Culture

Alzheimer's disease (AD) is progressive, but slow to develop -- or at least to reveal itself. In a new study, published online February 14, 2020 in the journal Biological Psychiatry, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, report that early, subtle differences in cognitive performance, such as fewer words recalled on a memory test, are a sign that harmful proteins are accumulating in the brain, even if levels of those proteins do not yet qualify as dangerous.

Pathologically, AD is primarily characterized by the accumulation of protein plaques called β-amyloid (Aβ), which gradually accumulate in the brain, disrupting cell function and eventually killing affected neurons. A second type of protein, called tau, also accumulates abnormally inside neurons, damaging functions.

In the progression of AD, Aβ levels build in the brain, but the process leading to abnormally high levels is typically long. It is often years or decades before consequential symptoms of severe cognitive impairment appear. A new framework from the National Institute on Aging and Alzheimer's Association defines the first stage of AD to be individuals with abnormal levels of Aβ who are still cognitively normal.

"Although AD pathology, and Aβ in particular, appear long before severe cognitive deficits appear," said first author Jeremy A. Elman, PhD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine, "recent evidence suggests more subtle cognitive changes may appear earlier in the disease than commonly appreciated."

Elman and colleagues, including senior author William S. Kremen, PhD, professor of psychiatry at UC San Diego School of Medicine, sought to determine whether poor cognitive performance, however subtle, might be a predictor that current Aβ-negative levels (accumulations below the threshold for AD diagnosis) were likely to become Aβ-positive.

"Once a person reaches the point of being Aβ-positive, it means that there is already substantial underlying pathology," said Kremen. "It would be advantageous to identify at-risk individuals before they develop substantial amyloid burden to improve treatment efficacy and slow progression to AD dementia."

The researchers conducted a pair of non-invasive cognitive tests on 292 participants in the Alzheimer's Disease Neuroimaging Initiative, an ongoing study to assess whether the use of medical imaging, biological markers and clinical assessments can be combined to measure the progression of cognitive decline and early AD.

All of the participants were Aβ-negative at baseline testing and displayed no dementia; 40 participants would progress to Aβ-positivity during the study and follow-up period.

The scientists found that participants who tested with lower baseline cognition were at significantly higher risk of progressing to Aβ-positivity. That is, low test scores indicating poorer cognitive function suggested amyloid plaque levels that, while not yet considered to be problematic, were likely rising and would ultimately reach the threshold definition of AD.

"We found that subthreshold levels of baseline Aβ were predictive of future accumulation, adding to evidence that even low levels of Aβ are clinically relevant, but that cognitive performance was still significantly predictive even after controlling for this pathology," said Elman.

The findings, wrote the researchers, suggest that low-cost, non-invasive cognitive testing is useful for identifying persons who may be at risk for developing AD, making them ideal candidates for therapeutic intervention and clinical trials.

MISSOULA - Every social network has its fake news. And in animal communication networks, even birds discern the trustworthiness of their neighbors, a study from the University of Montana suggests.

The study, recently published in the top science journal Nature, is the culmination of decades' worth of research from UM alumni Nora Carlson and Chris Templeton and UM Professor Erick Greene in the College of Humanities and Sciences. It sheds a new light on bird social networks.

"This is the first time people have shown that nuthatches are paying attention to the source of information, and that influences the signal they produce and send along," Greene said.

Carlson, Templeton and Greene shared an interest in trying to crack the Rosetta Stone of how birds communicate and collected bird calls over the years.

Each bird species has a song, usually sung by the males, for "letting the babes know 'here I am,'" Greene said, as well as staking out real estate. Their loud and complex calls usually ring out during breeding season.

But for warning calls, each sound stands for a specific threat, such as "snake on the ground," "flying hawk" and "perched hawk." The calls convey the present danger level and specific information. They also are heard by all species in the woods in a vast communication network that sets them on high alert.

"Everybody is listening to everybody else in the woods," Greene said.

In the study, Greene and his researchers wanted to determine how black-capped chickadees and red-breasted nuthatches encode information in their calls.

In bird communication, a high-pitched "seet" from a chickadee indicates a flying hawk and causes a strong reaction - other birds go silent, look up and then dive in the bushes. Alarm calls can travel quickly through the woods. Greene said in previous experiments they clocked the speed of the calls at 100 miles per hour, which he likens to the bow wave on a ship.

"Sometimes birds in the woods know five minutes before a hawk gets there," Greene said.

A harsh, intensified "mobbing call" drives birds from all species to flock together to harass the predator. When the predator hears the mobbing call, it usually has to fly a lot farther to hunt, so the call is very effective.

"The owl is sitting in the tree, going, 'Oh crap!" Greene said.

Greene calls it "social media networks - the original tweeting."

For the study with chickadees and nuthatches, the researchers focused on direct information - something a bird sees or hears firsthand - versus indirect information, which is gained through the bird social network and could be a false alarm.

"In a way, it kind of has to do with fake news, because if you get information through social media, but you haven't verified it, and you retweet it or pass it along, that's how fake news starts," Greene said.

Nuthatches and chickadees share the same predators: the great-horned owl and the pygmy owl. To the small birds, the pygmy owl is more dangerous than a great-horned owl due to its smaller turning radius, which allows it to chase prey better.

"If you are eating something that's almost as big as you are, it's worth it to go after it," Greene said.

Using speakers in the woods, the researchers played the chickadee's warning call for the low-threat great-horned owl and the higher-threat pygmy owl to nuthatches. The calls varied by threat level - great-horned owl versus pygmy owl - and whether they were direct (from the predators themselves) or indirect (from the chickadees).

What they discovered about the nuthatches was surprising.

Direct information caused the nuthatches to vary their calls according to the high threat and the low threat. But the chickadee's alarm call about both predators elicited only a generic, intermediate call from the nuthatch, regardless of the threat level.

Greene said the research points to the nuthatch's ability to make sophisticated decisions about stimuli in their environment and avoid spreading "fake news" before they confirm a predator for themselves.

"You gotta take your hat off to them," Greene said. "There's a lot of intelligence there."

The research, conducted by Carlson, Templeton and Greene around Montana and Washington throughout the years, wasn't without challenges.

Most of the set up happened during winter, and nuthatches had to be isolated from chickadees to ensure the warning calls were not a response to witnessing chickadees going crazy. Often a chickadee would appear after everything was set up, and the researchers had to take everything down and try a new location.

"It's quite hard to find nuthatches without chickadees somewhere in the area," Greene said. "That was the most difficult part - to find these conditions out in the wild."

But the results were worth the work.

Greene said the nuthatch study ultimately helps researchers better understand how animal communication networks work and how different species decode information, encode info and pass it along.

"We kind of wish people behaved like nuthatches," Greene said.

Seagrasses have long been known as some of Earth's most remarkable organisms--descendants of flowering land plants that have re-colonized the ocean by developing traits that allow them to grow, pollinate, and release seeded fruits while fully immersed in salty seawater.

Now, research by a joint Australian-U.S. team reveals that one group of seagrasses, Australian species of the genus Posidonia, have evolved yet another remarkable adaptation for ocean survival: a winged seed whose shape harnesses the force of underwater currents to hold it on the seafloor for rooting.

Results of the study offer valuable insights for efforts to restore seagrass populations in Australia, the Chesapeake Bay, and elsewhere. Seagrass meadows, which provide important nursery and feeding habitat for other marine life and play a key role in maintaining water quality, are under threat worldwide from warming and over-fertilization of coastal waters.

Published in a recent issue of Scientific Reports, the seagrass study is the first to record a winged seed among marine angiosperms, and to experimentally determine its adaptive benefit. It also shows that seeds of Posidonia species in areas with stronger currents have larger wings, further evidence of the trait's utility.

Lead author on the report was Dr. Gary Kendrick of the University of Western Australia. The research emerged from a long-term collaboration between Kendrick and Dr. Robert "JJ" Orth of William & Mary's Virginia Institute of Marine Science, a pioneer in monitoring and restoring seagrasses in the Chesapeake Bay and mid-Atlantic coastal lagoons. Also contributing to the study were Marion Cambridge, Jeremy Shaw, Lukasz Kotula, and Ryan Lowe of UWA and Andrew Pomeroy of the Australian Institute for Marine Science.

"Understanding the basic biology of seeds and their establishment allows us to optimize our seed-based restoration practices," says Kendrick. "Working with JJ and the team at VIMS--using their deep understanding of the world the seed experiences--has resulted in a truly interdisciplinary outcome that combines the skills of seagrass and restoration biologists, plant anatomists, and hydrodynamic modelers."

A serendipitous seed story

Winged seeds are commonly used by land plants for dispersal by wind, with the helicopter-like seeds of maple and ash trees a familiar example. So when Orth first noted the wing-like structure on Posidonia seeds during Australian fieldwork in the mid-1990s, his initial thought was that it served a similar function.

"My preliminary hypothesis was that [the wing] would serve to move the seed farther away from the parent plant when it was released from the fruit," says Orth. Posidonia produces large buoyant fruits that break off from the adult plant and can float kilometers away, releasing seeds as they mature.

But years of painstaking research showed the opposite. "When released from the fruit," says Orth, "the seeds drop really fast."

Based on that finding, Orth and colleagues developed a second working hypothesis, that the purpose of the wing was to get the seed to the bottom quickly, before it could be eaten by predators. But field research again proved them wrong. "It turns out not many creatures like to eat these seeds, except for crabs and other small crustaceans," says Orth.

The third time's the charm

The researchers' path to discovering the wing's true function began when Dr. Marion Cambridge of UWA's Oceans Institute suggested a third hypothesis--that the wing keeps the seed at the sediment surface until it can grow anchoring roots.

To test this hypothesis, the team carefully measured the surface area of the seeds using both scanning electron microscopy and X-ray tomography, gauged the flow of currents around seeds placed in a flume, and used these data to build a computer model of the relevant hydrodynamic forces.

"When we brought in Andrew [Pomeroy], a hydrodynamics expert, he got pretty excited about what he saw," says Orth. "He launched the modeling effort that's highlighted in the paper. Together with our microscopy and flume data, it clearly supports the idea that the wing helps the seed maintain its position on the bottom, very similar to how flatfishes can stay on the bottom in strong currents."

In sum, rather than helping to lift and disperse the seeds as with maples, the team's research shows that evolution has engineered the Posidonia wing to push the seed against the seafloor, like the downforce generated by the wing on the rear of a race car.

Stronger currents, larger wings

Further support for the team's hypothesis comes from their comparison of wing width in the seeds of Australia's three Posidonia species, which inhabit a gradient of coastal habitats from current-scoured open shorelines to more sheltered bays.

"The neatest thing about the project," says Orth, "is that the width of the wing differs in the three species that dominate the west coast of Australia, and correlates with each species' environment. Posidonia coriacea, which lives in the most wave-swept areas, has the widest wing, while the other two species --australis and sinuosa--live under calmer conditions and have smaller wings." This correlation extends all the way to the quiet waters of the Mediterranean, where a relict population of the same genus (P. oceanica) has seeds with barely any wing at all.

The findings have important implications for seagrass restoration. "Our modeling work and experiments will better inform Australian resource managers on where to place seeds of these different species," says Orth. "Hopefully armed with this information we can increase the low success rate we observed from one of our recent large-scale restoration efforts in Cockburn Sound."

The findings have also further piqued Orth's interest in traits exhibited by the eelgrass seeds that have long been at the heart of his team's restoration efforts in Virginia's seaside bays. Orth and colleagues first began sowing the bays' shallow waters with eelgrass seeds in 1999. Barren at the time, they today hold more than 7,000 acres of lush eelgrass meadow, making them the largest example of seagrass restoration in the world. In fact, they now hold 75% of the world's restored seagrass acreage.

"We've conducted a lot of experiments with our eelgrass seeds," says Orth, "but still know relatively little about the function of the ribs on these seeds and whether their barrel shape might play some role in keeping them from rolling along the bottom. Our work with Posidonia has added new intrigue to this work."

Memory performance and other cognitive abilities benefit from a good blood supply to the brain. This applies in particular to people affected by a condition known as "sporadic cerebral small vessel disease". Researchers of the German Center for Neurodegenerative Diseases (DZNE) and the University Medicine Magdeburg report on this in the journal "BRAIN". Their study suggests that blood perfusion of the so-called hippocampus could play a key role in age- and disease-related memory problems.

Inside the human brain there is a small structure, just a few cubic centimeters in size, which is called the "hippocampus" because its shape resembles a seahorse. Strictly speaking, the hippocampus exists twice: once in each brain hemisphere. It is considered the control center of memory. Damage to the hippocampus, such as it occurs in Alzheimer's and other brain diseases, is known to impair memory. But what role does blood supply in particular play? A team of scientists headed by Prof. Stefanie Schreiber and Prof. Emrah Duezel, both affiliated to the DZNE and the University Medicine Magdeburg, investigated this question. The researchers used high-resolution magnetic resonance imaging (MRI) to examine the blood supply to the hippocampus of 47 women and men aged 45 to 89 years. The study participants also underwent a neuropsychological test battery, which assessed, in particular, memory performance, speech comprehension and the abilty to concentrate.

A double supply line

"It has been known for some time that the hippocampus is supplied by either one or two arteries. It also happens that only one of the two hippocampi, which occur in every brain, is supplied by two vessels. This varies between individuals. The reasons are unknown," explained Schreiber. "Maybe there is a genetic predisposition. However, it is also possible that the individual structure of the blood supply develops due to life circumstances. Then the personal lifestyle would influence the blood supply to the hippocampus." In the cognition tests, those study participants in whom at least one hippocampus was doubly supplied generally scored better. "The fact that the blood supply is fundamentally important for the brain is certainly trivial and has been extensively documented. We were therefore particularly focused on the hippocampus and the situation of a disease of the brain vessels. Little is actually known about this."

Patients benefited in particular

Of the study subjects, 27 did not manifest signs of brain diseases. The remaining twenty participants showed pathological alterations in brain blood vessels, which were associated with microbleeding. "In these individuals, sporadic cerebral small vessel disease had been diagnosed prior to our investigations," said Dr. Valentina Perosa, lead author of the current study, who is currently doing postdoctoral research in Boston, USA. These individuals exhibited a broad spectrum of neurological anomalies, including mild cognitive impairment. "The healthy subjects generally scored better on cognitive tests than the study participants with small vessel disease. Among the participants with disease, those with at least one hippocampus supplied by two arteries reached better scores in cognition. They particularly benefited from the double supply. This may be due to a better supply not only of blood but also of oxygen. However, this is just a guess," said Perosa.

Starting point for therapies?

"Our study shows a clear link between blood supply to the hippocampus and cognitive performance," Schreiber summarised the results. "This suggests that brain blood flow might play a key role in the declining of memory performance, whether caused by age or disease." Such findings help to understand disease mechanisms and can also be useful for the development of novel treatment options, she indicates: "At present we can only speculate, because we don't know, but it is possible that lifestyle has an influence on the formation of the blood vessels that supply the hippocampus. This would then be a factor that can be influenced and thus a potential approach for therapies and also for prevention. This is a topic we intend to investigate."

BIRMINGHAM, Ala. - Influenza is a deadly virus, with about 290,000 to 650,000 deaths worldwide each year. When pandemics hit, the toll can soar: The Spanish flu of 1918 caused 40 million to 50 million deaths, the Asian flu of 1957 caused 2 million deaths, and the Hong Kong flu of 1968 caused 1 million deaths.

Chad Petit, Ph.D., and colleagues at the University of Alabama at Birmingham fight influenza at the molecular level, in part by finding natural mutations in the viral RNA genome that have a functional impact during infection. Discovering how the virus uses these unknown mechanisms to stop your body from mounting an effective defense against infection, Petit said, "will better prepare us to predict the pandemic potential of influenza A virus and aid in the development of vaccines and antivirals."

Influenza A is dangerous because each year it adapts to various hosts and undergoes genetic reassortment. This generates a constant stream of unique strains that have unknown degrees of pathogenicity, transmissibility and ability to cause international pandemics.

Petit's latest research, published in the Journal of Biological Chemistry, takes a detailed look at a naturally occurring mutation in a flu strain from a 1972 Russian outbreak that the UAB team described in 2015, while comparing that Russian strain to the 1918 strain responsible for Spanish flu.

The mutation is in the flu protein NS1. In 2015, Petit and his UAB colleagues were the first to show that NS1 from the 1918 strain had a direct interaction with RIG-I, the cell's main sensor to detect flu virus infection and to then launch an innate immune defense. Furthermore, the portion of the 1918 NS1 RNA binding domain that bound to RIG-I had no previously known function. In contrast to the 1918 NS1, Petit's lab found that the NS1 from the influenza A strain 1972 Udorn was unable to bind to the RIG-I site that interacted with the 1918 NS1.

Now, Petit and colleagues report the biological effects of NS1 binding to RIG-I -- the binding directly quiets the alarm that activates the cellular innate immunity defense against the infection. This is a newly described way to antagonize the host cellular antiviral response.

"NS1 is almost like the Swiss army knife of proteins because it has so many functions," said Petit, an assistant professor in the UAB Department of Biochemistry and Molecular Genetics. NS1 appears to interact with 20 to 30 host proteins, and compared with other flu proteins, NS1 also has remarkable genetic plasticity, meaning that its effect on virulence can vary among strains.

Study details

The mutation in the Udorn NS1 protein is a change of a single amino acid at position 21 from arginine to glutamine. In the current research, the UAB researchers used reverse genetics to engineer that mutation into a 1934 Puerto Rico flu strain, and then they compared how the wild type NS1 and mutant NS1 proteins functioned.

Using a variety of molecular biology tools, the UAB researchers found that, while the wild type NS1 antagonizes RIG-I signaling to start the alarm sequence, the mutant NS1 permitted that signaling. Specifically, the mutant NS1 was significantly less able to bind to RIG-I, which allowed the triggering of innate immunity -- notably by increasing TRIM-25 ubiquitination of RIG-I, which is the critical step to activate RIG-I. That led to increased IRF3 phosphorylation and increased production of type I interferon.

However, the changed amino acid in the mutant NS1 had no effect on two other known ways that NS1 can block the cellular innate immunity response -- binding to double-stranded RNA and binding with the TRIM-25 cellular protein. Thus, Petit and colleagues have described an additional tool on NS1 to increase viral survival.

But the UAB researchers are left with a particularly outstanding question -- why does the arginine-to-glutamine mutation at amino acid-21 naturally occur if it leads to an increased antiviral response during infection? This seems counterintuitive in terms of evolution.

Comparison of multiple NS1 sequences in the Influenza Research Database, Petit says, suggests that the different amino acids at position 21 may relate to species-specific adaptation. Multiple strains of influenza A from humans were 63 percent arginine and 36.7 percent glutamine at amino acid-21; strains from swine were 92.1 percent arginine and 6.4 percent glutamine; and strains from birds were 79.9 percent arginine, 0.8 percent glutamine and 19.1 percent leucine. There were small percentages of other amino acids among the strains at position 21.

There is a striking difference among two human serotypes that cause seasonal disease and two human serotypes that are more highly pathogenic. The two seasonal serotypes, H1N1 and H3N2, were 75.4 percent arginine and 24.5 percent glutamine, and 1 percent arginine and 98.8 percent glutamine, respectively, at position 21. The two highly pathogenic strains, H5N1 and H7N9, were 100 percent arginine and 0 percent glutamine, and 95.9 percent arginine and 2.3 percent glutamine, respectively, at position 21. There were small percentages of other amino acids for the H7N9 strains at position 21.

"Taken together, the work presented in this study," Petit said, "stresses the importance of how strain-specific polymorphisms in NS1 can affect its ability to antagonize the host cellular immune response in ways that are yet to be appreciated."

DALLAS, February 14, 2020 -- Consumption of cocoa may improve walking performance for patients with peripheral artery disease, according to the results of a small, preliminary, phase II research trial published today in the American Heart Association's journal Circulation Research.

In a small study of 44 peripheral artery disease patients over age 60, those who drank a beverage containing flavanol-rich cocoa three times a day for six months were able to walk up to 42.6 meters further in a 6-minute walking test, compared to those who drank the same number and type of beverages without cocoa. Those who drank the flavanol-rich cocoa also had improved blood flow to their calves and some improved muscle function compared to the placebo group.

Peripheral artery disease or PAD, a narrowing of the arteries that reduces blood flow from the heart to the legs, affects over 8.5 million people 40 years of age and older nationwide. The most common symptoms are pain, tightness, cramping, weakness or other discomfort in leg muscles in while walking.

"Few therapies are available for improving walking performance in people with PAD," said lead study author Mary McDermott, M.D., the Jeremiah Stamler professor of medicine and preventive medicine at the Feinberg School of Medicine at Northwestern University in Chicago. "In addition to reduced blood flow to the legs, people with peripheral artery disease have been shown to have damaged mitochondria in their calf muscles, perhaps caused by the reduced blood flow. Mitochondria are known as the powerhouse of the cell, converting food to energy. Previous research has shown that better mitochondrial health and activity are associated with better walking performance and improving the health of damaged mitochondria could lead to walking improvements."

Researchers hypothesized that epicatechin, a major flavanol component of cocoa, may increase mitochondrial activity and muscle health in the calves of patients with lower extremity peripheral artery disease, potentially improving patient walking ability. Epicatechins and flavanols also have the potential to improve blood flow.

Study participants were randomly assigned to drink milk or water mixed with the contents of a powder packet containing flavanol-rich cocoa (15 grams of cocoa and 75 mgs of epicatechin daily) or a placebo powder packet without cocoa or epicatechin three times daily over six months. Walking performance was measured at the beginning of the study and at six months, with a 6-minute walking measured test twice - 2.5 hours after drinking the beverage and at 24 hours after drinking the beverage. Participants were also given a treadmill walking test and had the blood flow to their legs measured using magnetic resonance imaging (MRI). Participants who consented had a calf muscle biopsy to evaluate muscle health.

The cocoa used in the study is commonly available natural unsweetened cocoa powder., which is rich in the flavanol epicatechin, found in larger quantities in dark chocolate (>85% cacao) than in milk chocolate. Regular chocolate would not be expected to have the same effect.

Researchers found that the patients who consumed cocoa showed significant improvement - walking an average of almost 43 meters further in the 6-minute walking test compared to their baseline results during the test performed at 2.5 hours after the final study beverage. Researchers also found increased mitochondrial activity, increased capillary density, and other improvements to muscle health in those who consumed the cocoa. Patients who drank the placebo beverage had a decline of 24.2 meters in their walking distance at 2.5 hours after the final study beverage compared to their baseline results. This is consistent with other studies, in which people with PAD without treatment have declines in their six-minute walk distance over time.

Cocoa appeared to have no effect on treadmill walking performance. However, McDermott said the treadmill walking and the 6-mile walking test are distinct measures of walking endurance and do not respond identically to the same therapy. The improvement in 6-minute distance walking better reflects the type of walking required in daily life, and therefore, these results are a more relevant outcome for patients with PAD.

"While we expected the improvements in walking, we were particularly pleased to see that cocoa treatment was also associated with increased capillary density, limb perfusion, mitochondrial activity, and an additional measure of overall skeletal muscle health," McDermott said. "If our results are confirmed in a larger trial, these findings suggest that cocoa, a relatively inexpensive, safe and accessible product, could potentially produce significant improvements in calf muscle health, blood flow, and walking performance for PAD patients."

Limits to this pilot study include: a small sample size; an imbalance between the two study groups in the number of participants of each sex, race and in body mass index; and a lack of data for overall dietary consumption.

"Patients with PAD have difficulty walking that is as bad as people with advanced heart failure. Leg muscles don't get enough blood supply in PAD leading to injury and in this study, cocoa appeared to be protecting the muscle and improving metabolism," said Naomi Hamburg, M.D., FAHA, Chair of the American Heart Association's Peripheral Vascular Disease Council and author of an editorial on the study that also appears in this issue. "We know that exercise therapy helps people with PAD walk farther, and this early study suggests that cocoa may turn out to be a new way to treat people with PAD. We will need larger studies to confirm whether cocoa is an effective treatment for PAD, but maybe, someday, if the research supports it, we may be able to write a prescription for chocolate for our patients with PAD."

The smallest proteins travel in our cells, completing deeply important tasks to keep our molecular mechanisms moving. They are responsible for transporting cargo, duplicating cells and more. Now, a research team based in Japan has uncovered more about how these proteins move.

They published their results on Jan. 23 in Scientific Reports, a Nature journal. Researchers hope the work on biological molecular motors, such as the kinesin and dynein proteins they study, will lead to the development of synthetic motors that could be applied to autonomous material transportation, mechanical actuation, and other energy conversion means.

"Synthetic molecular motors have great potential to realize novel functions beyond the capabilities of biological molecules," said paper author Ryota Iino, professor at the Institute for Molecular Science in the National Institutes of Natural Sciences. "As Richard Feynman said, 'What I cannot create, I do not understand.' We strongly believe that we need to create synthetic molecular motors to completely understand their operational and design principles."

The first step to creating synthetic molecular motors is to fully understand how biological motors move. In order to do this, Iino and his team used high-speed, highly precise imaging to track how a single molecule -- specifically dynein -- moves along a microtubule, which helps provide structure in cells. The researchers previously used the same imaging technique to study kinesin, which was found to move to with precision along a single rail of a microtubule.

However, they found the dynein moved far more erratically than kinesin.

"In contrast to the precise movement of kinesin, dynein movement involves not only forward steps, but also frequent backward steps and side steps to adjacent rails," Iino said. "In other words, dynein walks like a drunk person."

Next, Iino and his team will continue to image dynein in detail, with the goal of understanding how the protein coordinates -- or doesn't coordinate at all -- to perform its molecular motor tasks.

"Our result indicates that linear molecular motors do not have to move precisely to achieve an important function of the cargo transport in the cell," Iino said. "It is important for us to understand both the commonality and diversity in the walking mechanism of the linear molecular motors to eventually realize motors made of synthetic molecules.

DGIST identified causes of hypersensitivity accompanied by neurodevelopmental disorder such as autism-spectrum disorder (ASD). This is expected to make huge contributions to the early diagnosis of sensory-defective symptom brought with neurodevelopmental disorder and cancer as well as the improvement of anti-cancer drug side effects.

DGIST announced that the Department of Brain and Cognitive Sciences found the important mechanism of 'Abl1' gene, which is involved in the early developmental stage of inhibitory neuron for forming normal sensory circuits.

Before formation of cognitive or verbal neural circuits in brain development, sensory circuits are developed explosively for one year after birth. An ASD with cognitive and sensory defects is caused if inhibitory neural circuit is not formed properly due to genetic and environmental factors during the brain development. While studies on ASD treatment have focused on the abnormal development of inhibitory neurons related to cognitive disorder, no sufficient research has been made on the specific causes and mechanisms of sensory defects that occur first.

The DGIS research team discovered for the first time that Abl1 gene is expressed and activated explosively during the early development of inhibitory neurons in the mouse olfactory bulb. They also learned that if the expression or activation of Abl1 is inhibited using lenti-virus , inhibitory neurons cannot reach their cell layers accurately due to structural defects.

A candidate gene of ASD, Abl1 is also well-known to cause cancer. If Chronic Myelogenous Leukemia (CML) patients aged 2-9 with active brain development intake target anti-cancer drug Gleevec (Imatinib), an Abl1 deactivator, more than 60% of them show sensory related-side effects such as olfactory hallucination. Based on this, the research team confirmed that the inhibition of Abl1 expression and activation greatly increased the olfactory sensitivity of mouse as the side effect of Gleevec intake.

The research team also discovered that using proteomics , Abl1 temporarily phosphorylated doublecortin (Dcx), a cytoskeletal protein that plays a crucial role in the structural development of brain. This proposed that Abl1 regulates the dynamic of microtubule with a new signal transmission system between Abl1 and Dcx.

Professor Cheil Moon in the Department of Brain and Cognitive Sciences at DGIST said "We found a very important clue to understand the mechanism of hypersensitivity appearing in neurodevelopmental disorder or cancer disease, which are yet to be known clearly. We hope to see follow-up research to overcome other sensory disorders based on our research."

A world first review of the importance of nature play could transform children's play spaces, supporting investment in city and urban parks, while also delivering important opportunities for children's physical, social and emotional development.

Conducted by the University of South Australia the systematic review explored the impacts of nature play on the health and development of children aged 2-12 years, finding that nature play improved children's complex thinking skills, social skills and creativity.

Led by UniSA masters student Kylie Dankiw and researcher Associate Professor Katherine Baldock, this study is the first to provide evidence that supports the development of innovative nature play spaces in childcare centres and schools.

"In recent years, nature play has become more popular with schools and childcare centres, with many of them re-developing play spaces to incorporate natural elements, such as trees, plants and rocks. But as they transition from the traditional 'plastic fantastic' playgrounds to novel nature-based play spaces, they're also looking for empirical evidence that supports their investments," Dankiw says.

"Our research is the first to rigorously, transparently and systematically review the body of work on nature play and show the impact it has on children's development. We're pleased to say that the findings indicate a positive connection between nature play and children's development.

"For early childhood educators, health practitioners, policymakers and play space designers, this is valuable information that may influence urban play environments and re-green city scapes."

Comprising a systematic review of 2927 peer-reviewed articles, the research consolidated 16 studies that involved unstructured, free play in nature (forest, green spaces, outdoors, gardens) and included natural elements (highly vegetated, rocks, mud, sand, gardens, forests, ponds and water) to determine the impact of nature play on children's health and development.

It found that nature play improved children's levels of physical activity, health-related fitness, motor skills, learning, and social and emotional development. It also showed that nature play may deliver improvements in cognitive and learning outcomes, including children's levels of attention and concentration, punctuality, settling in class (even after play), constructive play, social play, as well as imaginative and functional play.

"Nature play is all about playing freely with and in nature. It's about making mud pies, creating stick forts, having an outdoor adventure, and getting dirty," Dankiw says.

"These are all things that children love to do, but unfortunately, as society has become more sedentary, risk averse and time-poor, fewer children are having these opportunities.

"By playing in nature, children can build their physical capabilities - their balance, fitness, and strength. And, as they play with others, they learn valuable negotiation skills, concepts of sharing and friendships, which may contribute to healthy emotional and social resilience."

EVANSTON, Ill. --- Using data from the Northwestern Juvenile Project, Linda Teplin of Northwestern University will examine the persistence and progression of substance use disorders -- including opioid use disorder -- in delinquent youth in a talk at the American Association for the Advancement of Science (AAAS) annual meeting in Seattle on Friday, Feb. 14.

Substance use disorders are the most common disorders among delinquent youth. However, little is known about the persistence and progression of these disorders during adulthood.

Teplin will present "Persistence and Progression of Substance Use Disorders in At-risk Youth," which includes an examination of disorders after detention, up to median age 31. Her presentation will focus on differences by sex and among African-Americans, Hispanics and non-Hispanic whites.

She is the Owen L. Coon Professor of Psychiatry and Behavioral Sciences and director of the Health Disparities and Public Policy Program in the department of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.

Teplin's presentation is part of the session "The Drug Abuse Crisis: Key Findings From Three Landmark Studies" to be held from 8 to 9:30 a.m. on Friday, Feb. 14, at the Washington State Convention Center.

Researchers at Kobe University's Graduate School of Medicine have developed the world's first congenital pituitary hypoplasia (CPH) (*1,*2) model using patient-derived iPS cells. The research group consisting of Associate Professor TAKAHASHI Yutaka, medical researcher MATSUMOTO Ryusaku and Professor AOI Takashi et al. succeeded in using the model to illuminate the mechanisms underlying CPH. The team has been attempting to apply this model to other pituitary diseases and drug discovery.

The results of this study were published in the American Scientific Journal 'J Clinical Investigation' on December 17, 2019.

Main points:

>Successfully created the world's first model of pituitary disease using human iPS cells.
>iPS cells were generated from a patient with CPH. These iPS cells enabled the recapitulation of the disease in vitro; an impaired differentiation into the pituitary.
>The causal gene mutation was identified in the patient by exome sequencing analysis (*3). Using this disease model, it was revealed that a deficiency in the FGF10 produced in the neighboring hypothalamus (*4) caused CPH.
>Expected application of this model to other pituitary diseases, leading to the clarification of the underlying mechanisms and drug discovery.

Research Background

Hypopituitarism caused by CPH is not uncommon and it is sometimes life-threating. Patients with this disease require lifelong hormone replacement therapy. The causes and underlying mechanisms are not well understood.

Prior research on pituitary diseases has been mainly conducted using animal models, such as knock out mouse (*5). However, sometimes there are differences in the phenotypes between animal and human. This means that human models are necessary in order to fully understand the mechanisms of such diseases.

In recent years, iPS (induced pluripotent stem) cells have been utilized in the development of disease models, regenerative medicine, and drug discovery. In addition, a method using iPS cells to induce differentiation of both the pituitary and hypothalamus in vitro has been developed; however it had yet to be applied to pituitary disease modeling.

With this in mind, researchers at Kobe University's Graduate School of Medicine have applied this strategy to develop a human model of CPH in vitro using iPS cells to understand the pathophysiology and causes of the disease (Figure 1).

Research Methodology

iPS cells were generated from blood samples taken from a patient with CPH. This patient exhibited congenital pituitary hypoplasia and was undergoing pituitary hormone replacement therapy. These patient-derived iPS cells were utilized to elucidate the underlying mechanisms in vitro. Interestingly, control iPS cells differentiated into hormone-producing cells, however, the CPH patient-derived iPS cells were not able to differentiate into these cells. Further analysis of the differentiation process revealed that the transcription factor LHX3, which is essential for pituitary differentiation, was not expressed in the pituitary progenitor from patient-derived iPS cells (Figure 2). Exome sequencing analysis revealed a mutation in the OTX2 gene and that its function was impaired. Correction of the OTX2 mutation in patient-derived iPS cells restored the pituitary differentiation ability, demonstrating that the OTX2 mutation was responsible.

Interactions between the pituitary and the adjacent hypothalamus are essential for pituitary differentiation and regulation. An advantage of this model is that it can simultaneously develop the pituitary and hypothalamus in vitro from iPS cells. This allowed the researchers to investigate the significance of interaction between these tissues. They clarified that the hypothalamus was responsible for the disease by performing chimera formation experiments using both patient-derived iPS cells and healthy iPS cells. Subsequent analysis exhibited that FGF10 (fibroblast growth factor 10) from the hypothalamus plays a pivotal role in the expression of the transcription factor LHX3 in the pituitary. Furthermore, expression levels of LHX3 were restored by adding FGF10 in vitro. These results demonstrated that FGF10 deficiency in the hypothalamus associated with OTX2 mutation was responsible.

Collectively, the OTX2 mutation caused a decrease in hypothalamic FGF10, resulting in a lack of LHX3 expression in the oral ectoderm, which is the precursor of the pituitary. Consequently, loss of LHX3 caused apoptosis of the precursor cells, therefore causing the impaired development of the pituitary. These underlying mechanisms were illuminated for the first time by this study (Figure 3).

This pituitary disease model utilizing human iPS cells has elucidated the detailed underlying mechanisms, which animal models were unable to reveal.

Further Research

This research revealed the pathophysiology of CPH through disease-specific iPS cells (*6). Furthermore, the model was also useful for understanding the pituitary differentiation process in humans.

This research team is also investigating the causes, pathogenesis and treatment of other pituitary diseases (such as autoimmune disorders and pituitary tumors) using the same strategy. In particular, they are continuing to develop pituitary disease models to investigate the pathophysiology and precise mechanisms underlying the 'Anti-PIT-1 antibody syndrome' (*7), which is a novel type of autoimmune pituitary disease that the team has established as a new clinical entity. Using this model, they have already demonstrated the antigen presentation of PIT-1 protein epitope on the anterior pituitary cells derived from patient iPS cells.

In addition, there are many other incurable pituitary diseases, for which the causes remain unknown. It is hoped that these iPS cell-based research methods for the diseases will lead to the clarification of the underlying mechanisms and drug discovery.

What clues does our memory use to connect a current situation to a situation from the past? The results of a study conducted by researchers from the University of Geneva (UNIGE), Switzerland, - working in collaboration with CY Cergy Paris University in France - contrast sharply with the explanations found until now in the existing literature. The researchers have demonstrated that similarities in structure and essence (the heart of a situation) guide our recollections rather than surface similarities (the general theme, for example, or the setting or protagonists). It is only when individuals lack sufficient knowledge that they turn to the surface clues - the easiest to access - to recollect a situation. These results, published in the journal Acta Psychologica, are particularly relevant in the field of education. They underline the need to focus on the conceptual aspects of situations that are tackled in class to help pupils make use of the relevant features, and not to be misled by apparent similarities.

Our memory organises our experiences based on two main features: surface features, which include superficial similarities between situations (the setting, for instance, or the people present); and structural features, which characterize the depth of the situation and its key issues. The existing literature argues that people tend to favour surface clues when dealing with a given situation. "This is often attributed to the fact that our brain looks for the easiest option when it comes to memory recall, and that in general the surface of a recollection correlates to its structure", begins Emmanuel Sander, a professor in the Faculty of Psychology and Educational Sciences (FPSE) at UNIGE.

On analysing the existing literature, the researchers realised that earlier work was based on frequent recalls of situations that did not only share surface features but also a part of the structure. They also noticed that participants did not possess the knowledge needed to grasp the deep stucture of the situations presented to them. "We wondered whether the surface features really dominate the structural features when a situation elicits the recollection of another one", explains Lucas Raynal, a researcher at CY Cergy Paris Université and an FPSE associate member.

Essence more important than form

To solve this problem, the researchers created six narratives that shared the surface, the structure or neither of the two (known as distractors) with a target narrative. "Our target narrative told the story of a pizzaiolo , Luigi, who worked in a busy square. A second pizzaiolo, Lorenzo, set up shop next door in direct competition with Luigi. But Lorenzo's pizzas weren't as good as Luigi's, who gave the newcomer a piece of advice about how to improve the way he made his pizzas. To thank him, Lorenzo moved his pizzeria to put an end to the direct competition", explains Evelyne Clément, a professor at CY Cergy Paris University. Some of the six stories created as part of the research put the emphasis on the pizzaioli; others emphasised the principle of competition that was amicably resolved; and others still did not highlight either of these features.

In the first experiment, the six stories were read by 81 adult participants before they came face-to-face with the story of Luigi and Lorenzo. They then had to say to what previous situation they related the story. "81.5% of the participants chose the story that had the same structure, i.e. the competition principle, compared to 18.5% for the account that shared the same surface (pizzaioli) and 0% for the distracting stories", says professor Sander. This indicates a clear predominance for structural features, contrary to the claims made by the existing literature. The researchers now took the experiment a stage further: they presented six stories to other participants once more, but this time the story highlighting the earlier competition principle was accompanied by several stories about pizzaioli (experiment 2). The third and fourth experiment also aimed to confirm the robustness of the results by increasing the number of stories to be remembered and by distracting the participants with activities unrelated to the task during a variable timeframe (5 minutes in experiment 3 and 45 minutes in experiment 4) before the target story was presented. "The results of the four experiments were clear-cut, with around 80% of participants choosing the story with the same structure rather than those that shared the same surface or had no similarity", points out Lucas Raynal.

And what happens at school?

The research calls into question the received idea that our memory is guided by the principle of the easiest option and that surface features dominate recall. "A human being's way of remembering is less superficial than was thought, and in all likelihood favours structure over surface", adds professor Sander. "It's only out of ignorance that superficial clues will take precedence. This is a real challenge at school, because educational concepts can be opaque when students begin learning, hence the risk is that the surface would be prioritised." It follows that these results play a fundamental role in education. "It's a question of highlighting the relevant features for students. In other words, the conceptual aspects of the notions that are taught, helping them categorise the situations that are worked on in class by overlooking the superficial aspects that mislead them", says professor Clément by way of conclusion.

Experts have been unable to explain why cells from bacteria to humans leak essential chemicals necessary for growth into their environment. New mathematical models reveal that leaking metabolites - substances involved in the chemical processes to sustain life with production of complex molecules and energy - may provide cells both selfish and selfless benefits.

Previously, biologists could only say that leaking is an inherent property of cell membranes caused by fundamental rules of chemistry.

"It is in the nature of membranes to leak, but if leaking is undesirable, why has evolution not stopped it? This question of 'Why?' was never solved," said Professor Kunihiko Kaneko, a theoretical biology expert from the University of Tokyo Research Center for Complex Systems Biology.

The research team used calculations that can measure the changes of multiple factors over time, called dynamical-system modeling, in combination with computer simulations. In this modeling, the researchers considered the nonlinear processes for cell growth where a cell takes in external nutrients and converts them to cellular body and energy by intracellular chemical reactions, by representing the cellular state as the concentrations of intracellular chemicals including nutrients, enzymes, and components to synthesize cellular body. All calculations assumed that the model cells were in a steady state of growth where their internal metabolism and relative concentration of chemicals inside the cells were all stable.

The calculations were designed to identify what types of chemical synthesis pathways would become more efficient if some of their components leaked out to the environment. The mathematical models of chemical synthesis paths are simpler than the complex branching pathways in living cells, but allow researchers to look for fundamental patterns.

Researchers identified two such model chemical pathways with catalytic reactions that use enzymes to enhance the reaction rate, which they call the "flux control" and "growth-dilution" mechanisms. In both mechanisms, leaking one essential upstream chemical component of the pathway allows the end product to be produced more efficiently. Thus, leaking is something cells do to selfishly enhance their own growth.

"In theory, the flux control mechanism enhances the pathway for biomass synthesis by the leakage of an essential chemical in an alternative branching pathway, whereas the growth-dilution mechanism enhances the biomass synthesis by the leakage of the precursors of biomass (e.g., amino acids) essential for cell growth. These are a result of the balance between chemical reactions and concentration dilution associated with cellular volume growth," said Jumpei Yamagishi, a first-year graduate student who has worked in Kaneko's laboratory since his undergraduate years.

The models that the research team created so far only consider one type of cell at a time. However, leaking upstream components might become a problem for cells living only with identical types of cells leaking the same components.

"In many cases, if all cells are leaking the same molecule, their environment will become 'polluted.' But if multiple cell types live together, then they can leak one chemical and use a different chemical leaked by the others," said Kaneko.

This mutually beneficial exchange of leaked essential nutrients may be a selfless way to enhance the growth of the whole community of cells.

"Our work may partially answer why the natural environment is so different from artificial lab conditions where bacteria are grown in pure monocultures, but we will need additional models to be sure," said Yamagishi.

The researchers are planning to design more complex mathematical calculations to better simulate natural conditions where multiple types of cells coexist to see if that reveals other types of synthesis pathways that benefit from leaking.

A promising molecule has offered hope for a new treatment that could stop or slow Parkinson's, something no treatment can currently do.

Researchers from the University of Helsinki found that molecule BT13 has the potential to both boost levels of dopamine, the chemical that is lost in Parkinson's, as well as protect the dopamine-producing brain cells from dying.

The results from the study, co-funded by Parkinson's UK and published online today in the journal Movement Disorders, showed an increase in dopamine levels in the brains of mice following the injection of the molecule. BT13 also activated a specific receptor in the mouse brains to protect the cells.

Typically, by the time people are diagnosed with Parkinson's, they have already lost 70-80 per cent of their dopamine-producing cells, which are involved in coordinating movement.

While current treatments mask the symptoms, there is nothing that can slow down its progression or prevent more brain cells from being lost, and as dopamine levels continue to fall, symptoms get worse and new symptoms can appear.

Researchers are now working on improving the properties of BT13 to make it more effective as a potential treatment which, if successful, could benefit the 145,000 people living with Parkinson's in the UK.

The study builds on previous research on another molecule that targets the same receptors in the brain, glial cell line-derived neurotrophic factor (GDNF), an experimental treatment for Parkinson's which was the subject of a BBC documentary in February 2019. While the results were not clear cut, GDNF has shown promise to restore damaged cells in Parkinson's.

However, the GDNF protein requires complex surgery to deliver the treatment to the brain because it's a large molecule that cannot cross the blood-brain barrier - a protective barrier that prevents some drugs from getting into the brain.

BT13, a smaller molecule, is able to cross the blood-brain barrier - and therefore could be more easily administered as a treatment, if shown to be beneficial in further clinical trials.

Professor David Dexter, Deputy Director of Research at Parkinson's UK, said:

"People with Parkinson's desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms.

"One of the biggest challenges for Parkinson's research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson's.

"More research is needed to turn BT13 into a treatment to be tested in clinical trials, to see if it really could transform the lives of people living with Parkinson's."

Dr Yulia Sidorova, lead researcher on the study, said: "We are constantly working on improving the effectiveness of BT13. We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

"Our ultimate goal is to progress these compounds to clinical trials in a few coming years."

Water is split into hydrogen and oxygen by electrolysis, but if CO2 is also added to the mixture, compounds can be generated to make textiles, diapers and even spirits. American scientists, led by a Spaniard, have developed a catalyst that accelerates this reaction, while also removing a greenhouse gas.

A team of researchers from Canada and the U.S. has developed a catalyst that quickly and efficiently converts carbon dioxide into simple chemicals. In this way, they transform the most important greenhouse gas into useful products for industry.

"The technology of water electrolysers is well known: they transform water and electricity into hydrogen and oxygen, but in our case, we add CO2 to the cocktail and, instead of producing hydrogen, we can generate various hydrocarbons, such as ethylene, which is the most widely used organic compound worldwide," researcher F. Pelayo García de Arquer, of the University of Toronto (Canada), has told SINC.

"Thus," he explains, "we can obtain raw materials for the manufacture of products such as construction materials, textiles, paints, electronic device components, diapers... or even spirits."

The key to the new device is a polymer coating that facilitates the transport of CO2 through the surface of the metal or electrode of the catalyst. Carbon dioxide, generally speaking, has difficulty penetrating aqueous solutions and reaching the entire surface of this material; so when the flow of electrons (electric current) is increased to carry out the reaction, there is not enough CO2 to be transformed.

But the authors, who have published their study in Science magazine, show that this limitation can be overcome: "We have discovered that a certain configuration of ionomers (polymers that conduct ions and water to the catalyst) allows us to considerably increase the ease with which CO2 is distributed along the catalytic surface, thus allowing us to achieve higher productivity," García de Arquer points out.

This ionomer coating contains hydrophobic (water-repellent) and hydrophilic (water-attracting) parts and is grouped together to form an ultra-thin layer of about 10 nanometres that helps to maintain the reaction where, from the CO2 gas and the hydrogen in the water (H+ protons), the hydrocarbon is built.

"About two years ago, CO2 electrolysis systems were limited to electrical outputs or currents of tens of milliamps per square centimetre, meaning that only a few molecules of this gas can be transformed into something useful," says the researcher, "but our discovery allows them to operate at currents a hundred times higher, more than one ampere per square centimetre. In this way, many more CO2 molecules can be transformed, reaching activities that were unthinkable a few years ago."

Another benefit that García de Arquer highlights is that the source of electricity needed for the process "can be perfectly renewable, such as solar, wind or hydraulic energy, so it is a way of building likewise renewable hydrocarbons."

The researchers are now working on further increasing the efficiency of the system and its stability, which, although now at about tens of hours, is still far from the thousands of operating hours of the water electrolysers.