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Harnessing the power of proteins in our cells to combat disease

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UNLV scientist Gary Kleiger at the forefront of a potential new drug modality; research published in the journal Nature.

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Credit: Lonnie Timmons III/UNLV Photo Services

Over many decades now, traditional drug discovery methods have steadily improved at keeping diseases at bay and cancer in remission. And for the most part, it’s worked well.

But it hasn’t worked perfectly.

A lab on UNLV’s campus has been a hub of activity in recent years, playing a significant role in a new realm of drug discovery — one that could potentially provide a solution for patients who have run out of options.

“It’s starting to get to the point where we’ve kind of taken traditional drug discovery as far as we can, and we really need something new,” said UNLV biochemist Gary Kleiger.

Traditional drug discovery involves what is called the small molecule approach. To attack a protein that’s causing disease in a cancer cell, for instance, a traditional drug has to – in a very targeted way – find that protein and shut down its activities.

It’d be like filling a baseball player’s glove with a bunch of cement.

“The glove gives a baseball player the ability to do his job and catch a baseball,” Kleiger said. “But if we were to take cement, and fill the pocket of the baseball glove with that cement, it would effectively shut down the ability of that baseball player to function on the team. That’s what traditional drugs do.”

There’s a big but, however. Up until this point, traditional drugs have only had the capability to target proteins that are participating in the disease that also have activities that are amenable to the small molecule approach, or, like the baseball player, actively engaging in the sport on the field.

These proteins make up a seemingly small percentage of the disease-causing proteins in our bodies.

So, as you can imagine, Kleiger said, while this model has helped effectively treat HIV and cancer, and helped treat everyday diseases through the use of antibiotics, it has some major setbacks.

“Cancer cells are clever,” Kleiger said. “They can evolve very, very quickly. So, a drug might be working at first – targeting an enzyme and telling that enzyme, ‘stop doing your activity,’ which can stop the cancer cells from growing. Those cancer cells appear to lie dormant, but all the while there are still little things that happen that eventually enable those cancer cells to bypass that drug.” The upshot is that, to stay ahead of cancer’s capacity to evolve drug resistance, we need to be able to target many additional disease-causing proteins, and thus, limiting the landscape of druggable proteins is a serious disadvantage.

There might be a better way, and recent research published in the journal Nature by Kleiger and his collaborator Dr. Brenda Schulman (Max Planck Institute of Biochemistry in Munich, Germany), is helping a consortium of both academic and industry-based researchers who are developing this novel approach.

An ‘unbelievable new playing field’

The new approach uses a family of human enzymes called ubiquitin ligases that exist in human cells. Enzymes are proteins in the cells of the body that speed up chemical reactions occurring at the cellular level and which help your body perform essential functions. There are roughly 20,000 known proteins in the human body, and perhaps some 5-10% are enzymes.

Kleiger first became interested in the ubiquitin protein as a postdoctoral fellow at the California Institute of Technology in the 2000s. At the time, Kleiger heard of a researcher who was working in what was then already appreciated to be an important field but that had yet to fully blossom.

“I didn’t have any idea that the field was going to become this important. I just thought it sounded really cool, and something I wanted to explore,” he said.

Now, nearly 20 years later, Kleiger and colleagues are helping to uncover how ubiquitin ligases work in molecular detail. And this has become especially important, considering that these enzymes are now being employed in a totally novel type of drug discovery modality.

Instead of targeting enzymes that have an active role in the disease – like the baseball player on the field – there might be a way to target practically any protein that has a role in making a person sick. Think of a baseball team manager or the owner, Kleiger said.

“They’re not a part of the team on the field, but they nevertheless can have a huge role to play in making the baseball team work,” he said. “If I want to get rid of that protein, I can’t use the traditional approach.”

That’s where the ubiquitin ligase comes in. In the presence of special new drugs first envisioned by Kleiger’s post-doctoral mentor Dr. Ray Deshaies and his collaborator Dr. Craig Crews, the ubiquitin ligase is now guided to the disease-causing protein to strategically target that protein for degradation, essentially killing it.

“People believe in this new modality, this new therapy so much that every major pharmaceutical company is now at various stages of developing this,” Kleiger said. Indeed, a phase two clinical trial led by the pharmaceutical company Arvinas is already testing the approach in patients for the treatment of prostate cancer. “This would be like the equivalent of you stepping into a batting cage for the old modality, to now being inside of Allegiant Stadium – this is an unbelievable new playing field.”

Why it’s happening now

To do this work effectively, scientists needed to understand the biology of ubiquitin ligases — work that has been going on for less than 30 years, which is a short time in the grand scheme of science and discovery, Kleiger said. And in that time, the technology has gotten sharper and more efficient.

So efficient that for the first time, Kleiger’s collaborators are using new, state-of-the-art cryo electron microscopes to be able to take pictures of what the ubiquitin ligases look like when they’re at work.

“It’s enabling us for the first time to really be able to see how they work, which is going to have huge impacts on the pharmaceutical industry’s ability to make new drug therapies,” Kleiger said. “It’s truly a sea change moment.”

The microscope is able to photograph these enzymes, and in his lab on UNLV’s campus, Kleiger and collaborators use the photographs to hypothesize how the enzymes are working. He then measures the activity of ‘mutated’ enzymes that should now be defective in their activities if their hypothesis is correct.

The work would be similar to a 50,000-year old society being given a picture of a bicycle, and asked to explain how it works.

“They might hypothesize that it’s a bicycle, and that you would use it to ride from point A to point B, or if there was a cart attached, you would use it to transport stuff,” Kleiger said. “You’d then have to test that hypothesis, and that’s what we do at UNLV.”

Kleiger examines the picture, and if it were the bicycle, uncovers that a gear on the bike is very important to its operational ability.

“If you were to bend that gear, now the bike’s not going to work — the chain will just fall off,” Kleiger said. “We can do that at the molecular level with the enzymes.”

His work, in collaboration with colleagues at the Max Planck Institute of Biochemistry and published in the journal Nature, has implications for how diseases will be treated in the future, and could especially be a lifeline for those suffering from diseases beyond cancers such as autoimmune conditions — diseases like rheumatoid arthritis, inflammatory bowel disease, lupus, or multiple sclerosis.

“These are diseases that millions of people around the world suffer from, so that’s one of the reasons why this is such great news,” Kleiger said. “For the first time ever, we’re seeing atomic resolution pictures of the ubiquitin ligase at work, and that’s undoubtedly going to be synergistic with pharmaceutical companies that are creating drugs harnessing the power of the ubiquitin ligase. It really could be a game changer.”

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Media Contact
Natalie Bruzda
natalie.bruzda@unlv.edu

Original Source

http://www.unlv.edu/news/release/harnessing-power-proteins-our-cells-combat-disease

Related Journal Article

http://dx.doi.org/10.1038/s41586-021-03197-9

Source: https://bioengineer.org/harnessing-the-power-of-proteins-in-our-cells-to-combat-disease/

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USC Stem Cell study identifies molecular ‘switch’ that turns precursors into kidney cells

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Kidney development is a balancing act between the self-renewal of stem and progenitor cells to maintain and expand their numbers, and the differentiation of these cells into more specialized cell types. In a new study in the journal eLife from Andy McMahon’s laboratory in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, former graduate student Alex Quiyu Guo and a team of scientists demonstrate the importance of a molecule called β-catenin in striking this balance.

β-catenin is a key driver at the end of a complex signaling cascade known as the Wnt pathway. Wnt signaling plays critical roles in the embryonic development of multiple organs including the kidneys. By partnering with other Wnt pathway molecules, β-catenin controls the activity of hundreds to thousands of genes within the cell.

The new study builds on the McMahon Lab’s previous discovery that Wnt/β-catenin can initiate progenitor cells to execute a lengthy and highly orchestrated program of forming structures in the kidney called nephrons. A healthy human kidney contains a million nephrons that balance body fluids and remove soluble waste products. Too few nephrons results in kidney disease.

Previous studies from the UT Southwestern Medical Center laboratory of Thomas Carroll, a former postdoctoral trainee in the McMahon Lab, suggested that Wnt/β-catenin signaling plays opposing roles in ensuring the proper number of nephrons: promoting progenitor maintenance and self-renewal, and stimulating progenitor cell differentiation.

“It sounded like Wnt/β-catenin is doing two things–both maintenance and differentiation–that seem to be opposite operations,” said Guo. “Therefore, the hypothesis was that different levels of Wnt/β-catenin can dictate different fates of the nephron progenitors: when it’s low, it works on maintenance; when it’s high, it directs differentiation.”

In 2015, it became more possible to test this hypothesis when Leif Oxburgh, a scientist at the Rogosin Institute in New York and a co-author of the eLife study, developed a system for growing large numbers of nephron progenitor cells, or NPCs, in a Petri dish.

Relying on this game-changing new system, Guo and his collaborators grew NPCs, added different levels of a chemical that activates β-catenin, and saw their hypothesis play out in the Petri dishes.

They observed that high levels of β-catenin triggered a “switch” in part of the Wnt pathway that relies on another family of transcription factors known as TCF/LEF. There are two types of TCF/LEF transcription factors: one type inhibits genes related to differentiation, and the other activates these genes. In response to high levels of β-catenin, the “activating” members of TCF/LEF switched places with the “inhibiting” members, effectively taking charge. This “switch” triggered NPCs to differentiate into more specialized types of kidney cells.

When they looked at low levels of β-catenin, they saw NPCs self-renewing and maintaining their populations, as expected. However, they were surprised to learn that β-catenin was not engaged with any of the known genes related to self-renewal and maintenance.

“β-catenin does something,” said Guo. “That is for sure. But how it does it is kind of mysterious right now.”

After publishing these results in eLife, Guo earned his PhD from USC, and began his postdoctoral training at UCLA. Helena Bugacov, a current PhD student in the McMahon Lab and a co-author of the eLife study, is now taking the lead in continuing the project–which has implications far beyond the kidney field, due to the broad role of Wnt throughout the body.

“Understanding how Wnt regulates these two very distinct cell outcomes of self-renewal and differentiation, which is very important for kidney development, is also important for understanding the development of other organs and adult stem cells, as Wnt signaling plays important roles in almost all developmental systems,” said Bugacov. “There is also a lot of attention from cancer researchers, as this process can go awry in cancer. Many therapeutics are trying to target this process.”

She added, “The more we know about things, the better we can inform work on developing human kidney organoid cultures, which can be more readily used to understand problems in human health, regeneration and development.”

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Additional co-authors of the eLife study include: Albert Kim, Andrew Ransick, Xi Chen, and Nils Lindstrom from USC; Aaron Brown from the Maine Medical Center Research Institute; and Bin Li and Bing Ren from the University of California, San Diego. The research was supported by federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grant number R01 DK054364).

https://stemcell.keck.usc.edu/usc-stem-cell-study-identifies-molecular-switch-that-turns-precursors-into-kidney-cells/

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Evidence of Antarctic glacier’s tipping point confirmed for first time

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Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level

Researchers have confirmed for the first time that Pine Island Glacier in West Antarctica could cross tipping points, leading to a rapid and irreversible retreat which would have significant consequences for global sea level.

Pine Island Glacier is a region of fast-flowing ice draining an area of West Antarctica approximately two thirds the size of the UK. The glacier is a particular cause for concern as it is losing more ice than any other glacier in Antarctica.

Currently, Pine Island Glacier together with its neighbouring Thwaites glacier are responsible for about 10% of the ongoing increase in global sea level.

Scientists have argued for some time that this region of Antarctica could reach a tipping point and undergo an irreversible retreat from which it could not recover. Such a retreat, once started, could lead to the collapse of the entire West Antarctic Ice Sheet, which contains enough ice to raise global sea level by over three metres.

While the general possibility of such a tipping point within ice sheets has been raised before, showing that Pine Island Glacier has the potential to enter unstable retreat is a very different question.

Now, researchers from Northumbria University have shown, for the first time, that this is indeed the case.

Their findings are published in leading journal, The Cryosphere.

Using a state-of-the-art ice flow model developed by Northumbria’s glaciology research group, the team have developed methods that allow tipping points within ice sheets to be identified.

For Pine Island Glacier, their study shows that the glacier has at least three distinct tipping points. The third and final event, triggered by ocean temperatures increasing by 1.2C, leads to an irreversible retreat of the entire glacier.

The researchers say that long-term warming and shoaling trends in Circumpolar Deep Water, in combination with changing wind patterns in the Amundsen Sea, could expose Pine Island Glacier’s ice shelf to warmer waters for longer periods of time, making temperature changes of this magnitude increasingly likely.

The lead author of the study, Dr Sebastian Rosier, is a Vice-Chancellor’s Research Fellow in Northumbria’s Department of Geography and Environmental Sciences. He specialises in the modelling processes controlling ice flow in Antarctica with the goal of understanding how the continent will contribute to future sea level rise.

Dr Rosier is a member of the University’s glaciology research group, led by Professor Hilmar Gudmundsson, which is currently working on a major £4million study to investigate if climate change will drive the Antarctic Ice Sheet towards a tipping point.

Dr Rosier explained: “The potential for this region to cross a tipping point has been raised in the past, but our study is the first to confirm that Pine Island Glacier does indeed cross these critical thresholds.

“Many different computer simulations around the world are attempting to quantify how a changing climate could affect the West Antarctic Ice Sheet but identifying whether a period of retreat in these models is a tipping point is challenging.

“However, it is a crucial question and the methodology we use in this new study makes it much easier to identify potential future tipping points.”

Hilmar Gudmundsson, Professor of Glaciology and Extreme Environments worked with Dr Rosier on the study. He added: “The possibility of Pine Island Glacier entering an unstable retreat has been raised before but this is the first time that this possibility is rigorously established and quantified.

“This is a major forward step in our understanding of the dynamics of this area and I’m thrilled that we have now been able to finally provide firm answers to this important question.

“But the findings of this study also concern me. Should the glacier enter unstable irreversible retreat, the impact on sea level could be measured in metres, and as this study shows, once the retreat starts it might be impossible to halt it.”

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The paper, The tipping points and early warning indicators for Pine island Glacier, West Antarctica, is now available to view in The Cryosphere.

Northumbria is fast becoming the UK’s leading university for research into Antarctic and extreme environments.

As well as the £4m tipping points study, known as TiPPACCs, Northumbria is also the only UK university to play a part in two projects in the £20m International Thwaites Glacier Collaboration – the largest joint project undertaken by the UK and USA in Antarctica for more than 70 years – where Northumbria is leading the PROPHET and GHC projects. This particular study was funded through both TiPPACCs and PROPHET.

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Source: https://bioengineer.org/evidence-of-antarctic-glaciers-tipping-point-confirmed-for-first-time/

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Diversity can prevent failures in large power grids

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Integrated power grids offer benefits, but also pose challenges best addressed by leveraging differences

The recent power outages in Texas brought attention to its power grid being separated from the rest of the country. While it is not immediately clear whether integration with other parts of the national grid would have completely eliminated the need for rolling outages, the state’s inability to import significant amounts of electricity was decisive in the blackout.

A larger power grid has perks, but also has perils that researchers at Northwestern University are hoping to address to expedite integration and improvements to the system.

An obvious challenge in larger grids is that failures can propagate further — in the case of Texas, across state lines. Another is that all power generators need to be kept synchronized to a common frequency in order to transmit energy. The U.S. is served by three “separate” grids: The Eastern interconnection, the Western interconnection and the Texas interconnection, interlinked only by direct-current power lines. Any persistent deviation in frequencies within a region can lead to an outage.

As a result, researchers are searching for ways to stabilize the grid by looking for methods to mitigate deviations in the power generators’ frequencies.

The new Northwestern research shows that counter to assumptions held by some, there are stability benefits to heterogeneity in the power grid. Examining several power grids across the U.S. and Europe, a team led by Northwestern physicist Adilson Motter recently reported that generators operating on different frequencies return to their normal state more quickly when they are damped by “breakers” at different rates than generators around them.

The paper was published March 5 in the journal Nature Communications.

Motter is the Charles E. and Emma H. Morrison Professor in the department of physics and astronomy in the Weinberg College of Arts and Sciences. His research focuses on nonlinear phenomena in complex systems and networks.

Motter compares power grids to a choir: “It’s a little bit like a choir without a conductor. The generators have to listen to others and speak in sync. They react and respond to each other’s frequencies.”

Listen to an out-of-whack frequency, and the result can be a failure. Given the interconnected makeup of the system, a failure can propagate across the network. Historically, these malfunctions have been prevented by using active controllers. However, failures are often caused precisely by control and equipment errors. This points to a need to build additional stability within the design of the system. To achieve that, the team looked into leveraging the natural heterogeneities of the grid.

When the frequencies of the power generators are moved away from the synchronous state, they can swing around for a long time and even become more erratic. To mitigate these fluctuations, they came up with something akin to a door mechanism used to close a door the fastest, but without slamming.

“Mathematically, the problem of damping frequency deviations in a power generator is analogous to the problem of optimally damping a door to get it to close the fastest, which has a known solution in the case of a single door,” Motter said. “But it’s not a single door in this analogy. It’s a network of many doors that are coupled with each other, if you can imagine the doors as power generators.”

When creating an “optimal damping” effect, they discovered that rather than making each damper identical, damping the power generators in a way that is suitably different from each other can further optimize their ability to synchronize to the same frequency as quickly as possible. That is, suitably heterogenous damping across the network can lead to improved stability in the power grids studied by the team.

This discovery could have implications for future grid design as developers work to optimize technology and in considerations to further integrate now separated networks.

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The paper is titled “Asymmetry underlies stability in power grids.” Additional co-authors include former postdoctoral researcher Ferenc Molnar and research professor Takashi Nishikawa.

The study was supported by Northwestern University’s Finite Earth Initiative (supported by Leslie and Mac McQuown) and ARPA-E Award No. DE-AR0000702 and also benefited from logistical support from the Northwestern Institute for Sustainability and Energy.

https://news.northwestern.edu/stories/2021/04/diversity-can-prevent-failures-in-large-power-grids/

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How Fortnite and Zelda can up your surgical game (no joke!)

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Scalpel? Check. Gaming console? Check. Study finds video games can be a new tool on surgical tray for medical students

Video games offer students obvious respite from the stresses of studies and, now, a study from a University of Ottawa medical student has found they could benefit surgical skills training.

Arnav Gupta carries a heavy course load as a third-year student in the Faculty of Medicine, so winding down with a game of Legend of Zelda always provides relief from the rigorous of study. But Zelda may be helping improve his surgical education, too, as Gupta and a team of researchers from the University of Toronto found in a paper they recently published in the medical journal Surgery.

“Given the limited availability of simulators and the high accessibility of video games, medical students interested in surgical specialties should know that video games may be a valuable adjunct training for enhancing their medical education, especially in surgical specialties where it can be critical,” says Gupta, whose findings were deciphered from a systematic review of 16 studies involving 575 participants.

“Particularly, in robotic surgery, being a video gamer was associated with improvements in time to completion, economy of motion, and overall performance. In laparoscopic surgery, video games-based training was associated with improvement in duration on certain tasks, economy of motion, accuracy, and overall performance,” explains Gupta, who has been a gamer since age 8.

This study builds on past reviews and is the first to focus on a specific medical student population where this style of training could be feasibly implemented. Their timely study found some of the most beneficial games for students of robotic surgery and laparoscopy were: Super Monkey Ball, Half Life, Rocket League and Underground. Underground is purposely designed to assist medical students with their robotic surgery training via a video game console.

“While video games can never replace the value of first-hand experience, they do have merit as an adjunctive tool, especially when attempting to replicate important movements to surgery. For example, first-person shooting games require you to translate three dimensional motions onto a two-dimensional screen, which is like the concept of laparoscopic surgery,” says Gupta, whose studies are focused on surgery in ophthalmology, which makes games like Resident Evil 4 or Trauma Center: New Blood fitted for his own ambitions.

“I’m not joking when I say that games such as Fortnite have the potential to enhance those necessary movements, providing stronger motivational components and in a low stakes environment.”

Reports suggest 55 percent of university students are gamers and enjoy proficiency with video consoles. Yet, many medical students don’t admit to owning and using a gaming console.

“I think there definitely is some ambivalence towards video games in medicine,” says Gupta, who is also a fan of Witcher 3. “Given how accessible games have become and how video game technology is advancing, video games definitely are an easy go-to for the students who do love them in some capacity. The hope is that maybe this study can inspire someone to take advantage of video games’ unique capabilities, reduce the general ambivalence towards it, and develop some fun ways to let students engage with surgical education.”

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https://media.uottawa.ca/news/how-fortnite-and-zelda-can-your-surgical-game-no-joke

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