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Scientists work out the effects of exercise at the cellular level
The health benefits of exercise are well known but new research shows that the body’s response to exercise is more complex and far-reaching than previously thought. In a study on rats, a team of scientists from across the United States has found that physical activity causes many cellular and molecular changes in all 19 of the organs they studied in the animals.
To take a more comprehensive look at the biology of exercise, scientists with the Molecular Transducers of Physical Activity Consortium (MoTrPAC) used an array of techniques in the lab to analyze molecular changes in rats as they were put through the paces of weeks of intense exercise. Their findings appear in Nature.
The team studied a range of tissues from the animals, such as the heart, brain, and lungs. They found that each of the organs they looked at changed with exercise, helping the body to regulate the immune system, respond to stress, and control pathways connected to inflammatory liver disease, heart disease, and tissue injury.
The data provide potential clues into many different human health conditions; for example, the researchers found a possible explanation for why the liver becomes less fatty during exercise, which could help in the development of new treatments for non-alcoholic fatty liver disease.
The team hopes that their findings could one day be used to tailor exercise to an individual’s health status or to develop treatments that mimic the effects of physical activity for people who are unable to exercise. They have already started studies on people to track the molecular effects of exercise.
Launched in 2016, MoTrPAC draws together scientists from the Broad Institute of MIT and Harvard, Stanford University, the National Institutes of Health, and other institutions to shed light on the biological processes that underlie the health benefits of exercise. The Broad project was originally conceived of by Steve Carr, senior director of Broad’s Proteomics Platform; Clary Clish, senior director of Broad’s Metabolomics Platform; Robert Gerszten, a senior associate member at the Broad and chief of cardiovascular medicine at Beth Israel Deaconess Medical Center; and Christopher Newgard, a professor of nutrition at Duke University.
Co-first authors on the study include Pierre Jean-Beltran, a postdoctoral researcher in Carr’s group at Broad when the study began, as well as David Amar and Nicole Gay of Stanford. Courtney Dennis and Julian Avila, both researchers in Clish’s group, were also co-authors on the manuscript.
“It took a village of scientists with distinct scientific backgrounds to generate and integrate the massive amount of high quality data produced,” said Carr, a co-senior author of the study. “This is the first whole-organism map looking at the effects of training in multiple different organs. The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration.”
The team has made all of the animal data available in an online public repository. Other scientists can use this site to download, for example, information about the proteins changing in abundance in the lungs of female rats after eight weeks of regular exercise on a treadmill, or the RNA response to exercise in all organs of male and female rats over time.
Whole-body analysis
Conducting such a large and detailed study required a lot of planning. “The amount of coordination that all of the labs involved in this study had to do was phenomenal,” said Clish.
In partnership with Sue Bodine at the Carver College of Medicine at the University of Iowa, whose group collected tissue samples from animals after up to eight weeks of training, other members of the MoTrPAC team divided the samples up so that each lab — Carr’s team analyzing proteins, Clish’s studying metabolites, and others — would examine virtually identical samples.
“A lot of large-scale studies only focus on one or two data types,” said Natalie Clark, a computational scientist in Carr’s group. “But here we have a breadth of many different experiments on the same tissues, and that’s given us a global overview of how all of these different molecular layers contribute to exercise response.”
In all, the teams performed nearly 10,000 assays to make about 15 million measurements on blood and 18 solid tissues. They found that exercise impacted thousands of molecules, with the most extreme changes in the adrenal gland, which produces hormones that regulate many important processes such as immunity, metabolism, and blood pressure. The researchers uncovered sex differences in several organs, particularly related to the immune response over time. Most immune-signaling molecules unique to females showed changes in levels between one and two weeks of training, whereas those in males showed differences between four and eight weeks.
Some responses were consistent across sexes and organs. For example, the researchers found that heat-shock proteins, which are produced by cells in response to stress, were regulated in the same ways across different tissues. But other insights were tissue-specific. To their surprise, Carr’s team found an increase in acetylation of mitochondrial proteins involved in energy production, and in a phosphorylation signal that regulates energy storage, both in the liver that changed during exercise. These changes could help the liver become less fatty and less prone to disease with exercise, and could give researchers a target for future treatments of non-alcoholic fatty liver disease.
“Even though the liver is not directly involved in exercise, it still undergoes changes that could improve health. No one speculated that we’d see these acetylation and phosphorylation changes in the liver after exercise training,” said Jean-Beltran. “This highlights why we deploy all of these different molecular modalities — exercise is a very complex process, and this is just the tip of the iceberg.”
“Two or three generations of research associates matured on this consortium project and learned what it means to carefully design a study and process samples,” added Hasmik Keshishian, a senior group leader in Carr’s group and co-author of the study. “Now we are seeing the results of our work: biologically insightful findings that are yielding from the high quality data we and others have generated.That’s really fulfilling.”
Other MoTrPAC papers published today include deeper dives into the response of fat and mitochondria in different tissues to exercise. Additional MoTrPAC studies are underway to study the effects of exercise on young adult and older rats, and the short-term effects of 30-minute bouts of physical activity. The consortium has also begun human studies, and are recruiting about 1,500 individuals of diverse ages, sexes, ancestries, and activity levels for a clinical trial to study the effects of both endurance and resistance exercise in children and adults.
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‘Ice bucket challenge’ reveals that bacteria can anticipate the seasons
Bacteria use their internal 24-hour clocks to anticipate the arrival of new seasons, according to research carried out with the assistance of an ‘ice bucket challenge.’
The team behind the findings gave populations of blue-green algae (cyanobacteria) different artificial day lengths at a constant warm temperature. Samples on plates received either short days, equinox days (equal light and dark), or long days, for eight days.
After this treatment, the blue-green algae were plunged into ice for two hours and survival rates monitored.
Samples that had been exposed to a succession of short days (eight hours light and 16 hours dark) in preparation for the icy challenge achieved survival rates of 75%, up to three times higher than colonies that had not been primed in this way.
One short day was not enough to increase the bacteria’s resistance to cold. Only after several short days, and optimally six to eight days, did the bacteria’s life chances significantly improve.
In cyanobacteria which had genes that make up their biological clock removed, survival rates were the same regardless of day lengths. This indicates that photoperiodism (the ability to measure the day-night cycle and change one’s physiology in anticipation of the upcoming season) is critical in preparing bacteria for longer-term environmental changes such as a new season or shifts in climate.
“The findings indicate that bacteria in nature use their internal clocks to measure day length and when the number of short days reaches a certain point, as they do in autumn/fall, they ‘switch’ to a different physiology in anticipation of the wintry challenges that lie ahead,” explained first author of the study, Dr Luísa Jabbur, who was a researcher at Vanderbilt University, Tennessee, in the laboratory of Prof. Carl Johnson when this study took place, and is now a BBSRC Discovery Fellow at the John Innes Centre.
The Johnson lab has a long history of studying the circadian clock of cyanobacteria, both from a mechanistic and an ecological perspective.
Previous studies have shown that bacteria have a version of a biological clock, which could allow them to measure differences in day-night length, offering an evolutionary advantage.
This study, which appears in Science, is the first time that anyone has shown that photoperiodism in bacteria has evolved to anticipate seasonal cues.
Based on these findings a whole new horizon of scientific exploration awaits. A key question is: how does an organism with a lifespan of between six and 24 hours evolve a mechanism that enables it not merely to react to, but to anticipate, future conditions?
“It’s like they are signalling to their daughter cells and their granddaughter cells, passing information that the days are getting short, you need to do something,” said Dr Jabbur.
Dr Jabbur and colleagues at the John Innes Centre will, as part of her BBSRC Discovery Fellowship, use cyanobacteria as a fast-reproducing model species to understand how photoperiodic responses might evolve in other species during climate change, with hopeful applications to major crops.
A key part of this work will be to understand more about the molecular memory systems by which information is passed from generation to generation in species. Research will investigate the possibility that an accumulation of compounds during the night on short days acts as a molecular switch that triggers change to a different physiology or phenotype.
For Dr Jabbur the findings amount to an early-career scientific breakthrough in the face of initial scepticism from her scientific mentor and the corresponding author of the paper, Professor Carl Johnson.
“As well as being a fascinating person and an inspiration, Carl sings in the Nashville Symphony Chorus, and he has an operatic laugh! It echoed round the department when I first outlined my idea for the icy challenge, to see if photoperiod was a cue for cyanobacteria in their natural element,” said Dr Jabbur.
“To be fair he told me to go away and try it, and as I went, he showed me a sign on his door with the Frank Westheimer quote: ‘Progress is made by young scientists who carry out experiments that old scientists say would not work.’
“It did work, first time. Then I repeated the experiments. There is something very precious about looking at a set of plates with bacteria on them and realizing that in that moment you know something that nobody else knows.”
Bacteria can anticipate the seasons: Photoperiodism in cyanobacteria appears in Science.
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New filtration material could remove long-lasting chemicals from water
Water contamination by the chemicals used in today’s technology is a rapidly growing problem globally. A recent studyby the U.S. Centers for Disease Control found that 98 percent of people tested had detectable levels of PFAS, a family of particularly long-lasting compounds, also known as forever chemicals, in their bloodstream.
The findings are described in the journal ACS Nano, in a paper by MIT postdoc Yilin Zhang, professor of civil and environmental engineering Benedetto Marelli, and four others from MIT.
PFAS chemicals are present in a wide range of products, including cosmetics, food packaging, water-resistant clothing, firefighting foams, and antistick coating for cookware. A recent study identified 57,000 sites contaminated by these chemicals in the U.S. alone. The U.S. Environmental Protection Agency has estimated that PFAS remediation will cost $1.5 billion per year, in order to meet new regulations that call for limiting the compound to less than 7 parts per trillion in drinking water.
Contamination by PFAS and similar compounds “is actually a very big deal, and current solutions may only partially resolve this problem very efficiently or economically,” Zhang says. “That’s why we came up with this protein and cellulose-based, fully natural solution,” he says.
“We came to the project by chance,” Marelli notes. The initial technology that made the filtration material possible was developed by his group for a completely unrelated purpose — as a way to make a labelling system to counter the spread of counterfeit seeds, which are often of inferior quality. His team devised a way of processing silk proteins into uniform nanoscale crystals, or “nanofibrils,” through an environmentally benign, water-based drop-casting method at room temperature.
Zhang suggested that their new nanofibrillar material might be effective at filtering contaminants, but initial attempts with the silk nanofibrils alone didn’t work. The team decided to try adding another material: cellulose, which is abundantly available and can be obtained from agricultural wood pulp waste. The researchers used a self-assembly method in which the silk fibroin protein is suspended in water and then templated into nanofibrils by inserting “seeds” of cellulose nanocrystals. This causes the previously disordered silk molecules to line up together along the seeds, forming the basis of a hybrid material with distinct new properties.
By integrating cellulose into the silk-based fibrils that could be formed into a thin membrane, and then tuning the electrical charge of the cellulose, the researchers produced a material that was highly effective at removing contaminants in lab tests.
The electrical charge of the cellulose, they found, also gave it strong antimicrobial properties. This is a significant advantage, since one of the primary causes of failure in filtration membranes is fouling by bacteria and fungi. The antimicrobial properties of this material should greatly reduce that fouling issue, the researchers say.
“These materials can really compete with the current standard materials in water filtration when it comes to extracting metal ions and these emerging contaminants, and they can also outperform some of them currently,” Marelli says. In lab tests, the materials were able to extract orders of magnitude more of the contaminants from water than the currently used standard materials, activated carbon or granular activated carbon.
While the new work serves as a proof of principle, Marelli says, the team plans to continue working on improving the material, especially in terms of durability and availability of source materials. While the silk proteins used can be available as a byproduct of the silk textile industry, if this material were to be scaled up to address the global needs for water filtration, the supply might be insufficient. Also, alternative protein materials may turn out to perform the same function at lower cost.
Initially, the material would likely be used as a point-of-use filter, something that could be attached to a kitchen faucet, Zhang says. Eventually, it could be scaled up to provide filtration for municipal water supplies, but only after testing demonstrates that this would not pose any risk of introducing any contamination into the water supply. But one big advantage of the material, he says, is that both the silk and the cellulose constituents are considered food-grade substances, so any contamination is unlikely.
“Most of the normal materials available today are focusing on one class of contaminants or solving single problems,” Zhang says. “I think we are among the first to address all of these simultaneously.”
The research team included MIT postdocs Hui Sun and Meng Li, graduate student Maxwell Kalinowski, and recent graduate Yunteng Cao PhD ’22, now a postdoc at Yale. The work was supported by the Office of Naval Research, the National Science Foundation, and the Singapore-MIT Alliance for Research and Technology.
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‘Some pterosaurs would flap, others would soar’ — new study further confirms the flight capability of these giants of the skies
Some species of pterosaurs flew by flapping their wings while others soared like vultures, demonstrates a new study published in the peer-reviewed Journal of Vertebrate Paleontology.
However, “remarkable” and “rare” three-dimensional fossils of two different large-bodied azhdarchoid pterosaur species — including one new-to-science — have enabled scientists to hypothesize that not only could the largest pterosaurs take to the air, but their flight styles could differ too.
The new findings are led by experts from the University of Michigan, in the US, the Natural Resources Authority and Yarmouk University, in Jordan, and the Saudi Geological Survey, in Saudi Arabia.
Their paper details how these fossils — which date back to the latest Cretaceous period (approximately 72 to 66 million years ago) — were remarkably three-dimensionally preserved within the two different sites that preserve a nearshore environment on the margin of Afro-Arabia, an ancient landmass that included both Africa and the Arabian Peninsula. The research team used high-resolution computed tomography (CT) scans to then analyze the internal structure of the wing bones.
“The dig team was extremely surprised to find three-dimensionally preserved pterosaur bones, this is a very rare occurrence,” explains lead author Dr Kierstin Rosenbach, from the Department of Earth and Environmental Sciences of the University of Michigan.
“Since pterosaur bones are hollow, they are very fragile and are more likely to be found flattened like a pancake, if they are preserved at all.
“With 3D preservation being so rare, we do not have a lot of information about what pterosaur bones look like on the inside, so I wanted to CT scan them.
“It was entirely possible that nothing was preserved inside, or that CT scanners were not sensitive enough to differentiate fossil bone tissue from the surrounding matrix.”
Luckily, though, what the team uncovered was “remarkable,” via “exciting internal structures not only preserved, but visible in the CT scanner.”
CT scans reveal one soars; one flaps!
Newly collected specimens of the already-known giant pterosaur, Arambourgiania philadelphiae, confirm its 10-meter wingspan and provide the first details of its bone structure. CT images revealed that the interior of its humerus, which is hollow, contains a series of ridges that spiral up and down the bone.
This resembles structures in the interior of wing bones of vultures. The spiral ridges are hypothesized to resist the torsional loadings associated with soaring (sustained powered flight that requires launch and maintenance flapping).
The other specimen analyzed was the new-to-science Inabtanin alarabia, which had a five-meter wingspan. The team named it after the place where it was excavated — near a large grape-colored hill, called Tal Inab. The generic name combines the Arabic words “inab,” for grape, and “tanin” for dragon. ‘Alarabia’ refers to the Arabian Peninsula.
Inabtanin is one of the most complete pterosaurs ever recovered from Afro-Arabia, and the CT scans revealed the structure of its flight bones was completely different from that of Arambourgiania.
The interior of the flight bones were crisscrossed by arrangement with struts that match those found in the wing bones of modern flapping birds.
This indicates it was adapted to resist bending loads associated with flapping flight, and so it is likely that Inabtanin flew this way — although this does not preclude occasional use of other flight styles too.
“The struts found in Inabtanin were cool to see, though not unusual,” says Dr Rosenbach.
“The ridges in Arambourgiania were completely unexpected, we weren’t sure what we were seeing at first!
“Being able to see the full 3D model of Arambourgiania’s humerus lined with helical ridges was just so exciting.”
What explains this difference?
The discovery of diverse flight styles in differently-sized pterosaurs is “exciting,” the experts state, because it opens a window into how these animals lived. It also poses interesting questions, like to what extent flight style is correlated with body size and which flight style is more common among pterosaurs.
“There is such limited information on the internal bone structure of pterosaurs across time, it is difficult to say with certainty which flight style came first,” Dr Rosenbach adds.
“If we look to other flying vertebrate groups, birds and bats, we can see that flapping is by far the most common flight behavior.
“Even birds that soar or glide require some flapping to get in the air and maintain flight.
“This leads me to believe that flapping flight is the default condition, and that the behavior of soaring would perhaps evolve later if it were advantageous for the pterosaur population in a specific environment; in this case the open ocean.”
Co-author Professor Jeff Wilson Mantilla, Curator at Michigan’s Museum of Paleontology, and Dr Iyad Zalmout, from the Saudi Geological Survey, found these specimens in 2007 at sites in the north and south of Jordan.
Professor Jeff Wilson Mantilla says the “variations likely reflect responses to mechanical forces applied on the pterosaurs’ wings during flight.”
Enabling further study of vertebrate flight
Concluding, Dr Rosenbach states: “Pterosaurs were the earliest and largest vertebrates to evolve powered flight, but they are the only major volant group that has gone extinct.
“Attempts to-date to understand their flight mechanics have relied on aerodynamic principles and analogy with extant birds and bats.
“This study provides a framework for further investigation of the correlation between internal bone structure and flight capacity and behavior, and will hopefully lead to broader sampling of flight bone structure in pterosaur specimens.”
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