Research

Biochemist brothers identify “RNA Chaperone”

Anonymous — Fri, 10 Jan 2020 18:50:02 +0000

Biochemist brothers identify “RNA Chaperone” Anonymous (not verified) Fri, 01/10/2020 - 11:50

Giulia Corbet

Stress granules comprised of RNA (red) and protein assemblies (green) formed in part through RNA-RNA interactions.

A recent study from CU �鶹ӰԺ researchers shows that cells must actively work to keep sticky molecules, known as ribonucleic acid (RNA), apart, or they may form large assemblies that could cause problems for the cell. RNA is the biomolecule that serves as the template for protein synthesis in cells. Protein synthesis halts when cells become stressed, and RNAs assemble into complexes known as “stress granules” with other RNAs and proteins. Not much is known about the function of stress granules. However, aggregates that resemble stress granules are commonly found in neurodegenerative diseases, suggesting a possible role for stress granules in these diseases.

“While proteins have long been recognized to form aberrant complexes that can trigger disease, RNA has generally not been thought to form promiscuous assemblies that might have functional roles in cells as well as cause problems in some contexts,” said Roy Parker, Distinguished Professor of Biochemistry at CU �鶹ӰԺ.

The study, published recently in Cell, highlights how energetically favorable RNA self-assembly is and identifies one way to actively prevent this assembly from growing out of control. Parker has long studied the properties of stress granules and has pioneered the model that RNA-RNA interactions are a significant contributor to stress granule assembly.

This study, spearheaded by two brothers in the Parker research group at CU �鶹ӰԺ, presents two meaningful conclusions. First, stress granules and other ribonucleoprotein (RNP) complexes readily form favorable interactions with free RNAs. These interactions recruit new RNAs onto the surface of the RNP, thereby growing and stabilizing the complex. Second, a highly abundant enzyme within cells, known as eIF4A1, functions as an “RNA chaperone” to prevent the unregulated growth of RNPs within cells by binding to RNAs.

Devin (L) and Gabriel (R) Tauber, Parker Research Group, �鶹ӰԺ

Co-first authors and brothers Devin and Gabriel Tauber used their complementary expertise in Parker’s lab to understand RNA recruitment to RNPs both in a test tube and in living cells. Devin is a Ph.D. student, and Gabriel was an undergraduate at the time of the study. While unplanned, the brotherly collaboration resulted in an elegant characterization of RNA self-assembly and uncovered the role of the enzyme eIF4A1 in limiting this process in cells.

“Gabe and I have always been interested in science, but we never thought we’d publish a research article together, let alone work in the same lab. Yet, we both fell in love with RNA research and became engaged in understanding the many ways in which RNA can function in the cell beyond simply serving as a middle-man between DNA and protein synthesis,” said Devin. “Since we are brothers, when one of us comes up with an off the wall idea, we are comfortable letting each other have it without the risk of endangering a professional relationship.”

Gabriel sought to understand RNA recruitment into RNPs by watching fluorescently-labeled RNA species assemble under the microscope. Gabriel observed robust recruitment of RNAs with every type of RNP tested. This result raised the question – how do cells limit the growth of RNPs such as stress granules?

The authors believed that the enzyme eIF4A1 was the most likely mechanism to prevent aberrant RNA assembly. eIF4A1 is one of the most abundant RNA binding proteins in the cell and uses energy in the form of ATP to disrupt RNA-RNA interactions. Using fluorescence microscopy to view individual cells, they saw that eIF4A1 is concentrated at the periphery of stress granules, providing further support for the idea that eIF4A1 disrupts RNA-RNA interactions at the surface of RNPs. Thus, Devin sought out to ask whether modulating the levels of eIF4A1 in the cell would affect stress granule assembly.

The Tauber brothers observed that depleting the cell of eIF4A1 can induce stress granule assembly under conditions where they typically do not form. Conversely, they found that increasing the amount of eIF4A1 in the cell is sufficient to prevent stress granule formation under conditions where they would normally develop. However, a mutant form of eIF4A1 which cannot bind to RNA was unable to repress stress granule formation. Together, these experiments solidified the role of eIF4A1 as an inhibitor of RNA recruitment to stress granules and helped to shape the model of RNP assembly as a highly favorable process which requires the cell to use energy to limit it.

“This work will trigger a new set of studies on understanding how cells control RNA-RNA interactions to keep RNAs in the proper balance between functional and specific interactions while limiting inappropriate interactions,” said Parker.

eIF4A’s “RNA chaperone” function could be considered analogous to heat shock proteins, which prevent protein aggregation by binding to unfolded proteins. Protein aggregates that may contain RNA are commonly found in neurodegenerative diseases such as Alzheimer’s disease and Amyotrophic lateral sclerosis. Identifying the respective roles of RNA and protein in the formation of these aggregates could provide critical insight into the cause of these diseases.

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Mimicking the heart's microenvironment

Anonymous — Wed, 11 Sep 2019 06:00:00 +0000

Mimicking the heart's microenvironment Anonymous (not verified) Wed, 09/11/2019 - 00:00

Trent Knoss

CU �鶹ӰԺ engineers and faculty from the Consortium for Fibrosis Research & Translation (CFReT) at the CU Anschutz Medical Campus have teamed up to develop biomaterial-based “mimics” of heart tissues to measure patients’ responses to an aortic valve replacement procedure, offering new insight into the ways that cardiac tissue re-shapes itself post-surgery.

Aortic valve stenosis (AVS), a progressive disease characterized by heart valve tissue stiffening and obstructed blood flow from the heart, is known as a “silent killer,” affecting 12.4 percent of the population over 75 years old with a mortality range of 2-5 years if left untreated. Transcatheter aortic valve replacement (TAVR) procedures, which place an artificial valve at the site of the blockage, have been widely and successfully adopted as a remedy in recent decades.

Details of the broader biological reaction to the valve replacement have remained largely unknown, but nevertheless hold significant ramifications for quantifying the quality of recovery, the risk of complications and the assessment of overall patient outcomes.

During AVS disease progression, tissue-specific cells known as fibroblasts transition into myofibroblasts, which promote tissue stiffening. The researchers were interested in understanding how and why, post TAVR, myofibroblasts revert to the more benign fibroblasts.

“Previous studies have shown significant remodeling of cardiac tissues post-intervention,” said Dr. Brian Aguado, lead author of the study and a post-doctoral researcher in CU �鶹ӰԺ’s Department of Chemical and Biological Engineering. “Our hypothesis was that perhaps there are biochemical cues in a patient’s blood that may revert myofibroblasts back to fibroblasts.”

Modeling such a transformation in the lab is one thing, Aguado said, but the key to the new study was obtaining blood samples from real AVS patients and then using biomaterials to replicate the microenvironment of the heart.

“The heart is not made of plastic like a petri dish is,” he said. “We needed to engineer materials that could reflect the various stiffnesses of both healthy and diseased valve and cardiac tissue.”

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Nobel Laureate, Tom Cech, Ph.D., suggests new way to target third most common oncogene, TERT

Anonymous — Tue, 10 Sep 2019 06:00:00 +0000

Nobel Laureate, Tom Cech, Ph.D., suggests new way to target third most common oncogene, TERT Anonymous (not verified) Tue, 09/10/2019 - 00:00

Garth Sundem

Healthy cells have a built-in self-destruct mechanism: Strands of DNA called "telomeres" act as protective caps on the ends of your chromosomes. Each time a cell replicates, telomeres get a little shorter. Think of it like filing your nails with an Emory board - after enough filing, you hit your fingertip - ouch! In the case of healthy cells, after enough replications, telomeres are "filed" away, leaving bare ends of the chromosomes exposed. At that point, healthy cells are inactivated or die. The eventual loss of telomeres is a major reason you are not immortal. This cellular mortality is also a major way your body fights cancer.

That's because a hallmark of cancer is cellular immortality. And for that to happen, somehow, some way, cancer cells have to break the body's system of telomere degradation - cancer needs to keep chromosomes safely capped. One way they do it is by spackling new DNA onto telomeres faster than it's lost. This involves supercharging the gene that codes for new telomere material.

The TERT gene is the third most commonly mutated gene in cancer. When cancer over-activates TERT, it manufactures more of the enzyme "telomerase," which rebuilds telomeres faster than they are degraded. With telomeres being built faster than they degrade, cancer cells gain immortality. Especially cancer like melanoma, glioblastoma, and bladder cancers (among others) are defined by TERT mutation. It's likely that without TERT mutation, there would be none of these cancers.

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Do plants have social networks?

Anonymous — Wed, 15 May 2019 06:00:00 +0000

Do plants have social networks? Anonymous (not verified) Wed, 05/15/2019 - 00:00

Josh Rhoten

Humans interact in social networks every day around the office coffee pot, online with Facebook and in their communities through political elections. The structure and connections within these networks and others shape how information is shared. That in turn defines much of our modern life and collective behavior, though little is known about how or why these processes work.

That is because it’s difficult to study how these systems, with so many inputs and variables, actually work or affect one another in humans. The same goes for animals where small factors like touch, sight and sound can similarly change the whole dynamic of a network. Research being led by CU �鶹ӰԺ Assistant Professor Orit Peleg is trying to untangle this question by studying social systems in sunflowers through an award from the Human Frontier Science Program.

Peleg acknowledges most people don’t think of plants as having social networks – that is, they don’t think of plants being alive in that way. But for her, that kind of philosophical question is one of the most important aspects of the project.

“There are basic science and philosophical questions to be answered in this work,” said Peleg, who is a member of the Multi-Functional Materials and Autonomous Systems IRTs. “We will be using methodology from physics, engineering and math to understand problems in biology. How do you define a living organism? How do you differentiate between physical and social interactions?”

The Human Frontier Science Program links researchers from different continents and backgrounds. Peleg is joined in the project by Alex Jordan from the University of Konstanz in Germany and Yasmine Meroz from Tel Aviv University in Israel. Their $1.1 million, three-year grant is one of only nine 2019 Young Investigator Grants awarded this cycle to researchers specifically within five years of establishing their independent research group and no more than 10 years from their doctoral degree. In total, the program selected just 34 teams from more than 800 applications representing 60 countries.

Portrait of Orit Peleg

Orit Peleg

Peleg’s team is using sunflowers for this project because they are known to adjust their flower heads and leaves to earn maximum sun exposure, throwing shade on nearby plants in the process. Those neighboring plants then move to avoid being shaded themselves. The ripple effect from this dynamic creates a large network of interactions in the neighboring community of plants.

Peleg said plants are also great for this work because they do not move from location to location like humans or animals, making it easier to collect data. It also opens up agricultural applications for the work in the future as well for things like maximizing planting space.

Peleg, who is based in the BioFrontiers Institute and the Computer Science Department in the College of Engineering and Applied Science, will be working on computer modeling for the project. Her team will be looking at different planting arrangements of the sunflowers, comparing their growth to different light sources.

“By comparing those inside a model, we can say something a bit more microscopic about the interactions between the plants,” she said. “How do they communicate? Is there a benefit to the entire collection from their actions? We may be able to use this knowledge to project on to more complicated networks in the future.”

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'Pedigree is not destiny' when it comes to scholarly success

Anonymous — Wed, 01 May 2019 17:50:44 +0000

'Pedigree is not destiny' when it comes to scholarly success Anonymous (not verified) Wed, 05/01/2019 - 11:50

By: Sante Fe Institute

What matters more to a scientist’s career success: where they currently work, or where they got their Ph.D.? It’s a question a team of researchers teases apart in a new paper published in PNAS. Their analysis calls into question a common assumption underlying academia: that a researcher’s productivity reflects their scientific skill, which is reflected in the prestige of their doctoral training.

It’s true that faculty at prestigious universities publish more scientific papers and receive more citations and awards than professors at lower-ranked institutions. It’s also true that prestigious schools tend to hire new faculty who hold Ph.D.s from similarly prestigious programs. But according to the authors of the new study, an early career researcher’s current working environment is a better predictor of their future success than is the prestige of their doctoral training.

“Pedigree is not destiny,” says SFI External Professor Aaron Clauset (CU �鶹ӰԺ), a co-author on the paper. “Our analysis supports the fairly radical idea for academia that where you train doesn’t directly impact your future productivity.”

The team looked at two basic measures of academic success — productivity (how many papers a researcher publishes) and prominence (how often their work is cited) — of 2453 tenure-track faculty in all 205 Ph.D.-granting computer science departments in the US and Canada during the five years before and five years following those individual’s first faculty appointment.

“We wanted to disentangle the impact of environment on productivity and prominence, and to isolate the effects of where someone trained versus where they went on to work as faculty,” says lead author Samuel Way (CU �鶹ӰԺ). “On the prominence side, people do retain some benefit from having studied in a prestigious Ph.D. program. They continue to accumulate citations from their doctoral work.”

But the prestige of the training program seems to play little role in how many papers researchers go on to produce once they begin their appointments in a new place. “Someone like me, who trained at Colorado, and someone from MIT… if we both end up at Stanford, our productivity will look the same,” says Way.

The authors identify several possible mechanisms driving the increased productivity of faculty at more prestigious institutions. Selection criteria in hiring, expectations for high productivity once hired, and selective retention of productive faculty were all considered. “We only find weak evidence for each,” says Way. However, the prestige of the current work environment had a strong effect on productivity.

Identifying the underlying “forces that tilt the scientific playing field in favor of some scientists over others,” as Clauset says, is important for identifying and potentially correcting the systemic biases that may be limiting the production of scientific knowledge.

“…our findings have direct implications for research on the science of science, which often assumes, implicitly if not explicitly, that meritocratic principles or mechanisms govern the production of knowledge,” write the authors. “Theories and models that fail to account for the environmental mechanism identified here, and the more general causal effects of prestige on productivity and prominence, will thus be incomplete.”

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Kristin Powell Serves on Interdisciplinary Teaching, Research and Creative Work Committee

Anonymous — Tue, 26 Feb 2019 07:00:00 +0000

Kristin Powell Serves on Interdisciplinary Teaching, Research and Creative Work Committee Anonymous (not verified) Tue, 02/26/2019 - 00:00

Academic Futures

Jim White, interim dean of the College of Arts and Sciences, today announced the composition of the Interdisciplinary Teaching, Research and Creative Work committee, which he chairs. The committee will explore what the campus needs to effectively embrace interdisciplinarity in both education and scholarship.

“Interdisciplinarity is a theme that recurs strongly in the life of the CU �鶹ӰԺ campus,” said White. “It is a key recommendation of the Academic Futures Committee, the subject of a variety of Academic Futures white papers and of conversations within academic units and during last year’s town halls. I’m looking forward to the committee taking on a topic with such strong implications for our teaching, research and creative work.”

White said the campus “is at a watershed moment in which we can consider the full potential of interdisciplinary research while removing barriers to interdisciplinary teaching and creative work.”

“This is the right moment, and this committee has the right people, to take on these vital and exciting questions,” White said.

The committee will begin its work this spring and is expected to deliver its recommendations to campus on Sept. 1, 2019.

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Research here could speedup clinical trials around Type 1 diabetes

Anonymous — Thu, 06 Dec 2018 07:00:00 +0000

Research here could speedup clinical trials around Type 1 diabetes Anonymous (not verified) Thu, 12/06/2018 - 00:00

Josh Rhoten

Researchers at CU �鶹ӰԺ have developed virtual clinical trials for an artificial pancreas that could significantly improve treatments for those with Type 1 diabetes by tailoring medical devices and speeding up trials.

The work was done through a four-year, $600,000 award from the National Science Foundation and was headed at the CU �鶹ӰԺ College of Engineering and Applied Science by Sriram Sankaranarayanan, an associate professor and the Roubos Engineering Endowed Faculty Fellow in the Department of Computer Science. Sankaranarayanan said the project has led to research papers in journals and conferences across many disciplines and created numerous areas of collaboration between his group, chemical engineers, mathematicians, statisticians, biologists and physicians focused on the treatment of Type 1 diabetes.

“Type 1 diabetes is one of the few diseases where the treatment could be technological, so it sits at the convergence of health, human behavior, computer science and mathematics. It’s a really interesting sweet spot for us to explore and a field that has grown a lot since we started the work,” he said.

There were many collaborators on the project, including other faculty at CU �鶹ӰԺ, researchers from the Rensselaer Polytechnic Institute (RPI) in New York, the Barbara Davis Center at the University of Colorado Anschutz Medical Campus and the Stanford University Medical Center. The project also involved CU computer science PhD student Taisa Kushner.

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Personalized biomaterials tailor made to fix what ails you

Anonymous — Mon, 26 Nov 2018 07:00:00 +0000

Personalized biomaterials tailor made to fix what ails you Anonymous (not verified) Mon, 11/26/2018 - 00:00

The complexities that make each of us unique could result in medications, surgeries or health care devices that treat only the symptoms but not the specific causes.

At CU �鶹ӰԺ, engineers are inventing novel biomaterials able to decrease pain and extend life when the body gets out of kilter. And they’re doing it in such a way that can be tailored to each individual’s needs, thus eliminating the guesswork from diagnosis and treatment.

A relatively new area of study, biomaterials are making an impact on people’s lives. They include implanted materials and devices, such as a knee or hip replacements, or artificial lenses that clear the vision of cataract patients.

In the future, researchers

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Barn swallows may indeed have evolved alongside barns, humans

Anonymous — Tue, 30 Oct 2018 06:00:00 +0000

Barn swallows may indeed have evolved alongside barns, humans Anonymous (not verified) Tue, 10/30/2018 - 00:00

Cay Leytham-Powell

As humans evolved and expanded, so too did barn swallows, new research from CU �鶹ӰԺ suggests

The evolution of barn swallows, a bird ubiquitous to bridges and sheds around the world, might be even more closely tied to humans than previously thought, according to new study from the �鶹ӰԺ.

Chris Smith (left) and Rebecca Safran (right) re-examined the evolution of barn swallows and found that they may indeed have evolved alongside barns. Photographs courtesy of Rebecca Safran and Patrick Campbell/�鶹ӰԺ.

The research, published this week in Molecular Ecology, offers preliminary insight suggesting that the barn swallow and its subspecies evolved alongside—but independently from—humans. These new results make it one of the only known species, in addition to microscopic organisms like bacteria or viruses, to have developed in such a way, upending previous assumptions that barn swallows evolved prior to human settlement.

“Humans could be a really big part of the story,” said Rebecca Safran, a co-author of the study and an ecology and evolutionary biology (EBIO) associate professor at CU �鶹ӰԺ. “There’s very few studies that can point to the exact influence of humans, and so here, this coincidence of human expansion and permanent settlement and the expansion of a group that relies really, really heavily on humans is compelling.”

Barn swallows are found across the northern hemisphere and are characterized by their mud-cup nests that are built nearly exclusively on human-made structures. Despite their prevalence, however, not much is known about their evolutionary history, the timing of their expansion from northern Africa (where they originated) or how the six subspecies evolved so physically and behaviorally different yet remain almost genetically identical.

Previous studies published in the Proceedings of the Royal Society of London and Molecular Phylogenetics and Evolution looked into these questions and found that the different subspecies split early, well before human settlement.

This new study, however, gave the topic a fresh look by examining the whole genome of 168 barn swallows from the two sub-species farthest apart on an evolutionary scale: H. r. savignii in Egypt (a non-migratory species that lives along the Nile) and H. r. erythrogaster in North America (a species found throughout North America that migrates seasonally to South America).

Barn swallow subspecies are found throughout the northern hemisphere. Barn Swallow illustrations courtesy of Hilary Burn, and map courtesy of the Safran lab.

These data—which are on the order of 100,000 times bigger than the previous dataset used—were then analyzed with more sophisticated computational resources and methods than previously available. This allowed researchers to get a more complete picture that places the timing of barn swallow differentiation or speciation (i.e., when the barn swallow subspecies separated) closer to that of when humans began to build structures and settlements.

“The previous studies were playing with the idea of potential impact on population sizes due to humans,” said Chris Smith, a graduate student in EBIO and the Interdisciplinary Quantitative Biology program, and the study’s lead author. “Our results suggest a much more substantial link with humans.”

These new preliminary findings also suggest that this evolutionary link may have been forged through a “founder event,” which is when a small number of individuals in a species take over a new environment and are able to expand their new population there thanks to an availability of resources and an absence of competitors. For barn swallows, this event may have occurred rapidly when they moved into a new, relatively empty environment: alongside humans.

“Everyone is always wondering how do you study speciation? It’s been viewed as this long-term, million-year (process), but in barn swallows, we are not talking about differentiation within several thousands of years,” said Safran. “Things are really unfolding rather rapidly.”

Smith concurred: “It’s interesting to study speciation in the beginning steps.”

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Riboglow improves live cell RNA imaging

Anonymous — Wed, 26 Sep 2018 06:00:00 +0000

Riboglow improves live cell RNA imaging Anonymous (not verified) Wed, 09/26/2018 - 00:00

Jessica Miller

In a multidisciplinary study recently published in Nature Chemical Biology, researchers at the �鶹ӰԺ have developed a novel tool for visualizing RNA. This project centered on a collaboration between the Palmer Lab, with expertise in live cell imaging, the Batey Lab, with expertise in RNA, and the Gryko Lab with expertise in chemical synthesis. Researchers from the Parker and Jimenez labs also contributed to the study.

RNA, or ribonucleic acid, is a macromolecule essential to all forms of life. RNA plays a key role in gene expression and regulation, catalyzes the formation of polypeptides, and facilitates the transformation of genetic information from DNA to protein. Considering the many functions of this diverse molecule, visualizing RNA is essential to understanding a wide array of cellular processes.

Visualization of U-bodies in live mammalian cells

“As the community continues to discover new functions for coding and non-coding RNAs, the desire to look at them over time in live cells can provide unique functional insights“, commented Esther Braselmann, the lead author on this study and member of the Palmer Lab at the BioFrontiers Institute. Dr. Braselmann recently won a prestigious NIH K99 award, which helps outstanding postdoctoral researchers transition to tenure-track positions.

Established techniques to fluorescently tag and track RNA have several limitations. These tags are not compatible with all types of RNA, perform poorly in live cell studies, and can interfere with normal RNA activity due to their large size. The authors of this study sought to create a versatile imaging platform applicable to real-time experiments in live cells.

The methodology presented in this study relies on a Cobalamin-fluorophore probe which fluoresces upon binding to riboswitch RNA. This system is highly adaptable, allowing researchers to target diverse types of RNA and customize the probe with fluorophores of different colors.

The authors employed this Riboglow technology to visualize mRNA dynamics in live mammalian cells. They were able to record mRNA localization to stress granules, and visualize U1 snRNA in live cells for the first time. When compared to other imaging techniques, Riboglow was less susceptible to photobleaching and demonstrated a robust fluorescent signal.

“We view Riboglow as a complementary platform to existing tools and an addition to the growing toolbox for labeling RNAs,” remarked Dr. Braselmann. The versatility of the Riboglow platform will allow for widespread application to continue illuminating the many roles of RNA in live cells.

This research was supported by the Human Frontiers Science Project, the National Institute of Health, and the National Science Centre.

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