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Your Microbiome Shapes Your Life. but Where Did It Come From?

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Baltimore, MD— The gut microbiome is an ecosystem of hundreds to thousands of microbial species living within the human body. These populations affect our health, fertility, and even our longevity. But how do they get there in the first place?

Credit: By Navid Marvi, courtesy of the Carnegie Institution for Science.

Baltimore, MD— The gut microbiome is an ecosystem of hundreds to thousands of microbial species living within the human body. These populations affect our health, fertility, and even our longevity. But how do they get there in the first place?

New collaborative work led by Carnegie’s William Ludington reveals crucial details about how the bacterial communities that comprise each of our individual gut microbiomes are acquired. These findings, published in the Proceedings of the National Academy of Sciences, have major implications for treatments such as fecal transplants and probiotic administration.

“There is a huge amount of variation in microbiome composition between individuals,” Ludington explained. “For example, if you look at the sum total of all of the bacterial species that are adapted to live in the gastrointestinal systems of humans, most of these are not present in a majority of people. That’s how incredibly diverse these gut microbial populations are.”

A combination of elements, including genetics, diet, and environment contribute to the differences between our microbiomes. But there isn’t a direct line between these inputs and the species that successfully colonize our guts. There’s an element of chance at play each time we are exposed to a new microbe as to whether it will be acquired and become a member of our gut ecosystem. Ludington and his collaborators set out to understand the factors that shape the odds of this colonization process.

Although many researchers have studied microbiome compositions in natural populations, there have been few attempts to use a controlled environment to reveal the process by which new species successfully join the gut microbial ecosystem. Ludington and his collaborators—Eric Jones and David Sivak of Simon Fraser University and Jean Carlson of UC Santa Barbara—developed a new ecological model to understand how we acquire the specific mix of microbes that are individual to our own particular gut communities.  

Working in the comparatively much less complicated microbiomes of fruit flies, the team showed that exposure to a microbial species does not guarantee its successful incorporation into the microbiome ecosystem. They found that the state of the microbiome, and interactions between existing microbiome member species, sets the odds for whether a newly encountered bacteria is added into the mix.

“Even among genetically identical flies that lived in the same housing and were fed the same diets, we saw variations in microbiome composition,” Sivak said.

The researchers then used these results to build mathematical models that could probe increasingly complex scenarios by which new microbiome species could be acquired, leading to their breakthrough understanding of the community factors that shape membership in the microbiome ecosystem.

“Think of microbiome composition as a big party where the social dynamics determine who leaves early and who stays until dawn,” said Ludington.

Added Jones, the paper’s first author: “Bacterial colonization depends on a number of complicated factors that we’re just starting to understand.  We showed, for example, that some groups of species facilitate each other’s colonization and are therefore more likely to coexist.”

These group interactions have exciting implications for how microbiomes are transmitted between individuals, including how medical professionals might drive a person’s microbiome towards a desired composition.

“The beauty of the mathematical approach we deployed is that it acknowledges that colonization is a roll of the dice, but we are now able to attribute the weighting of the dice to biological interactions with a molecular basis that has been honed by evolution,” said Carlson.

The team’s findings provide a framework for quantitatively examining the mechanisms that therapies such as fecal transplants and probiotics depend upon, advancing toward the eventual goal of personalized microbiome medicine.        

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This work was supported by the Banting Postdoctoral Fellowship, the Pacific Institute for the Mathematical Sciences Postdoctoral Fellowship, the David and Lucile Packard Foundation, the Institute for Collaborative Biotechnologies, the U.S. Army Research Office, a Natural Sciences and Engineering Research Council of Canada Discovery Grant, the Canada Research Chairs program, a National Institutes of Health grant, National Science Foundation Integrative Organismal Systems award, the Carnegie Institution for Science endowment, and a Carnegie Institution of Canada grant.

The Carnegie Institution for Science (carnegiescience.edu) is a private, nonprofit organization headquartered in Washington, D.C., with three research divisions on both coasts. Since its founding in 1902, the Carnegie Institution has been a pioneering force in basic scientific research. Carnegie scientists are leaders in the life and environmental sciences, Earth and planetary science, and astronomy and astrophysics.

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Original Post: 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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