Culture

Australia needs a new whooping cough vaccine to ensure our most vulnerable are protected from the emergence of superbug strains, new UNSW research has shown.

The current vaccine, widely used since 2000, targets three antigens in the bacteria of the highly contagious respiratory disease which can be fatal to infants.

All babies under six months old - in particular, newborns not protected by maternal immunisation - are at risk of catching the vaccine-preventable disease because they are either too young to be vaccinated or have not yet completed the three-dose primary vaccine course.

Australia's whooping cough epidemic from 2008 to 2012 saw more than 140,000 cases - with a peak of almost 40,000 in 2011 - and revealed the rise of evolving strains able to evade vaccine-generated immunity.

In a series of UNSW studies, with the latest published today in Vaccine, UNSW researchers took this knowledge further and showed, in a world-first discovery, that the evolving strains made additional changes to better survive in their host, regardless of that person's vaccination status. They also identified new antigens as potential vaccine targets.

First author and microbiologist Dr Laurence Luu, who led the team of researchers with Professor Ruiting Lan, said whooping cough's ability to adapt to vaccines and survival in humans might be the answer to its surprise resurgence despite Australia's high vaccination rates.

"We found the whooping cough strains were evolving to improve their survival, regardless of whether a person was vaccinated or not, by producing more nutrient-binding and transport proteins, and fewer immunogenic proteins which are not targeted by the vaccine," Dr Luu said.

"This allows whooping cough bacteria to more efficiently scavenge nutrients from the host during infection, as well as to evade the body's natural immune system because the bacteria are making fewer proteins that our body recognises.

"Put simply, the bacteria that cause whooping cough are becoming better at hiding and better at feeding - they're morphing into a superbug."

Dr Luu said it was therefore possible for a vaccinated person to contract whooping cough bacteria without symptoms materialising.

"So, the bacteria might still colonise you and survive without causing the disease - you probably wouldn't know you've been infected with the whooping cough bacteria because you don't get the symptoms," he said.

"Another issue with the vaccine is that immunity wanes quickly - so, we do need a new vaccine that can better protect against the evolving strains, stop the transmission of the disease and provide longer lasting immunity."

Vaccination still key but new vaccine needed

Prof Lan said while he would like to see a new vaccine developed and introduced in the next five to 10 years, the research team's important discovery did not render Australia's whooping cough vaccine redundant.

"It is critical that people are vaccinated to prevent the spread of whooping cough - the current vaccine is still effective for protecting against the disease - but new vaccines need to be developed in the long-term," Prof Lan said.

"We need more research to better understand the biology of the whooping cough bacteria, how they cause disease and what proteins are essential for the bacteria to cause infection, so that we can target these proteins in a new and improved vaccine.

"This will all help to future-proof new vaccines against the evolving whooping cough strains."

Dr Luu agreed it was crucial that Australia maintained its high vaccination coverage for whooping cough.

"Although the number of whooping cough cases has increased during the past decade, it's still nowhere near as high as what it was before the introduction of whooping cough vaccines," Dr Luu said.

"Therefore, we emphasise that Australia must maintain its high vaccination coverage to protect vulnerable newborns who are not protected by maternal immunity and cannot complete the three-dose primary vaccine course until they are six months old.

"So, vaccination is especially important for children, people who are in contact with children and pregnant women who need the vaccine to produce antibodies to protect their newborns from developing whooping cough in the first few weeks of life."

In addition to babies under six months having a high risk of catching the disease, the elderly, people living with someone who has whooping cough and people who have not had a booster in the past 10 years, are also most at risk.

Whooping cough is characterised by a "whooping" sound and sufferers find it difficult to breathe.

The disease is more common during spring and spreads when an infected person coughs or sneezes and other people breathe in the bacteria.

An analysis of cyclical changes in the light spectrum emitted by Proxima Centauri, the star closest to the Sun, suggests it may be orbited by a second planet. Mario Damasso and colleagues present data suggesting that this candidate planet orbits Proxima Centauri every 5.2 years and may be a "super-Earth", with a mass higher than Earth's, though much lower than that of the Solar System ice giants Uranus and Neptune. If its existence is confirmed, this planet may provide insights into how low-mass planets form around low-mass stars. It could also challenge models of how super-Earths are born; most are believed to form near the "snowline," the minimum distance from a star at which water can turn to solid ice, but the candidate planet's orbit lies far beyond this sweet spot. A previous study of Proxima Centauri using the Atacama Large Millimeter/submillimeter Array (ALMA)--an astronomical observatory in northern Chile--reported an unknown source of light spectrum signals that could belong to a second planet or may simply have been the product of a neighboring galaxy or an unrelated phenomenon. To better understand if the signal originated from another planet orbiting the star, Mario Damasso and colleagues analyzed a 17.5-year-long time series of high-precision radial velocities using an exoplanet detection method that tracks a star's light spectrum. If this spectrum oscillates between red and blue, it indicates that the star is moving towards and away from the Earth at regular intervals, a cycle usually caused by an orbiting body's presence. The researchers found that the signal occurs over a 1,900-day period, suggesting it is likely unrelated to cyclical shifts in the star's magnetic field. However, the authors emphasize that more evidence is needed to confirm their conclusion.

The brain is a sort of fortress, equipped with barriers designed to keep out dangerous pathogens. But protection comes at a cost: These barriers interfere with the immune system when faced with dire threats such glioblastoma, a deadly brain tumor for which there are few effective treatments.

Yale researchers have found a novel way to circumvent the brain's natural defenses when they're counterproductive by slipping immune system rescuers through the fortresses' drainage system, they report Jan. 15 in the journal Nature.

"People had thought there was very little the immune system could do to combat brain tumors," said senior corresponding author Akiko Iwasaki. "There has been no way for glioblastoma patients to benefit from immunotherapy."

Iwasaki is the Waldemar Von Zedtwitz Professor of Immunobiology and professor of molecular, cellular, and developmental biology and an investigator for the Howard Hughes Medical Institute.

While the brain itself has no direct way for disposing of cellular waste, tiny vessels lining the interior of the skull collect tissue waste and dispose of it through the body's lymphatic system, which filters toxins and waste from the body. It is this disposal system that researchers exploited in the new study.

These vessels form shortly after birth, spurred in part by the gene known as vascular endothelial growth factor C, or VEGF-C.

Yale's Jean-Leon Thomas, associate professor of neurology at Yale and senior co-corresponding author of the paper, wondered whether VEGF-C might increase immune response if lymphatic drainage was increased. And lead author Eric Song, a student working in Iwasaki's lab, wanted to see if VEGF-C could specifically be used to increase the immune system's surveillance of glioblastoma tumors. Together, the team investigated whether introducing VEGF-C through this drainage system would specifically target brain tumors.

The team introduced VEGF C into the cerebrospinal fluid of mice with glioblastoma and observed an increased level of T cell response to tumors in the brain. When combined with immune system checkpoint inhibitors commonly used in immunotherapy, the VEGF-C treatment significantly extended survival of the mice. In other words, the introduction of VEGF-C, in conjunction with cancer immunotherapy drugs, was apparently sufficient to target brain tumors.

"These results are remarkable," Iwasaki said. "We would like to bring this treatment to glioblastoma patients. The prognosis with current therapies of surgery and chemotherapy is still so bleak."

Astronomers from UCLA's Galactic Center Orbits Initiative have discovered a new class of bizarre objects at the center of our galaxy, not far from the supermassive black hole called Sagittarius A*. They published their research today in the journal Nature.

"These objects look like gas and behave like stars," said co-author Andrea Ghez, UCLA's Lauren B. Leichtman and Arthur E. Levine Professor of Astrophysics and director of the UCLA Galactic Center Group.

The new objects look compact most of the time and stretch out when their orbits bring them closest to the black hole. Their orbits range from about 100 to 1,000 years, said lead author Anna Ciurlo, a UCLA postdoctoral researcher.

Ghez's research group identified an unusual object at the center of our galaxy in 2005, which was later named G1. In 2012, astronomers in Germany made a puzzling discovery of a bizarre object named G2 in the center of the Milky Way that made a close approach to the supermassive black hole in 2014. Ghez and her research team believe that G2 is most likely two stars that had been orbiting the black hole in tandem and merged into an extremely large star, cloaked in unusually thick gas and dust.

"At the time of closest approach, G2 had a really strange signature," Ghez said. "We had seen it before, but it didn't look too peculiar until it got close to the black hole and became elongated, and much of its gas was torn apart. It went from being a pretty innocuous object when it was far from the black hole to one that was really stretched out and distorted at its closest approach and lost its outer shell, and now it's getting more compact again."

"One of the things that has gotten everyone excited about the G objects is that the stuff that gets pulled off of them by tidal forces as they sweep by the central black hole must inevitably fall into the black hole," said co-author Mark Morris, UCLA professor of physics and astronomy. "When that happens, it might be able to produce an impressive fireworks show since the material eaten by the black hole will heat up and emit copious radiation before it disappears across the event horizon."

But are G2 and G1 outliers, or are they part of a larger class of objects? In answer to that question, Ghez's research group reports the existence of four more objects they are calling G3, G4, G5 and G6. The researchers have determined each of their orbits. While G1 and G2 have similar orbits, the four new objects have very different orbits.

Ghez believes all six objects were binary stars -- a system of two stars orbiting each other -- that merged because of the strong gravitational force of the supermassive black hole. The merging of two stars takes more than 1 million years to complete, Ghez said.

"Mergers of stars may be happening in the universe more often than we thought, and likely are quite common," Ghez said. "Black holes may be driving binary stars to merge. It's possible that many of the stars we've been watching and not understanding may be the end product of mergers that are calm now. We are learning how galaxies and black holes evolve. The way binary stars interact with each other and with the black hole is very different from how single stars interact with other single stars and with the black hole."

Ciurlo noted that while the gas from G2's outer shell got stretched dramatically, its dust inside the gas did not get stretched much. "Something must have kept it compact and enabled it to survive its encounter with the black hole," Ciurlo said. "This is evidence for a stellar object inside G2."

"The unique dataset that Professor Ghez's group has gathered during more than 20 years is what allowed us to make this discovery," Ciurlo said. "We now have a population of 'G' objects, so it is not a matter of explaining a 'one-time event' like G2."

The researchers made observations from the W.M. Keck Observatory in Hawaii and used a powerful technology that Ghez helped pioneer, called adaptive optics, which corrects the distorting effects of the Earth's atmosphere in real time. They conducted a new analysis of 13 years of their UCLA Galactic Center Orbits Initiative data.

In September 2019, Ghez's team reported that the black hole is getting hungrier and it is unclear why. The stretching of G2 in 2014 appeared to pull off gas that may recently have been swallowed by the black hole, said co-author Tuan Do, a UCLA research scientist and deputy director of the Galactic Center Group. The mergers of stars could feed the black hole.

The team has already identified a few other candidates that may be part of this new class of objects, and are continuing to analyze them.

Ghez noted the center of the Milky Way galaxy is an extreme environment, unlike our less hectic corner of the universe.

"The Earth is in the suburbs compared to the center of the galaxy, which is some 26,000 light-years away," Ghez said. "The center of our galaxy has a density of stars 1 billion times higher than our part of the galaxy. The gravitational pull is so much stronger. The magnetic fields are more extreme. The center of the galaxy is where extreme astrophysics occurs -- the X-sports of astrophysics."

Ghez said this research will help to teach us what is happening in the majority of galaxies.

Other co-authors include Randall Campbell, an astronomer with the W.M. Keck Observatory in Hawaii; Aurelien Hees, a former UCLA postdoctoral scholar, now a researcher at the Paris Observatory in France; and Smadar Naoz, a UCLA assistant professor of physics and astronomy.

The research is funded by the National Science Foundation, W.M. Keck Foundation and Keck Visiting Scholars Program, the Gordon and Betty Moore Foundation, the Heising-Simons Foundation, Lauren Leichtman and Arthur Levine, Jim and Lori Keir, and Howard and Astrid Preston.

In July 2019, Ghez's research team reported on the most comprehensive test of Einstein's iconic general theory of relativity near the black hole. They concluded that Einstein's theory passed the test and is correct, at least for now.

Tokyo, Japan--Earthquakes are generally thought of as abrupt, violent events that last for only moments. However, movement of the Earth's tectonic plates is often less sudden and more sustained - slow earthquakes can last for hours, months, or even longer.

Researchers led by The University of Tokyo have discovered signals due to slow slip events with large amounts of slip along the Nankai Trough subduction zone just southeast of Japan, reported in a new study published in Science Advances.

Slow earthquakes such as these slow slip events are exceedingly difficult to detect using conventional seismological techniques, especially in offshore areas. However, because understanding slow earthquake events is essential for evaluating the risks posed by more violent seismic events like megathrust earthquakes, new methods have been developed to address this problem.

For this research, a Global Navigation Satellite System-Acoustic ranging (GNSS-A) combination technique was used to monitor changes in the absolute position of the seafloor. According to study first author Yusuke Yokota, "GNSS-A was first proposed in the 1980s, but has really been developed and applied over the last two decades for detection of slow earthquakes. This method combines satellite detection of movements at the sea surface with undersea data from an acoustic ranging system, and can reliably detect deformation of 5 cm or more in offshore areas."

Slip sites generally were detected below the shallow undersea interplate boundary of the trough, adjacent to regions with strong interplate coupling. Recurrent offshore slow slip event signals were detected in the Kii and Bungo Channel areas, and were correlated with strong activity of very low frequency seismic events.

Slow slip event signals were not clearly identified in the Tosa Bay or Enshu-nada regions, although this may have been a matter of insufficient resolution. However, their absence may also support the possibility that these are the main slip regions of the megathrust zone of the Nankai Trough.

"Differences in the features between these regions may be related to earthquake history and reflect different friction conditions," explains Dr. Yokota. "Detailed understanding of these friction conditions and how they relate spatiotemporally to megathrust earthquake events is essential for accurate earthquake simulation. Therefore, studying these newly discovered slow slip events in the Nankai Trough will contribute to earthquake disaster prevention and preparedness."

In addition to informing earthquake disaster research, these findings also shed light on the marine sedimentary environment and plate tectonics of the Nankai Trough.

Brightly coloured male songbirds not only have to attract the female's eye, but also make sure their sperm can last the distance, according to new research.

In the study, published today in the Royal Society journal Biology Letters, a team of scientists led by Dr Kate Durrant from the School of Life Sciences at the University of Nottingham, looked at how evolution shapes the plumage and the sperm cells of songbird species so that they mate successfully and pass on their genes.

Previous studies have focussed on a bird's appearance alone, but this is the first study that has looked at this together with the shape of the sperm, to understand if intense competition shapes both plumage (to compete before mating) and the sperm (to compete after mating).

The team looked at 278 species of song bird from around the world and a combination of data on their plumage and the shape of their sperm, to see how they have evolved to ensure successful mating.

The eye-catching plumage of some male songbirds has long been explained as a result of sexual selection: brighter males compete more successfully for mates, and leave more offspring, so evolution favours them. Female birds, by contrast, remain drab, because for them it is more important to be camouflaged on the nest.

How much competition for mates a male song bird faces varies between species, and depends on factors such as the number of available females, how dense the population is, and other things such as the structure of the vegetation they are in.

Dr Durrant said: "The intensity of sexual selection varies between species. If mate competition is really strong, not only are males really colourful and attractive, but they also need to have the best sperm too if they are going to compete."

The 'midpiece' in the bird's sperm produces energy-containing molecules, called ATP, to power movement. Previously, experts thought that if the sperm had a large midpiece, it produced a lot of ATP, and the sperm 'swam' really quickly and got to the egg first. Whilst this is true in some species, it is not always the case and it is more likely that a large midpiece allows the sperm to last longer, rather than swim faster.

Data on plumage from previous studies were used, together with data on the shape of sperm, for 278 species of song birds. The team found that males from species with more elaborate and colourful plumage, had longer sperm midpieces, which allows the sperm to last for a long time after the male mates with the female, who then stores it for when she is ready to release an egg.

"In a really competitive environment, lots of males are competing with each other for the female's attention, and there can be a high number that mate with the same female, and this is where sperm and how long it lasts is really important," said Dr Durrant.

"If a female bird mates with a number of males, she will keep the sperm until she is ready to release an egg. At this point, long-lived sperm can reactivate and fertilise the egg. So it is not enough to be colourful, you have to have the total package and produce sperm that can last.

"What we are seeing is what evolution has done to these species to solve the problem of competing for mates," adds Dr Durrant.

BIRMINGHAM, Ala. - In preclinical experiments, University of Alabama at Birmingham researchers have revealed a key missing piece of the Alzheimer's disease puzzle. That allowed proof-of-concept experiments -- using an existing drug -- that dramatically reduced Alzheimer's pathology and symptoms in two mouse models, potentially offering an immediate treatment for this devastating disease.

The research was published today in the journal Science Translational Medicine. It included human brain tissue analysis and longitudinal clinical data that supported the in vivo mouse model data.

"Our study provides translational insights into mechanisms underlying amyloid-beta protein toxicity, which may have strong implications for future drug design," said Qin Wang, M.D., Ph.D. "It identifies an amyloid-beta/G protein-coupled receptor interaction that represents an attractive, disease-specific therapeutic target for Alzheimer's disease."

Interestingly, the pathologic mechanism found may also explain the failure of numerous Alzheimer's clinical trials that targeted reduction of the culprit in Alzheimer's disease -- amyloid protein buildup in the brain.

At the UAB School of Medicine, Wang is professor in the Department of Cell, Developmental and Integrative Biology.

It is widely accepted, Wang says, that buildup of amyloid-beta oligomers in the brain acts as a trigger to induce pathological changes in tau protein, and that altered tau protein is the bullet that targets and kills neurons in Alzheimer's disease. However, the pathway connecting these two was unknown.

Wang and colleagues have found that amyloid-beta oligomers hijack norepinephrine signaling at brain neurons, which falsely redirects this signal to activate a kinase called GSK3-beta. That activated kinase enzyme, in turn, hyper-phosphorylates tau protein, making it toxic for neurons.

This rewiring of the norepinephrine signaling takes place at a cell membrane receptor on the surface of neurons called the alpha-2A adrenergic receptor. This receptor is part of a large family of G protein-coupled receptors that detect molecules outside of a cell and then activate an internal signal that causes a cellular response. While a certain concentration of amyloid-beta oligomers can activate GSK3-beta, the presence of norepinephrine vastly sensitized that activation by up to two orders of magnitude, Wang and colleagues found.

Thus, the UAB researchers speculate that nanomolar concentrations of amyloid-beta oligomers in human brains induce a pathogenic GSK3-beta/tau cascade at the earliest stages of Alzheimer's disease. This theory suggests why multiple clinical trials to reduce levels of amyloid-beta oligomers in Alzheimer's disease patients have failed -- they cannot reduce the amyloid levels to such low concentrations.

Study details

The alpha-2A adrenergic receptor normally works this way -- it has a binding site for the neurotransmitter norepinephrine, and that binding activates a signaling process that mobilizes the brain and body for action. The UAB researchers found that amyloid-beta oligomers bind to a separate site on the alpha-2A adrenergic receptor, distinct from the site for norepinephrine binding. This initiates the pathological hijacking.

Such binding at a second site is called allosteric binding. In G protein-coupled receptors, allosteric ligands are known to often alter signaling of the receptor as part of normal physiology. After the researchers realized the allosteric binding, they searched to see which kinase might be activated by that binding, which is how they identified GSK3-beta.

Some clinical data supports this mechanism. The researchers found that alpha-2A adrenergic receptor from the postmortem prefrontal cortexes of Alzheimer's disease patients had a significant increase in alpha-2A adrenergic receptor activity, compared with non-demented, low-pathology controls. Also, epidemiologic analysis of cases from the National Alzheimer's Coordinating Center showed that taking the drug clonidine -- an activator of alpha-2A adrenergic receptor used to lower blood pressure -- worsened cognitive function in patients with cognitive deficits. Furthermore, the adverse effects of clonidine were stronger in patients with more severe dementia. Clonidine usage had no effect on subjects with normal cognition.

Wang and colleagues tested an existing drug -- idazoxan -- in a mouse model of Alzheimer's. Idazoxan is an alpha-2A adrenergic receptor antagonist that has been under investigation in clinical trials for depression. The hypothesis was that idazoxan blockage of alpha-2A adrenergic receptor in the presence of amyloid-beta pathology would show therapeutic potential. That was borne out in Alzheimer's-model mice.

The mice were treated with idazoxan for eight weeks beginning at age 8 months, a point when amyloid-beta plaques are already present in the brain and alpha-2A adrenergic receptor shows enhanced activity. Compared with controls, the UAB researchers found that: 1) Idazoxan reversed hyperactivation of GSK3-beta in the mouse brains, giving additional support for the critical role of alpha-2A adrenergic receptor in mediating amyloid-beta-induced activation of GSK3-beta in vivo; 2) In the cerebral cortex of idazoxan-treated Alzheimer's-model mice, the extent of amyloid-beta load was lower, showing that blockage of alpha-2A adrenergic receptor slowed the progression of amyloid-beta pathology; 3) Idazoxan treatment decreased the density of inflammatory microglial cells, suggesting a reduction of neuroinflammation; 4) Idazoxan treatment reduced tau hyper-phosphorylation, suggesting that blockade of the alpha-2A adrenergic receptor effectively alleviated amyloid-beta-induced tau pathology; and 5) Idazoxan-treated Alzheimer's-model mice performed nearly as well as normal mice, and significantly better than untreated Alzheimer's-model mice, in two tests for cognitive function.

"These data collectively demonstrate that blocking norepinephrine signaling through the alpha-2A adrenergic receptor is an effective strategy to ameliorate pathological and cognitive deficits associated with amyloid-beta," Wang said.

"The alpha-2A adrenergic receptor blockers such as idazoxan have been developed for use in other disorders, and repurposing these drugs could be a potentially effective, readily available strategy for Alzheimer's disease treatment," Wang said. "In addition, our data suggest that the amyloid-beta/alpha-2A adrenergic receptor interaction is an attractive, disease-specific therapeutic target for Alzheimer's because the alpha-2A adrenergic receptor/GSK3-beta/tau cascade can be activated only in the presence of amyloid-beta oligomers."

"Directly targeting the allosteric amyloid-beta/alpha-2A adrenergic receptor interface would not interfere with normal alpha-2A adrenergic receptor functions," Wang said, "and therefore would be less likely to result in complications associated with an extended dosing period necessary for Alzheimer's disease treatment."

A stem cell transplant -- also called a bone marrow transplant -- is a common treatment for blood cancers, such as acute myeloid leukemia (AML). Such treatment can cure blood cancers but also can lead to life-threatening complications, including heart problems and graft-versus-host disease, in which new immune cells from the donor attack a patient's healthy tissues.

A new study from Washington University School of Medicine in St. Louis suggests that extremely rare, harmful genetic mutations present in healthy donors' stem cells -- though not causing health problems in the donors -- may be passed on to cancer patients receiving stem cell transplants. The intense chemo- and radiation therapy prior to transplant and the immunosuppression given after allow cells with these rare mutations the opportunity to quickly replicate, potentially creating health problems for the patients who receive them, suggests the research, published Jan. 15 in the journal Science Translational Medicine.

Among the concerns are heart damage, graft-versus-host disease and possible new leukemias.

The study, involving samples from patients with AML and their stem cell donors, suggests such rare, harmful mutations are present in surprisingly young donors and can cause problems for recipients even if the mutations are so rare as to be undetectable in the donor by typical genome sequencing techniques. The research opens the door to a larger study that will investigate these rare mutations in many more healthy donors, potentially leading to ways to prevent or mitigate the health effects of such genetic errors in patients receiving stem cell transplants.

"There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didn't have a way to identify them because they are so rare," said senior author Todd E. Druley, MD, PhD, an associate professor of pediatrics. "This study raises concerns that even young, healthy donors' blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further."

Added co-author Sima T. Bhatt, MD, an assistant professor of pediatrics who treats pediatric patients with blood cancers at Siteman Kids at St. Louis Children's Hospital and Washington University School of Medicine: "Transplant physicians tend to seek younger donors because we assume this will lead to fewer complications. But we now see evidence that even young and healthy donors can have mutations that will have consequences for our patients. We need to understand what those consequences are if we are to find ways to modify them."

The study analyzed bone marrow from 25 adult patients with AML whose samples had been stored in a repository at Washington University. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced. The donors' samples were provided by the Center for International Blood and Marrow Transplant Research in Milwaukee.

The 25 AML patients were chosen because they each had had samples banked at four separate times: before the transplant, at 30 days post-transplant, at 100 days post-transplant, and one year post-transplant.

Druley co-invented a technique called error-corrected sequencing, to identify extremely rare DNA mutations that would be missed by conventional genome sequencing. Typical next-generation sequencing techniques can correctly identify a mutation that is present in one in 100 cells. The new method, which can distinguish between true mutations and mistakes introduced by the sequencing machine, allows the researchers to find true mutations that are extremely rare -- those present in as few as one in 10,000 cells.

The healthy donors ranged in age from 20 to 58, with an average age of 26. The researchers sequenced 80 genes known to be associated with AML, and they identified at least one harmful genetic mutation in 11 of the 25 donors, or 44%. They further showed that 84% of all the various mutations identified in the donors' samples were potentially harmful, and that 100% of the harmful mutations present in the donors later were found in the recipients. These harmful mutations also persisted over time, and many increased in frequency. Such data suggest the harmful mutations from the donor confer a survival advantage to the cells that harbor them.

"We didn't expect this many young, healthy donors to have these types of mutations," Druley said. "We also didn't expect 100% of the harmful mutations to be engrafted into the recipients. That was striking."

According to the researchers, the study raises questions about the origins of some of the well-known side effects of stem cell transplantation.

"We see a trend between mutations from the donor that persist over time and the development of chronic graft-versus-host disease," said first author Wing Hing Wong, a doctoral student in Druley's lab. "We plan to examine this more closely in a larger study."

Though the study was not large enough to establish a causal link, the researchers found that 75% of the patients who received at least one harmful mutation in the 80 genes that persisted over time developed chronic graft-versus-host disease. Among patients who did not receive mutations in the 80 genes, about 50% developed the condition. Because the study was small, this difference was not statistically significant, but it is evidence that the association should be studied more closely. In general, about half of all patients who receive a stem cell transplant go on to develop some form of graft-versus-host disease.

The most common mutation seen in the donors and the cancer patients studied is in a gene associated with heart disease. Healthy people with mutations in this gene are at higher risk of heart attack due to plaque buildup in the arteries.

"We know that cardiac dysfunction is a major complication after a bone marrow transplant, but it's always been attributed to toxicity from radiation or chemotherapy," Druley said. "It's never been linked to mutations in the blood-forming cells. We can't make this claim definitively, but we have data to suggest we should study that in much more detail."

Added Bhatt: "Now that we've also linked these mutations to graft-versus-host disease and cardiovascular problems, we have a larger study planned that we hope will answer some of the questions posed by this one."

Could feces offer hope to survivors of spinal cord injuries?

It's a question University of Alberta physical therapy researcher Karim Fouad never thought he'd ask. But the expert in spinal cord injuries said the digestive tract could help explain the link between spinal injuries and changes in mental health, such as increased anxiety and depression.

"You would think that if you have a stroke or spinal injury, 'no wonder you're depressed,'" said Fouad. "But it turns out there might be more to it than that."

In a new study, Fouad's team discovered that rats with spinal injuries experienced changes to their gut bacteria and a rise in anxiety-like behaviour. When rats with spinal injuries were given fecal transplants from healthy rats, their behaviour--and gut bacteria--remained normal.

Fouad suggests that bacteriotherapy, in the form of "poop pills," could one day be used to improve well-being following spinal cord injuries and diseases of the central nervous system.

"I think it has huge potential," Fouad said. "The beauty of it is that if this translates to humans, we'd have a simple tool that could potentially improve mental health."

Gut health

Researchers have long observed a deterioration of mental health following spinal cord injuries.

Patients who experience paralysis are at an increased risk of suicide. The increased prevalence of depression also means patients often miss their best window for recovery by losing interest in rehab, Fouad said, leading to a worse quality of life.

Connections between poor intestinal health and mental state have also been found outside of spinal cord research. Research at the U of A has even pointed to how gut health could help explain a disease like multiple sclerosis.

Fouad decided to test for similar connections on spinal cord injuries. When rats received minor spinal cord injuries, he observed a dramatic change in gut flora. It took up to four weeks for digestive tracts to return to normal.

To test anxiety-like behaviour, Fouad and his team also tested the rats on an elevated plus maze, gauging their willingness to risk venturing onto an exposed platform. Three weeks after recovery, injured rats remained far more reluctant to overcome their natural aversion to open spaces than the typical rats.

The next part of the experiment flipped those findings upside down. Some of the injured rats were given a fecal transplant. They made an astonishing recovery, becoming even more willing to venture out on the exposed platform.

"It's dramatic," said Fouad. "Diseases and injuries seem to trigger changes of the microbiome, and this can have much further effects."

Implications

Fouad hopes to test the effectiveness of fecal transplants over time, and to see whether anxiety could be induced simply by adding the wrong gut bacteria to animals raised in sterile environments.

He said there could be wider implications for these findings. Scientists often house animals together in experiments. But since rats are notorious omnivores--known to eat the feces of other rats--researchers may have inadvertently skewed thousands of experiments in which gut health was a potential modifying factor.

"How many generations of experiments have been done where microbiome changes were a potential influence and animals were eating the poo and maybe negating the effect?" Fouad said. "That's a scary thought."

Fecal transplants might not have the same allure as stem cells for spinal cord patients, Fouad said, but for patients facing a condition in which incremental gains can make a pivotal difference, poop pills could make a big difference.

"Is it going to cure spinal injury? No," he said. "But if you're in a wheelchair and dealing with it in a good mindset, it could make a big difference."

A new study finds that an interactive voice application using artificial intelligence is an effective way to monitor the wellbeing of patients being treated for serious mental illness.
Researchers from UCLA followed 47 patients for up to 14 months using an application called MyCoachConnect. All of the patients were being treated by physicians for serious mental illnesses, including bipolar disorder, schizophrenia and major depressive disorder.

For the study, published in PLOS ONE, participants called a toll-free number one or two times a week and answered three open-ended questions when prompted by a computer-generated voice. The questions were: How have you been over the past few days?; What's been troubling or challenging over the past few days?; and What's been particularly good or positive?

MyCoachConnect was designed to collect personalized patient responses, said lead author Dr. Armen Arevian, director of the Innovation Lab at the Jane and Terry Semel Institute for Neuroscience and Human Behavior. Specifically, the AI was trained to use an individual's own words to offer a personalized analysis for each patient. The application focused primarily on the choice of words the patients used in their responses, how their responses changed over time, with a smaller emphasis on audio features like tone of voice.

The analysis of the data, conducted in collaboration with researchers from USC's Signal Analysis and Interpretation Laboratory (SAIL), found that the application's analysis was as accurate at monitoring patients' mental states as their treating physicians

"The way people answer questions and the way they change their answers over time is unique to each patient," Arevian said. "We were looking at a person as a person and not as a diagnosis."

For the study, patients made calls either from a mobile phone, landline, or pay phone, and were asked to speak for two to three minutes for each question.

"Technology doesn't have to be complicated," Arevian said. "In this study, patients didn't need a smartphone or any a phone at all. It could be simple and low tech on the patient end, and high tech on the backend."

Researchers hope that artificial intelligence that can analyze data collected from apps such as MyCoachConnect will enable more proactive and personalized care for individuals. The application, for example, may help improve treatment by intervening early when someone is experiencing more symptoms.

"Artificial intelligence allowed us to illuminate the various clinically-meaningful dimensions of language use and vocal patterns of the patients over time and personalized at each individual level" said senior author Dr. Shri Narayanan, Niki and Max Nikias Chair in Engineering and Director of SAIL at the USC Viterbi School of Engineering.

Some participants were interviewed after the study ended, and said they found the system easy and enjoyable to use, Arevian said.

"They said speaking to a computer-generated voice allowed them to speak more freely," Arevian said. "They also said it helped them feel less lonely because they knew that someone would be listening to it, and to them that meant that someone cared."

MyCoachConnect was developed and hosted on the Chorus platform, which was developed by Arevian at UCLA and allows people to visually create mobile and other computer applications without computer programming in as little as a few minutes.

How do female insects manage to keep the sperm fresh for months after mating? This is a central question of the sperm biologists of the Chair of Applied Zoology headed by Prof. Dr. Klaus Reinhardt. Now the scientists presented their first promising results in the journal Scientific Reports.

Dr. Cornelia Wetzker borrowed an innovative label-free technique from cancer research in order to investigate the metabolism of living biological tissues. This involves the measurement of the decay of the intrinsic fluorescence of the metabolic coenzyme NADH - a matter of nanoseconds, requiring a specialised microscope. This measure, also known as fluorescence lifetime, serves as a cell-specific signature and characterises the specific metabolic pathways of the tissue. Cancer cells have a shorter NADH fluorescence lifetime, are thus more glycolytic and can therefore be distinguished from healthy cells.

With this method, Dr. Cornelia Wetzker has now succeeded in examining the metabolism of intact tissues of the fruit fly outside the body. She analysed the metabolism of sperm in the storage organs of male and female animals as well as other tissues of the insect. The sperm were investigated in still intact closed organs, which in the male serve for storage before and in the females after mating. The team thus found that the sperm had a highly glycolytic metabolism similar to that of cancer cells. Other cells, such as intestinal, gland and fat cells, were in a much more oxidative state.

Using this method, the biologists found a first clue to their initial question of how the sperm remain fresh in the body of the insect females. They discovered that the fluorescence lifetime of another autofluorescent metabolic coenzyme called FAD differs between the sperm in the male and in the female body.

With regard to the clinical application of this technique, fluorescence lifetime imaging microscopy (FLIM) is proving to be highly promising. "The fluorescence lifetime signature analysis could even be automated with the help of neural networks", suspects Dr. Cornelia Wetzker. "And since the method is not dangerous, there is no reason why it should not be used on living humans or animals," adds Professor Klaus Reinhardt.

All living organisms need energy for their survival, and this energy indirectly comes from the sun. Some organisms, such as plants, cyanobacteria, and algae, are capable of directly converting this light energy into chemical energy via a process called "photosynthesis". These photosynthetic organisms contain special structures to mediate photosynthesis, called "photosystems". There are two photosystems that carry out light-energy conversion reactions, each of which is composed of a number of proteins and pigments. Among photosynthetic pigments, chlorophyll is the most crucial one, which not only captures light energy from the sun but also participates in the "electron transfer chain", a molecular pathway through which photons (from the sunlight) are converted into electrons (which are used as an energy source). There are different types of chlorophyll molecules, each having a specific function ranging from absorbing light and converting it into energy. Moreover, each chlorophyll molecule absorbs light in different regions. Recently, a new type of chlorophyll called Chl f was discovered, but details like exactly where it is located and how it functions have remained a mystery until now.

In a new study published in Nature Communications, a team of researchers led by Prof. Tatsuya Tomo at the Tokyo University of Science, Japan, and including collaborating researchers from Okayama University, Tsukuba University, Kobe University, and RIKEN, revealed new details about the location and functions of Chl f. They wanted to gain insight into the complex process of photosynthesis, as an in-depth understanding of this process could have various future applications, such as the development of solar cells. Talking about the study, Prof. Tomo says, "The initial course of photosynthesis begins when the photosynthetic pigment bound to this photochemical complex absorbs light. We analyzed the structure of a newly discovered photochemical complex, photosystem I with Chl f that has an absorption maximum on the lower energy side of light (far-red light). Moreover, we analyzed the function of Chl f."

What the scientists knew so far was that Chl f is "far-red shifted," which means that this molecule absorbs far-red light from the lower end of the light spectrum. Prof. Tomo and his team wanted to dig deeper, and for this, they studied the alga in which Chl f was first discovered. By using techniques such as cryo-electron microscopy, they analyzed the high-resolution structure of the photosystem in this alga in detail and found that Chl f is located at the periphery of photosystem I (one of the two types of photosystems) but is not present in the electron transfer chain. They also found that far-red light causes structural changes in the photosystem, which are accompanied by the synthesis of Chl f in the algae, leading them to conclude that Chl f causes these structural changes in photosystem I. This was exciting, as this finding is the first to explain how exactly Chl f works. Prof Tomo says, "Our findings revealed that the appearance of Chl f is well correlated with the expression of photosystem I genes induced under far-red light. This indicates that Chl f functions to harvest the far-red light and enhance up-hill energy transfer. We also found that the amino acid sequence of photosystem I was altered so as to accommodate the structure of Chl f."

Understanding the intricacies of photosynthesis has several important applications. For example, mimicking the process of photosynthesis in an artificial system is an elegant method of capturing solar energy and converting it into electricity. Prof Tomo elaborates, "About half of the solar energy that falls on the earth is visible light, and the other half is infrared light. Our research puts forth a mechanism that can use light on the lower energy spectrum, which has never been seen before. Our findings show how to improve the efficiency of energy transfer in photosynthesis and, by extension, also provide important insights into artificial photosynthesis."

Biologists from The University of Manchester have explained for the first time why having a good night's sleep really could prepare us for the rigours of the day ahead.

The study in mice and published in Nature Cell Biology, shows how the body clock mechanism boosts our ability to maintain our bodies when we are most active.

And because we know the body clock is less precise as we age, the discovery, argues lead author Professor Karl Kadler, may one day help unlock some of the mysteries of aging.

The discovery throws fascinating light on the body's extracellular matrix -which provides structural and biochemical support to cells in the form of connective tissue such as bone, skin, tendon and cartilage.

Over half our body weight is matrix, and half of this is collagen - and scientists have long understood it is fully formed by the time we reach the age of 17.

But now the researchers have discovered there are two types of fibrils - the rope-like structures of collagen that are woven by the cells to form tissues.

Thicker fibrils measuring about 200 nanometres in diameter - a million million times smaller than a pinhead - are permanent and stay with us throughout our lives, unchanged from the age of 17.

But thinner fibrils measuring 50 nanometres, they find, are sacrificial, breaking as we subject the body to the rigours of the day but replenishing when we rest at night.

The collagen was observed by mass spectrometry and the mouse fibrils were observed using state of the art volumetric electron microscopy - funded by the Wellcome Trust - every 4 hours over 2 days.

When the body clock genes where knocked out in mice, the thin and thick fibrils were amalgamated randomly.

"Collagen provides the body with structure and is our most abundant protein, ensuring the integrity, elasticity and strength of the body's connective tissue," said Professor Kadler

"It's intuitive to think our matrix should be worn down by wear and tear, but it isn't and now we know why: our body clock makes an element which is sacrificial and can be replenished, protecting the permanent parts of the matrix.

He added: "So if you imagine the bricks in the walls of a room as the permanent part, the paint on the walls could be seen as the sacrificial part which needs to be replenished every so often.

"And just like you need to oil a car and keep its radiator topped up with water, these thin fibrils help maintain the body's matrix."

"Knowing this could have implications on understanding our biology at its most fundamental level. It might, for example, give us some deeper insight into how wounds heal, or how we age.

The ability to learn new motor skills is critical to almost all aspects of our lives. From the time a baby is born, it learns to move its arms and hands, to pronounce words and to walk. Such skills are often learned through practice, over the course of many thousands of repetitions. Some repetitions are better than others, and overall they keep on improving.

Underlying these improvements are changes in the wiring of the brain. Millions of connections between neurons across many brain areas, and between the brain and the muscles, have to be adjusted. These changes later have to be consolidated to make sure that they are not lost when the same brain areas are called upon to learn a different skill.

General principle underlies complex movements

A big challenge in understanding the biological underpinning for this kind of learning is the distinct nature of different skills: "Very similar mechanisms are thought to underlie learning to play the piano or learning to speak, but the muscles and movements involved are completely different," says Sepp Kollmorgen, postdoc at the Institute of Neuroinformatics of the University of Zurich.

In a new study at the Institute of Neuroinformatics, researchers of the University of Zurich and ETH Zurich analyzed the general principles underlying the learning of skills. Kollmorgen and the team of researchers introduced a general framework to distill the myriad of changes occurring in a complex motor skill into a simple "trajectory", which allows them to tell how and when a skill is changing without having to consider all the details of the involved movements.

Zebra finches repeat a song thousandfold per day

The researchers used this novel framework to study how juvenile male zebra finches gradually learn to sing. In the wild, they try to imitate the song of an adult zebra finch and later use it to court females. When they're about 40 days old, they start to try to reproduce the song, practicing many thousands of times per day over the next three months.

"We think that the brain processes involved in this learning might be analogous to the ones at work in humans when they learn a motor skill," says Richard Hahnloser, professor of neuroinformatics at ETH Zurich. One great advantage of studying this process in birds is that the researchers have much more precise tools to observe what is happening in the brain during the learning process.

Good songs improve steadily, bad songs much less

The learning trajectories the research team found in the zebra finches revealed a few surprises: For one, they showed that the learning process is multilayered, in the sense that good songs and bad songs change in different ways. On any given day, most of the songs sound similar to each other, but occasionally the bird manages to produce a song that is particularly good or one that sounds really bad. The scientists found that the very best songs improve slowly but steadily during a day and do not change overnight. The next morning, the best songs sound like the best songs from the previous evening. On the other hand, the very bad songs improve quickly during the day, but then overnight the bird forgets most of what it learned. The next morning the very bad songs sound almost as bad as those from the previous morning.

For another, the learning trajectories showed that of the many changes occurring during a day, most are reset overnight, presumably because they are unrelated to what the bird is trying to sing. "One interpretation of this is that the birds are incredibly efficient. Sleep allows them to perfectly remember all the good things they learned during the day, and to forget all the things that are not important," explains Valerio Mante, professor at the University of Zurich and last author of the study.

Therapeutic potential for humans

The better understanding of the behavior lays the groundwork for understanding what happens in the brain during learning. This knowledge has great therapeutic potential. If we could understand why it is so hard to remember improvements in bad parts of a behavior, more efficient training schedules could be developed in rehabilitation for adults recovering from a stroke or accident. Ultimately, it might even be possible to improve and stimulate learning and consolidation by intervening directly in specific brain areas, the researchers conclude.

Journal

Nature

DOI

10.1038/s41586-019-1892-x

Replacing the volatile and flammable liquid or polymer electrolytes now used in lithium-ion batteries with inorganic solid-state lithium-ionic ceramic conductors could significantly improve both safety and performance of the cells. Solid-state conductors would allow for novel cathode and anode chemistry, prevent the growth of Li-metal dendrites and push miniaturization.

Though researchers have investigated several structural families of promising solid-state Li-ion conductors over the past decades, the fact that there are many desired properties--including fast-ionic/superionic diffusion of Li ions, very low electronic mobility, wide electrochemical stability windows, and high mechanical stability--means that no one material has emerged as an ideal candidate for development and so the search continues.

Previous research has been largely led by chemical intuition and carried out through immediate experimental investigation. Synthesizing ionic compounds and measuring ionic conductivity are labor intensive tasks though and experimental results can be difficult to interpret. Computational methods, on the other hand, are easy to automate and run in parallel. That is, they can efficiently identify materials that merit the hassle and expense of experimental investigation in the search for new solid-state electrolytes.

Current approaches to computational screening rely on simulations of the electronic structure to determine the insulating character of a material and on molecular dynamics simulations to predict the Li-ion diffusion coefficients. This means running thousands of calculations and so automation and reproducibility are essential. Computational methods need to be inexpensive enough to be run for thousands of materials, yet accurate enough to be predictive. In the paper High-throughput computational screening for solid-state Li-ion conductors, the researchers present a new framework that meets these requirements. Screening compounds through several stages of computational filter, they probe new structural families for promising Li-ionic conductors in a cost-effective, accurate way.

The new approach was used to screen two repositories of experimental structures, the ICSD and COD, which describe some 1,400 unique crystal structures between them. After identifying electronically insulating systems, the scientists used their recently introduced pinball model -- a framework that is based on physical observations of how electrons behave in an ionic system and which greatly simplifies the modeling of ionic conductors--to identify materials likely to display fast-ionic diffusion. Some 115 identified structures were then simulated with accurate first-principles molecular dynamics for a total of 45 nanoseconds at high and intermediate temperatures.

The approach resulted in the identification of five materials with fast ionic diffusion--some in the range of the well-known superionic conductor Li10GeP2S12--as well as 40 materials that at least showed significant diffusion at 1000 K. Though it is not possible to say whether these latter materials can be considered fast-ion conductors at lower temperatures because of the short time scales of the study, they are promising for more detailed study.

The authors expect the data, new methods and analysis techniques described in the paper to be useful in the ongoing search for novel descriptors of fast Li-ion diffusion in the solid state. They have made the first-principles simulations carried out in the paper publicly available in an open-source archive on MaterialsCloud