Monday, December 11, 2023

 

Immersive VR goggles for mice unlock new potential for brain science

Goggles enabled researchers to study responses to overhead threats for first time

Peer-Reviewed Publication

NORTHWESTERN UNIVERSITY

VR goggles 

IMAGE: 

THIS ILLUSTRATION SHOWS THE VR SETUP, WITH AN "OVERHEAD THREAT" PROJECTED INTO THE TOP FIELD OF VIEW. 

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CREDIT: DOM PINKE/NORTHWESTERN UNIVERSITY

Northwestern University researchers have developed new virtual reality (VR) goggles for mice.

Besides just being cute, these miniature goggles provide more immersive experiences for mice living in laboratory settings. By more faithfully simulating natural environments, the researchers can more accurately and precisely study the neural circuitry that underlies behavior.

Compared to current state-of-the-art systems, which simply surround mice with computer or projection screens, the new goggles provide a leap in advancement. In current systems, mice can still see the lab environment peeking out from behind the screens, and the screens’ flat nature cannot convey three-dimensional (3D) depth. In another disadvantage, researchers have been unable to easily mount screens above mice’s heads to simulate overhead threats, such as looming birds of prey.

The new VR goggles bypass all those issues. And, as VR grows in popularity, the goggles also could help researchers glean new insights into how the human brain adapts and reacts to repeated VR exposure — an area that is currently little understood.

The research will be published on Friday (Dec. 8) in the journal Neuron. It marks the first time researchers have used a VR system to simulate an overhead threat.

“For the past 15 years, we have been using VR systems for mice,” said Northwestern’s Daniel Dombeck, the study’s senior author. “So far, labs have been using big computer or projection screens to surround an animal. For humans, this is like watching a TV in your living room. You still see your couch and your walls. There are cues around you, telling you that you aren’t inside the scene. Now think about putting on VR goggles, like Oculus Rift, that take up your full vision. You don’t see anything but the projected scene, and a different scene is projected into each eye to create depth information. That’s been missing for mice.”

Dombeck is a professor of neurobiology at Northwestern’s Weinberg College of Arts and Sciences. His laboratory is a leader in developing VR-based systems and high-resolution, laser-based imaging systems for animal research.

The value of VR

Although researchers can observe animals in nature, it is incredibly difficult to image patterns of real-time brain activity while animals engage with the real world. To overcome this challenge, researchers have integrated VR into laboratory settings. In these experimental setups, an animal uses a treadmill to navigate scenes, such as a virtual maze, projected onto surrounding screens. 

By keeping the mouse in place on the treadmill — rather than allowing it to run through a natural environment or physical maze — neurobiologists can use tools to view and map the brain as the mouse traverses a virtual space. Ultimately, this helps researchers grasp general principles of how activated neural circuits encode information during various behaviors.

“VR basically reproduces real environments,” Dombeck said. “We’ve had a lot of success with this VR system, but it’s possible the animals aren’t as immersed as they would be in a real environment. It takes a lot of training just to get the mice to pay attention to the screens and ignore the lab around them.”

Introducing iMRSIV

With recent advances in hardware miniaturization, Dombeck and his team wondered if they could develop VR goggles to more faithfully replicate a real environment. Using custom-designed lenses and miniature organic light-emitting diode (OLED) displays, they created compact goggles.

Called Miniature Rodent Stereo Illumination VR (iMRSIV), the system comprises two lenses and two screens — one for each side of the head to separately illuminate each eye for 3D vision. This provides each eye with a 180-degree field-of-view that fully immerses the mouse and excludes the surrounding environment.

Unlike VR goggles for a human, the iMRSIV (pronounced “immersive”) system does not wrap around the mouse’s head. Instead, the goggles are attached to the experimental setup and closely perch directly in front of the mouse’s face. Because the mouse runs in place on a treadmill, the goggles still cover the mouse’s field of view.

“We designed and built a custom holder for the goggles,” said John Issa, a postdoctoral fellow in Dombeck’s laboratory and study co-first author. “The whole optical display — the screens and the lenses — go all the way around the mouse.”

Reduced training times

By mapping the mice’s brains, Dombeck and his team found that the brains of goggle-wearing mice were activated in very similar ways as in freely moving animals. And, in side-by-side comparisons, the researchers noticed that goggle-wearing mice engaged with the scene much more quickly than mice with traditional VR systems.

“We went through the same kind of training paradigms that we have done in the past, but mice with the goggles learned more quickly,” Dombeck said. “After the first session, they could already complete the task. They knew where to run and looked to the right places for rewards. We think they actually might not need as much training because they can engage with the environment in a more natural way.”

Simulating overhead threats for the first time

Next, the researchers used the goggles to simulate an overhead threat — something that had been previously impossible with current systems. Because hardware for imaging technology already sits above the mouse, there is nowhere to mount a computer screen. The sky above a mouse, however, is an area where animals often look for vital — sometimes life-or-death — information.

“The top of a mouse’s field of view is very sensitive to detect predators from above, like a bird,” said co-first author Dom Pinke, a research specialist in Dombeck’s lab. “It’s not a learned behavior; it’s an imprinted behavior. It’s wired inside the mouse’s brain.”

To create a looming threat, the researchers projected a dark, expanding disk into the top of the goggles — and the top of the mice’s fields of view. In experiments, mice — upon noticing the disk — either ran faster or froze. Both behaviors are common responses to overhead threats. Researchers were able to record neural activity to study these reactions in detail.

“In the future, we’d like to look at situations where the mouse isn’t prey but is the predator,” Issa said. “We could watch brain activity while it chases a fly, for example. That activity involves a lot of depth perception and estimating distances. Those are things that we can start to capture.”

Making neurobiology accessible

In addition to opening the door for more research, Dombeck hopes the goggles open the door to new researchers. Because the goggles are relatively inexpensive and require less intensive laboratory setups, he thinks they could make neurobiology research more accessible.

“Traditional VR systems are pretty complicated,” Dombeck said. “They’re expensive, and they’re big. They require a big lab with a lot of space. And, on top of that, if it takes a long time to train a mouse to do a task, that limits how many experiments you can do. We’re still working on improvements, but our goggles are small, relatively cheap and pretty user friendly as well. This could make VR technology more available to other labs.”

The study, “Full field-of-view virtual reality goggles for mice,” was supported by the National Institutes of Health (award number R01-MH101297), the National Science Foundation (award number ECCS-1835389), the Hartwell Foundation and the Brain and Behavior Research Foundation.

VR goggles (IMAGE)

NORTHWESTERN UNIVERSITY

An artist's interpretation of a cartoon mouse wearing VR goggles.

CREDIT

@rita

 

MIT engineers design a robotic replica of the heart’s right chamber


The realistic model could aid the development of better heart implants and shed light on understudied heart disorders.


Peer-Reviewed Publication

MASSACHUSETTS INSTITUTE OF TECHNOLOGY




MIT engineers have developed a robotic replica of the heart’s right ventricle, which mimics the beating and blood-pumping action of live hearts. 

The robo-ventricle combines real heart tissue with synthetic, balloon-like artificial muscles that enable scientists to control the ventricle’s contractions while observing how its natural valves and other intricate structures function. 

The artificial ventricle can be tuned to mimic healthy and diseased states. The team manipulated the model to simulate conditions of right ventricular dysfunction, including pulmonary hypertension and myocardial infarction. They also used the model to test cardiac devices. For instance, the team implanted a mechanical valve to repair a natural malfunctioning valve, then observed how the ventricle’s pumping changed in response. 

They say the new robotic right ventricle, or RRV, can be used as a realistic platform to study right ventricle disorders and test devices and therapies aimed at treating those disorders. 

“The right ventricle is particularly susceptible to dysfunction in intensive care unit settings, especially in patients on mechanical ventilation,” says Manisha Singh, a postdoc at MIT’s Institute for Medical Engineering and Science (IMES). “The RRV simulator can be used in the future to study the effects of mechanical ventilation on the right ventricle and to develop strategies to prevent right heart failure in these vulnerable patients.”

Singh and her colleagues report details of the new design in a paper appearing today in Nature Cardiovascular Research. Her co-authors include Associate Professor Ellen Roche, who is a core member of IMES and the associate head for research in the Department of Mechanical Engineering at MIT, along with Jean Bonnemain, Caglar Ozturk, Clara Park, Diego Quevedo-Moreno, Meagan Rowlett, and Yiling Fan of MIT, Brian Ayers of Massachusetts General Hospital,  Christopher Nguyen of Cleveland Clinic, and Mossab Saeed of Boston Children’s Hospital.

A ballet of beats

The right ventricle is one of the heart’s four chambers, along with the left ventricle and the left and right atria. Of the four chambers, the left ventricle is the heavy lifter, as its thick, cone-shaped musculature is built for pumping blood through the entire body. The right ventricle, Roche says, is a “ballerina” in comparison, as it handles a lighter though no-less-crucial load.

“The right ventricle pumps deoxygenated blood to the lungs, so it doesn’t have to pump as hard,” Roche notes. “It’s a thinner muscle, with more complex architecture and motion.”

This anatomical complexity has made it difficult for clinicians to accurately observe and assess right ventricle function in patients with heart disease. 

“Conventional tools often fail to capture the intricate mechanics and dynamics of the right ventricle, leading to potential misdiagnoses and inadequate treatment strategies,” Singh says. 

To improve understanding of the lesser-known chamber and speed the development of cardiac devices to treat its dysfunction, the team designed a realistic, functional model of the right ventricle that both captures its anatomical intricacies and reproduces its pumping function.  

The model includes real heart tissue, which the team chose to incorporate because it retains natural structures that are too complex to reproduce synthetically. 

“There are thin, tiny chordae and valve leaflets with different material properties that are all moving in concert with the ventricle’s muscle.Trying to cast or print these very delicate structures is quite challenging,” Roche explains. 

A heart’s shelf-life

In the new study, the team reports explanting a pig’s right ventricle, which they treated to carefully preserve its internal structures. They then fit a silicone wrapping around it, which acted as a soft, synthetic myocardium, or muscular lining. Within this lining, the team embedded several long, balloon-like tubes, which encircled the real heart tissue, in positions that the team determined through computational modeling to be optimal for reproducing the ventricle’s contractions. The researchers connected each tube to a control system, which they then set to inflate and deflate each tube at rates that mimicked the heart’s real rhythm and motion. 

To test its pumping ability, the team infused the model with a liquid similar in viscosity to blood. This particular liquid was also transparent, allowing the engineers to observe with an internal camera how internal valves and structures responded as the ventricle pumped liquid through. 

They found that the artificial ventricle’s pumping power and the function of its internal structures were similar to what they previously observed in live, healthy animals, demonstrating that the model can realistically simulate the right ventricle’s action and anatomy. The researchers could also tune the frequency and power of the pumping tubes to mimic various cardiac conditions, such as irregular heartbeats, muscle weakening, and hypertension. 

“We’re reanimating the heart, in some sense, and in a way that we can study and potentially treat its dysfunction,” Roche says.

To show that the artificial ventricle can be used to test cardiac devices, the team surgically implanted ring-like medical devices of various sizes to repair the chamber’s tricuspid valve — a leafy, one-way valve that lets blood into the right ventricle. When this valve is leaky, or physically compromised, it can cause right heart failure or atrial fibrillation, and leads to symptoms such as reduced exercise capacity, swelling of the legs and abdomen, and liver enlargement

The researchers surgically manipulated the robo-ventricle’s valve to simulate this condition, then either replaced it by implanting a mechanical valve or repaired it using ring-like devices of different sizes. They observed which device improved the ventricle’s fluid flow as it continued to pump. 

“With its ability to accurately replicate tricuspid valve dysfunction, the RRV serves as an ideal training ground for surgeons and interventional cardiologists,” Singh says. “They can practice new surgical techniques for repairing or replacing the tricuspid valve on our model before performing them on actual patients.”

Currently, the RRV can simulate realistic function over a few months. The team is working to extend that performance and enable the model to run continuously for longer stretches. They are also working with designers of implantable devices to test their prototypes on the artificial ventricle and possibly speed their path to patients. And looking far in the future, Roche plans to pair the RRV with a similar artificial, functional model of the left ventricle, which the group is currently fine-tuning.

“We envision pairing this with the left ventricle to make a fully tunable, artificial heart, that could potentially function in people,” Roche says. “We’re quite a while off, but that’s the overarching vision.”

This research was supported in part by the National Science Foundation.

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Written by Jennifer Chu, MIT News

 WAIT, WHAT?!

New genes can arise from nothing


Peer-Reviewed Publication

UNIVERSITY OF HELSINKI

Hairpin structures 

IMAGE: 

RESEARCHERS STUDIED AN ERROR MECHANISM IN DNA REPLICATION, AND NOTICED THAT SOME ERRORS CREATE PALINDROMES THAT CAN FOLD INTO HAIRPIN STRUCTURES.

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CREDIT: ARI LÖYTYNOJA




The complexity of living organisms is encoded within their genes, but where do these genes come from? Researchers at the University of Helsinki resolved outstanding questions around the origin of small regulatory genes, and described a mechanism that creates their DNA palindromes. Under suitable circumstances, these palindromes evolve into microRNA genes.

The human genome contains ca. 20,000 genes that are used for the construction of proteins. Actions of these classical genes are coordinated by thousands of regulatory genes, the smallest of which encode microRNA molecules that are 22 base pairs in length. While the number of genes remains relatively constant, occasionally new genes emerge during evolution. Similar to the genesis of biological life, the origin of new genes has continued to fascinate scientists.

All RNA molecules require palindromic runs of bases that lock the molecule into its functional conformation. Importantly, the chances of random base mutations gradually forming such palindromic runs are extremely small, even for the simple microRNA genes. Hence, the origin of these palindromic sequences has puzzled researchers. Experts at the Institute of Biotechnology, University of Helsinki, Finland resolved this mystery, describing a mechanism that can instantaneously generate complete DNA palindromes and thus create new microRNA genes from previously noncoding DNA sequences.

In a project funded by the Academy of Finland, researchers studied errors in DNA replication. Ari Löytynoja, the project leader, compares DNA replication to typing of text.

“DNA is copied one base at a time, and typically mutations are erroneous single bases, like mis-punches on a laptop keyboard. We studied a mechanism creating larger errors, like copy-pasting text from another context. We were especially interested in cases that copied the text backwards so that it creates a palindrome.”

Researchers recognised that DNA replication errors could sometimes be beneficial. They described these findings to Mikko Frilander, an expert in RNA biology. He immediately saw the connection to the structure of RNA molecules.

“In an RNA molecule, the bases of adjacent palindromes can pair and form structures resembling a hairpin. Such structures are crucial for the function of the RNA molecules,” he explains.

Researchers decided to focus on microRNA genes due to their simple structure: the genes are very short – just a few tens of bases – and they have to fold into a hairpin structure to function correctly.

A central insight was to model the gene history using a custom computer algorithm. According to postdoctoral researcher Heli Mönttinen, this enables the closest inspection of the origin of genes thus far.

“The whole genome of tens of primates and mammals is known. A comparison of their genomes reveals which species have the microRNA palindrome pair, and which lack it. With a detailed modelling of the history, we could see that whole palindromes are created by single mutation events,” says Mönttinen.

By focusing on humans and other primates, researchers in Helsinki demonstrated that the newly found mechanism can explain at least a quarter of the novel microRNA genes. As similar cases were found in other evolutionary lineages, the origin mechanism appears universal.

In principle, the rise of microRNA genes is so easy that novel genes could affect human health. Heli Mönttinen sees the significance of the work more broadly, for example in understanding the basic principles of biological life.

“The emergence of new genes from nothing has fascinated researchers. We now have an elegant model for the evolution of RNA genes,” she highlights.

Although the results are based on small regulatory genes, researchers believe that the findings can be generalised to other RNA genes and molecules. For example, by using the raw materials generated by the newly found mechanism, natural selection may create much more complex RNA structures and functions.

The study was published in PNAS.


A central insight was to model the gene history using information from related species. The modelling demonstrated that the palindromes of microRNA genes are generated by single mutation events.

CREDIT

Ari Löytynoja

 

What happens when the brain loses a hub? 


Rare experiment during brain surgery helps researchers better understand neural networks


Peer-Reviewed Publication

UNIVERSITY OF IOWA HEALTH CARE



A University of Iowa-led team of international neuroscientists have obtained the first direct recordings of the human brain in the minutes before and after a brain hub crucial for language meaning was surgically disconnected. The results reveal the importance of brain hubs in neural networks and the remarkable way in which the human brain attempts to compensate when a hub is lost, with immediacy not previously observed. 

Hubs are critical for connectivity 

Hubs are everywhere. The hub of a bicycle wheel, with spokes shooting out from the center, keeps the wheel from collapsing when the bicycle is ridden. Airport hubs connect cities across the world. And social hubs like coffee shops or online social networks are places people gather for interaction. 

The human brain has hubs, too – the intersection of many neuronal pathways that help coordinate brain activity required for complex functions like understanding and responding to speech. However, whether highly interconnected brain hubs are irreplaceable for certain brain functions has been controversial. By some accounts the brain, as an already highly interconnected neural network, can in principle immediately compensate for the loss of a hub, in the same way that traffic can be redirected around a blocked off city center.  

With a rare experimental opportunity, the UI neurosurgical and research teams led by Matthew Howard III, MD, professor and DEO of neurosurgery, and Christopher Petkov, PhD, professor and vice chair for research in neurosurgery, have achieved a breakthrough in understanding the necessity of a single hub. By obtaining evidence for what happens when a hub required for language meaning is lost, the researchers showed both the intrinsic importance of the hub as well as the remarkable and rapid ability of the brain to adapt and at least partially attempt to immediately compensate for its loss. The findings were reported recently in the journal Nature Communications.  

Evaluating the impact of losing a brain hub 

The study was conducted during surgical treatment of two patients with epilepsy. Both patients were undergoing procedures that required surgical removal of the anterior temporal lobe—a brain hub for language meaning—to allow the neurosurgeons access to a deeper brain area causing the patients’ debilitating epileptic seizures. Before this type of surgery, neurosurgery teams often ask the patients to conduct speech and language tasks in the operating room as the team uses implanted electrodes to record activity from parts of the brain close to and distant from the planned surgery area. These recordings help the clinical team effectively treat the seizures while limiting the impact of the surgery on the patient’s speech and language abilities.  

Typically, the recording electrodes are not needed after the surgical resection procedure and are removed. The innovation in this study was that the neurosurgery team was able to safely complete the procedure with the recording electrodes left in place or replaced to the same location after the procedure. This made it possible to obtain rare pre- and post-operative recordings allowing the researchers to evaluate signals from brain areas far away from the hub, including speech and language areas distant from the surgery site. Analysis of the change in responses to speech sounds before and after the loss of the hub revealed a rapid disruption of signaling and subsequent partial compensation of the broader brain network.  

“The rapid impact on the speech and language processing regions well removed from the surgical treatment site was surprising, but what was even more surprising was how the brain was working to compensate, albeit incompletely within this short timeframe,” says Petkov, who also holds an appointment at Newcastle University Medical School in the UK. 

The findings disprove theories challenging the necessity of specific brain hubs by showing that the hub was important to maintain normal brain processing in language. 

“Neurosurgical treatment and new technologies continue to improve the treatment options provided to patients,” says Howard, who also is a member of the Iowa Neuroscience Institute. “Research such as this underscores the importance of safely obtaining and comparing electrical recordings pre and post operatively, particularly when a brain hub might be affected.”  

According to the researchers, the observation on the nature of the immediate impact on a neural network and its rapid attempt to compensate provides evidence in support of a brain theory proposed by Professor Karl Friston at University College London, which posits that any self-organizing system at equilibrium works towards orderliness by minimizing its free energy, a resistance of the universal tendency towards disorder. These neurobiological results following human brain hub disconnection were consistent with several predictions of this and related neurobiological theories, showing how the brain works to try to regain order after the loss of one of its hubs.  

In addition to Petkov and Howard, the research team included researchers in the UI Departments of Neurosurgery, Radiology, and Psychological and Brain Sciences, as well as colleagues from Newcastle University, UCL, and University of Cambridge in the UK, and from Carnegie Mellon University, University of Wisconsin-Madison, and Gonzaga University in the United States. 

The research was funded in part by grants from National Institutes of Health, the Wellcome Trust. and the European Research Council. 

 

How health system hesitancies contributed to COVID risks


Experts at Cincinnati Children’s explore issues that need resolving before next public health crisis strikes


Peer-Reviewed Publication

CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER




More than 1.2 million people have died in the United States during the COVID-19 pandemic to date, more documented deaths than any other nation on Earth.

While many have attributed the high death toll on widespread personal hesitancy to wear masks, avoid crowded places or receive vaccines once they were developed, there were several “system hesitancies” that contributed to the tragic outcomes that need addressing, according to an analysis published Dec. 6, 2023, in Health Affairs Forefront.

The analysis was written by first author David Hartley, PhD, MPH, and corresponding author Andrew Beck, MD, MPH, at Cincinnati Children’s and several co-authors based in Cincinnati and Boston.

“Such hesitancies continue to stand in our way, placing the public at risk for infection, hospitalization, and even death during times of uncertainty and danger. Moreover, disruptive effects of system hesitancies are not shared equally across populations, with disproportionate clinical and economic burdens for the elderly, communities of color, those living with poverty, and children who were forced to see a safe return to school politicized,” the co-authors state.

These systemic hesitancies included:

  • Hesitancy to comprehend and act on warnings
  • Hesitancy to share, integrate, and learn from diverse data streams across sectors
  • Hesitancy to coordinate
  • Hesitancy to enable and empower local leadership

Newer technology has made near real-time disease surveillance possible on wide scales, but wider adoption is needed. Many lessons learned about coordinated response to natural disasters still need to be translated to public health responses to disease outbreaks.

System improvements should not focus only on top-down command and control, but rather top-down and bottom-up organizational approaches that support flexible, adaptive, and timely responses, the co-authors say.

In previous research about COVID response, several of the co-authors on the Health Affairs Forefront article also co-authored a report in April 2021 in the Mayo Clinic Proceedings that described how a number of organizations collaborated in southwest Ohio to rapidly build a “regional learning health system” to respond to the pandemic.

In southwest Ohio, a history of routine meetings between otherwise disconnected and often competitive hospitals, health departments and other agencies helped cut red tape, speed data sharing, and smooth resource sharing. That experience may serve as a model for other communities, the co-authors suggest.

“We can design a resilient public health system resistant to hesitancies, a system capable of detecting dynamic public health emergencies, and responding nimbly and efficiently,” the co-authors say. “To do so, we need an integrated system that works across sectors, approaches leadership in a new way, and enables rapid learning from the top-down and bottom-up.”

Co-authors included Peter Margolis, MD, PhD, and Robert Kahn, MD, MPH, from Cincinnati Children’s; Steve Miff, PhD, president and CEO at the Parkland Center for Clinical Innovation; Muhammad Zafar, MD, University of Cincinnati; Kate Schroder, president and CEO at Interact for Health in Cincinnati; Tiffany Mattingly, vice president, clinical strategies at The Health Collaborative in Cincinnati; and Pierre Barker, MD, MBChB, chief global partnerships and programs officer for the Institute for Healthcare Improvement in Boston.

More than 1.2 million people have died in the United States during the COVID-19 pandemic to date, more documented deaths than any other nation on Earth.

While many have attributed the high death toll on widespread personal hesitancy to wear masks, avoid crowded places or receive vaccines once they were developed, there were several “system hesitancies” that contributed to the tragic outcomes that need addressing, according to an analysis published Dec. 6, 2023, in Health Affairs Forefront.

The analysis was written by first author David Hartley, PhD, MPH, and corresponding author Andrew Beck, MD, MPH, at Cincinnati Children’s and several co-authors based in Cincinnati and Boston.

“Such hesitancies continue to stand in our way, placing the public at risk for infection, hospitalization, and even death during times of uncertainty and danger. Moreover, disruptive effects of system hesitancies are not shared equally across populations, with disproportionate clinical and economic burdens for the elderly, communities of color, those living with poverty, and children who were forced to see a safe return to school politicized,” the co-authors state.

These systemic hesitancies included:

  • Hesitancy to comprehend and act on warnings
  • Hesitancy to share, integrate, and learn from diverse data streams across sectors
  • Hesitancy to coordinate
  • Hesitancy to enable and empower local leadership

Newer technology has made near real-time disease surveillance possible on wide scales, but wider adoption is needed. Many lessons learned about coordinated response to natural disasters still need to be translated to public health responses to disease outbreaks.

System improvements should not focus only on top-down command and control, but rather top-down and bottom-up organizational approaches that support flexible, adaptive, and timely responses, the co-authors say.

In previous research about COVID response, several of the co-authors on the Health Affairs Forefront article also co-authored a report in April 2021 in the Mayo Clinic Proceedings that described how a number of organizations collaborated in southwest Ohio to rapidly build a “regional learning health system” to respond to the pandemic.

In southwest Ohio, a history of routine meetings between otherwise disconnected and often competitive hospitals, health departments and other agencies helped cut red tape, speed data sharing, and smooth resource sharing. That experience may serve as a model for other communities, the co-authors suggest.

“We can design a resilient public health system resistant to hesitancies, a system capable of detecting dynamic public health emergencies, and responding nimbly and efficiently,” the co-authors say. “To do so, we need an integrated system that works across sectors, approaches leadership in a new way, and enables rapid learning from the top-down and bottom-up.”

Co-authors included Peter Margolis, MD, PhD, and Robert Kahn, MD, MPH, from Cincinnati Children’s; Steve Miff, PhD, president and CEO at the Parkland Center for Clinical Innovation; Muhammad Zafar, MD, University of Cincinnati; Kate Schroder, president and CEO at Interact for Health in Cincinnati; Tiffany Mattingly, vice president, clinical strategies at The Health Collaborative in Cincinnati; and Pierre Barker, MD, MBChB, chief global partnerships and programs officer for the Institute for Healthcare Improvement in Boston.

 

Study reveals Zika’s shape-shifting machinery—and a possible vulnerability


Zika’s crucial enzyme performs multiple tasks, but a wrench in the system could bring it to a screeching halt


Peer-Reviewed Publication

SANFORD-BURNHAM PREBYS

Alexey Terskikh, Ph.D. 

IMAGE: 

ALEXEY TERSKIKH, PH.D.

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CREDIT: SANFORD BURNHAM PREBYS




Viruses have limited genetic material—and few proteins—so all the pieces must work extra hard. Zika is a great example; the virus only produces 10 proteins. Now, in a study published in the journal PLOS Pathogensresearchers at Sanford Burnham Prebys have shown how the virus does so much with so little and may have identified a therapeutic vulnerability.

 

In the study, the research team showed that Zika’s enzyme—NS2B-NS3—is a multipurpose tool with two essential functions: breaking up proteins (a protease) and dividing its own double-stranded RNA into single strands (a helicase).

 

“We found that Zika’s enzyme complex changes function based on how it’s shaped,” says Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys and senior author of the paper. “When in the closed conformation, it acts as a classic protease. But then it cycles between open and super-open conformations, which allows it to grab and then release a single strand of RNA—and these functions are essential for viral replication.”

 

Zika is an RNA virus that’s part of a family of deadly pathogens called flaviviruses, which include West Nile, dengue fever, yellow fever, Japanese encephalitis and others. The virus is transmitted by mosquitoes and infects uterine and placental cells (among other cell types), making it particularly dangerous for pregnant women. Once inside host cells, the virus re-engineers them to produce more Zika.

 

Understanding Zika on the molecular level could have an enormous payoff: a therapeutic target. It would be difficult to create safe drugs that target the domains of the enzyme needed for protease or helicase functions, as human cells have many similar molecules. However, a drug that blocks Zika’s conformational changes could be effective. If the complex can’t shape-shift, it can’t perform its critical functions, and no new Zika particles would be produced.

 

 

An efficient machine

Researchers have long known that Zika’s essential enzyme was composed of two units: NS2B-NS3pro and NS3hel. NS2B-NS3pro carries out protease functions, cutting long polypeptides into Zika proteins. However, NS2B-NS3pro’s abilities to bind single-stranded RNA and help separate the double-stranded RNA during viral replication were only recently discovered.

 

In this study, the researchers leaned on recent crystal structures and used protein biochemistry, fluorescence polarization and computer modeling to dissect NS2B-NS3pro’s life cycle. NS3pro is connected to NS3hel (the helicase) by a short amino acid linker and becomes active when the complex is in its closed conformation, like a closed accordion. The RNA binding happens when the complex is open, whereas the complex must transition through the super-open conformation to release RNA.

 

These conformational changes are driven by the dynamics of NS3hel activity, which extends the linker and eventually “yanks” the NS3pro to release RNA. NS3pro is anchored to the inside of the host cell’s endoplasmic reticulum (ER)—a key organelle that helps shepherd cellular proteins to their appropriate destinations—via NS2B and, while in the closed conformation, cuts up the Zika polypeptide, helping generate all viral proteins.

 

On the other side of the linker, NS3hel separates Zika’s double-stranded RNA and conveniently hands a strand over to NS3pro, which has positively charged “forks” to grab on to the negatively charged RNA.

 

“There’s a very nice groove of positive charges,” says Terskikh. “So, RNA just naturally follows that groove. Then the complex shifts to the closed conformation and releases the RNA.”

 

As NS3hel reaches forward to grab the double-stranded RNA, it pulls the complex with it; however, since the NS3pro is anchored in the ER membrane, and the linker can only extend so far, the complex snaps into the super-open conformation and releases RNA. The complex then relaxes back to the open conformation, ready for a new cycle.

 

Meanwhile, when NS3pro detects a viral polypeptide to cut, it forces the complex into the closed conformation, becoming a protease. The authors call this process “reverse inchworm,” because grabbing and releasing the single-stranded RNA resembles inchworm movements, but backward, with the jaws (the protease) trailing behind.

 

In addition to providing a possible therapeutic target for Zika, this detailed understanding could be applied to other flaviviruses, which share similar molecular machinery.

 

“Versions of the NS2B-NS3pro complex are found throughout the flaviviruses,” says Terskikh. “It could potentially constitute a whole new class of drug targets for multiple viruses.”

 

New study reveals latest data on global burden of cardiovascular disease


Cardiovascular disease remains leading cause of death; urgent action is needed for a heart-healthy world


Peer-Reviewed Publication

AMERICAN COLLEGE OF CARDIOLOGY




A world without cardiovascular disease (CVD) is possible, yet millions of lives are lost prematurely to heart disease each year, according to the new Global Burden of Disease (GBD) special report published today in the Journal of the American College of Cardiology. The report provides an update of health estimates for the global, regional and national burden and trends of CVD from 1990-2022 by analyzing the impact of cardiovascular conditions and risk factors across 21 global regions.

Research from this study reflects an urgent need for countries to establish public-health strategies aimed at preventing cardiovascular diseases by underscoring the global action needed to disseminate information and implement health programs, especially in hard-to-reach countries. While cardiovascular disease rates are high globally, regions of Asia, Europe, Africa and the Middle East were estimated to have the highest burden of CVD mortality. High blood pressure, high cholesterol, dietary risks and air pollution remain its leading causes.

“Cardiovascular diseases are a persistent challenge that lead to an enormous number of premature and preventable deaths,” said Gregory A. Roth, MD, MPH, senior author of the paper and associate professor in the Division of Cardiology and director of the Program in Cardiovascular Health Metrics at the Institute for Health Metrics and Evaluation at the University of Washington. “There are many inexpensive, effective treatments. We know what risk factors we need to identify and treat. There are simple healthy choices that people can make to improve their health. This atlas provides detailed information on where countries stand in their efforts to prevent and treat cardiovascular diseases.”

The mortality rates are broken down by location, along with age, sex and time categories. The report identifies disability-adjusted life years (DALYs), the years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs). The results presented include several updates to previously published estimates, reflecting new data and new disease modelling methods.

The paper specifically addresses 18 cardiovascular conditions and provides estimates for 15 leading risk factors for cardiovascular disease: environmental (air pollution, household air pollution, lead exposure, low temperature, high temperature), metabolic (systolic blood pressure, LDL-C, body mass index, fasting plasma glucose, kidney dysfunction) and behavioral (dietary, smoking, secondhand smoke, alcohol use, physical activity.

“We formed the Global Burden of Cardiovascular Diseases Collaboration three years ago to help bring state-of-the-art research to the forefront of the global cardiovascular community,” said Valentin Fuster, MD, PhD, an author of the paper, President of Mount Sinai Fuster Heart Hospital, physician-in-chief of The Mount Sinai Hospital, and editor-in-chief of JACC. “We are excited to publish this 2023 Almanac as a dedicated issue of the Journal to inform the realities of CVD risk and inspire strategies for a heart-healthy world.”

Key takeaways from the report:

  • Ischemic heart disease remains the leading cause of global CVD mortality with an age-standardized rate per 100,000 of 108.8 deaths, followed by intracerebral hemorrhage and ischemic stroke.
  • High systolic blood pressure accounted for the largest contribution to attributable age-standardized CVD disability-adjusted life years (DALYs) at 2,564.9 per 100,000 globally.
  • Dietary risks were the leading contributor to age-standardized CVD DALYs among the behavioral risks, while ambient particulate matter pollution led the environmental risks.
  • Between 2015-2022, age-standardized CVD mortality increased in 27 out of 204 locations.
  • Global death counts due to CVD increased from 12.4 million in 1990 to 19.8 million in 2022 reflecting global population growth and aging and the contributions from preventable metabolic, environmental, and behavioral risks.
  • Eastern Europe had the highest age-standardized total CVD mortality at 553 deaths per 100,000. In contrast, countries in Australasia had the lowest age-standardized total CVD mortality at 122.5 deaths per 100,000 people.
  • Central Asia, Eastern Europe, North Africa and the Middle East had the highest age-standardized mortality rate per 100,000 people attributable to high systolic blood pressure. The regions with the highest rates of CVD burden attributable to dietary risk were Central Asia, Oceania, and parts of North Africa and the Middle East.

 

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for heart disease is essential for reducing the global burden of heart disease,” said George A. Mensah, M.D., F.A.C.C., F.A.H.A., director of the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute (NHLBI). “The 2023 Almanac represents an important resource for using locally relevant data to inform local-level actions for heart-healthy and thriving communities.”

Launched in 2020, the Global Burden of Cardiovascular Diseases Collaboration is an alliance between the Journals of the American College of Cardiology, the Institute for Health Metrics and Evaluation at the University of Washington, and the National Heart, Lung, and Blood Institute. Serving as an update to 2022’s GBD Study, the 2023 publication includes data from 204 countries and territories, highlighting the leading global modifiable cardiovascular risk factors, their contribution to disease burden and recent prevention advancements.

The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at www.ACC.org or follow @ACCinTouch.

The ACC’s family of JACC Journals rank among the top cardiovascular journals in the world for scientific impact. The flagship journal, the Journal of the American College of Cardiology (JACC) — and family of specialty journals consisting of JACC: Advances, JACC: Asia, JACC: Basic to Translational Science, JACC: CardioOncology, JACC: Cardiovascular ImagingJACC: Cardiovascular InterventionsJACC: Case Reports, JACC: Clinical Electrophysiology and JACC: Heart Failure — pride themselves on publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.org.

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