Category Archives: Transhuman News

Researchers at Baylor College of Medicine have uncovered a new mechanism showing how microbes can alter the physiology of the organisms in which they live. In a paper published in Nature Cell Biology, the researchers reveal how microbes living inside the laboratory worm C. elegans respond to environmental changes and generate signals to the worm that alter the way it stores lipids.

Microbe-host interactions have been known for a long time, but the actual molecular mechanisms that mediate the interactions were largely unknown, said senior author Dr. Meng Wang, associate professor of molecular and human genetics at Baylor and the Huffington Center On Aging. Microbes living inside another organism, the host, can respond to changes in the environment, change the molecules they produce and consequently influence the normal workings of the hosts body, including disease susceptibility.

In this study, Wang and first author Dr. Chih-Chun Lin working in the Wang Lab have dissected for the first time a molecular mechanism by which E. coli bacteria can regulate C. elegans lipid storage.

How E. coli changes lipid storage in C. elegans

C. elegans is a laboratory worm model scientists use to study basic biological mechanisms in health and disease.

This worm naturally consumes and lives with bacteria in its gut and interacts with them in ways that are similar to those between humans and microbes. In the laboratory, we can study basic biological mechanisms by controlling the type of bacteria living inside this worm as well as other variables and then determining the effect on the worms physiology, Wang said.

In this study, Wang and Lin compared two groups of worms. One group received bacteria that had been grown in a nutritionally rich environment. The other group of worms received the same type of bacteria, but it had grown in nutritionally poor conditions. Both groups of worms received the same amount and type of nutrients, the only difference was the type of environment in which the bacteria had grown before they were administered to the worms.

Interestingly, the worms carrying bacteria that came from a nutritionally poor environment had in their bodies twice the amount of fat present in the worms living with the bacteria coming from the nutritionally rich environment.

The researchers then carried out more experiments and determined that it was the lack of the amino acid methionine in the nutritionally poor environment that had triggered the bacteria to adapt by producing different compounds that then initiated a cascade of events in the worm that led to extra fat accumulation. In addition, the researchers observed that the tissues showing extra fat accumulation also had their mitochondria fragmented. The activities of the mitochondria, the balance between their fusion and breaking apart, are known to be tightly coupled with metabolic activities.

A mechanism that reveals unsuspected connections

The researchers found that the bacteria were able to trigger mitochondrial fragmentation and then extra lipid accumulation because the molecular intermediates the bacteria had triggered allowed them to establish communication with the mitochondria.

We have found evidence for the first time that bacteria and mitochondria can talk to each other at the metabolic level, Wang said.

Bacteria and mitochondria are like distant relatives. Evolutionary evidence strongly suggests that mitochondria descend from bacteria that entered other cell types and became incorporated into their structure. Mitochondria play essential roles in many aspects of the cells metabolism, but also maintain genes very similar to those of their bacterial ancestors.

Its interesting that the molecules bacteria generate can chime in the communication between mitochondria and regulate their fusion-fission balance, Wang said. Our findings reveal this kind of common language between bacteria and mitochondria, despite them being evolutionary distant from each other.

Some components of this common language involve proteins such as NR5A, Patched and Sonic Hedgehog. The latter is of particular interest to the researchers because it has not been involved in regulating lipid metabolism and mitochondrial dynamics before.

Microbes in the microbiome can affect many aspects of their hosts functions, and here we present a new molecular mechanism mediating microbe-host communication, Wang said. Having discovered one mechanism encourages us to investigate others that may be related to other physiological aspects, such as the stress response and aging, among others.

This project is supported by the National Institutes of Health grants R01AG045183, R01AT009050, DP1DK113644 and grants from the Howard Hughes Medical Institute. It also is supported in part by a training fellowship from the Burroughs Wellcome Fund and The Houston Laboratory and Population Science Training Program in Gene-Environment Interaction of the University of Texas Health Science Center at Houston (BWF Grant 1008200).

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Mechanism of environment-microbe-host interactions revealed ... - Baylor College of Medicine News (press release)

Researchers from the Global Research Cluster in Japan have developed a potential mouse model for the genetic disorder known as an NGLY1 deficiency. Published in the journal PLOS Genetics, the study describes how a complete knockout of the Ngly1 gene in mice leads to death just before birth, which can be partially rescued by a second knockout of another gene called Engase. When related genes in the mice used for making the knockouts are variable, the doubled-deletion mice survive and have symptoms that are analogous to humans with NGLY1-deficiency, indicating that these mice could be useful for testing potential therapies.

NGLY1-deficiency is a relatively newly discovered genetic disorder, with the first patient identified in 2012. The symptoms are severe, and include delayed development, disordered movement, low muscle tone and strength, and the inability to produce tears. Understanding how lack of NGLY1 leads to these symptoms is critical when considering targets for therapeutic interventions, and creating useful animal models of the disease is therefore equally important.

The RIKEN team has already had some success studying the consequences of Ngly1 deficiency in cultured animal cells. The Ngly1 gene codes for an enzyme that helps remove sugar chains from proteins that are scheduled for degradation. Their research showed that when Ngly1 was absent, sugars normally removed by Ngly1 were improperly removed by another enzyme called ENGase. Knocking out the ENGase gene led to normal protein degradation.

In the current study, the researchers first examined the effects of knocking out Ngly1 in mice. They found that when mice lacked both Ngly1 genesone from each parentthey always died just before birth. However, a double knockout of both Ngly1 and ENGase genes resulted in mice that survived after birth, but not for very long.

This positive result was actually unexpected. We thought that ENGase acted further downstream to Ngly1 in the catabolism of glycoproteins notes team leader Tadashi Suzuki, and were surprised when the double knockout was able to suppress the lethality of Ngly1-KO mice. If ENGase was merely an enzyme downstream of Ngly1, nothing should have happened. This was truly a case of serendipity.

Although the double knockout mice survived, they shared several defects that are similar to the symptoms observed in people with NGLY1-deficiency. As these mice aged, they developed characteristics such as bent spines, trembling, limb-clasping and shaking, and by 45 weeks, the survival rate was reduced to 60%. These mice could therefore be useful model mice for developing treatments for the human genetic disorder.

Another factor affecting survival and symptoms turned out the be the genetic background of the mice, that is, the genotypes of all genes related to Ngly1 and Engase, which likely affect how they function. When mice were crossed with an outbred strain, the single Ngly1 knockout proved less lethal, and the double knockout proved to be even more helpful, with mice only showing hind-limb clasping after 30 weeks.

These findings show that the biological processes involved are quite complicated. Despite this however, it is clear that preventing ENGase from acting can alleviate symptoms of Ngly1 deficiency in mice. Figuring out which aspects of the genetic background help reduce symptoms is perhaps a long-term goal.

Although the condition was only recently discovered, research into NGLY1-deficiency has been facilitated through efforts from the Grace Science Foundation, and the RIKEN team has recently begun a collaboration with Takeda Pharmaceuticals and T-CiRA at Kyoto University.

For now, the next step, says Suzuki, will be to isolate an in vivo inhibitor for ENGase and determine whether it can improve the symptoms related to NGLY1-deficiency. As we do not know much about the pathophysiology of the disorder, this might help us find potential targets for therapy, but also might lead to a better understanding of other diseases. Such chains of unexpected results are the beauty of basic science!

This article has been republished frommaterialsprovided byRIKEN. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Fujihira, H., Masahara-Negishi, Y., Tamura, M., Huang, C., Harada, Y., Wakana, S., . . . Suzuki, T. (2017). Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene. PLOS Genetics, 13(4). doi:10.1371/journal.pgen.1006696

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A Promising Model for a Devastating Genetic Deficiency ... - Technology Networks

SYRACUSE A conference held last week at SUNY Upstate Medical University in Syracuse brought together scientists studying autism from different aspects and emphases of the disorder in a way that will benefit one another's research.

That is what Dr. Brian Howell, a Skaneateles resident who researches autism as it relates to brain development at Upstate, observed following the two-day "Autism Symposium 2017: Where We Are, Where We Are Going" that he organized through Upstate's Department of Neuroscience & Physiology.

Calling the symposium a success, Howell said it was the first such event that tried to include the public along with the scientists. The first day which featured "Nightline" correspondent John Donvan speaking about changing attitudes about autism was geared toward the general public.

But, Howell said, some people came back for the second day when scientists from a variety of institutions and backgrounds came together to share their research in a series of presentations.

Those presentations included "a good mix of people that probably don't even necessarily go to the same meetings," Howell said, because of the differences in their disciplines.

"We got people talking across sub-fields in this area, so a lot of scientists said to me that they really appreciated this in terms of not only the science that they heard but also the interpersonal connections that they made," he said.

That goes for him and his department as well, he added. He and his team work with mouse genetics in their research but follow the research in human genetics. There is so much data out there, though, that one needs to be a computer specialist in order to use the data.

"For us, to meet some really good data miners, I think, will help drive our research that we now can set up some collaborations and look more closely at the human data and see how that might inform our work in mice," Howell said. "For me, probably the most benefit I got out of all this work is being able to call up people in different specialties and get their point of view on things."

Along with Donvan, the first day of talks included Dr. Stephan Sanders, from University of California San Francisco, discussing his work sequencing the genomes of thousands of families with autism spectrum disorder to look for gene mutations that might be able to predict autism in children.

Following Sanders, Dr. Arthur Beaudet, from Baylor College of Medicine, talked about a new technology he is developing a blood test for pregnant mothers to isolate fetal cells in the bloodstream, sequence those cells and look for mutations known to be predictors for autism.

On the second day of presentations:

Dr. Steven Hicks, of Penn State College of Medicine, talked about a start-up company, Motion Intelligence, that is developing a noninvasive oral swab to test children's saliva for signs of autism and determine a treatment program when early intervention is most effective.

Dr. Gahan Pandina, of Janssen Research & Development, a branch of Johnson & Johnson, presented on the Autism Anchor app that allows parents to document the behavior of their children with autism in order to provide clinicians with more information during appointments.

Dr. Joseph Dougherty, of Washington University in St. Louis, spoke about computer programs he is using to determine what brain regions and cell types are being impacted by autism and the databases that can put together mutations, cell types and brain regions involved in autism.

Dr. Janine LaSalle, of University of California Davis, highlighted the environmental factors that lead to autism, citing a study that found that prenatal exposure to polychlorinated biphenyls may cause a particular chromosome duplication that leads a child to develop autism.

Weirui Guo, from University of Texas Southwestern, shared his research about a sub-class of autism found in those with fragile X syndrome, a male-specific disorder caused by a defect in the X chromose that results in the overproduction of a certain protein.

Howell gave a presentation about the developmental genes with which he and his team work mice and how mutations in those genes might contribute to autism in both mice and people when autism, unlike mental retardation, does not present obvious brain defects.

As far as where the research in autism goes from here following the symposium both personally and in the wider community, Howell said he and his team hope to take a closer look at human genetics to complement their studies using mice but need partners to be able to do that.

"The human genetic data now, there's so much of it. It's in these massive databases that you basically need a computer degree to be able to access," he said. "We hope to reach out to the computer experts that we've met and mine the genetic data to see if we can develop networks of genes that are involved in autism."

He noted that there is no single mutation that causes autism, but a collection of mutations in an individual adds up to the disorder. Using human genetic data and testing that data in mice, his team might be able to figure out what series of mutations in people lead to autism.

"There are hundreds of genes that might make you at risk for autism, but no one mutation on its own is sufficient," Howell said.

Journal Editor Jonathan Monfiletto can be reached at jonathan.monfiletto@lee.net or (315) 283-1615. Follow him on Twitter @WOC_Monfiletto.

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Research presentations at Syracuse autism symposium connect scientists across disciplines - Auburn Citizen