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New protein linked to early-onset dementia identified
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Most neurodegenerative diseases, including dementias, involve proteins aggregating into filaments called amyloids. In most of these diseases, researchers have identified the proteins that aggregate, allowing them to target these proteins for diagnostic tests and treatments.
Frontotemporal dementia results from the degeneration of the frontal and temporal lobes of the brain, which control emotions, personality and behaviour, as well speech and understanding of words. It tends to start at a younger age than Alzheimer’s disease, often being diagnosed in people aged 45 to 65, although it can also affect younger or older people.
In a paper published today in the journal Nature, research led by scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology, in Cambridge, UK, has identified aggregated structures of a protein that could provide a target for the future development of diagnostic tests and treatments.
Dr Benjamin Ryskeldi-Falcon, who led the study at the MRC Laboratory of Molecular Biology, said: “This discovery transforms our understanding of the molecular basis of frontotemporal dementia. It is a rare finding of a new member of the small group of proteins known to aggregate in neurodegenerative disease.
“Now that we have identified the key protein and its structure, we can start to target it for the diagnosis and therapy of this type of frontotemporal dementia, similar to strategies already in the pipeline for targeting the aggregates of amyloid-beta and tau proteins that characterise Alzheimer’s disease.”
The scientists used cutting-edge cryo-electron microscopy (cryo-EM) to study protein aggregates from the brains of four people who had this type of frontotemporal dementia at atomic resolution. The donated brains were identified by Tammaryn Lashley at the University College London Queen Square Institute of Neurology and Bernardino Ghetti at the Indiana University School of Medicine.
In this type of dementia, scientists had long thought that a protein called FUS aggregated, based on similarities with other neurodegenerative diseases.
Using cryo-EM, the researchers at the MRC Laboratory of Molecular Biology were able to identify that the protein aggregates from each brain had the same atomic structure. Surprisingly, the protein was not FUS — it was another protein called TAF15.
Dr Stephan Tetter, also from the MRC Laboratory of Molecular Biology, who is first author on the paper, said: “This is an unexpected result because, before this study, TAF15 was not known to form amyloid filaments in neurodegenerative diseases and no structures of the protein existed. Cryo-EM is transforming our understanding of the molecular pathology of dementia and neurodegenerative diseases more broadly by giving us insights that were beyond the capabilities of previous technologies.”
Dr Ryskeldi-Falcon added: “The technical challenge of performing cryo-EM meant that we were only able to look at the brains of four individuals. However, now that we know the key protein and its structure, we have the potential to develop tools to screen for these abnormal protein aggregates in hundreds of patient samples to test how widespread they are.”
Frontotemporal dementia and motor neuron disease
Some people who have frontotemporal dementia also have motor neuron disease, a condition in which individuals progressively lose control over their muscles. In this study, two of the individuals who donated their brains had signs of both diseases. For these individuals, the researchers identified the same aggregated structure of TAF15 in brain regions associated with motor neuron disease.
Dr Ryskeldi-Falcon said: “The presence of the same TAF15 aggregates in two individuals who had frontotemporal dementia and signs of motor neuron disease raises the possibility that TAF15 may contribute to both diseases. We are now studying whether aberrant aggregated TAF15 is present in people who have motor neurone disease in the absence of frontotemporal dementia.”
This study was funded by the Medical Research Council, Alzheimer’s Research UK, the US National Institutes of Health, the Alzheimer’s Society, the Association for Frontotemporal Degeneration, the Swiss National Science Foundation, and the Leverhulme Trust.
Dr Charlotte Durkin, Head of the Medical Research Council’s Molecular and Cellular Medicine Board, said:
“Decades of world-leading research at the MRC Laboratory of Molecular Biology brought the breakthrough of cryoelectron microscopy — gaining Dr Richard Henderson a Nobel Prize in 2017. This latest study identifying the protein linked to a type of frontotemporal dementia continues the MRC LMB’s success in elucidating dementia-related protein structures by cryoEM, which includes the first structure for the key dementia protein tau. Knowing the identity and basic structure of these filaments in this rare form of early-onset dementia is vital to developing early diagnostic tests and drugs to combat their formation.”
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‘Ice bucket challenge’ reveals that bacteria can anticipate the seasons
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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
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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
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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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