Publications

Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation

Anonymous — Thu, 17 Oct 2019 18:23:00 +0000

Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation Anonymous (not verified) Thu, 10/17/2019 - 12:23

The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about 1 month afterward (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR–mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient disease severity measured via echocardiography and multimorbidity scores, and correlations were dependent on hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, alterations in serum composition after TAVR may lead to an antifibrotic fibroblast phenotype, which suggests earlier interventions may be beneficial for patients with advanced AVS to prevent further disease progression.

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Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties

Anonymous — Thu, 17 Oct 2019 18:18:01 +0000

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties Anonymous (not verified) Thu, 10/17/2019 - 12:18

Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known.

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Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments

Anonymous — Thu, 17 Oct 2019 18:10:10 +0000

Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments Anonymous (not verified) Thu, 10/17/2019 - 12:10

Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful biophysical technique being increasingly applied to a wide variety of problems. As the HDX-MS community continues to grow, adoption of best practices in data collection, analysis, presentation and interpretation will greatly enhance the accessibility of this technique to nonspecialists. Here we provide recommendations arising from community discussions emerging out of the first International Conference on Hydrogen-Exchange Mass Spectrometry (IC-HDX; 2017). It is meant to represent both a consensus viewpoint and an opportunity to stimulate further additions and refinements as the field advances.

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Academic ideas are supposed to thrive on their merits. If only.

Anonymous — Wed, 24 Oct 2018 06:00:00 +0000

Academic ideas are supposed to thrive on their merits. If only. Anonymous (not verified) Wed, 10/24/2018 - 00:00

Henry Farrell

Allison C. Morgan, Dimitrios J. Economou, Samuel F. Way and Aaron Clauset are all scholars in the department of computer science at the University of Colorado at �鶹ӰԺ. They have just published an important new article about how ideas spread within the academy. I asked them a series of questions about their work.

People say that science is about the open spread of ideas. However, your research suggests that it really matters whether the scientist who has the idea is working at a highly prestigious university. How does prestige affect the flow of ideas inside the academic community?

Our paper examines a simple hypothesis: Ideas spread in academia by people carrying them from one university to another. This idea is reasonable because academic research is highly specialized, and most researchers spend much of their careers working on topics close to what they trained on during graduate school. So, if a researcher had started studying deep learning in graduate school, and was then hired by a university where no one else was working on it, then that person carried the idea of deep learning from one university to another. In this way, if a small set of universities train the majority of all the academics in a field, ideas that originate at those universities will be overrepresented in the field. And, it turns out that in some of our past research, we showed that prestigious universities dominate the hiring market, meaning ideas that are born at prestigious universities will tend to spread further than those born elsewhere, simply because they have enormous alumni networks. The hiring market dominance of universities like Stanford, MIT, Harvard, etc. means that the other 200+ research universities in the U.S. are likely working on ideas that originated from this tiny group of elite places. In this paper, we test the hypothesis that where an idea is born matters for how far it could spread in academia, showing that prestige can create systematic “epistemic inequality” as a result of the hiring imbalance.

You treat the spread of ideas as a contagious process, which spreads through the population a little like the flu. How exactly do ideas become infectious, spreading from scientist to scientist or university to university?

There’s a long history of thinking of ideas spreading through a population by some kind of transfer process. Memes are classic example of this way of thinking. We use a slightly more narrow definition in our study, in which we define an “idea” as academic scholarship on a well-defined topic, like deep learning or quantum computing. An idea can thus “spread” across universities if a researcher who studies that idea changes jobs from one university to another. In our analysis, we were most interested in the situation where a university “adopted” an idea by hiring a new researcher who had a track record of working on it. Of course, the range of ideas being studied in a university is much more dynamic than this simple model allows, since researchers can pick up ideas from professional meetings, reading the literature, collaborating with other researchers, or developing them from scratch. Our aim was to show that the process of hiring new researchers (typically young professors) is one mechanism by which ideas spread through the system. This way, we don’t need to account for all the different ways ideas circulate in academia. We only need to show that hiring does indeed influence who works on what ideas where.

Your results suggest that really good ideas are likely to spread, no matter who has them, but that mediocre ideas tend to spread further and stick around longer when they come from scientists at highly prestigious institutions. What implications does this have for the ways we should do science?

It’s heartening that we find that good ideas will spread well no matter where they are born. It’s a bit less encouraging that mediocre ideas can spread just as far as good ones if they originate at a prestigious university. If we want academia to act more like a meritocracy, then we should try harder to ensure that our evaluations of ideas are not biased by the prestige of their birthplace, but instead focus on their independent merits. In practice, this is much harder than it sounds, but some things do help. For instance, recent researchshows that peer review based on a double-blind system mitigates prestige biases. Double-blind review works by removing the simple signals that tend to tilt evaluations in favor of prestigious universities. Working out other ways to mitigate prestige biases, for example, in faculty hiring itself, is less clear, but perhaps even more important. That said, our findings show that the advantage of prestige in terms of influencing the circulation of ideas in academia can be very large. This suggests that many good ideas may not be getting the attention they might deserve as a result of not having a prestigious university name associated with them. Another implication is that in a system that incentivizes researchers to produce a large quantity of incremental ideas, ideas produced by researchers at more prestigious universities will tend to be more visible than similarly good, or even slightly better ideas from less prestigious universities.

As you say, it’s easy to study the spread of ideas among scientists, since there is lots of good data. What possible implications does your research have for the spread of ideas in other contexts, such as politics, or among the general public?

We suspect that similar structural advantages may exist in other systems with strong prestige hierarchies. For example, the small number of universities represented among the educational backgrounds of Supreme Court justices and their clerks may be suggestive of less diverse approaches, and less creative judicial solutions. When differences in social prestige exist, then a high-quality idea originating from the bottom of the hierarchy in a business or government will have a harder time catching on than if it came from the top, not due to any conscious or unconscious bias by individuals but rather because of the structure of the system itself. If we want to solve hard problems, of which there are many in science, technology, and society, we need to find better ways to incentivize and recognize good ideas, regardless of where they originate from, rather than relying so heavily on characteristics like reputations or affiliations of the person suggesting it.

Allison C. Morgan, Dimitrios J. Economou, Samuel F. Way, and Aaron Clauset are at the department of computer science at the University of Colorado at �鶹ӰԺ. Aaron Clauset is also affiliated with the BioFrontiers Institute at University of Colorado at �鶹ӰԺ and the Santa Fe Institute.

This article is one in a series supported by the MacArthur Foundation Research Network on Opening Governance that seeks to work collaboratively to increase our understanding of how to design more effective and legitimate democratic institutions using new technologies and new methods. Neither the MacArthur Foundation nor the network is responsible for the article’s specific content. Other posts can be found here.

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Work with bees could unlock potential strength of natural designs in new materials

Anonymous — Mon, 17 Sep 2018 06:00:00 +0000

Work with bees could unlock potential strength of natural designs in new materials Anonymous (not verified) Mon, 09/17/2018 - 00:00

Josh Rhoten

The natural world has had billions of years of evolution to perfect systems, creating elegant solutions to tricky problems. CU �鶹ӰԺ Assistant Professor Orit Peleg’s work hopes to illuminate and explore those solutions with the long-term goal of applying the answers she finds to the materials we interact with daily.

Her most recent research with bees, recently published in Nature Physics, is a small step toward that goal. The project looked at the honeybee cluster swarms that hang in cone shapes from tree branches and are made up of hundreds of individual insects clinging to one another. While these swarms are hundreds of times the size of a single organism, the individual bees that comprise it are able to maintain the structure’s stability despite wind and gravity forcing changes in the overall shape.

Peleg, who is based in the Computer Science Department and the BioFrontiers Institute at CU �鶹ӰԺ, conducted the research during her time as a post-doctoral fellow at Harvard in 2017. She said the use of bees for the project “was a bit crazy,” but presented a good opportunity to work more on modeling and testing these types of systems at a low cost and with relatively simple imaging equipment.

“It is a good way to connect experiments to theory and go back and forth until we have a good understanding of the system,” she said.

The project tried to untangle how the cluster stayed together in various conditions by attaching one to a board that was shaken with varying amplitude, frequency and duration. The results showed that horizontally shaken clusters spread out to form wider, flatter cones, adapting to the movement, but also going back to normal given time. Something similar happened with sharp, pendular movements, but measurements before and after showed that the flattened cones deform less and relaxed faster than the elongated ones. Meanwhile, vertical movement put less strain on the structure which, in turn, required less change from the bees to adapt to the motion.

In the end, the experiment confirmed what Peleg’s agent-based simulations predicted and opened up new questions.

“Our goal in this experiment was to try to pinpoint local rules for behaviors of bees that dictate the mechanical stability of the structure. A bee on one side of swarm can’t say what another bee at the other side of the swarm is doing. It can only say what is happening in its local environment,” Peleg said. “So, by creating this structure, they have to solve this mechanical problem of stability by only using local information.”

But how do they know to do this? Or why? Peleg’s hypothesis is that individual bees respond to the strain they feel during movement, changing their position in the swarm to match it.

“We can think about a local role, where a bee senses those deformations through connections to other bees. If this exceeds a certain threshold, it moves around to address that,” she said. “It doesn’t consider up or down, it just takes the local gradient information. Going up gradient (magnitude) makes it harder for individual bee, but better for the swarm overall.”

Peleg is part of the Multi-functional Materials Interdisciplinary Research Theme at CU and said this work fits well with that theme’s goal of exploring new materials and applications. While there is still more work to be done in studying the fundamental biology at work, she said this research could have applications in swarm robotics or the creation of materials that can sense their environment and respond to it.

“There is a clear connection to structures that insects make like swarms or ant-towers, for example, that are dynamic and respond to things like temperature or mechanical changes,” she said. “The grandiose vison of this, which we are still far away from, is the creation of construction materials that can sense and respond to earthquakes and become more stable in the same sort of way.”

Peleg has an apiary on East Campus and is planning on continuing this kind of work and this project in particular. Specifically, she said there was still work to be done with imaging the inside of the swarms to help with overall understanding of how this process works.

“We still need to look at the internal structure of the swarm through x-rays, for example, as that is completely unknown right now and could be informative,” she said.

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Nothing unusual about 'the long peace' since WWII

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

Nothing unusual about 'the long peace' since WWII Anonymous (not verified) Mon, 02/26/2018 - 00:00

Jenna Marshall

Since the end of World War II, few violent conflicts have erupted between major powers. Scholars have come to call this 73-year period “the long peace.” But is this stretch of relative calm truly unusual in modern human history – and evidence that peace-keeping efforts are working? Or is it a cyclical peace, destined to be broken, with few lessons for preventing interstate conflict?

A new analysis by Aaron Clauset, an assistant professor of computer science at the University of Colorado at �鶹ӰԺ and the BioFrontiers Institute and an external faculty member of the Santa Fe Institute, aims to answer that long-standing question using novel statistical techniques to tease out how the “long peace” stacks up against historical trends of calm and conflict.

“There’s been a debate among people who think about conflict and war, policymakers and researchers, whether or not the pattern since World War II represents a trend,” Clauset says. Resolving this debate “is important because it shapes how we think about peace,” he adds.

Determining whether we are truly in the midst of a prolonged period of peace can help us understand what is an effective deterrent to war and what is not. If this really is a “long peace,” we can then examine why — and identify the mechanisms that have contributed to that peace. But if it’s not an anomaly, we may need to use caution in ascribing the current calm to particular policies or actions.

Using data on interstate conflicts worldwide between 1823 and 2003, Clauset looked for trends in the magnitude of those conflicts and the years between them, and then used that information to create models to determine the plausibility of a trend toward peace since World War II. “The tools, the framework and the models we built in this paper haven’t been used before, and they allow us to distinguish trends from fluctuations,” Clauset says.

What he found is that this prolonged period of peace is not so unusual. “The results of the study are that at least statistically speaking, the efforts to create peace have not changed the frequency of war,” Clauset says. “These periods of peace are relatively common. It doesn’t appear that the rules that generate war have changed.”

Between 1823 and 1939, there were 19 large wars, and a major conflict occurred about every 6.2 years. Then came an especially violent period: Between 1914 and 1939, which encompasses the onsets of the first and second world wars, 10 large wars erupted — about one every 2.7 years. In contrast, during the long peace of the 1940–2003 post-war period, there were only 5 large wars — about one every 12.8 years. So essentially, the long peace “has simply balanced the books,” counterbalancing the “great violence” of the early to mid 20th century, Clauset writes.

That’s not to say, however, that the current calm is insignificant. “This fact does not detract from the importance of the long peace, or the proposed mechanisms that explain it,” such as the spread of democracy and international diplomacy, he writes in the paper. “However, the models indicate that the post-war pattern of peace would need to endure at least another 100–140 years to become a statistically significant trend.”

Clauset compares this to flipping a coin over a period of time. “If I’m seeing a low number of heads out into the future, how long will the coins need to flip before the pattern really looks different? At what point does this pattern start to look unusual?”

Clauset says he is hopeful that the study will encourage a rethink of “the long peace.”

“I hope it will encourage caution,” Clauset says. “It’s a worthwhile exercise to check our assumptions about whether there’s a real trend or not.”

Part of the reason we tend to overstate the significance of the lack of major interstate conflict since World War II may be because of a human tendency to overestimate our ability to understand complexity, he notes in the paper. “Human agency certainly plays a critical role in shaping shorter-term dynamics and specific events in the history of interstate wars,” he writes. “But, the distributed and changing nature of the international system evidently moderates the impact that individuals or coalitions can have on longer-term and larger-scale system dynamics.

The research was supported by the One Earth Future Foundation, whose mission is to catalyze systems that eliminate the root causes of war.

Read the paper, “Trends and Fluctuations in the Severity of Interstate Wars," in Science Advances (February 21, 2018)

Read the article, "Are we in the middle of a long peace—or on the brink of a major war?" in Science (February 21, 2018)

Read the article, "War may be closer than we think," in Pacific Standard (February 23, 2018)

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Arthritis, autoimmune disease discovery could lead to new treatments

Anonymous — Mon, 20 Nov 2017 21:13:07 +0000

Arthritis, autoimmune disease discovery could lead to new treatments Anonymous (not verified) Mon, 11/20/2017 - 14:13

Lisa Marshall

More than 23.5 million Americans suffer from autoimmune diseases like rheumatoid arthritis, scleroderma and lupus, in which an overzealous immune response leads to pain, inflammation, skin disorders and other chronic health problems. The conditions are so common that three of the top five selling drugs in the United States aim to ease their symptoms. But no cure exists, and treatments are expensive and come with side effects.

Now CU �鶹ӰԺ researchers have discovered a potent, drug-like compound that could someday revolutionize treatment of such diseases by inhibiting a protein instrumental in prompting the body to start attacking its own tissue.

“We have discovered a key to lock this protein in a resting state,” said Hang Hubert Yin, a biochemistry professor in the BioFrontiers Institute and lead author of a paper, published today in Nature Chemical Biology, describing the discovery. “This could be paradigm shifting.”

For years, scientists have suspected that a protein called Toll-like receptor 8 (TLR8) plays a key role in the innate immune response. When it senses the presence of a virus or bacteria, it goes through a series of steps to transform from its passive to active state, triggering a cascade of inflammatory signals to fight off the foreign invader. But, as Yin explained, “it can be a double-edged sword” leading to disease when that response is excessive.

Because TLR8 has a unique molecular structure and is hidden inside the endosome — an infinitesimal bubble inside the cell — rather than on the cell’s surface, it has proven an extremely difficult target for drug development.

“This is a long-sought-after target with very little success,” Yin said.

But his study shows a drug-like molecule called CU-CPT8m binds to and inhibits TLR8 and exerts “potent anti-inflammatory effects” on the tissue of patients with arthritis, osteoarthritis and Still’s disease, a rare autoimmune illness.

For the study, Yin and his co-authors used high-throughput screening to look through more than 14,000 small molecule compounds to determine whether they had the right chemical structure to bind to TLR8. They identified four that shared a similar structure. Using that structure as a model, they chemically synthesized hundreds of novel compounds in an effort to find one that perfectly bound to and inhibited TLR8.

Previous efforts to target the protein have focused on shutting it down when it is in its active state. But the compound Yin discovered prevents it from activating while still in its passive state.

“Before, people were trying to close the open door to shut it down. We found the key to lock the door from the inside so it never opens,” Yin said.

Much more research is necessary, but that could lead to treatments that strike at the root cause of autoimmune diseases, rather than just treating symptoms. With help from CU’s Technology Transfer Office, Yin has already filed a patent application and hopes to move on to animal studies and clinical trials within the next two years.

“Given the prevalence of these diseases, there is a big push for alternatives,” Yin said.

In the meantime, the new compound can serve as a first-of-its kind tool to understand exactly what TLR8 and the other nine toll-like receptors do in the body.

“Our study provides the first small molecule tool to shut this protein down so we can understand its pathogenesis,” Yin said.

The National Institutes of Health funded the study and researchers from the University of Tokyo, Tsinghua University and Peking Union Medical College Hospital in Beijing contributed to it.

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Flu researchers discover new mechanism for battling influenza

Anonymous — Thu, 02 Nov 2017 06:00:00 +0000

Flu researchers discover new mechanism for battling influenza Anonymous (not verified) Thu, 11/02/2017 - 00:00

Lisa Marshall

Just as flu season swings into full gear, researchers from the �鶹ӰԺ and University of Texas at Austin have uncovered a previously unknown mechanism by which the human immune system tries to battle the influenza A virus. The discovery sheds new light on how the virus — which kills 12,000 to 56,000 people in the United States annually — often wins, and it could ultimately lead to new treatments.

“We’ve solved a mystery, revealing a new aspect of our innate immune system and what flu has to do to get around it,” says Nicholas Meyerson, a postdoctoral researcher in the BioFr ontiers Institute and lead author of a paper published in the Nov. 8 issue of Cell Host and Microbe.

The findings, several years in the making, could lead to a better understanding of how the seasonal flu virus, which typically originates in birds, makes its way to humans. They could also inform development of next-generation antivirals able to combat a broad spectrum of influenza strains, says co-senior author Robert Krug, a leading influenza researcher and professor at the University of Texas at Austin.

The paper focuses on two key molecular players in the story of influenza infection: a human protein called TRIM25, which was recently discovered to play an important role in the human immune response to flu infection; and a protein called NS1 present in all strains of the influenza A virus and shown to bind TRIM25 to keep it from doing its job.

“We were basically trying to find out what TRIM25 was doing that flu did not want it to be doing and the role NS1 was playing in blocking that function,” Krug said.

Through a series of laboratory tests, the team revealed two main findings:

TRIM25 acts earlier than previously believed, latching on to a critical and unique flu virus structure like a “molecular clamp” to keep the virus from replicating as soon as TRIM25 detects this unique structure.

NS1 produced by the flu virus can block this function of TRIM25, enabling flu to circumvent the immune response and cause infection.

Previous research had suggested that TRIM25 fought off flu by switching on what is known as the “interferon response” — a complex signaling pathway that arms cells through the body to fight off pathogens. But not all strains of influenza block this interferon signaling pathway, which led Meyerson to suspect another mechanism was at play in helping TRIM25 fight flu.

The paper reveals that TRIM25 is also a “restriction factor,” a special protein present in the fastest-acting arm of the immune system, before spreading infection occurs.

“Restriction factors lie in wait, and should a virus be detected in one of your cells, they have immediate destructive ability,” explains co-senior author Sara Sawyer, an associate professor of Molecular, Cellular and Developmental Biology (MCDB) at CU �鶹ӰԺ.

Flu uses its NS1 protein to evade TRIM25’s early flu-fighting response, the researchers found.

To do the study, the researchers first infected transgenic cell lines loaded with nonhuman primate versions of TRIM25 with the human influenza A virus. They found that the cells fought off the virus far better than human versions of the TRIM25 protein.

“This told us that TRIM25 has the capacity to crush influenza, but that its human form was less active,” Meyerson said.

To find out how it crushes influenza, the researchers combined purified TRIM25 with purified viral ribonucleoproteins (vRNPs) — eight-piece protein chains that house the influenza genome — and used state-of-the-art electron microscopy to take pictures of what happened.They found that TRIM25 appears to swiftly recognize the unique structure of vRNPs and clamps down on them to keep them from replicating inside the cell.Other experiments confirmed that the NS1 protein in flu virus inhibits this function.

They also found that TRIM25 (previously believed to be present only in the cell cytoplasm) is also present in the cell nucleus, which is the same cellular location where flu replication occurs.

Sawyer and Meyerson are now looking to further investigate the role TRIM25 plays in cross-species transmission of influenza.

More studies are needed, but Krug believes new therapeutics could be designed to block the NS1 protein produced by the flu virus, hobbling its ability to evade the human immune system.

“If you could somehow block NS1 from acting, you could block all strains of the virus,” he says.

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The possibilities and limits of using data to predict scientific discoveries

Anonymous — Fri, 03 Feb 2017 18:51:49 +0000

The possibilities and limits of using data to predict scientific discoveries Anonymous (not verified) Fri, 02/03/2017 - 11:51

CUBT - CU �鶹ӰԺ Today

Amidst the vast and varied ecosystem of modern science, the emerging interdisciplinary field known as the “science of science” is exploring a difficult, but provocative, question: In the age of data science, are future discoveries now predictable?

In an article published this week in the journal Science, CU �鶹ӰԺ researcher Aaron Clauset and co-authors Daniel Larremore (Santa Fe Institute) and Roberta Sinatra (Central European University) examine the possibilities and limits of using massive data sets of scientific papers and information on scientific careers to study the social processes that underlie discoveries.

“There is more interest than ever in quantifying scientific behavior,” said Aaron Clauset, an assistant professor in CU �鶹ӰԺ’s Department of Computer Science and a faculty member in the BioFrontiers Institute. “The question is: Can we use the abundant data on the scientific process in order to make better predictions about scientific discoveries, which could improve funding decisions, peer review and hiring decisions?”

Historically, scientific discoveries have fallen on a spectrum between highly expected (such as the Higgs boson, which evidence pointed to years in advance) and entirely unexpected (such as penicillin, which arrived with minimal preceding research). Predicting such advances has value to scientists (when choosing a research field), funding agencies (who want to allocate dollars effectively), hiring committees (who want to hire successful faculty) and taxpayers (who fund a large percentage of research projects).

The recent proliferation of bibliographic databases such as Google Scholar, Web of Science, PubMed, ORCID and others has given researchers new tools by which to examine various aspects of the scientific community as a whole, such as the number of citations a given article receives or how many journal articles a given researcher publishes. But, do such metrics make some kinds of discoveries easier to predict?

Feedback loops

One problem with using such data to make predictions is the likelihood that the scientific community and the various incentives for scientists may currently be structured in a way that creates self-reinforcing feedback loops in which future opportunity depends on being lucky, undermining the potential for other less-heralded projects to advance science.

“We tend to reward and reinvest in people and subjects that have paid off in the past, but there’s no guarantee they will continue to do so. This can create a kind of purifying selection,” said Clauset, who is also an external faculty member at the Santa Fe Institute. “Ecology teaches us that the most robust systems in the face of uncertainty are diverse systems. We may be killing the golden goose of scientific discovery very slowly by focusing on minutiae at the expense of variety.”

Clauset’s data also questions the conventional academic narrative that scientists achieve an early productivity peak followed by a long and slow decline. In a related paper published in December 2016, he and his co-authors analyzed over 200,000 publications from 2,453 tenure-track faculty in all 205 PhD-granting computer science departments in the U.S. and Canada. They found the conventional pattern accurately described only one-third of faculty while the remaining two-thirds exhibited a wide variety of productivity patterns over the course of their careers.

Sleeping beauties

Another insight into the unpredictability of scientific advances comes from so-called “sleeping beauties.” While bibliographic data illuminate that some aspects of scientific impact are predictable, the broad existence of “sleeping beauty” papers, which lay dormant for years before a sudden uptick in relevance, implies that some aspects of discovery may be fundamentally unpredictable. A notable example is a now-famous 1935 Albert Einstein paper on quantum mechanics that was only modestly cited for several decades before fairly recently becoming one of the most important papers in quantum mechanics.

“This suggests that there’s another scale to consider, one in which we need to zoom out even farther to understand how these various scientific fields and subfields are interacting with one another,” said Clauset.

The article also states that while publication data is useful in some ways, citations are fundamentally lagging indicators, which only look backward at the past, and thus may have limited utility for predicting the future.

Looking forward, Clauset and his co-authors suggest that better predictions could be made using data sets on scientific preprints, workshop papers, conference presentations and rejected grant proposals. Such databases—should they ever become available—might provide additional trends and insights that are not being captured currently by better illustrating how the frontier of scientific discovery is moving.

Overall, the authors state, the limits of data in predicting future advances point to the importance of maintaining a wide-ranging scientific community.

“We would be wise to hedge our bets by building a diverse ecosystem of scientists and approaches to science rather than focus on predicting individual discoveries,” said Clauset.

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Live Cells reveal cancer process

Anonymous — Thu, 11 Aug 2016 06:00:00 +0000

Live Cells reveal cancer process Anonymous (not verified) Thu, 08/11/2016 - 00:00

BioFrontiers

A deep look inside the live cells reveals a key cancer process

Telomerase, a powerful enzyme found at the ends of chromosomes, can keep humans healthy, or promote cancer growth. Researchers at the University of Colorado in �鶹ӰԺ used a process called single-molecule imaging to look into the complicated processes that this enzyme uses to attach itself to the ends of chromosomes. This new understanding could help researchers develop better diagnostics and drugs for treating cancer and other diseases.

The findings, which were recently published in the journal Cell, show that telomerase has a small window of opportunity, lasting only minutes, to connect to the telomeres at the ends of chromosomes. The team was surprised to find that telomerase may probe each telomere thousands of times, rarely forming a stable connection, in order to be successful at connecting to the chromosomes. Researchers believe that inhibiting telomerase from attaching to cancer cells is a target for better treatment of the disease.

Telomeres have been studied since the 1970’s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow. This extra material protects the ends of the chromosomes from deteriorating, or fusing, with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting. The enzyme, telomerase, replenishes telomeres throughout their lifecycles.

Telomerase is the enzyme that keeps cells young. From stem cells to germ cells, telomerase helps cells continue to live and multiply. Too little telomerase produces diseases of bone marrow, lungs and skin. Too much telomerase results in cells that over proliferate and may become “immortal.” As these immortal cells continue to divide and replenish, they build cancerous tumors. Scientists estimate that telomerase activation is a contributor in up to 90 percent of human cancers.

“This discovery changes the way we look at how telomerase recruitment works in general,” says �鶹ӰԺ Distinguished Professor and Nobel laureate Thomas Cech, who is director of CU’s BioFrontiers Institute and the lead author on the study. “It’s exciting to see this in living cells as it happens. Single-molecule imaging freezes the process, allowing us to study it. We are the only ones who have done this type of imaging of telomerase.”

The research team included coauthors, Jens Schmidt (pictured, left), a postdoctoral fellow and staff scientist, Arthur Zaug. They used the CRISPR genome editing and single molecule imaging to track telomerase’s movements in the nuclei of living human cancer cells. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, uses segments of DNA that contain short copies of base sequences. The team used single-molecule imaging, attaching fluorescent protein tags to human cancer cells so that the enzymatic process was visible under a powerful microscope.

“At the end of the day, the goal is to target telomerase as an approach to treat cancer,” say Schmidt. “You can inhibit telomerase across the board, but the challenge is isolating the telomerase in cancer cells from the telomerase participating in the normal processes of healthy cells. This research brings us closer to understanding these processes.”

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