Participants reported that videoconferencing helped introduce new family members to the baby and explain the complicated issue of neonatal hospitalization.

“In our interviews, we heard over and over again that that videoconferencing improved the pumping experience and gave motivation to continue to provide breast milk for their hospitalized infant. Participants also felt that seeing their baby while pumping strengthened the bond between the family with their newborn,” said Hoyt-Austin. “We hope that the use of videoconferencing for NICU parents will become a more widely available tool in NICUs that can help new parents in their breastfeeding journey.”       

The study co-authors are Iesha Miller, Kara Kuhn-Riordon, Jennifer Rosenthal, Caroline Chantry, James Marcin, Kristin Hoffman and Laura Kair, all of UC Davis Health.

The project was funded by the Children’s Miracle Network at UC Davis and the Clinical and Translational Science Center Highly-Innovative Award (UL1-TR001860). The researchers were supported by HRSA T32HP30037 grant, NIH’s Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) award (K12 HD051958) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) K23HD1015-50 grant.

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