OREGON STATE UNIVERSITY

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Nanofiber sutures promote production of infection-thwarting peptide

CORVALLIS, Ore. – Loading nanofiber sutures with vitamin D induces the production of an infection-fighting peptide, new research shows.

The discovery could represent an important advance in the prevention of surgical site infections, a multibillion-dollar challenge each year in the United States alone.

A collaboration that included Adrian Gombart of the Linus Pauling Institute at Oregon State University used coaxial electrospinning deposition and rolling to fabricate sutures that contained 25-hydroxyvitamin D3 and the pam3CSK4 peptide.

A peptide is a compound consisting of two or more amino acids linked in a chain; pam3CSK4’s function is to activate a cell’s toll-like receptor, which in turn triggers immune responses, in which vitamin D plays a key role.

The research showed the sutures released 25D3 – the same form of the vitamin that’s measured in the blood when a patient’s vitamin D levels are tested – on a sustained basis over four weeks. The sutures released pam3CSK4 via an initial burst followed by a four-week prolonged release.

“When the toll-like receptor is activated, you induce a particular enzyme to convert 25D3 to its bioactive form, known as 1,25-dihydroxy vitamin D3, that activates the vitamin D receptor,” Gombart said. “When activity increases, that increases expression of vitamin D receptor target genes, one of which produces the LL-37 peptide, which kills microbes by disrupting their membranes.

“The idea is, if you were to have an infection, the sutures would activate the toll-like receptors and start increasing production of 1,25D3 from the 25D3 that’s being released from sutures – so you get both local induction and an increase in the production of the antimicrobial peptide.”

The study’s corresponding author, Jingwei Xie of the University of Nebraska Medical Center, notes that the anti-infective sutures currently in use contain triclosan, an antibacterial and antifungal agent also found in a variety of consumer products.

“However, the frequent use has resulted in bacterial resistance,” Xie said. “Triclosan also shows a wide range of health risks including endocrine disruption, impaired muscle function, liver damage and the development of cancerous tumors. Compared to the currently available products and treatment options, the anti-infective sutures we develop could circumvent the selection for multidrug resistance and other health-associated shortcomings. The new sutures are also highly configurable and can deliver a variety of bioactive compounds to minimize infection risk, optimize healing and minimize scarring. None of the currently available sutures has this level of function.”

Gombart adds that the vitamin D delivered by the sutures could also affect additional genes involved in the immune response as well as LL-37.

“So a compound like vitamin D not only targets bacteria via the antimicrobial peptide, but other immune responses can also be modulated to help combat infection,” he said. “Targeting on multiple fronts helps minimize the chance of resistance.”

The University of Nebraska Medical Center, the National Institutes of Health, and the Otis Glebe Medical Research Foundation supported this research.

Also involved in the collaboration were researchers from the Joan C. Edwards School of Medicine at Marshall University in Huntington, West Virginia, and the Chongqing Academy of Animal Sciences & Key Laboratory of Pig Industry Sciences in Chongqing, China.

Findings were recently published in Nanomedicine.

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Assessment shows metagenomics software has much room for improvement

CORVALLIS, Ore. – A recent critical assessment of software tools represents a key step toward taming the “Wild West” nature of the burgeoning field of metagenomics, said an Oregon State University mathematical biologist who took part in the research.

Metagenomics refers to the science of genetically studying whole communities of microorganisms, as opposed to sequencing single species grown in culture.

“Microbes are ridiculously important to life,” said David Koslicki, assistant professor of mathematics in the OSU College of Science. “They not only can cause terrible things to happen, like blight and disease, but in general, overwhelmingly, microbes are our friends. Without them doing their jobs, crops couldn’t grow as well, it would be hard to digest our food, we might not get sleepy at appropriate times. Microbes are so fundamental to life, to health, we really need to know as much as we can about them.”

Koslicki, a leader in a university-wide research and education program known as OMBI – the OSU Microbiome Initiative – described the findings, published recently in Nature Methods, as “sobering." 

“There are not a lot of well-established, well-characterized computational techniques and tools that biologists can use,” he said. “And the assessment showed that a lot of the tools being used do not do nearly as well as had been initially thought, so there’s definitely room for improvement there.

“That said, depending on the situation that a biologist is interested in, there are definitely different tools that have proven to be the best so far.”

Metagenomics is a relatively new field that developed quickly once next-generation sequencing grew inexpensive enough that looking at entire microbial communities became economically feasible, said Koslicki.

“The typical view of biology is a wet lab and everything like that, but a whole other facet has to do with these high-throughput ways of accessing genetic material,” he said. “You end up with a ton of data, and when you end up with a ton of data, you introduce new problem: How do I get the important information out of it? You have to come up with an algorithm that allows biologists to answer the questions they find important: What critters are there, how many are there, what are they doing, are there any viruses? We need to answer those questions and not just answer them quickly but also have some sort of idea how accurate the answer is.”

The dizzying array of tools biologists are using to try to answer those questions is “kind of like the Wild West,” Koslicki said. “If you want to learn what bacteria are in a sample, there are no less than three or four dozen different tools people have come up with, and in a rather disjointed manner. You have teams of statisticians, mathematicians, biologists, microbiologists, engineers all looking at this from their own perspectives and coming up with their own tools. Then the end-user biologist comes along and is faced with 40 different tools, and how do they know how good they are at answering the questions they need answered?”

Koslicki’s research, known as the CAMI challenge – critical assessment of metagenome interpretation –was aimed at ranking those tools to provide a road map for biologists.

“The challenge engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from roughly 700 newly sequenced microorganisms and about 600 novel viruses and plasmids and representing common experimental setups,” he said. “This was an independent initiative. Typically when tools are compared, it’s attached to the publication of a new method that’s compared to other tools that do worse, so the new method looks good. There hasn’t been a lot of independent research into which tools actually work, how well they work, what kind of data do they well on, etc.”

The UK Engineering and Physical Sciences Research Council, the U.S. Department of Energy, the Cluster of Excellence on Plant Sciences, the Australian Research Council, the European Research Council, the Agency for Science, Technology and Research Singapore, the Lundbeck Foundation, and the National Science Foundation supported this research.

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Gamma-ray burst detection just what OSU researchers exclusively predicted

CORVALLIS, Ore. – More than a month before a game-changing detection of a short gamma-ray burst – a finding announced today – scientists at Oregon State University predicted such a discovery would occur.

Scientists from U.S. and European collaborations converged on the National Press Club in Washington, D.C., today to say they’ve detected an X-ray/gamma-ray flash that coincided with a burst of gravitational waves, followed by visible light from a new cosmic explosion called a kilonova.

Gravitational waves were first detected in September 2015, and that too was a red-letter event in physics and astronomy; it confirmed one of the main predictions of Albert Einstein’s 1915 general theory of relativity and earned a Nobel prize for the scientists who discovered them.

“A simultaneous detection of gamma rays and gravitational waves from the same place in the sky is a major milestone in our understanding of the universe,” said Davide Lazzati, a theoretical astrophysicist in the OSU College of Science. “The gamma rays allow for a precise localization of where the gravitational waves are coming from, and the combined information from gravitational and electromagnetic radiation allows scientists to probe the binary neutron star system that’s responsible in unprecedented ways. We can tell things like which galaxy the waves come from, if there are other stars nearby, and whether or not the gravitational waves are followed by visible radiation after a few hours or days.”

Collaborators from the Laser Interferometer Gravitational-Wave Observatory, known as LIGO, and the European Gravitational Observatory’s Virgo team on Aug. 17, 2017, detected gravitational waves – ripples in the fabric of space-time – produced by the coalescence of two neutron stars.

Roughly two seconds later, NASA’s Fermi Gamma-ray Space Telescope detected a short flash of X- and gamma rays from the same location in the sky.

“The Fermi transient is more than 1,000 times weaker than a ‘normal’ short gamma-ray burst and has the characteristics that we predicted,” Lazzati said. “No other prediction of such flashes had been made. Just by pen and paper almost, we could say hey, we might see the bursts, even if they’re not in a configuration that makes them obvious.”

On July 6, Lazzati’s team of theorists had published a paper predicting that, contrary to earlier estimates by the astrophysics community, short gamma-ray bursts associated with the gravitational emission of binary neutron star coalescence could be detected – whether or not the gamma-ray burst was pointing at Earth.

The paper appeared in the journal Monthly Notices of the Royal Astronomical Society.

“X- and gamma rays are collimated, like the light of a lighthouse, and can be easily detected only if the beam points toward Earth,” Lazzati said. “Gravitational waves, on the other hand, are almost isotropic and can always be detected. We argued that the interaction of the short gamma-ray burst jet with its surroundings creates a secondary source of emission called the cocoon. The cocoon is much weaker than the main beam and is undetectable if the main beam points toward our instruments. However, it could be detected for nearby bursts whose beam points away from us.”

Since the first gravitational wave discovery, there have been three more confirmed detections, including the one from August that was jointly seen by scientists from the LIGO and Virgo groups.

“All observations until the last one were from the coalescence of binary black hole systems,” Lazzati said. “While these systems are interesting, they are dark in any other form of radiation and relatively little can be understood from them compared to binary neutron star systems.

“It’s a really lucky set of circumstances for a theorist, where you have a working theory to use to make predictions and new instruments such as LIGO and Virgo coming online to test them,” Lazzati said. “Scientists don’t make predictions because we want to be right – we make predictions because we want to test them. Even if we’re wrong, we’re still learning something – but it’s much more exciting to be right.”

The term neutron star refers to the gravitationally collapsed core of a large star; neutron stars are the smallest, densest stars known. According to NASA, neutron stars’ matter is packed so tightly that a sugar-cube-sized amount of it weighs in excess of a billion tons.

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‘Transformative’ research unrealistic to predict, scientists tell granting agencies

CORVALLIS, Ore. – Research-funding agencies that require scientists to declare at the proposal stage how their projects will be “transformative” may actually be hindering discovery, according to a study by Oregon State University ecologists.

The requirement can result in decreased funding for the “incremental” research that often paves the way for paradigm-shifting breakthroughs, the OSU scientists assert.

Their findings, as well as their recommendation for how to best foster transformative research, were published recently in Trends in Ecology and Evolution.

Sarah Gravem, postdoctoral scholar in integrative biology in Oregon State’s College of Science, was the lead author on the paper, titled “Transformative Research is Not Easily Predicted.”

Gravem, integrative biology professor Bruce Menge and the other collaborators note that the National Science Foundation, which funds roughly one-quarter of the federally supported research at U.S. colleges and universities, “has made the pursuit of transformative research a top priority by asking for a transformative research statement in every major research proposal solicited.”

The NSF defines transformative research as being “driven by ideas that have the potential to radically change our understanding of an important existing scientific or engineering concept or leading to the creation of a new paradigm … . Such research is also characterized by its challenge to current understanding or its pathway to new frontiers.”

Gravem says asking scientists to attempt to create new paradigms or fields in every proposal is unrealistic and potentially harmful.

The OSU scientists argue that a better approach, and one that was suggested more than a decade ago by the board that oversees the National Science Foundation, would be to create a funding subset: a separate NSF-wide program to solicit and support transformational research proposals.

“The board had been concerned that the U.S. was lagging behind other countries in scientific advances, concerned that creative and risky research was not getting funding,” Menge said. “It concluded that what the NSF should do is set aside some funds for risky research proposals, those defined by reviewers as they may or may not work, the chances are sort of slim, but they could turn out to be pretty cool.”

What the NSF did instead, Menge said, was require all proposals to show how the research being proposed would be transformative.

“Instructions to reviewers include the expectation that the reviewer will comment on how transformative the proposed research is,” Menge added.

The problem, the Oregon State collaborators say, is that it’s rarely possible to know at the proposal stage whether a project will turn out to be transformative; their assertion follows interviews and surveys of 78 highly cited ecologists who began with incremental goals and only later realized the transformative potential of their work.

“To start out with that transformative question is a backward way of thinking,” Gravem said. “Surely you have to think big to come up with big answers, and everyone is striving for that, but truly transformative research is an unobtainable standard to place on people at the proposal stage. Trying to make every project paradigm shifting can mean ignoring the incremental and basic science that eventually goes into shifting paradigms. It’s a detriment to ignore the building blocks in favor of the building.”

Gravem said the necessity of incremental research was also explained recently on Freakonomics Radio.

“Economist Ed Glaeser noted that Nobel Prizes are not typically given for single transformative research papers but are often given for a body of incremental research,” she said. “If transformations arise from incremental research, then the transformative criterion is redundant with the solicitation of incremental research. This is reflected by mixed evidence that soliciting transformative research led to increases in transformative outcomes compared with the typical model.”

Expanding fields of knowledge, adding to bodies of evidence, and comparing two fields that haven’t been compared before are the types of gains researchers can reasonably predict, Gravem added. Being asked to forecast how a project will turn out to be transformative puts “researchers in an awkward position that nobody likes.”

“We’re being forced to hype our work at the beginning of a proposal, which doesn’t do anything to help science or to help build trust in science,” Gravem said. “And it turns the funding process into an essay competition that favors people who take more liberty in predicting what their research might show.”

Menge notes that NSF’s plan all along was to reassess the transformative research statement requirement at some point, “and now is the time.”

“Research funding is effectively decreasing, but the demand for funding is increasing, so they look for ways to prune the field of who gets funded – I recognize that as a problem,” he said. “But making artificial hurdles is just wrong. Funding agencies should concentrate on the goals of the research rather than the unknowable outcome.” 

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Bruce Menge, mengeb@oregonstate.edu; Sarah Gravem, sgravem@gmail.com

New blue pigment discovered at Oregon State earns EPA approval

CORVALLIS, Ore. – The vibrant YInMn blue pigment discovered at Oregon State University has been approved for commercial sale by the Environmental Protection Agency.

The Shepherd Color Co., which licensed the pigment from OSU, announced that the EPA has granted the company a “low volume exemption” that paves the way for the pigment, commercially known as Blue 10G513, to be used in industrial coatings and plastics.

YInMn refers to the elements yttrium, indium and manganese, which along with oxygen comprise the pigment. It features a unique chemical structure that allows the manganese ions to absorb red and green wavelengths of light while only reflecting blue.

The pigment, created in OSU’s College of Science, has sparked worldwide interest, including from crayon maker Crayola, which used the color as the inspiration for its new Bluetiful crayon.

The pigment is so durable, and its compounds are so stable – even in oil and water – that the color does not fade. Those characteristics make the pigment versatile for a variety of commercial products; used in paints, for example, they can help keep buildings cool by reflecting the infrared part of sunlight.

The EPA approval announced this week does not include making the pigment available for artists’ color materials, but Shepherd is in the process of seeking approval for its use in all applications and is confident that will happen, company spokesman Mark Ryan said.

YInMn blue was discovered by accident in 2009 when OSU chemist Mas Subramanian and his team were experimenting with new materials that could be used in electronics applications.

The researchers mixed manganese oxide – which is black in color – with other chemicals and heated them in a furnace to nearly 2,000 degrees Fahrenheit. One of their samples turned out to be a vivid blue. Oregon State graduate student Andrew Smith initially made these samples to study their electrical properties.

“This was a serendipitous discovery, a happy accident,” said Subramanian, the Milton Harris Chair of Materials Science at OSU. “But in fact, many breakthrough discoveries in science happen when one is not looking for it. As Louis Pasteur famously said, ‘In the fields of observation, chance favors only the prepared mind.’

“Most pigments are discovered by chance,” Subramanian added. “The reason is because the origin of the color of a material depends not only on the chemical composition, but also on the intricate arrangement of atoms in the crystal structure. So someone has to make the material first, then study its crystal structure thoroughly to explain the color.”  

Subramanian notes that blue is associated with open spaces, freedom, intuition, imagination, expansiveness, inspiration and sensitivity.

“Blue also represents meanings of depth, trust, loyalty, sincerity, wisdom, confidence, stability, faith, heaven and intelligence,” he said. “Through much of human history, civilizations around the world have sought inorganic compounds that could be used to paint things blue but often had limited success. Most had environmental and/or durability issues. The YInMn blue pigment is very stable and durable. There is no change in the color when exposed to high temperatures, water, and mildly acidic and alkali conditions.”

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Oregon State University students receive almost $40 million in scholarships

CORVALLIS, Ore. – More than $39.5 million in scholarship money has been awarded to students at Oregon State University for the 2017-18 academic year, a key component of OSU President Ed Ray’s Student Success Initiative.

Roughly $24.5 million of the total is spread among 7,271 scholarships to those who were students prior to this academic year. The rest is for awards to 2,532 incoming students, including 34 who received a $10,000-per-year Presidential Scholarship, OSU’s most prestigious undergraduate scholarship.

Approximately 35 percent of this year’s first-year students are receiving scholarship support.

The same percentage applies to the College of Engineering, whose students account for almost one-third of the $39.5 million total. Engineering students are receiving $12.7 million, with $7.9 million divided among 1,948 scholarships to students enrolled prior to this fall. Nineteen of the 804 incoming scholarship students are Presidential Scholars.

“Over the past decade, our total enrollment has increased by 150 percent, making us the 11th-largest engineering program in the United States,” said Scott Ashford, Kearney Professor and dean of the College of Engineering. “We need to make the OSU engineering degree financially accessible to every qualified Oregonian and underrepresented populations, and scholarships help us achieve that goal.”

More than $7.5 million in scholarship money is going to College of Science students, the college’s highest total ever, said Roy Haggerty, dean of the college. That is triple the amount awarded two years ago. Reasons for the jump include increases in university scholarships and in high-achieving students enrolling in the college.

Nearly $5 million is spread among 1,344 scholarships to students enrolled prior to fall term. The rest is for awards to 570 incoming students, including nine who received a Presidential Scholarship.

More than half of the college’s first-year students are receiving scholarship support.

“Scholarships enable the college to attract, retain and inspire top science students, most of whom go on to high-achieving careers in industry, graduate school, medical school and other professional programs after graduation,” Haggerty said. “Oregon State’s financial-need-based scholarships also help academically talented low-income and first-generation students from Oregon and elsewhere stay and excel in college.”

First-generation students typically have a greater financial need so scholarships are a crucial part of their educational equation, said Haggerty, who was the first in his family to attend college.

“In our college, the number of first-generation students has risen from 20 percent to 29 percent in the last five years,” he said. “Many scholarship students in the College of Science attest to the value of scholarships in easing the financial burden on their families and enabling them to focus on academics, research, volunteer activities and post-college career goals.”

At the College of Business, more than $3.7 million in scholarship money has been awarded, including roughly $2.3 million spread among 761 scholarships to students enrolled before fall term. The remainder is for awards to 276 incoming students, including one Presidential Scholar.

About 29 percent of this year’s first-year business students are receiving scholarship support.

“It’s very important for us to remove as many financial obstacles as possible for our students to help make their decision to attend college and return year after year easier,” said Mitzi Montoya, Sara Hart Kimball dean of the College of Business. “Our students are working hard in and outside the classroom, gaining experiences that are preparing them to be profession-ready. Scholarship support means they can focus more on being successful students and less on how they’ll pay for tuition or textbooks.”

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Groundbreaking investigative effort identifies gonorrhea vaccine candidates

CORVALLIS, Ore. – Researchers at Oregon State University have identified a pair of proteins that show promise as the basis for a gonorrhea vaccine.

The findings are an important step toward a potential new weapon in the fight against a sexually transmitted disease that affects millions of people around the globe, with nearly 80 million new cases estimated each year.

The pathogen that causes the disease, Neisseria gonorrhoeae, is considered a “superbug” because of its resistance to all classes of antibiotics available for treating infections. 

Gonorrhea is highly damaging to reproductive and neonatal health if untreated or improperly treated. It can lead to endometritis, pelvic inflammatory disease, ectopic pregnancy, epididymitis and infertility. Also, babies born to infected mothers are at increased risk of blindness.

More than half of infected women don’t have symptoms, but those asymptomatic cases can still lead to severe consequences for the patient’s reproductive health, including miscarriage or premature delivery, said OSU College of Pharmacy researcher Aleksandra Sikora.

Subjecting N. gonorrhoeae to the phenotypic microarray screening method for the first time, Sikora’s team focused on seven proteins from the bacteria’s cell envelope, which consists of the outer membrane, the cell wall and the inner membrane. 

Phenotypic microarrays are a high-throughput system featuring plates with 96 wells per plate, each well representing a different condition under which to research the phenotypes – the observable characteristics – of the examined mutants.

The goal was to see which if any of the seven proteins would show strong potential as a vaccine antigen – a molecule that sends the immune system into action. Vaccines prevent disease because the antigens they contain trigger an immune response that allows antibodies to recognize and attack pathogens to prevent future infection.

“Proteins in the cell envelope play key roles in cell function and bacterial physiology,” Sikora said. “That and their location make them attractive candidates for developing vaccines. But a lot of them are hypothetical proteins – we know bacteria have them but we don’t know for sure how they function. Learning what they contribute to cell structure, permeability, membrane biogenesis and so on is important in vaccine research because antibodies against protein antigens can disable the protein’s function.”

In all, more than 1,000 conditions were used to study the effects of knocking out each of the seven proteins.

“It’s like a football coach trying to choose the top quarterback among seven candidates by looking at their performance on many different teams during many different games,” Sikora said. “Imagine being able to look at those seven quarterbacks in over a thousand different games simultaneously. Of course, that’s not possible with football, but this is what we are doing here to identify the most promising vaccine candidates.”

Researchers found 91 conditions that had uniquely positive or negative effects on one of the mutants, and a cluster analysis of 37 commonly beneficial compounds and 57 commonly detrimental compounds revealed three separate phenotype groups.

Two of the proteins, NGO1985 and NGO2121, showed extensive sensitivity to antimicrobial compounds and thus emerged as the most promising vaccine candidates. This study serves as a jumping-off point for further characterization of proteins in the cell envelope. 

“Neisseria gonorrhoeae is a difficult bacteria to work with, and it’s very diverse,” Sikora said. “It has great genome plasticity – there are huge variations between strains. Phenotypic screening allows us to see how similar and how different they are.”

The National Institutes of Health supported this research. Findings were recently published in the Journal of Bacteriology.

The study was designed by Sikora and performed by Ph.D. candidate Benjamin Baarda in collaboration with Philip Proteau, a colleague of Sikora in the Department of Pharmaceutical Sciences, and Sarah Emerson in the Statistics Department of the OSU College of Science.

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New assay leads to step toward gene therapy for deaf patients

CORVALLIS, Ore. – Scientists at Oregon State University have taken an important step toward gene therapy for deaf patients by developing a way to better study a large protein essential for hearing and finding a truncated version of it.

Mutations in the protein, otoferlin, are linked to severe congenital hearing loss, a common type of deafness in which patients can hear almost nothing.

The research suggests otoferlin, which is in the cochlea of the inner ear, acts as a calcium-sensitive linker protein. The study also shows that a mutation in otoferlin weakens the binding between the protein and a calcium synapse in the ear, and deficiencies in that interaction might be at the root of hearing loss related to otoferlin.

The size of the otoferlin molecule and its low solubility have made it difficult to study, including how otoferlin works differently than another neuronal calcium sensor in the brain, synaptotagmin.

To combat those challenges, researchers in OSU’s College of Science developed a single-molecule colocalization binding titration assay – smCoBRA – for quantitatively probing otoferlin.

“It’s a one-trick pony of a protein,” said corresponding author Colin Johnson, associate professor of biochemistry and biophysics. “A lot of genes will find various things to do, but otoferlin seems only to have one purpose and that is to encode sound in the sensory hair cells in the inner ear. And small mutations in otoferlin render people profoundly deaf.”

The work by Johnson and collaborators in the Department of Physics and Department of Biochemistry and Biophysics provides a molecular-level explanation for the observation that otoferlin and synaptotagmin don’t have the same functional role.

The research, performed using recombinant protein from cell lysate isolated in vitro, also validates a methodology for characterizing large, multivalent membrane proteins in general.

“The otoferlin gene is really big, and it makes a huge protein,” Johnson said. “The traditional method for making a recombinant protein is using E. coli, but they loathe big proteins. This paper came up with a way of getting around that challenge.

“We were trying to shorten the gene, to find a truncated form that can be used for gene therapy. There is a size limit in terms of what you can package into the gene delivery vehicle, and otoferlin is too large. That’s the holy grail, trying to find a miniature version of otoferlin that that can be packaged into the delivery vehicle and then hopefully the patient can start hearing.”

Otoferlin’s size has precluded rescue experiments in which a modified mRNA for otoferlin is transfected into an animal model to replace a suppressed or knocked-down otoferlin gene causing deafness.

The study by Johnson, doctoral biochemistry student Nicole Hams, former biochemistry doctoral student Murugesh Padmanaryana and biophysicist Weihong Qiu identified a truncated form of otoferlin that can function in the encoding of sound.

The National Institutes of Health supported this study. Results were recently published in the Proceedings of the National Academy of Sciences.

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Protein transport channel offers new target for thwarting pathogen

CORVALLIS, Ore. – A bacterium that attacks people suffering from chronic lung disease and compromised immune systems could be halted by disrupting the distribution channels the organism uses to access the nutrient-rich cytoplasm of its host cell.

The findings by researchers in Oregon State University’s colleges of science and veterinary medicine are important because they suggest a new therapeutic target for one of the leading causes of bacterial infection in patients with HIV/AIDS.

The bacterium is Mycobacterium avium, the most common pathogen among non-tuberculosis mycobacteria. Highly opportunistic, M. avium invades and proliferates within a variety of human cells; it resides in a cytoplasmic vacuole and survives by remodeling its vacuolar compartment and resisting its host’s antimicrobial mechanisms.

“Most bacteria that grow in phagocytic cells export their effector proteins that impair or redirect macrophage function by using a needle-like apparatus that perforates the vacuole membrane and delivers virulence-associated molecules to the cytoplasm,” said co-corresponding author Luiz Bermudez of OSU’s College of Veterinary Medicine. “But mycobacteria don’t have that, so the question has always been, how do all these proteins get exported, how do they cross the vacuole membrane?”

They likely do so because proteins of the pathogen dock to transport proteins of the phagosome in the host cell in a way that allows for the efficient secretion of effector proteins. Co-corresponding author Lia Danelishvili, also of the College of Veterinary Medicine, identified voltage-dependent anion channels as a possible means of exporting those proteins.

“A VDAC is very small, but it can become larger if several VDAC proteins get together through polymerization,” Bermudez said. “We found that yes, mycobacteria use surface proteins to bind to the VDAC. But although we tried to see if the proteins of the mycobacterium were exported by the VDAC, we couldn’t show that. However, we did show that another component of the cell wall of the mycobacterium, lipids, are exported by that mechanism.”

Next up is determining what specific physical and chemical interactions occur to make effector protein transport possible.

“The idea is to find out the mechanism bacteria use to secrete proteins produced in the cells that have important functions in controlling the phagocytic activity that’s supposed to kill them,” Bermudez said.

Findings were recently published in Scientific Reports. 

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As Tolstoy noted (sort of), all unhappy microbiomes are unhappy in their own way

CORVALLIS, Ore. – The bacterial communities that live inside everyone are quite similar and stable when times are good, but when stress enters the equation, those communities can react very differently from person to person.

A microbiological version of the “Anna Karenina principle,” it’s a new paradigm suggested by scientists at Oregon State University – one that has key implications for a more personalized approach to antibiotic therapy, management of chronic diseases and other aspects of medical care.

The principle gets its name from the opening line of the novel “Anna Karenina” by 19th century Russian author Leo Tolstoy: “All happy families are alike; each unhappy family is unhappy in its own way.”

It turns out that this observation also applies to perturbed microbiotas of humans and animals.

“When microbiologists have looked at how microbiomes change when their hosts are stressed from any number of factors – temperature, smoking, diabetes, for example – they’ve tended to assume directional and predictive changes in the community,” said Rebecca Vega Thurber, corresponding author on the perspective study funded by the National Science Foundation. “After tracking many datasets of our own we never seemed to find this pattern but rather a distinct one where microbiomes actually change in a stochastic, or random, way.”

Findings were published today in Nature Microbiology.

Lead author Jesse Zaneveld of the University of Washington-Bothell collaborated with Vega Thurber and her student, Ryan McMinds, to survey the literature on microbial changes caused by perturbation. Together they found those stochastic changes to be a common occurrence, but one that researchers have tended to discard as “noise” rather than report.

“Thus we present the Anna Karenina principle for microbiomes,” Vega Thurber said. “When microbiomes are happy they are all similar in their composition but during stress or unhappiness they change in a multitude of distinct ways. This piece draws together diverse microbiome research. We think this is an important emerging paradigm for thinking about microbiome data. We present ways of identifying it and distinguishing it from other patterns.”

In addition to the literary reference, Vega Thurber offers a wintry metaphor to explain what she and her collaborators have discovered.

“When healthy our microbiomes look alike, but when stressed each one of us has our own microbial snowflake,” she said. “You or I could be put under the same stress, and our microbiomes will respond in different ways – that’s a very important facet to consider for managing approaches to personalized medicine. Stressors like antibiotics or diabetes can cause different people’s microbiomes to react in very different ways.”

Humans and animals are filled with symbiotic communities of microorganisms that often fill key roles in normal physiological function and also influence susceptibility to disease. Predicting how these communities of organisms respond to perturbations – anything that alters the systems’ function – is one of microbiologists’ essential challenges.

Studies of microbiome dynamics have typically looked for patterns that shift microbiomes from a healthy stable state to a dysbiotic stable state; dysbiosis refers to the microbial communities being out of their natural balance, which can result in the interruption of basic biological functions for the host person or animal.

“The Anna Karenina principle is a complementary alternative,” Vega Thurber said. “The changes induced by many perturbations lead to transitions from stable to unstable community states – dysbiotic individuals vary more in microbial community composition than healthy individuals.”

Scientists found patterns consistent with Anna Karenina effects in a range of systems, from corals exposed to above-average temperatures to the lungs of smokers to patients suffering from HIV/AIDS.

“Our message to researchers is, don’t throw out these observations as noise, but include this principle in the microbiome pipelines and software so that scientists can press a button that gives you the answer to, ‘Do I see the Anna Karenina principle in the dataset,’” Vega Thurber said.

OSU researchers have already given multiple presentations on the principle and it’s been well received in the microbiology community, Vega Thurber said. 

Media Contact: 

Steve Lundeberg, 541-737-4039

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