Brain

A rare disease first identified in 2020 is much more common than first thought, say researchers at the University of Leeds investigating its origins.

VEXAS syndrome is a serious inflammatory condition which develops in men over 50, causing them to become very sick and fatigued, and can be fatal. It was originally thought to be rare, but a new study has identified genetic mutations which indicate that the disease is actually much more common.

The researchers developed a genetic test to identify patients who may have the disease, and now want to screen more people showing symptoms to understand exactly how common it is.

VEXAS syndrome causes unexplained fevers, painful skin rashes and affects the bone marrow resulting in a reduced number of red and white blood cells. The disease affects only men because it is caused by genetic mutations on the X chromosome, and men carry only one X chromosome. The mutations are not present at birth, instead they develop during the patient's lifetime.

The disease was identified in 2020 by a team of researchers which included Dr Sinisa Savic, Clinical Associate Professor at the University of Leeds' School of Medicine and Honorary Consultant immunologist at Leeds Teaching Hospitals NHS Trust. Now, further research led at Leeds by Dr Savic and Dr James Poulter, Academic Fellow in Molecular Neuroscience in the School of Medicine, has identified additional genetic mutations which show new ways in which the disease can develop.

The team, which included 13 academics and clinicians from Leeds, Hull, York and the US, examined DNA samples to establish the prevalence of the genetic mutations identified when the disease was first discovered.

Dr Poulter said: "In our new study, we screened a cohort of 18 local patients who matched the symptoms and found mutations in 10 of them. Eight had the known variant previously associated with the disease, but two patients had completely different variants. This identified a new way in which the mutations can cause VEXAS, meaning it is likely to be much more common than we currently think.

"We want to screen more people with these symptoms to really understand how common VEXAS is and to better understand the disorder.

"Most patients have had lots of tests, tried lots of treatments and have not been able to get an answer to what they have. Now, by sequencing their DNA for mutations in the VEXAS gene, we can identify those patients who do have VEXAS and get them on the best treatment that is available. This could be a bone marrow transplant or switching to a different drug."

Dr Savic runs a specialist Allergy and Clinical Immunology service at the Leeds Teaching Hospitals NHS Trust. It is one of four centres in the UK to be part of the European Reference Network for rare immunodeficiencies, autoinflammatory and autoimmune disorders.

He said: "I have been looking after a number of patients with what we now know is VEXAS syndrome for several years. Their care has been complicated by the fact that we did not have a diagnosis which made choosing their treatment and advising them about the prognosis very difficult.

"Having established the cause of VEXAS we now have a real opportunity to transform the care of these patients. We know there are still many patients who have a VEXAS-like condition, but in whom we do not know the cause. We plan to continue our research in the hope of discovering other genetic causes of these disorders."

What do you do after solving the answer to life, the universe, and everything? If you're mathematicians Drew Sutherland and Andy Booker, you go for the harder problem.

In 2019, Booker, at the University of Bristol, and Sutherland, principal research scientist at MIT, were the first to find the answer to 42. The number has pop culture significance as the fictional answer to "the ultimate question of life, the universe, and everything," as Douglas Adams famously penned in his novel "The Hitchhiker's Guide to the Galaxy." The question that begets 42, at least in the novel, is frustratingly, hilariously unknown.

In mathematics, entirely by coincidence, there exists a polynomial equation for which the answer, 42, had similarly eluded mathematicians for decades. The equation x3+y3+z3=k is known as the sum of cubes problem. While seemingly straightforward, the equation becomes exponentially difficult to solve when framed as a "Diophantine equation" -- a problem that stipulates that, for any value of k, the values for x, y, and z must each be whole numbers.

When the sum of cubes equation is framed in this way, for certain values of k, the integer solutions for x, y, and z can grow to enormous numbers. The number space that mathematicians must search across for these numbers is larger still, requiring intricate and massive computations.

Over the years, mathematicians had managed through various means to solve the equation, either finding a solution or determining that a solution must not exist, for every value of k between 1 and 100 -- except for 42.

In September 2019, Booker and Sutherland, harnessing the combined power of half a million home computers around the world, for the first time found a solution to 42. The widely reported breakthrough spurred the team to tackle an even harder, and in some ways more universal problem: finding the next solution for 3.

Booker and Sutherland have now published the solutions for 42 and 3, along with several other numbers greater than 100, this week in the Proceedings of the National Academy of Sciences.

Picking up the gauntlet

The first two solutions for the equation x3+y3+z3 = 3 might be obvious to any high school algebra student, where x, y, and z can be either 1, 1, and 1, or 4, 4, and -5. Finding a third solution, however, has stumped expert number theorists for decades, and in 1953 the puzzle prompted pioneering mathematician Louis Mordell to ask the question: Is it even possible to know whether other solutions for 3 exist?

"This was sort of like Mordell throwing down the gauntlet," says Sutherland. "The interest in solving this question is not so much for the particular solution, but to better understand how hard these equations are to solve. It's a benchmark against which we can measure ourselves."

As decades went by with no new solutions for 3, many began to believe there were none to be found. But soon after finding the answer to 42, Booker and Sutherland's method, in a surprisingly short time, turned up the next solution for 3:

5699368212219623807203 + (?569936821113563493509)3 + (?472715493453327032)3 = 3

The discovery was a direct answer to Mordell's question: Yes, it is possible to find the next solution to 3, and what's more, here is that solution. And perhaps more universally, the solution, involving gigantic, 21-digit numbers that were not possible to sift out until now, suggests that there are more solutions out there, for 3, and other values of k.

"There had been some serious doubt in the mathematical and computational communities, because [Mordell's question] is very hard to test," Sutherland says. "The numbers get so big so fast. You're never going to find more than the first few solutions. But what I can say is, having found this one solution, I'm convinced there are infinitely many more out there."

A solution's twist

To find the solutions for both 42 and 3, the team started with an existing algorithm, or a twisting of the sum of cubes equation into a form they believed would be more manageable to solve:

k ? z3 = x3 + y3 = (x + y)(x2 ? xy + y2)

This approach was first proposed by mathematician Roger Heath-Brown, who conjectured that there should be infinitely many solutions for every suitable k. The team further modified the algorithm by representing x+y as a single parameter, d. They then reduced the equation by dividing both sides by d and keeping only the remainder -- an operation in mathematics termed "modulo d" -- leaving a simplified representation of the problem.

"You can now think of k as a cube root of z, modulo d," Sutherland explains. "So imagine working in a system of arithmetic where you only care about the remainder modulo d, and we're trying to compute a cube root of k."

With this sleeker version of the equation, the researchers would only need to look for values of d and z that would guarantee finding the ultimate solutions to x, y, and z, for k=3. But still, the space of numbers that they would have to search through would be infinitely large.

So, the researchers optimized the algorithm by using mathematical "sieving" techniques to dramatically cut down the space of possible solutions for d.

"This involves some fairly advanced number theory, using the structure of what we know about number fields to avoid looking in places we don't need to look," Sutherland says.

A global task

The team also developed ways to efficiently split the algorithm's search into hundreds of thousands of parallel processing streams. If the algorithm were run on just one computer, it would have taken hundreds of years to find a solution to k=3. By dividing the job into millions of smaller tasks, each independently run on a separate computer, the team could further speed up their search.

In September 2019, the researchers put their plan in play through Charity Engine, a project that can be downloaded as a free app by any personal computer, and which is designed to harness any spare home computing power to collectively solve hard mathematical problems. At the time, Charity Engine's grid comprised over 400,000 computers around the world, and Booker and Sutherland were able to run their algorithm on the network as a test of Charity Engine's new software platform.

"For each computer in the network, they are told, 'your job is to look for d's whose prime factor falls within this range, subject to some other conditions,'" Sutherland says. "And we had to figure out how to divide the job up into roughly 4 million tasks that would each take about three hours for a computer to complete."

Very quickly, the global grid returned the very first solution to k=42, and just two weeks later, the researchers confirmed they had found the third solution for k=3 -- a milestone that they marked, in part, by printing the equation on t-shirts.

The fact that a third solution to k=3 exists suggests that Heath-Brown's original conjecture was right and that there are infinitely more solutions beyond this newest one. Heath-Brown also predicts the space between solutions will grow exponentially, along with their searches. For instance, rather than the third solution's 21-digit values, the fourth solution for x, y, and z will likely involve numbers with a mind-boggling 28 digits.

"The amount of work you have to do for each new solution grows by a factor of more than 10 million, so the next solution for 3 will need 10 million times 400,000 computers to find, and there's no guarantee that's even enough," Sutherland says. "I don't know if we'll ever know the fourth solution. But I do believe it's out there."

Philadelphia, March 12, 2021 - Researchers from Children's Hospital of Philadelphia (CHOP) have determined what happens at a cellular level as the lung alveolus forms and allows newborns to breathe air. Understanding this process gives researchers a better sense of how to develop therapies and potentially regenerate this critical tissue in the event of injury. The findings were published online today by the journal Science.

The lung develops during both embryonic and postnatal stages, during which lung tissue forms and a variety of cell types perform specific roles. During the transition from embryo to newborn is when the alveolar region of the lung refines its primary function of exchanging gas, which includes the critical process of ridding the body of carbon dioxide.

Despite these critical steps involved in the formation of the lung, little is known about what happens at a cellular and genomic level. Not only is the lung alveolar critical, it can also suffer damage caused by pathogens such as influenza and the SARS-CoV2 virus that causes COVID-19. Knowing which cells are involved in the formation of healthy lung tissue at birth may provide a basis for therapies that help regenerate this critical portion of the lung.

"Extensive morphological changes properly shape the alveolar niche, but prior to this study, the research community was unsure as to the extent of cellular signaling involved to promote its proper architecture," said first author Jarod A. Zepp, PhD, a research faculty member of the Division of Pulmonary and Sleep Medicine at CHOP and an Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania. "Recent advances in technology allowed us to assess the intracellular communication that drives the generation of this critical portion of the lung."

The study team used a multimodal approach to investigate intercellular relationships that drive the formation of the alveolus. They discovered that alveolar type 1 (AT1) epithelial cells, which form the outer layer of the alveolus tissue, represent a signaling hub that coordinates cell development, especially during the transition to air breathing. They also traced the lineage of AT1 cells and show that they align with myofibroblasts, which are a special cell type involved in tissue remodeling. Finally, the researchers also demonstrated that AT1-restricted ligands, or secreted binding molecules, are required to form these myofibroblasts and the alveolus.

"Our study reveals the complexity of the cell-types and their extensive communication with one another as they form this critical part of the lung," Zepp said. "The recent COVID-19 pandemic has provided the research community with an increased appreciation of the intercellular communication that helps form the alveolar structure and maintain its function and provides us with vital clues on how we might be able to repair damaged tissue at a cellular level."

New research by the National Institutes of Health found that unbalanced progesterone signals may cause some pregnant women to experience preterm labor or prolonged labor. The study in mice -- published online in the Proceedings of the National Academy of Sciences -- provides novel insights for developing treatments.

During pregnancy, the hormone progesterone helps to prevent the uterus from contracting and going into labor prematurely. This occurs through molecular signaling involving progesterone receptor types A and B, referred to as PGR-A and PGR-B. In this first-of-its-kind study, the scientists showed how unbalanced PGR-A and PGR-B signaling can affect pregnancy duration.

"We used genetically engineered mouse models to alter the ratio of PGR-A and PGR-B in the muscle compartment of the uterus, called the myometrium," said senior author Francesco DeMayo, Ph.D., head of the National Institute of Environmental Health Sciences Reproductive and Developmental Biology Laboratory. "Our team found that PGR-A promotes muscle contraction and PGR-B prevents such contraction, and we identified the biological pathways influenced by both forms."

Previous research showed that PGR-A regulates processes involved in initiating childbirth and that PGR-B affects molecular pathways related to maintaining the normal course of pregnancy. This study builds on those findings, revealing that the relative abundance of PGR-A and PGR-B may be critical in promoting healthy pregnancy. The public health implications are significant.

Preterm birth affects 10% of all pregnancies and is the primary cause of neonatal morbidity and mortality worldwide, while prolonged labor increases the risks of infection, uterine rupture, and neonatal distress, according to the researchers.

The scientists pointed out that care for preterm deliveries can result in high social and economic costs, with infants born preterm at greater risk for experiencing disorders ranging from blindness to cerebral palsy. Prolonged labor can harm both mother and infant and lead to cesarean delivery.

Progesterone treatment aimed at preventing premature labor can help a subset of patients, but for other individuals, confounding factors may reduce effectiveness, noted Steve Wu, Ph.D., first author on the study and a staff scientist in DeMayo's lab. Wu said that the research team found novel molecules that control uterine muscle contraction, and they could serve as future therapeutic targets. He added that the current study also may help to advance treatment for labor dystocia -- the clinical name for abnormally slow or protracted labor.

"Although labor stimulation by oxytocin infusion is an approved measure to mitigate labor dystocia, serious side effects have been associated with this treatment," said Wu. "Novel proteins that we identified as being part of progesterone signaling could serve as a key molecular switch of uterine contraction, through drug-dependent regulation of their activities," he explained.

"Hormone signaling in pregnancy is complicated and involves both the hormone levels and the types of receptors in the uterus that sense the hormones," said co-first author Mary Peavey, M.D., from the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. "This publication sheds light on how hormones influence labor and can thus be used to help women when the uterus goes into labor too soon or for a prolonged period."

The unprecedented discovery of an ancient lamprey growth series, published in the prestigious scientific journal, Nature, is overturning long-held ideas as to what modern lampreys may tell us about the origin of vertebrates (all animals with a backbone such as goldfish, lizards, crows and people).

"Lampreys and modern hagfish are the only jawless fish alive that branched off from the family tree of vertebrates before they got jaws," says Dr Rob Gess from the Albany Museum in Makhanda, who discovered the ancient fossils. "This makes them very interesting for researchers attempting to understand the earliest stages of vertebrate history."

Until now, it was commonly believed that modern lampreys were swimming time capsules that could give unique insights into the biology and genome (DNA) of a truly ancient lineage.

This belief was supported by the discovery, published in Nature in 2006, of an exquisitely preserved lamprey fossil (Priscomyzon) at the 360-million-year-old Waterloo Farm black shales near Makhanda/Grahamstown, South Africa. The discovery was met with excitement worldwide as it was the oldest lamprey ever found, yet it appeared to have been essentially almost identical to modern adult lampreys. Modern lampreys are bizarre fish, eel-like in shape, that feed by latching onto other fish with a sucker around their mouth, securing their grip with circles of teeth and then drinking their victim's blood after rasping a hole with special teeth on their tongue. Therefore, adult lampreys are clearly successful, having arisen before the first four-legged-animals moved onto land and survived, with little change, ever since.

In many ways, modern lampreys indeed provide unique insights into their ancient ancestry. But new evidence shows that this is not the case when it comes to the juvenile larval stage.

Since the 19th century, biologists have treated the larvae/juveniles of modern lampreys as a relic of deep evolutionary ancestry. These blind, filter-feeding, worm-like larvae (ammocoetes) burrow in stream beds and filter water for minute food particles before slowly transforming into free-swimming, eyed, actively feeding adults. Crucially, this strange life history was thought to echo transformations some 500 million years ago, which gave rise to all fish lineages, including the one that ultimately led to humans. Hence, the last invertebrate ancestor of vertebrates is often portrayed as ammocoete-like, and the earliest vertebrate as being lamprey-like. But for this to be a reasonable model, both ammocoetes and lampreys would need to hark back to the dawn of our (vertebrate) history.

However, the new fossil discoveries contradict the conventional wisdom that our long chain of ancestors ever included a lamprey-larva-like fish. Painstaking excavation of shale samples from Waterloo Farm has revealed a growth series of Priscomyzon illustrating its development from hatchling to adult. Remarkably, the smallest preserved individuals, barely 15mm in length, still carried a yolk sac, signalling that these had only just hatched before entering the fossil record.

Of crucial importance: even the hatchlings were already sighted with large eyes and armed with a toothed sucker, much like the blood-sucking adult phase of modern lampreys, and completely unlike their modern larval counterparts. This drastically different structure of ancient lamprey infants provides evidence that modern lamprey larvae are not evolutionary relics. Instead, the modern filter-feeding phase is a more recent innovation that allowed lampreys to populate and thrive in rivers and lakes. A less complete (previously unpublished) partial growth series of three types of slightly younger lampreys from North America support the finding. Therefore, distant human ancestry seemingly did not include a lamprey-larva-like stage. Modern lampreys now appear to be a highly evolved side branch, which shared a common ancestor with us - probably a jawless fish enclosed in bony armour.

Truly a new entry for the textbooks.

ften, humans display biases, i.e., unconscious tendencies towards a type of decision. Despite decades of study, we are yet to discover why biases are so persistent in all types of decisions. "Biases can help us make better decisions when we use them correctly in an action that has previously given us great reward. However, in other cases, biases can play against us, such as when we repeat actions in situations when it would be better not to", says Rubén Moreno Bote, coordinator of the UPF Theoretical and Cognitive Neuroscience Laboratory.

In these cases, decisions are guided by tendencies, or inclinations, that do not benefit our wellbeing. For example, playing the lottery more regularly after winning a small consolation prize is a common bias that unfortunately does not tend to improve our financial situation.

The aim of the research was to establish how biases arise in decision-making using mathematical models and neural recordings

A study led by professor Rubén Moreno Bote's laboratory, with Grabriela Mochol, researchers at the Center for Brain and Cognition (CBC) at the UPF Department of Information and Communication Technologies (DTIC), in collaboration with the experimental laboratory of professor Roozbeh Kiani of New York University (USA), has studied how biases arise in decision-making using mathematical models and neural recordings in primates. The study was published by the authors on 26 February in the journal Current Biology.

A task dealing with the perception of visual stimuli

The experimental block of the study consisted of a visual perception task in which a monkey observed a certain stimulus, specifically moving dots. The primate had to decide whether there were more dots moving to the right or to the left. Trial after trial, the animal performed this monotonous decision-making process.

The authors found that primate developed two types of bias: a "slow" tendency to indicate right (or left) that lasted several minutes, despite not having any net tendency in the set of stimuli used, and a "fast" tendency that lasted scarcely a few seconds, resulting from the actions had just been made in the previous decision.

The neural representation of biases is similar to the neural representation of relevant information for solving a certain task

"For this research, we study how the prefrontal cortex, which is crucial in decision-making, encodes the two identified biases (slow and fast). The main result of the study shows that the neural representation of biases is similar to the neural representation of relevant information for solving a certain task. This would seem to indicate that the format in which biases and information are coded in the brain are very similar, so similar that it is difficult to distinguish them", points out Moreno Bote, study principal investigator.

And he adds: "We still have much to understand, but the results of this research could explain why biases are so prevalent in decision-making, and why, much to our regret, they are so difficult to eradicate".

"Phase transitions" are a central phenomenon in physical sciences. Despite being technical-sounding, they are actually something we all experience in everyday life: ice melting into liquid water, or hot water evaporating as steam. Solid, liquid, and gas are three well known "phases" and, when one turns into another, that is a phase transition.

Rare-earth nickelate oxides, also called nickelates, have attracted a lot of interest from researchers because they display an electronic phase transition, which may be exploited in future electronic devices. This particular phase transition consists of turning from a metallic state that conducts electricity into an electrically-insulating state as temperature drops.

Behind this behaviour is a strong interaction between the electronic properties of these compounds and their "lattice" structure - the well-ordered arrangement of atoms that forms a crystal. However, uncovering the true nature of this metal to insulator phase transition in nickelates, and being able to control it for potential electronic devices, requires knowing how each characteristic phase emerges and evolves across the transition.

Now, scientists from EPFL and the University of Geneva have combined two cutting-edge techniques to achieve nanoscale mapping of each distinct electronic phase. Published in the journal Nano Letters, the study was led by Dr Duncan Alexander at EPFL's School of Basic Sciences and the group of Professor Jean-Marc Triscone at the University of Geneva.

The study's first author, Dr Bernat Mundet, says: "To fully understand the physics displayed by novel electronic materials and to control them in devices, new atomic-scale characterization techniques are required. In this regard, we have been able for the first time to precisely determine the metallic and insulating regions of atomically engineered devices made from two nickelate compounds with near atomic resolution. We believe that our methodology will help to better understand the physics of this important family of electronic materials."

The researchers combined aberration-corrected scanning transmission electron microscopy (STEM) with monochromated electron energy-loss spectroscopy (EELS).

In STEM, images are formed by scanning a beam of electrons, focused to a spot of about 1 Ångstroms in size, across a sufficiently thin specimen - in this case a sliver of nickelate - and collecting the transmitted and scattered electrons with the use of annular detectors. Though technically demanding, this technique allows researchers to precisely visualise a crystal's lattice structure, atomic row by atomic row.

For the second technique, EELS, those electrons passing through the central hole of the annular detector are instead collected. Some of these electrons have previously lost some energy due to their interaction with the Ni atoms of the nickelate crystal. By measuring how this energy difference changes, we can determine the metallic or insulating state of the nickelate compound.

Since all electrons are scattered and collected simultaneously, the researchers were able to correlate the electronic state changes with the associated lattice positions in the different nickelate compounds. This approach allowed them to map, for the first time, the spatial configuration of their metallic or insulating regions, reaching a very high spatial resolution of around 3.5 Ångstroms (0.35 nanometers). The technique will be a valuable tool for studying and guiding the atomic engineering of these novel electronic materials.

"The latest electron microscopes give us an amazing ability to measure a variety of materials physical properties with atomic or nanometric spatial resolution," says Duncan Alexander. "Here, by pushing the capabilities of EPFL's Titan Themis microscope to the limits, we take an exciting step forward in this domain, by proving that we can measure the changes in electronic state across a thin film structure precisely made from two different nickelates. Our approach opens up new avenues for investigating the physics of these nickelate compounds, which have sparked research interest worldwide."

"The combination of amazing artificial materials that display a metal to insulator transition and very advanced electron microscopy has allowed unprecedented detailed investigations of their electronic properties," adds Jean-Marc Triscone. "In particular, it revealed, at the atomic scale, whether the material is conducting or insulating - an important question for better understanding these materials that may be used in future computing approaches."

The protein α-synuclein is one of the most abundant proteins in the human brain. It is often referred to as the "Parkinson protein", as deposition of this protein in brain cells is a hallmark of Parkinson's disease. Despite the high interest of biomedical research in the protein, many questions concerning the function and physiology of α-synuclein in living cells still remain to be answered. For example, it was previously unclear whether and to what extent the protein binds to and interacts with internal cell components such as membranes. As such processes could play a role in the development of the disease, the team led by Konstanz-based physical chemist Professor Malte Drescher used the further development of an established measurement method called "electron paramagnetic resonance spectroscopy" (EPR spectroscopy) to learn more about the binding properties of the "Parkinson protein". The study, published in the scientific periodical "The Journal of Physical Chemistry Letters", furnishes proof of concept that the advanced method is fundamentally suitable for elucidating protein-lipid interactions in cells. Furthermore, this first practical test yielded direct evidence of the binding of α-synuclein to intracellular membranes.

Slower is not always more thorough

The advanced version of EPR spectroscopy, in the current study used for the first time in practice, is called rapid-scan EPR spectroscopy. In both methods, the conventional and the advanced, the proteins to be studied are first fitted with so-called spin probes. These chemical probes make it possible to detect changes in protein structure. Spin probes each have a free electron whose spin is excited by irradiation with microwaves. "We can imagine spins as small compass needles that are influenced by microwave irradiation during the measurement," Drescher explains. In conventional EPR spectroscopy, for each group of excited spins it is necessary to wait until this influence decays before the group can be excited again. This relatively time-consuming process must be repeated over many passes to achieve the complete measurement.

With rapid-scan EPR spectroscopy, by contrast, it is no longer necessary to wait until the influence on a spin group abates before continuing the measurement. "Instead, you rush the influence spectrally from spin group to spin group and then return to the first group at the very moment when its excitation has just subsided," says Drescher. On the one hand, this procedure shortens the required measurement time, while on the other it allows application of higher microwave power, leading to improved accuracy of the method. The researchers have made use of both of these advantages in their current study on the binding behaviour of α-synuclein.

The new method in practice

From previous studies conducted in vitro ("in the test tube") it was already known that the "Parkinson protein" α-synuclein can attach itself to electrically negatively charged lipid membranes. In EPR spectroscopy, this binding process is accompanied by a characteristic change in the measured signal. "The initially disordered α-synuclein assumes an ordered form upon binding to the membrane. This reduces the mobility of the spin probe, and the binding of the protein can be directly detected by the measurement method," explains Theresa Braun, doctoral student in Drescher's research team and, jointly with Juliane Stehle, lead author of the study.

Using synthetic, negatively charged membrane vesicles and purified α-synuclein, Drescher and his colleagues were able to detect the same signal change in rapid-scan EPR spectroscopy. However, they succeeded not only in vitro, but also inside cells of the African clawed frog (Xenopus laevis), into which first the artificial membrane vesicles were introduced and, a short time later, the protein was. The research team then carried out time-dependent measurements and was able to directly observe, based on the change in the measurement signal, how the proportion of the protein bound in the cell increased over time.

A comparable - albeit significantly weaker - increase in the amount of bound α-synuclein over time was also seen when no artificial membranes were introduced into the cell. Thus, according to Drescher, only one explanation remained for this crucial observation. "This is the first time that we see direct evidence that α-synuclein interacts with the endogenous, i.e. naturally existing lipid membranes as well," the scientist concludes. Due to the comparatively small size of the effect, in experiments with less precise measurement methods this had previously remained hidden.

From frog to human

In future studies, Malte Drescher's team plans to build on this result and further elucidate the process of intracellular binding of α-synuclein to natural cell components, in order to learn more about the function of the protein. An important step in this process will be the move from frog cells as a model system to various mammalian cell types. The long-term goal is to better understand the protein-lipid interactions of the "Parkinson protein" and its role in the development of Parkinson's disease in order to be able to develop suitable therapeutic approaches.

There's a surprising amount of information stored in the hardened plaque, or calculus, between teeth. And if that calculus belongs to the remains of a person who lived in ancient times, the information could reveal new insights about the past. But the tiny samples can be difficult to work with. Now, in ACS' Journal of Proteome Research, scientists apply a new method to this analysis, finding more proteins than traditional approaches.

The human mouth is full of interesting molecules: DNA and enzymes in saliva, proteins and lipids from bits of food stuck between teeth, the bacterial citizens of the oral microbiome. Under the right conditions, those molecules can be preserved in dental calculus for thousands of years. Identifying the biomolecules preserved within ancient plaque gives researchers clues about how our ancestors lived, what they ate, what diseases they had and more. However, there's only so much plaque one can scrape off of old teeth, so it's important to apply methods that can extract the most information from minuscule samples. Although no gold-standard method for calculus analysis exists, filter-based techniques are often used, but they can be time consuming and can introduce contaminants. So, teams led by Michael Buckley and Cheryl Makarewicz wanted to see whether another method, called single-pot, solid-phase-enhanced sample preparation (SP3), could improve the number and complexity of protein fragments that could be analyzed from preserved plaque.

The researchers, led by Karren Palmer, applied SP3 to the analysis of calculus from 153 ancient individuals dating from between the 1st and 4th century BCE. With SP3, functionalized magnetic beads grabbed onto protein fragments, making them easy to analyze by mass spectrometry. The researchers found that SP3 reliably increased the number of unique protein fragments they could identify in samples, including smaller peptides that two other methods, ultrafiltration and acetone precipitation, missed. SP3 was also easy to perform and less likely to introduce contaminants than the other methods. Using this approach, the researchers identified fragments of dairy proteins from the subjects' diets, as well as bacterial proteins that could shed light on ancient diseases.

The mosquito protein AEG12 strongly inhibits the family of viruses that cause yellow fever, dengue, West Nile, and Zika and weakly inhibits coronaviruses, according to scientists at the National Institutes of Health (NIH) and their collaborators. The researchers found that AEG12 works by destabilizing the viral envelope, breaking its protective covering. Although the protein does not affect viruses that do not have an envelope, such as those that cause pink eye and bladder infections, the findings could lead to therapeutics against viruses that affect millions of people around the world. The research was published online in PNAS.

Scientists at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, used X-ray crystallography to solve the structure of AEG12. Senior author Geoffrey Mueller, Ph.D., head of the NIEHS Nuclear Magnetic Resonance Group, said at the molecular level, AEG12 rips out the lipids, or the fat-like portions of the membrane that hold the virus together.

"It is as if AEG12 is hungry for the lipids that are in the virus membrane, so it gets rid of some of the lipids it has and exchanges them for the ones it really prefers," Mueller said. "The protein has high affinity for viral lipids and steals them from the virus."

As a result, Mueller says the AEG12 protein has great killing power over some viruses. While the researchers demonstrated that AEG12 was most effective against flaviviruses, the family of viruses to which Zika, West Nile, and others belong, it is possible AEG12 could be effective against SARS-CoV-2, the coronavirus that causes COVID-19. But, Mueller said it will take years of bioengineering to make AEG12 a viable therapy for COVID-19. Part of the problem is AEG12 also breaks opens red blood cells, so researchers will have to identify compounds that will make the protein target viruses only.

Alexander Foo, Ph.D., an NIEHS visiting fellow and lead author of the paper, explained that mosquitoes produce AEG12 when they take a blood meal or become infected with flaviviruses. Like humans, mosquitoes mount a vigorous immune response against these viruses, with AEG12 bursting their viral covering. But, at the beginning of the project, Foo and his colleagues knew little about the function of AEG12.

"The prospect of studying a new protein is exciting, yet daunting," Foo said. "Thankfully, we had enough clues and access to a wide range of expertise at NIEHS to piece it together."

Co-author and crystallography expert Lars Pedersen, Ph.D., is leader of the NIEHS Structure Function Group. He routinely uses information about a molecule's physical makeup in his work and encourages more scientists to consider using this data in their studies. He said, "Our research shows that understanding the structure of a protein can be important in figuring out what it does and how it could help treat disease."

Parents of children with food allergies face significant worry, severe anxiety and post-traumatic stress - according to new research from the University of East Anglia.

Between six and eight per cent of children suffer a food allergy - with eggs, milk, and peanuts being the most common causes. They can cause vomiting, cramps, hives, swelling, eczema, breathing problems and in severe cases anaphylactic shock, which can lead to hospitalisation or death.

A new study published today finds that more than 80 per cent of parents face 'significant worry' about their child's food allergy, while 42 per cent met the clinical cut-off for post-traumatic stress symptoms (PTSS) and 39 per cent reported moderate to extremely severe anxiety.

Parents whose children have had to have an adrenaline auto-injector (for example an Epipen) administered were seven times more likely to experience PTSS.

Judith Young, from UEA's Norwich Medical School and Addenbrooke's Hospital, noticed in her work as an Honorary Consultant Clinical Psychologist that parents were describing psychological distress related to their child's allergy, but that there was little research into this.

Dr Kate Roberts carried out the study as part of her doctoral thesis at UEA, in collaboration with Judith Young,

Dr Alex Brightwell from Norfolk and Norwich University Hospitals NHS Foundation Trust and Prof Richard Meiser-Stedman, from UEA's Norwich Medical School.

Dr Roberts said: "Caring for a child with a food allergy can be really challenging - not least because they can be exposed to the foods they are allergic to, even with very careful management.

"We wanted to see how the parents of children with food allergies were affected by anxiety, worry and PTSS. And we also evaluated whether the level of anxiety and stress experienced was linked to factors such as the severity of the child's allergy."

A total of 105 parents of children with medically diagnosed food allergies completed online questionnaires about their experiences.

Around half of the children had been rushed to hospital at least once because of an allergic reaction.

As well as considering the level of the child's allergy, the team also looked at the parents' intolerance of uncertainty - how they manage unforeseen events, like the fact that they cannot completely control their child's exposure to food they're allergic to.

They also assessed the parents' 'self efficacy' - their confidence in allergy management.

Dr Roberts, who now works at Cambridgeshire Community Services NHS Trust and the Queen Elizabeth Hospital King's Lynn, said: "We found that a large proportion of the parents - 81 per cent - reported clinically significant worry and 42 per cent reported significant trauma symptoms related to their child's food allergy.

"Parents who reported their child to have had an adrenaline auto-injector (AAI) administered, were around seven times more likely to report clinically significant PTSS.

"Greater intolerance of uncertainty and lower food allergy self-efficacy were associated with poorer psychological outcomes. But we found mixed results for the relationship between allergy severity and parent mental health, with PTSS observed in parents of children with both life-threatening and milder allergies.

"This really highlights the need for greater awareness about the mental health problems that parents of children with food allergies may be experiencing.

"Knowing which factors could predict different psychological outcomes is important because it could help identify those parents who may be struggling with their mental health and help them overcome some of the problems they may be experiencing," she added.

Dr Alex Brightwell, Consultant Paediatrician, said: "I am delighted to have had the opportunity to work with UEA in this important area to contribute to an emerging body of evidence and ongoing research about the impact of food allergies on families. Anxiety and worry about having a child with food allergies is something we are seeing on a day to day basis. We are looking forward to working with UEA on further research to develop tools to support families affected by food allergy."

First grade teachers can find out who is on track with math and who is lagging, using an accurate diagnostic test that they can administer in the classroom.

After Covid-19 school reopening, or during catch-up sessions in the holidays, this is instrument can also be useful, especially in large, multilingual classrooms.

The test is supplemented by a 15-week 1-hour-a week "maths boost" invention program for first graders.

The program provides teachers good instructional material to support children in an efficient way.

Uniquely, the test measures numeracy skills along with listening comprehension and executive functions, pinpointing additional reasons why students improve after intervention.

Six-year-olds can't really talk to adults about the problems they may experience with mathematics. It is hard for teachers to know for certain who is keeping up and who is lagging, says Prof Elizabeth Henning from the University of Johannesburg.

The teacher could be facing 45 or even 60 little faces in the classroom, she says.

Some children may appear to cope after a few weeks' school holiday or closures due to Covid-19. But early childhood teachers need to understand what children remember and what may have been forgotten. School reopening is a good time to find out where everyone is with math and reading, she continues.

Henning is a South Africa Research Chair of the country's National Research Foundation.

"When kids come to school, even for first grade, you don't know what they already know. At home they may have learned to recite number words and use them as if to state 'how many', but that does not mean that they understand number yet," says Henning.

"They see their care-givers bake and cook and clean. Some children are sent to the shops before they can read. They learn some maths at home - but every home is different," she says.

Many kids learn this basic math in their home languages.

"Then they come to elementary school and 'parallel track' if this school teaches through medium of English. They start learning the same concepts in a new language, which in South Africa is mostly English.

"When the first grade teacher doesn't know the home languages of the young learners, they can't translate or code switch when they see the kids struggling," says Henning.

Prof Henning is one of the researchers in the study who adapted a Finnish evidence-based test for first graders in South Africa.

In South Africa many kids learn in English at school, but most speak a variety of African languages at home.

The test itself is not unique, but measuring numeracy and other relevant control measures in school-based intervention is, says Prof Pirjo Aunio. Aunio is from the Department of Education at the University of Helsinki.

She is corresponding author of the study, and one of the lead designers of the original Finnish test and the 15-week 1-hour-a week maths boost programme for first graders. The study has been published in the Early Childhood Research Quarterly.

"The most important result in our study was that the intervention group, those children who had extra practice in early numeracy skills with the 15-week program, had a bigger and sustained increase in their numerical relational skills, compared to children who followed business as usual instruction," continues Aunio.

"The effect was not a result of better language or executive functions skills, nor kindergarten attendance, but because of our intervention program," she says.

"What made me extremely happy is that this program's materials are cheap and easy to use. So the program is potentially very useful on a large scale as well," says Aunio.

The study provides an unusual follow-up view of first graders' progress in basic numeracy, says Henning.

"We found out how reliable the test is because we tested the first graders at the beginning of their school year, again after the 15-week maths boost program and again a few months after they completed the maths boost. Children learning in English as a second language are especially responsive to the test," she says.

"Many kids get lost to mathematics and science in middle school. But it doesn't have to be that way," says Henning.

"Far more students can arrive at middle school with the foundation needed to graduate from high school with good math scores", she says. That means more students can go onto college for technical, business and engineering careers.

The foundation starts in first grade, when the teacher digs deep to find out what is at the bottom of the kids' math knowledge, so that she can teach with different individuals' math competence in mind. One way of doing so is to test the kids at the beginning of the school year with a reliable test, such as the one in the study.

Says Henning: "We like this test and 15-week intervention program because they are easy to use and they work. With a sturdy foundation in first grade, teachers in other grades can build on it in a systematic progression. But if the early building blocks are missing, it is very hard to catch upon maths lost early on."

Computational models of air quality have long been used to shed light on pollution control efforts in the United States and Europe, but the tools have not found widespread adoption in Latin America. New work from North Carolina State University and Universidad de La Salle demonstrates how these models can be adapted to offer practical insights into air quality challenges in the Americas outside the U.S.

Computational air quality models can be used in multiple ways. For example, they can be used to determine which sources are responsible for what fraction of air pollution. They can also help authorities predict how air pollution might change if different pollution control methods are adopted.

"Historically, it's been very challenging to apply these modeling tools in Latin America, so it has rarely been done," says Fernando Garcia Menendez, corresponding author of a paper on the work and an assistant professor of environmental engineering at NC State. "This is important because the region has many areas that are dealing with significant air pollution, and these modeling tools can help governments identify the most cost-effective ways of achieving air quality improvements."

One challenge to using computational air quality models in Latin America is that the relevant modeling frameworks were developed largely in the context of the U.S. and Europe. That means that some of the assumptions that modelers took for granted when developing the tools don't always apply in Latin American cities. Furthermore, computational resources and trained environmental modelers are still scarce in the region.

For example, there are often substantially less air emissions data available. In addition, there are some contributors to air pollution that are common across Latin American metro areas, but that differ from what we see in the U.S. - more unpaved roads, an older cargo fleet, a large number of motorcycles, informal economies, and so on.

With that in mind, Garcia Menendez developed a research project with collaborators at the Universidad de La Salle, in Bogotá, Colombia. Specifically, the research team fine-tuned a modeling framework to reflect the air pollution dynamics in Bogotá and investigate the city's air quality problems. The collaborators at Universidad de La Salle also collected air pollution data that allowed the team to assess the accuracy of its modeling results.

"Our paper outlines the techniques we've used to perform computational modeling of air quality issues in a large Latin American city," says James East, first author of the paper and a Ph.D. student at NC State. "This not only demonstrates that it can be done, but provides an approach that others can use to provide insights into air pollution in other parts of the region that are experiencing similar issues."

While the paper focuses on an air quality model for fine particulate matter (PM2.5), the researchers say that the model could be used to look at other air pollutants. Exposure to PM2.5 is associated with a wide variety of health problems, including heart and lung disease.

In their proof-of-concept demonstration, the researchers found that the largest local sources of PM2.5 in Bogotá were dust from unpaved roads and emissions from heavy-duty vehicles. However, when the model was used to project future air quality, the study also found that while paving roads would decrease air pollution in some parts of the city, different emission sources would still lead to increased air pollution in other parts of the city - unless other emission control measures were also implemented.

In short, the model offered practical insights into possible solutions for a complex metropolitan area of 10 million people.

"These findings are of interest to environmental authorities, from the local to the national level, who are pursuing ways to effectively address air pollution in Bogotá and other Colombian cities," says Jorge Pachon, a co-author of the paper and an associate professor at the Universidad de La Salle.

A unique curved barrier has been designed by researchers at Imperial College London, who publish new findings in the peer-reviewed journal Cities & Health on how the structure can protect people from the damaging effects of air pollution.

With air pollution becoming an increasingly dangerous global health challenge, researchers are constantly working on innovating novel solutions to tackle these 21st century problems. At Imperial College London, researchers are using airflow modelling techniques to study the effects of unique roadside structures to deflect particulates away from pedestrians.

The health concerns arising from lower air quality are more significant amongst lower income communities which are more likely to be situated near heavily traffic-laden thoroughfares. Similarly, children are both more vulnerable to and more readily exposed to air pollution simply due to their proximity to the ground, where heavier pollutants settle over time. Real-time data on air pollution in London and south east England can be found on London Air, a tool run by the London Air Quality Network at Imperial.

Dr Tilly Collins found this issue particularly worrying, especially after noticing the severe pollution in the air while watching her child playing netball in a school playground alongside a busy London A-road.

"I thought to myself, what could be done? And done now? So, I started researching the effect of walls along roads," Dr Collins, from Imperial's Centre for Environmental Policy, said. "It became evident that along the pedestrian side of these roadside walls, there are vortices where the air quality can actually be even worse as the pollutants get trapped in them."

Initially building off simple models, Dr Collins, Dr Huw Woodward, also from the Centre for Environmental Policy, and Agamemnon Otero of Energy Garden, explored ideas of urban design that would mitigate these vortex effects and improve air quality for pedestrians and especially children.

The curved barriers deflect pollution away from pedestrians and back onto the road.

Inspired by airfield baffles and the curved sound-walls alongside motorways in Germany and the Netherlands, the researchers found that curved structures would more effectively disperse and reflect pollutants back towards the roads and would very rapidly improve air quality for pedestrians in an inexpensive manner.

Although there are challenges in implementing this sort of urban furniture, such as road visibility, the researchers are confident that the net gain in air quality and health is immediate and significant enough to warrant further exploration of these ideas. Beyond air quality, these curved barriers would also mitigate noise pollution, and would be able to act as scaffolds to increase green infrastructure throughout large cities.

When asked about the challenges faced during this research project, Dr Collins said: "Initially, it was difficult to convince others to get on board. The focus is very much on successfully reducing exhaust fumes, but there are these things we can do now to protect our children. The different sciences, urban designers and architects should collaborate more to design these solutions achieve air quality improvements at local scales more effectively and quickly."

Despite the hurdles, Dr Collins is optimistic for the future of the project. With increased attention being placed on the challenges associated with air pollution, there is a need for unique and effective urban design, and these curved baffling barriers are able to tackle these challenges head on, providing immense benefits to the general public.

News Release -- LOGAN, UT -- Mar. 9, 2021 -- Researchers at Utah State University are using silkworm silk to grow skeletal muscle cells, improving on traditional methods of cell culture and hopefully leading to better treatments for muscle atrophy.

When scientists are trying to understand disease and test treatments, they generally grow model cells on a flat plastic surface (think petri dish). But growing cells on a two-dimensional surface has its limitations, primarily because muscle tissue is three-dimensional. Thus, USU researchers developed a three-dimensional cell culture surface by growing cells on silk fibers that are wrapped around an acrylic chassis. The team used both native and transgenic silkworm silk, the latter produced by silkworms modified with spider silk genes.

Native silkworm silks have been used previously as three-dimensional cell culture models, but this is the first time that transgenic silkworm silk has been used for skeletal muscle modeling. Elizabeth Vargis, Matthew Clegg, and Jacob Barney of the Biological Engineering Department, and Justin Jones, Thomas Harris, and Xiaoli Zhang of the Biology Department published their findings in ACS Biomaterials Science & Engineering.

Cells grown on silkworm silk proved to more closely mimic human skeletal muscle than those grown on the usual plastic surface. These cells showed increased mechanical flexibility and increased expression of genes required for muscle contraction. Silkworm silk also encouraged proper muscle fiber alignment, a necessary element for robust muscle modeling.

Skeletal muscle is responsible for moving the skeleton, stabilizing joints, and protecting internal organs. The deterioration of these muscles can happen for myriad reasons, and it can happen swiftly. For example, after only two weeks of immobilization, a person can lose almost a quarter of their quadricep muscle strength. Understanding how muscles can atrophy so quickly must begin at a cellular level, with cells grown to better represent reality.

"The overarching goal of my research is to build better in vitro models," said Elizabeth Vargis, associate professor of biological engineering at USU. "Researchers grow cells on these 2D platforms, which aren't super realistic, but give us a lot of information. Based on those results, they usually transition into an animal model, then they move onto clinical trials, where a vast majority of them fail. I'm trying to add to that first step by developing more realistic in vitro models of normal and diseased tissue."