Researchers found patients who had the mitral valve surgery with the tricuspid annuloplasty were less likely to die, need a tricuspid valve reoperation, or have tricuspid regurgitation advance to a severe stage during a two-year period after treatment, compared to those who had the mitral valve surgery alone. However, patients who had both procedures were more likely to need a permanent pacemaker.

The surgical protocol aims to prevent regurgitation, which occurs when flaps on the heart valves don’t close properly and blood flows backward into the heart. This can make it harder for blood to move efficiently throughout the body. In severe cases, regurgitation can increase the risk for an irregular heart rhythm, stroke, or heart failure.

More than 8 million Americans are diagnosed with some form of heart valve disease each year. A standard procedure for regurgitation that affects the mitral and tricuspid valves typically involves mitral valve surgery — which usually starts with minor tissue repair but could advance to valve repair or replacement. Decisions for adding a tricuspid annuloplasty vary widely. In this procedure, surgeons use a ring to reshape or resize a widening valve. While many patients, about 78%, with severe tricuspid regurgitation pair a tricuspid annuloplasty with mitral valve surgery, only about 4% with mild tricuspid regurgitation and 35% with moderate tricuspid regurgitation do so.

To help health professionals and patients make informed decisions about what to do in these cases, researchers from the Cardiothoracic Surgical Trials Network (CTSN), which is supported by NHLBI, launched a multi-year randomized clinical trial in 2016 with patients being treated for worsening mitral valve regurgitation with mild to moderate tricuspid regurgitation. The surgical procedures took place at 39 medical centers in the United States, Canada and Germany.

For the study, researchers enrolled 401 patients who planned to have mitral valve surgery. They were then randomly assigned to one of two treatment groups. The first had the mitral valve surgery, and the other had mitral valve surgery, along with a tricuspid valve annuloplasty.

Researchers found that among patients who had the combined mitral valve and tricuspid valve repair, just 3.9% developed severe regurgitation, died, or needed a reoperation, compared to 10.2% who had the mitral valve surgery alone. Researchers observed no significant differences between patient groups in the number of major cardiovascular events, changes in functional status, or quality of life. However, 14.1% of patients who had the surgery and tricuspid annuloplasty needed a permanent pacemaker, compared to 2.5% who had the surgery alone.

In discussing these results, Annetine C. Gelijns, Ph.D., and Alan J. Moskowitz, M.D., the principal investigators of the study’s data and clinical coordinating center at the Icahn School of Medicine at Mount Sinai, New York City, indicated that this trial delineates the important trade-off that patients face in deciding between the benefits of reducing the risk of tricuspid regurgitation progressing and increasing the risk of requiring a permanent pacemaker. These types of decisions vary for each patient.

Over the next few years, researchers will evaluate other clinical measures among trial participants to assess if there is a long-term benefit in pairing the tricuspid valve annuloplasty with mitral valve surgery.

“In addition to following the health outcomes of patients who received a pacemaker, we look forward to following those with milder forms of tricuspid regurgitation to assess their outcomes also,” said Wendy C. Taddei-Peters, Ph.D., a clinical trials specialist in NHLBI’s Division of Cardiovascular Sciences and a study coauthor.

“This trial and others will support a larger body of research that surgeons, professional societies, and medical organizations can use as they update surgical treatment guidelines in the future,” said Marissa A. Miller, D.V.M., M.P.H., a study coauthor and senior advisor for cardiac surgical trials at NHLBI. “Our goal is to make these types of treatment decisions easier for patients and to support their long-term health outcomes.”

The clinical trial (NCT02675244) was funded by a cooperative research agreement from NHLBI (U01 HL088942) and a grant from DZHK, the German Centre of Cardiovascular Research.

“These findings tell us that anxiety disorders might be more than a lack of awareness of the environment or ignorance of safety, but rather that individuals suffering from an anxiety disorder cannot control their feelings and behavior even if they wanted to,” said Benjamin Suarez-Jimenez, Ph.D., assistant professor in the Del Monte Institute for Neuroscience at the University of Rochester and first author of the study published in Communications Biology. “The patients with an anxiety disorder could rationally say — I’m in a safe space — but we found their brain was behaving as if it was not.”

Watching anxiety in the brain

Using fMRI, the researchers observed the brain activity of volunteers with general and social anxiety as they navigated a virtual reality game of picking flowers. Half of the meadow had flowers without bees, the other half had flowers with bees that would sting them — as simulated by a mild electrical stimulation to the hand. Researchers found all study participants could distinguish between the safe and dangerous areas, however, brain scans revealed volunteers with anxiety had increased insula and dorsomedial prefrontal cortex activation — indicating their brain was associating a known safe area to danger or threat.

“This is the first time we’ve looked at discrimination learning in this way. We know what brain areas to look at, but this is the first time we show this concert of activity in such a complex ‘real-world-like’ environment,” said Suarez-Jimenez. “These findings point towards the need for treatments that focus on helping patients take back control of their body.”

The brain differences were the only differences seen in these patients. For example, sweat responses, a proxy for anxiety, which was also measured, failed to reveal any clear differences.

Suarez-Jimenez’s research

Understanding the neural mechanisms by which the brain learns about the environment is the focus of Suarez-Jimenez’s research, particularly how the brain predicts what is threatening and what is safe. He uses virtual reality environments to investigate neural signatures of anxiety disorders and post-traumatic stress disorder (PTSD). His goal is to understand how people build maps in the brain that are based on experience, and the role of those maps in psychopathologies of stress and anxiety.

Expanding research to other disorders

“For next steps in this recent research, we still need to clarify if what we found in the brain of these patients is also the case in other disorders, such as PTSD. Understanding the differences and similarities across disorders characterized by deficits in behavioral regulation and feelings in safe environments, can help us create better personalized treatment options.”

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“Even in the middle of this pristine Amazon rainforest, we are seeing the global effects of climate change caused by people, including us,” said Vitek Jirinec, LSU alumnus (Ph.D. ’21), associate ecologist at the Integral Ecology Research Center and lead author to this study published in the journal Science Advances.

Birds in the Amazon rainforest have become smaller and their wings have become longer over several generations, indicating a response to the shifting environmental conditions that may include new physiological or nutritional challenges.

This is the first study to discover these changes in non-migratory birds’ body size and shape, which eliminates other factors that may have influenced these physiological changes. Jirinec and colleagues studied data collected on more than 15,000 individual birds that were captured, measured, weighed, marked with a leg band and released, over 40 years of field work in the world’s largest rainforest. The data reveal that nearly all of the birds’ bodies have reduced in mass, or become lighter, since the 1980s. Most of the bird species lost on average about 2 percent of their body weight every decade. For an average bird species that weighed about 30 grams in the 1980s, the population now averages about 27.6 grams. How significant is this?

“These birds don’t vary that much in size. They are fairly fine-tuned, so when everyone in the population is a couple of grams smaller, it’s significant,” said co-author Philip Stouffer, who is the Lee F. Mason Professor in the LSU School of Renewable Natural Resources.

The data set covers a large range of the rainforest so the changes in the birds’ bodies and wings across communities are not tied to one specific site, which means that the phenomenon is pervasive.

“This is undoubtedly happening all over and probably not just with birds,” Stouffer said. “If you look out your window, and consider what you’re seeing out there, the conditions are not what they were 40 years ago and it’s very likely plants and animals are responding to those changes as well. We have this idea that the things we see are fixed in time, but if these birds aren’t fixed in time, that may not be true.”

The scientists investigated 77 species of rainforest birds that live from the cool, dark forest floor to the warmer, sunlit midstory. They discovered that the birds that reside in the highest section of the midstory and are the most exposed to heat and drier conditions, had the most dramatic change in body weight and wing size. These birds also tend to fly more than the birds that live on the forest floor. The idea is that these birds have adapted to a hotter, drier climate by reducing their wing loading therefore becoming more energy efficient in flight. Think of a fighter jet with a heavy body and short wings that requires a lot of energy to fly fast compared to a glider plane with a slim body and long wings that can soar with less energy. If a bird has a higher wing loading, it needs to flap its wings faster to stay aloft, which requires more energy and produces more metabolic heat. Reducing body weight and increasing wing length leads to more efficient resource use while also keeping cooler in a warming climate.

LSU alumnus Ryan Burner (Ph.D. ’19) conducted much of the analysis that revealed the variation among the groups of birds over the years. Burner, who is now a research wildlife biologist at the U.S. Geological Survey Upper Midwest Environmental Sciences Center, is the second author of this study.

The question of the future capacity of Amazonian birds to deal with increasingly hotter and drier surroundings, especially in the dry season, remains unanswered. The same question can be asked for a lot of places and species that live at the edges of even more environmental extremes.

“There may be other researchers in other places who have relevant data from the 1970s and 1980s that could be compared to modern data, because the bird banding protocol we used is pretty standard. So if you measure mass and wing, maybe there will be more datasets that will emerge and we’ll be able to get more of an idea of the variation across space and how it might be changing in different systems,” Stouffer said.

Cells of the same type are strikingly uniform in size, while cell size differs between different cell types. This raises the question of whether cell size is important for cellular physiology.

The new study suggests that cellular enlargement drives a decline in function of stem cells. The researchers found that blood stem cells, which are among the smallest cells in the body, lose their ability to perform their normal function — replenishing the body’s blood cells — as they grow larger. However, when the cells were restored to their usual size, they behaved normally again.

The researchers also found that blood stem cells tend to enlarge as they age. Their study shows that this enlargement contributes to stem cell decline during aging.

“We have discovered cellular enlargement as a new aging factor in vivo, and now we can explore if we can treat cellular enlargement to delay aging and aging-related diseases,” says Jette Lengefeld, a former MIT postdoc, who is now a principal investigator at the University of Helsinki.

Lengefeld is the lead author of the study, which appears today in Science Advances. The late Angelika Amon, an MIT professor of biology and member of the Koch Institute for Integrative Cancer Research, is the senior author of the study.

Outsized effects

It has been known since the 1960s that human cells grown in a lab dish enlarge as they become senescent — a nondividing cellular state

that is associated with aging. Every time a cell divides, it can encounter DNA damage. When this happens, division is halted to repair the damage. During each of these delays, the cell grows slightly larger. Many scientists believed that this enlargement was simply a side effect of aging, but the Amon lab began to investigate the possibility that large cell size drives age-related losses of function.

Lengefeld studied the effects of size on stem cells — specifically, blood stem cells, which give rise to the blood cells of our body throughout life. To study how size affects these stem cells, the researchers damaged their DNA, leading to an increase in their size. They then compared these enlarged cells to other cells that also experienced DNA damage but were prevented from increasing in size using a drug called rapamycin.

After the treatment, the researchers measured the functionality of these two groups of stem cells by injecting them into mice that had their own blood stem cells eliminated. This allowed the researchers to determine whether the transplanted stem cells were able to repopulate the mouse’s blood cells.

They found that the DNA-damaged and enlarged stem cells were unable to produce new blood cells. However, the DNA-damaged stem cells that were kept small were still able to produce new blood cells.

In another experiment, the researchers used a genetic mutation to reduce the size of naturally occurring large stem cells that they found in older mice. They showed that if they induced those large stem cells to become small again, the cells regained their regenerative potential and behaved like younger stem cells.

“This is striking evidence supporting the model that size is important for functionality of stem cells,” Lengefeld says. “When we damage the stem cells’ DNA but keep them small during the damage, they retain their functionality. And if we reduce the size of large stem cells, we can restore their function.”

Keeping cells small

When the researchers treated mice with rapamycin, beginning at a young age, they were able to prevent blood stem cells from enlarging as the mice got older. Blood stem cells from those mice remained small and were able to build blood cells like young stem cells even in mice 3 years of age — an old age for a mouse.

Rapamycin, a drug that can inhibit cell growth, is now used to treat some cancers and to prevent organ transplant rejection, and has raised interest for its ability to extend lifespan in mice and other organisms. It may be useful in slowing down the enlargement of stem cells and therefore could have beneficial effects in humans, Lengefeld says.

“If we find drugs that are specific in making large blood stem cells smaller again, we can test whether this improves the health of people who suffer from problems with their blood system — like anemia and a reduced immune system — or maybe even help people with leukemia,” she says.

The researchers also demonstrated the importance of size in another type of stem cells — intestinal stem cells. They found that larger stem cells were less able to generate intestinal organoids, which mimic the structure of the intestinal lining.

“That suggested that this relationship between cell size and function is conserved in stem cells, and that cellular size is a marker of stem cell function,” Lengefeld says.

The research was funded, in part, by the Howard Hughes Medical Institute, the Jane Coffin Childs Memorial Fund, the Swiss National Science Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Koch Institute Support (core) grant from the National Cancer Institute, and the MIT Stem Cell Initiative.

Working with the Tsleil-Waututh Nation and using new palaeogenetic analytical techniques developed in SFU Archaeology’s ancient DNA lab, directed by professor Dongya Yang, the results of a new collaborative study featured in Scientific Reports provides strong evidence that prior to European colonization, Coast Salish people were managing chum salmon by selectively harvesting males.

Selectively harvesting male salmon increases the overall size of the harvest, as male salmon are bigger than female salmon. It also helps ensure successful spawning as one male can mate with several females. This allows fisheries to maximize the size of their harvest without negatively impacting future returns.

“This management practice is also described in Coast Salish knowledge and, through archaeology, we were able to extend the time depth of this practice by 2,000 years,” says Thomas Royle, a postdoctoral fellow working in the lab.

The research team applied the new palaeogenetic methods to archaeological salmon vertebrae to identify the sex of each sample, finding evidence to corroborate Coast Salish traditional knowledge that has been shared for centuries.

The Tsleil-Waututh ancestors worked to keep salmon populations plentiful for millennia, passing their knowledge on from one generation to the next. With current declines and collapses in many commercial fisheries, these traditional Tsleil-Waututh practices can potentially inform current management and conservation.

This research collaboration included the Tsleil-Waututh Nation (Michael George, Michelle George), SFU (Thomas C.A. Royle, Hua Zhang, Miguel Alcaide, Ryan Morin, Dongya Yang), University of British Columbia (Jesse Morin, Camilla Speller, Morgan Ritchie), and McMaster University (Aubrey Cannon) as part of a Tsleil-Waututh Nation project to establish the state of pre-contact ecosystems in Burrard Inlet.

The leadership of the Tsleil-Waututh Nation was an integral piece of the success of the collaboration and allowed cutting-edge science methods to be used to understand the traditional ecological knowledge of Tsleil-Waututh ancestors.

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The printable polymer enables sand structures with intricate geometries and exceptional strength — and is also water soluble.

The study, published in Nature Communications, demonstrates a 3D-printed sand bridge that at 6.5 centimeters can hold 300 times its own weight, a feat analogous to 12 Empire State Buildings sitting on the Brooklyn Bridge.

The binder jet printing process is cheaper and faster than other 3D-printing methods used by industry and makes it possible to create 3D structures from a variety of powdered materials, offering advantages in cost and scalability. The concept stems from inkjet printing, but instead of using ink, the printer head jets out a liquid polymer to bind a powdered material, such as sand, building up a 3D design layer by layer. The binding polymer is what gives the printed sand its strength.

The team used polymer expertise to tailor a polyethyleneimine, or PEI, binder that doubled the strength of sand parts compared with conventional binders.

Parts printed via binder jetting are initially porous when removed from the print bed. They can be strengthened by infiltrating the design with an additional super-glue material called cyanoacrylate that fills in the gaps. This second step provided an eight-fold strength increase on top of the first step, making a polymer sand composite stronger than any other and any known building materials, including masonry.

“Few polymers are suited to serve as a binder for this application. We were looking for specific properties, such as solubility, that would give us the best result. Our key finding was in the unique molecular structure of our PEI binder that makes it reactive with cyanoacrylate to achieve exceptional strength,” said ORNL’s Tomonori Saito, a lead researcher on the project.

Parts formed with conventional binders are made denser with infiltrate materials, such as super glue, but none have reached close to the performance of the PEI binder. The PEI binder’s impressive strength stems from the way the polymer reacts to bond with cyanoacrylate during curing.

One potential application for the super-strength sand is to advance tooling for composites manufacturing.

Silica sand is a cheap, readily available material that has been gaining interest in automotive and aerospace sectors for creating composite parts. Lightweight materials, such as carbon fiber or fiberglass, are wrapped around 3D-printed sand cores, or “tools,” and cured with heat. Silica sand is attractive for tooling because it does not change dimensions when heated and because it offers a unique advantage in washable tooling. In composite applications, using a water-soluble binder to form sand tools is significant because it enables a simple washout step with tap water to remove the sand, leaving a hollow composite form.

“To ensure accuracy in tooling parts, you need a material that does not change shape during the process, which is why silica sand has been promising. The challenge has been to overcome structural weakness in sand parts,” said Dustin Gilmer, a University of Tennessee Bredesen Center student and the study’s lead author.

Current sand casting molds and cores have limited industrial use because commercial methods, such as washout tooling, apply heat and pressure that can cause sand parts to break or fail on the first try. Stronger sand parts are needed to support manufacturing at a large scale and enable rapid part production.

“Our high-strength polymer sand composite elevates the complexity of parts that can be made with binder jetting methods, enabling more intricate geometries, and widens applications for manufacturing, tooling, and construction,” said Gilmer.

The novel binder won a 2019 R&D 100 Award and has been licensed by industry partner ExOne for research.

The journal article is published as “Additive manufacturing of strong silica sand structures enabled by polyethyleneimine binder.”