Culture

For hundreds of thousands of years, monkeys and apes have been plagued by simian immunodeficiency virus (SIV), which still devastates primate groups in Africa.

Luckily, as humans evolved from these early primates, we picked up a mutation that made us immune from SIV -- at least until the early 20th century, when the virus evolved to get around our defenses, giving rise to human immunodeficiency virus (HIV) and an AIDS pandemic that today affects an estimated 38 million people worldwide.

University of California, Berkeley, researchers have now discovered how that long-ago human mutation interfered with SIV infection, a finding that could provide clues for the development of new therapies to thwart HIV and similar viral infections.

"The main importance for this paper is that it tells us what was one of the last major barriers before the crossover to humans happened," said James Hurley, a UC Berkeley professor of molecular and cell biology. "The current paper is an archeological look at how this happened."

The barrier was a mutation in human cells that blocked SIV from forcing these cells to shed thousands more copies of the virus. As a result, humans could not re-infect one another.

This genetic mutation interfered with the ability of an SIV protein to tightly bind two human proteins and send them for destruction within the cell, instead of fighting the virus. The researchers used cryo-electron microscopy, or cryoEM, to determine the structure of this protein complex and discovered that the mutation so effectively disrupted the protein binding sites that it took SIV a long time to find a work-around.

"The binding site involved is structurally very complex, so essentially it is not possible to adapt to it once the tight binding is lost. The virus had to invent a completely different way to do the same thing, which took a long time in evolution," Hurley said. "This conferred an advantage on our prehistoric ancestors: From chimps on down, every primate was susceptible to SIV, but humans were immune. That gave humans probably a grace period of tens to hundreds of thousands of years to develop without having to deal with this disease. I tend to think that really gave a leg up to humans in early evolution."

Though the SIV virus -- in this case, from a monkey called the sooty mangabey, the source of the less virulent HIV-2 strain in humans -- differs in several ways from the HIV strains that afflict humans, the findings could pinpoint targets for drugs as researchers look for "functional" cures for AIDS. These would be one-time treatments that prevent flare-ups of the disease, even if the virus remains in the body.

"The overall strategy in our lab is to try to find regions in the structures of human proteins that are attacked by viruses, but are not needed for normal purposes by the host, so that a drug can be designed to attack that region," Hurley said. "The virus will typically respond by mutating, which means it evolves drug resistance, but this new finding suggests that with the right point of attack, it could take SIV or HIV, in some cases, tens of thousands of years of evolution to catch up."

The work will be published in the Sept. 11 issue of the journal Cell Host & Microbe and was posted online Aug. 22.

Sooty mangabeys

SIV and HIV, which are lentiviruses, are hard to root out the body because they insert their DNA into the genomes of host cells, where it sits like a ticking time bomb, ready at any moment to revive, take over the host cell's machinery to makes copies of itself and send out thousands of these copies -- called virions -- to infect other cells.

These virions are formed when the newly copied viral DNA wraps itself in a piece of the host cell's membrane and buds off, safely ensconced in a bubble until it can reinfect.

Because budding is an important step in the spread of many viruses, primates long ago evolved natural defenses, including proteins on the surface of cells that staple the budding virions to the cell and prevent them from leaving. As they accumulate, the immune system recognizes these unbudded virions as abnormal and destroys the whole cell, virus and all.

In monkey, ape and human cells, the staple is called tetherin, because it tethers the budding virion to the cell membrane.

In the constant arms race between host and pathogen, SIV evolved a countermeasure that exploits another normal cell function: its recycling system. Cells have ways to remove proteins sitting on the surface, through which cells constantly take up and recycle tetherin if there's no indication it is needed to fight an invading virus. It does this by dimpling the membrane inward to form a little bubble inside the cell, capturing tetherin and other surface proteins in this vesicle and then digesting all the contents, including tetherin.

SIV's countermeasure was to produce a protein, called Nef, that revs up the recycling of tetherin, even during an infection. This enables virions to bud off and search for new victims.

Hurley and project scientist Xuefeng "Snow" Ren found that Nef forms a tight wedge between tetherin and a protein in the vesicle called AP-2, preventing tetherin from escaping the vesicle and dooming it to recycling.

"Nef is a bridge between AP2 and tetherin to recruit them into endocytosis, dragging the tetherin into the vesicle," Ren said. "So it tricks our own cells' machinery for getting rid of stuff we don't want into getting rid of stuff the virus doesn't want."

The five amino acids that humans lost in the tetherin protein -- the mutation that gave humans immunity against SIV -- loosened the binding between tetherin, Nef and AP-2, which allowed tetherin to escape recycling. This blocked the crossover of zoonotic virus transmission, Ren said, because the structural rearrangement was so extensive that SIV couldn't fix it by simple mutations in Nef.

SIV developed a new trick

Some variants of SIV did eventually find a way around this hurdle, however. At some point, a few SIVs acquired a second protein, Vpu, to do what Nef also did -- wedge itself between proteins to cement connections helpful to the virus. At some point, perhaps a hundred years ago, this strain of SIV moved into humans from chimpanzees, and a slight mutation in Vpu reignited the recycling of tetherin in humans, unleashing what we know today as group M HIV-1, the most virulent form of HIV worldwide.

"There were probably many crossovers into humans that failed, but eventually, some hunter in Africa, perhaps in the course of butchering a chimp, was exposed to the blood, and the virus then acquired an additional mutation, a small step that turned SIV into HIV," Hurley said.

Next up, Hurley, Ren and their colleagues plan to use cryoEM to determine the structure of the three-protein complex in gorilla variants of SIV, which evolved into the O strain of HIV-1, a less virulent strain that originated in the African country of Cameroon.

New research finds that a warming planet will also alter ocean waves along more than 50% of the world's coastlines. This research, published in Nature Climate Change, has significant implications for coastal flooding and erosion.

As part of the Coordinated Ocean Wave Climate Project, ten research organisations, including the National Oceanography Centre (NOC), combined to look at a range of different global wave models in a variety of future climate scenarios, to determine how waves might change in the future.

NOC scientist Dr Lucy Bricheno, who contributed to this study, said "The National Oceanography Centre is proud to be involved in this worldwide collaboration in wave science: this paper helps us to understand and quantify the future changes in global wind-wave climate".

While they identified some differences between different models, they found if the 2? Paris agreement target is kept, changes in wave patterns are likely to stay inside natural climate variability.

However, in a business-as-usual climate, where warming continues in line with current trends, the models agreed the planet is likely to see significant changes in wave conditions along 50% of the world's coasts, although these changes varied by region.

For example, if the climate warms by more than 2? beyond pre-industrial levels, southern Australia is likely to see longer, more southerly waves that could alter the stability of the coastline. For the UK coast the mean wave height is projected to decrease by about 10% by the end of the century under the most extreme global warming scenario.

Some areas will see the height of waves remain the same, but their wavelength or frequency will change. This can result in changes in the force exerted on the coast and any infrastructure there, and in some cases lead to increased wave-driven flooding.

Similarly, climate change induced alterations to the direction of waves can change how much sand they move along the coast. Infrastructure built on the coast, or offshore, is sensitive to these different characteristics of waves.

NOC scientist Professor Judith Wolf, also a co-author of the study, said "It is important to understand changes in the wave climate under climate change scenarios because waves are what cause damage to coastal defences and infrastructure, and erosion of natural coasts, beaches and ecosystems. They also contribute to increasing flood levels through wave setup, run-up and overtopping."

The overarching pattern emerging from this study is that robust changes in projected mean wave heights are seen in some areas, with increases in the Southern Ocean and the tropical eastern Pacific, but decreases in the North Atlantic Ocean and portions of the northern Pacific Ocean. These changes are consistent with a relatively uniform decrease in projected surface wind speeds over the northern hemisphere extra-tropical storm belt, partly driven by the polar amplification of climate change.

Previous research has looked at the way waves have shaped our coasts through the past, which is used as a guide to understanding past sea levels. However, this research has often assumed that while sea levels might change, wave conditions have stayed the same. This same assumption is used when considering how climate change will influence future coastlines. Although, importantly, climate change can alter waves both through changing wind patterns, and through changes to the water depth at the coast through sea-level rise.

An international team of researchers who analyzed data across multiple ethnicities has produced the largest genetic study to date associated with common childhood obesity. The Early Growth Genetics (EGG) Consortium discovered a robust new signal, fine-mapped previously reported genetic variants, and added to evidence that genetic influences on obesity operate across the lifespan.

"As we continue to deepen our research into the genetics of obesity, this knowledge is bringing us closer to pinpointing specific causal genes and how they function in giving rise to obesity," said lead investigator Struan F.A. Grant, PhD, a director of the Center for Spatial and Functional Genomics (CSFG) at Children's Hospital of Philadelphia (CHOP). "That detailed knowledge will help guide researchers toward developing more effective treatments." Grant co-led the new study with Vincent W. V. Jaddoe, MD, PhD, of Erasmus University Medical Center in Rotterdam, Netherlands.

As a major public health issue, obesity has increasingly received public attention, in light of a rising prevalence of the condition among children--now higher than 20 percent in the U.S. Obese adolescents tend to have a higher risk of mortality as adults. Although environmental factors, such as food choices and sedentary habits, contribute to rising rates of obesity in childhood, scientists have found strong evidence of genetic influences as well.

The current research appeared online July 5, 2019 in Human Molecular Genetics. It extends the work of a 2012 collaborative study, also led by Grant, that identified gene variants linked to common childhood obesity. That study, also from the EGG Consortium, was a meta-analysis focused on children of European ancestry only.

The new study included more diverse populations. The EGG Consortium scientists performed a meta-analysis of 30 genome-wide association studies comprising 13,000 cases and 15,600 controls, all from individuals of European, African, North and South American and East Asian ancestry. A replication study then covered a subset of samples of 1,888 cases and 4,689 controls from European and North/South American cohorts.

The scientists found a strong, novel variant associated with childhood obesity, closest to the METTL15 gene, and confirmed 18 variants previously linked to childhood obesity or body mass index (BMI). The team also used fine-mapping analyses to narrow down potential causal variants at four different locations to fewer than 10 specific single-base changes (single-nucleotide polymorphisms, or SNPs).

Among the study's co-investigators was Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics (CAG) at CHOP and a long-term collaborator of Grant. Hakonarson contributed a large quantity of diverse samples from the CAG to the study. Hakonarson said, "Obesity is becoming such an alarming health problem in children that we need to scale up translational efforts to develop innovative therapies."

"Follow-up functional studies," said Grant, "will be needed to connect potential causal variants with specific effector genes, to better understand the biology of obesity and offer insights into potential treatments." He added that the genetic roots of obesity and BMI are very similar in both children and adults, and that future treatments may reflect those commonalities.

Researchers at the University of Cincinnati found that Charles Darwin's famous finches defy what has long been considered a key to evolutionary success: genetic diversity.

The study of the finches of the Galapagos Islands could change the way conservation biologists think about species with naturally fragmented populations to understand their potential for extinction. 

UC graduate Heather Farrington and UC biologists Kenneth Petren and Lucinda Lawson found that genetic diversity was not a good predictor of whether populations of finches would survive. A UC lab analysis of century-old museum specimens found that six of eight extinct populations had more genetic diversity than similar museum specimens from which descendants survive today. In most other species, low genetic diversity is a signal of a population in decline.

Researchers examined 212 tissue samples from museum specimens and living birds. Some of the museum specimens in the study were collected by Darwin himself in 1835. Only one of the extinct populations, a species called the vegetarian finch, had lower genetic diversity compared to modern survivors.

Lawson said the findings are explained by the fact that these birds can migrate in between populations.

Specifically, researchers believe a biological phenomenon called sink-source dynamics is at play in which larger populations of birds from other islands act as a "source" of immigrants to the island population that is naturally shrinking, the "sink." Without these immigrant individuals, the natural population on the island likely would continue to dwindle to local extinction. The immigrants have diverse genetics because they are coming from a variety of healthier islands, giving this struggling "sink" population inflated genetic diversity.

Petren said the findings serve as a warning that the genetics of individuals in fragmented populations might not tell the whole story about a species. And that is important for scientists who increasingly use genetics to account for the flow of genes between populations when determining a threatened species' likelihood of extinction.

"The promise of genetics is to sample a few individuals to understand the whole population. But it's a cautionary note that you might be sampling a fragment. You could be misled," he said.

Petren has been studying the birds for 25 years at UC's McMicken College of Arts and Sciences. He said the island's 18 recognized species of finches are unusual for other reasons. Some finches that look most different are actually closely related, he said. And similar-looking finches that birders might have trouble telling apart are actually far apart on the evolutionary family tree.

"It's a paradox. If Darwin fully understood what was going on, it might have blown his mind," Petren said. "These finches are not the first case you would pick to formulate the notion that species can change over time because the patterns of change are so complicated."

The UC study was published in August in the journal Conservation Genetics after first appearing online in April. It suggests that genetic diversity may not be the best predictor of extinction risk for mobile species like the island-hopping finches. That’s because healthier populations may contribute individuals to declining ones.  

Lawson said factors such as historical diversity or the possibility of gene flow between populations should be considered in addition to the snapshot view provided by a genetic analysis for a fuller understanding of a species' potential for extinction.

"Typically, we would expect populations with high genetic diversity to have a greater potential for long-term survival," she said. "Meanwhile, the low-diversity populations would be more likely to go extinct because that's a common pattern as populations decline to few individuals. Surprisingly, we found that most of the extinct populations had higher genetic diversity."

The study was sponsored in part by the National Science Foundation, Sigma Xi, the American Ornithologists' Union and UC's Office of Research.

Darwin's "On the Origin of Species" was groundbreaking in our understanding of evolution through natural selection. "Survival of the fittest" is a household phrase and a shorthand description of any competition.

While scientists today know more about how new species are formed, the principles Darwin developed remain the foundation of evolutionary biology, Petren said.

"Certainly, genetics is new. But the fundamental principles still stand. It's amazing how much of his work remains fundamentally true today," Petren said.

The function of the visual photopigment rhodopsin and its action in the retina to facilitate vision is well understood. However, there remain questions about other biological functions of this family of proteins (opsins) and this has ramifications for our understanding of several evolutionary pathways. Now, an international research team led by the University of Göttingen has shown there are other functions of opsin outside vision and this provides insights into how the eye evolved. Their research was published in Current Biology.

Vision relies on rhodopsins, which are made from proteins (opsins) that bind with "retinal" (a small molecule derived from vitamin A). This molecule changes its structure when stimulated by light and enables us to see: without retinal, photoreceptor cells die and there is no vision. Intriguingly, in the fruit fly Drosophila, the same opsin proteins that enable vision also occur in the ear. Researchers from the Department of Cellular Neurobiology and the Institute of Molecular and Cellular Physics of the University of Göttingen therefore asked if these auditory receptors were light-sensitive, i.e. could the ears of this fly also sense light? The researchers quickly discovered that the fly's ear could not function as an eye. What the researchers deduced, however, is a completely new function of opsins independent from the molecule retinal and from the functioning of the eye. They tested this by making vitamin A unavailable to Drosophila through various experiments: taking vitamin A out of the fly's diet; disrupting the transport protein that mediates vitamin A uptake into gut cells; and blocking the enzyme that converts vitamin A into retinal. This rendered the insects blind - but they did not become deaf. Together with colleagues in the US, the researchers then manipulated the opsins so that they could no longer bind with retinal. As expected, this made the flies blind, but again their hearing remained intact. This showed that the fruit fly requires opsins (but not retinal) for hearing, adding a new twist to the function of photopigment proteins. The real surprise came when the scientists looked at those enzymes that, in the eye, recycle light-activated retinal back into its light-sensitive form. All those enzymes turned out to occur in the fly's ear as well as the eye and were essential for hearing, even though hearing works without retinal. Hence, not only opsins, but also all the retinal-enzymes, have other important biological functions that are independent of vision.

"From an evolutionary perspective, this is quite striking," explains Dr Radoslaw Katana, the first author of the study. "The receptor cells for vision and hearing are derived from common ancestor cells, which seem to have used opsins and retinal-enzymes even before vision and hearing were possible. This is also the case in vertebrates: opsins occur in mechanoreceptor cells and many of the retinal-enzymes have remained essentially unchanged throughout evolution and are also implicated in human hearing".

"The retinal cycle in the eye is the most thoroughly studied biological signalling cascade," remarks Professor Martin Göpfert. "It now seems that its molecular components originally had nothing to do with the eye or light, revolutionising our understanding of the early evolution of vision".

LA JOLLA--(August 22, 2019) Light touch plays a critical role in everyday tasks, such as picking up a glass or playing a musical instrument. The sensation is also an essential part of the body's protective defense system, alerting us to objects in our environment that could cause us to fall or injure ourselves. In addition, it is part of the detection system that has evolved to protect us from biting insects, such as those that cause malaria and Lyme disease, by eliciting a feeling of an itch when an insect lands on your skin.

Salk researchers have discovered how neurons in the spinal cord help transmit such itch signals to the brain. Published in the journal Cell Reports on July 16, 2019, their findings help contribute to a better understanding of itch and could lead to new drugs to treat chronic itch, which occurs in such conditions as eczema, diabetes and even some cancers.

"The takeaway is that this mechanical itch sensation is distinct from other forms of touch and it has this specialized pathway within the spinal cord," says Salk Professor Martyn Goulding, holder of the Frederick W. and Joanna J. Mitchell Chair and a senior author of the new work.

Goulding and his colleagues had previously discovered a set of inhibitory neurons in the spinal cord that act like cellular brakes, keeping the mechanical itch pathway in the spinal cord turned off most of the time. Without these neurons, which produce the neurotransmitter neuropeptide Y (NPY), the mechanical itch pathway is constantly on, causing chronic itch. What the researchers didn't know was how the itch signal, which under normal circumstances is suppressed by the NPY neurons, is transmitted to the brain to register the itch sensation.

David Acton, a postdoctoral fellow in the Goulding lab, hypothesized that when the NPY inhibitory neurons are missing, neurons in the spinal cord that normally transmit light touch begin to act like an accelerator stuck in the "on" position. Acton then identified a candidate for these "light touch neurons," a population of excitatory neurons in the spinal cord that express the receptor for NPY, the so-called Y1 spinal neurons.

To test whether these neurons were indeed acting like an accelerator, Acton undertook an experiment that involved selectively getting rid of both the NPY "brake" and Y1 "accelerator" neurons. Without Y1 neurons, mice didn't scratch, even in response to light-touch stimuli that normally make them scratch. Moreover, when Acton gave the animals drugs that activated the Y1 neurons, the mice scratched spontaneously even in the absence of any touch stimuli. The Goulding team was then able to show that the NPY neurotransmitter controls the level of Y1 neuron excitability; in other words, NPY signaling acts as a kind of thermostat to control our sensitivity to light touch. Data from other labs has found that some people with psoriasis have lower than average levels of NPY. This may mean their brakes on mechanical itching are less effective than other people's, a potential cause of their itching.

While Y1 neurons transmit the itch signal in the spinal cord, other neurons are thought to be responsible for mediating the final response in the brain but more research is needed to continue mapping out the full pathway, according to the researchers. Understanding this will help suggest targets for drugs to turn down the sensation of itch in people who are overly responsive and could lead to ways to address chronic itch.

"By working out mechanisms by which mechanical itch is signaled under normal circumstances, we might then be able to address what happens in chronic itch," says Acton.

In a pioneer study now published in Proceedings of the National Academy of Science - USA, led by Isabel Gordo research team, from the Instituto Gulbenkian de Ciencia (IGC) (Portugal), in collaboration with researcher Michael Lässig of Cologne University (Germany), used healthy mice to study real-time gut colonization and discovered a pivotal role for bacterial sex in the evolution of the mammalian microbiome. This discovery constitutes a paradigm shift and opens the possibility to design phage-targeted therapies capable of dealing with the aftermath of infection and antibiotic usage, as well as antibiotic-resistant bacteria.

Most of what we know about bacterial colonization of the gut comes from studies with pathogenic bacteria in highly artificial laboratory models or disease contexts. Standard experimental models, which focus on infections with pathogenic bacteria and continuous antibiotic treatment, have not detected phage-driven horizontal gene transfer (HGT) and suggest that bacteria colonizing the gut evolve mainly through accumulation of mutations. In a surprising finding, the work of the IGC researchers now shows that HGT, not mutations, is the first evolutionary mechanism driving the pace and outcome of bacterial evolution in a healthy gut.

Escherichia coli is a common colonizer of the human intestine as well as a potential pathogen. The colonization outcome is greatly influenced by different speeds and modes of evolution of this opportunistic bacterium. E. coli can evolve through mutations, which are then inherited by daughter cells, or through a process of recombination, i.e. bacterial sex, in which genetic material is shared between unrelated individuals. In the mouse and human intestine, this transfer of genetic material involves temperate bacteriophages (phages), viruses that infect bacteria and integrate into the bacterial chromosome as prophages, a process called lysogeny. Prophages can later extricate themselves (and their genetic information) from the bacterial DNA and infect other bacteria in the gut microbiome.

Nelson Frazão, a post-doctoral researcher in Isabel Gordo´s lab and junior author of the study, says: "phages often classified as selfish particles reveal their altruistic side in the gut, providing a metabolic advantage to their bacterial host to conquer and colonize the gut". The phage genetic material that is transferred enables bacteria to gain access to specific carbon sources present in the gut, which provides a fitness advantage to phage-carrying (lysogenic) invader bacteria.

"We found that the classical evolution model does not apply, and in fact horizontal gene transfer greatly overrides the contribution of evolution through accumulation of mutations in the intestine of a healthy mouse", says the investigator Isabel Gordo. "With this work, we now understand better how evolution works in normal, healthy hosts", says Nelson Frazão, junior author of the publication.

CHAPEL HILL, N.C. - August 22, 2019 - E-cigarette "vaping" is widely assumed to be safer than cigarette smoking, but scientists at the University of North Carolina School of Medicine have uncovered evidence suggesting that vaping promotes the same cellular responses found in smokers who suffer with emphysema.

In a study published in the American Journal of Respiratory and Critical Care Medicine, the UNC scientists found that the lungs of vapers - like the lungs of smokers - have elevated levels of protease enzymes, a condition known to cause emphysema in smokers. The researchers also found that the nicotine in vaping liquids is responsible for the increase in protease enzymes.

"Our findings in this study indicate that vaping may not be safer than cigarette smoking," said study senior author Robert Tarran, PhD, a professor in the department of cell biology and physiology and member of the Marsico Lung Institute at the UNC School of Medicine.

The U.S. Centers for Disease Control and Prevention (CDC) has estimated that in 2014 about 9 million adults in the country were regular vapers and that close to 30 million had tried vaping at least once. But vaping on this scale has been going on for less than a decade, and so the long-term health effects of vaping are not yet well understood.

Tarran and colleagues in the study measured levels of three key protease enzymes in lung fluid sampled from 41 subjects - nonsmokers, smokers, and vapers. The three protease enzymes are neutrophil elastase and matrix metalloproteases 2 and 9. Immune cells in the lungs are known to secrete these enzymes at higher levels in a reaction to cigarette smoke. Chronic over activity of these protein-chewing enzymes damages the tiny sensitive air sac structures in the lungs that allow people to breathe. In smokers, this damage is thought to be the cause of emphysema, a form of chronic obstructive pulmonary disease (COPD) involving progressive shortness of breath and for which there is no cure.

The UNC scientists found that the levels of these three proteases were significantly elevated in both smokers and vapers, but not in nonsmokers. This finding suggests vaping, like smoking, may promote emphysema.

The scientists also found evidence that nicotine in vaping liquids is the cause of the elevated-protease reaction. When Tarran's team administered nicotine to immune cells cultured in the laboratory - at concentrations like those seen in vapers sputum and lung fluid - they observed that the cells overproduced the proteases. And this overproduction increased when the researchers exposed the immune cells to higher nicotine levels.

Vaping is thought to be much safer than cigarette smoking, which involves the high-temperature burning of tobacco leaves and the creation of toxic and carcinogenic combustion products. Some researchers have urged that smokers switch to vaping as a much less harmful alternative. The jury is still very much out when it comes to cancer risk associated with vaping. But this latest study suggests that the potential harm of vaping may have been underestimated, especially when it comes to emphysema and COPD, two of the most common debilitating conditions historically associated with smoking.

Tarran noted that the findings are not the first to warn of vaping's potential adverse health effects. A different study in 2018, from a team led by UNC Marsico Lung Institute researcher Mehmet Kesimer, PhD, found that sputum from vapers and smokers contained elevated levels of emphysema-promoting proteases and other immune defense proteins.

Moreover, a study from Tarran's lab last year found evidence of toxic compounds in commonly used vaping liquids, and the CDC currently is investigating about 100 recent cases in the U.S. of sudden, serious lung disease in otherwise healthy young vapers.

Tarran and his colleagues plan to follow up their new study with a larger study of lung protease levels in hundreds of participants.

Microbiomes aren't just for understanding and modulating gut health - skin, our largest organ, hosts a vibrant and complex microbiome that can provide health insights. An international research team has developed an index to better understand skin health across human populations.

They published their results on August 20 in mSystems, a journal issued by the American Society for Microbiology.

"A central goal of human microbiome projects is to diagnose and predict the human's healthy or unhealthy state via the microbiome," said XU Jian, senior author and director of the Single-Cell Center and Shandong Key Laboratory of Energy Genetics at the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences (CAS).

In guts, the composition of microbes present can indicate health and diet issues. In skin, it can operate the same way. XU noted that by understanding the skin microbiome, researchers can also predict how the skin may react to specific treatments.

The issue, though, is that skin microbiome differs between human populations due to environment, health status, body locations, diet and other mitigating factors.

"Due to the variance, the ability to use skin microbiome as an indicator of skin health that applies across large geographic ranges has remained largely unexplored," XU said. "As such, the central question of this study is: can we harness the talent and power of our skin microbiome for precise skin care, such as diagnosis and treatment?"

To answer this question, the international team which consists of CAS, Procter & Gamble, UCLA and UCSD assessed children with healthy skin and those with Atopic Dermatitis (eczema), the irritating skin condition that causes the skin to turn red and itch. Eczema affects 15 to 30 percent of children around the globe, so the researchers examined children in three different cities: Beijing and Qingdao in China and Denver, Colorado in the United States. Qingdao is a coastal city approximately seven hours drive north of Beijing. Denver is a mountain city, with a higher elevation than the other two cities.

In these vastly different locations, the researchers identified 25 bacterial genera - the taxonomic ranking above species - in the skin microbiomes of children and developed a Microbial index of Skin Health (MiSH).

According to SUN Zheng, the first author of the paper, this index can identify skin conditions, such as eczema, and has implications in clinical settings. Currently, eczema is identified via a scaling system where a physician observes a patient with multiple symptoms than add up to eczema. MiSH identifies it with an 83 to 95 percent accuracy within each city and with 86.4 percent accuracy across all cities.

"MiSH can quantitatively assess pediatric skin health across cohorts from distinct countries over large geographic distances," SUN said, explaining that index serves to compare skin health via the microbes that live on the skin. "MiSH can identify a risk-prone skin state and predict treatment effect in children, suggesting applications in patient stratification and personalized treatment in the clinics and in the skin care industry."

Next, the researchers plan to further study the mechanisms by which the index helps predict skin health and refine how well it predicts treatment response in larger and wider cohorts.

Used as a propaganda tool by the Nazis and Soviets during the Second World War and Cold War, the remains of a 10th century male, unearthed beneath Prague Castle in 1928, have been the subject of continued debate and archaeological manipulation.

The mysterious skeleton and associated grave goods, including a sword and two knives, were identified as Viking by the Nazis, as a Slavonic warrior by the Soviets and became part of the Czech independence movement in more recent years.

Writing in the journal Antiquity, a team of archaeologists, including two emeritus professors from the University of Bristol, unravel the complex story of the discovery of the remains, which were kept out of public view until 2004, and attempt to answer the decades-long question of who this man actually was.

The remains were discovered under the courtyard of Prague Castle in July 1928 as part of an excavation project by the National Museum of the newly established Czechoslovakia to discover the earliest phases of the castle.

The body was located on the edge of an old burial ground from when a hill fort was built on the site, likely dating to AD 800-950/1000.

It was discovered by Ivan Borkovský, a Ukrainian who fought for both the Austro-Hungarians and the Russians in the early 20th century, before escaping to Czechoslovakia in 1920 but he did not immediately publicise or publish anything about the remains or the artefacts.

In 1939, the German army invaded Czechoslovakia and immediately accused Borkovský of not publishing because he was part of a Czech conspiracy to hide the truth¬--that the remains were German, rather than Slavic (or maybe Viking).

As a German ancestor, the remains supported the German propagandist efforts to argue for a German heritage that 'extended over national borders and reached deep into the past'.

Under the Nazi regime, the remains became 'proof' for the Germanic, rather than Slavic, origin of Prague Castle.

When Borkovský published a book identifying the oldest Slavic pottery in central Europe, the Nazi's condemned the text and he was forced to withdraw it under threat of imprisonment in a concentration camp. When he published the Prague Castle remains a year later, it was overt in its 'Nazi-influenced Nordic interpretation'.

After the war, Czechoslovakia was occupied by the Soviets and in 1945, Borkovský narrowly escaped being sent to a Siberian Gulag because of former anti-Communist activities.

He explained that he had been forced into the pro-Nazi interpretation of the remains and published a second article in 1946 which interpreted the burial 'as that of an important person who was related to the early Western Slav Przemyslid dynasty'.

Lead author Professor Nicholas Saunders, from Bristol's Department of Anthropology and Archaeology, said: "A number of studies have recently begun to re-interpret the remains and ours provides a new analysis.

"The goods found with the remains are a mix of foreign (non-Czech) items, such as the sword, axe and fire striker (a common piece of Viking equipment), and domestic objects, such as the bucket and the knives.

"The sword is especially unique as it is the only one discovered in 1,500 early medieval graves so far found in Prague Castle.

"Perhaps he was a Slav from a neighbouring region, who had mastered Old Norse as well as Slavonic, or perhaps he regarded himself as a genuine Viking.

"Identities were complex in the medieval period, and the story of Borkovský and the Prague Castle warrior grave reminds us that the identities of such past people frequently fuel modern political conflicts."

DALLAS, Aug. 22, 2019 -- High-intensity step training that mimics real-world conditions may better improve walking ability in stroke survivors compared to traditional, low-impact training, according to new research published in the American Heart Association's journal Stroke.

"People who suffer strokes often have difficulty walking and impaired balance. Rehabilitation after a stroke traditionally focuses on patients practicing low-intensity walking, usually only in a forward direction, which does not provide enough of a challenge to the nervous system to enable patients to negotiate real-world situations, such as uneven surfaces, stairs or changing direction," said study author T. George Hornby, Ph.D., professor of physical medicine and rehabilitation at Indiana University School of Medicine in Indianapolis. "Our study suggests that stroke patients can perform higher intensity walking exercises and more difficult tasks than previously thought possible. We need to move beyond traditional, low-intensity rehabilitation to challenge the nervous and cardiovascular systems so patients can improve function and perform better in the real world."

Researchers evaluated 90 people, 18- to 85-years-old with weakness on one side of the body who had survived a stroke at least six months prior.

Participants received training of either high-intensity stepping performing variable, difficult tasks; high-intensity stepping performing only forward walking; or low-intensity stepping of variable tasks. Variable tasks included walking on uneven surfaces, up inclines and stairs, over randomly placed obstacles on a treadmill and across a balance beam.

The researchers found:

Survivors in both the high-intensity, variable training and high-intensity, forward walking groups walked faster and farther than the low-intensity, variable training group.

For all walking outcomes, 57% to 80% of participants in the high-intensity groups had important clinical gains, while only 9% to 31% of participants did so following low-intensity training.

High-intensity variable training also resulted in improved dynamic balance while walking and improved balance confidence.

Hornby noted that no serious adverse events occurred during the training sessions, suggesting stroke survivors can be pushed to higher intensity walking with more variable tasks during rehabilitation.

"Rehabilitation that allows walking practice without challenging the nervous system doesn't do enough to make a statistical or clinically significant difference in a patient's recovery after a stroke," Hornby said. "We found that when stroke patients are pushed harder, they see greater changes in less time, which translates into more efficient rehabilitation services and improved mobility."

Ultimately, their goal is to incorporate high-intensity variable step training into regular clinical rehabilitation protocols.

The study was small compared to larger, multicenter clinical trials. Hornby said the next step would be to test high-intensity, variable step training in larger patient populations in a large, multicenter clinical trial.

Philadelphia, August 22, 2019 - Patient-reported experiences have potential for driving improvements in the quality of hospital care, according to a new study in the Canadian Journal of Cardiology, published by Elsevier. Investigators report on an analysis of the Canadian Patient Experience Survey responses obtained from cardiac patients in Alberta, which revealed areas that are highly rated by patients, but also reported findings around areas that could be the subject of future patient-centered quality improvements.

The term "patient-centered care" is gaining currency as it places the patient first, rather than reducing them to the sum of their symptoms or medical condition. Providing patients' first-hand reports of their care is important to help reinforce or confirm areas in which care is working well (from the patient perspective), as well as to guide quality improvement experts to where impactful improvements can be made. Patient-centered care is often measured through surveys, specifically those that measure the patient experience. Despite the proliferation of such surveys, there is limited research in this area.

Using records from the Canadian Patient Experiences Survey - Inpatient Care (CPES-IC), investigators analyzed the experiences of over 1,000 patients in Alberta who underwent coronary artery bypass graft (CABG) and/or valve replacement from April 2014 to March 2018.

"To our knowledge, this is the first study of its kind in Canada - one that uses linkage of patient experience surveys with routinely-collected administrative data to examine the comprehensive hospital experience of a particular clinical group," explained lead investigator Kyle A. Kemp, a PhD candidate working in the Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. "Examining the comprehensive experience of patients who have undergone cardiac procedures such as CABG and valve replacement may provide tremendous value, given the labor-intensive and costly nature of these procedures."

CPES-IC surveys are administered across 93 hospitals in Alberta using a standard script and responses to frequently asked questions. A random sample of 10 percent of eligible discharges is obtained from each hospital, resulting in approximately 25,000 completed surveys each year. Participants complete a 56-question telephone survey after being discharged from hospital. Questions assess many aspects of care, including communication with doctors and nurses, medications, patient/family involvement in care, pain control, the physical environment, coordination of care, and discharge planning.

The results were rated on a scale from 0 (worst) to 10 (best) and overall were quite positive. More than 73 percent of the 1,082 respondents rated their overall hospital care as a 9 or 10. Top performing questions pertained to discussing help needed after discharge (96.6 percent responding "yes") and receiving written discharge information (93.2 percent responding "yes"). The responses also identified areas that could be targeted in quality improvement efforts. For example, less than 40 percent of respondents reported that the space around their room was always quiet at night, and only about 45 percent reported that hospital staff had always described the potential side effects of any new medications that patients were given.

"These findings are important because historically, many efforts to improve hospital care have been driven by administrators or clinicians - largely in absence of the 'patient voice'," commented Mr. Kemp. "Being the first Canadian study of its kind, there is an opportunity for it to serve as a baseline when examining future data from this survey, both in Alberta and from other Canadian provinces. The study methodology can be also replicated elsewhere in Canada and throughout the world to examine the experience of other clinical populations such as joint replacement patients, labor and delivery patients, and seniors living with chronic diseases."

"The study by Kemp and colleagues is a step in the right direction and is in essence the first rung on the ladder towards meeting the much sought-after triple aim (better health, improved experiences of care, and lower costs for the system) of healthcare in Canada," commented Michelle M. Graham, MD, and Colleen M. Norris, PhD, GNP, both from the University of Alberta and the Mazankowski Alberta Heart Institute, Edmonton, AB, Canada, in an accompanying editorial. "The investigators have in fact provided a methodology for building a Pan-Canadian patient-centered database required to drive improvement in various demographic, regional, and clinical cohorts in the Canadian health care system. Patients have been given a new way to speak; we just have to listen. Providing truly relevant, patient-centered care is dependent on it."

Neurons communicate with each other by sending out rapid pulses of electrical signals called spikes. At first glance, the generation of these spikes can be very reliable: when an isolated neuron is repeatedly given exactly the same electrical input, we find the same pattern of spikes. Why, then, does the activity of cortical neurons in a live animal fluctuate and actually seem so variable?

There are two reasons for this. Firstly, when transmitting a signal to another neuron, the process can sometimes fail and these failures are unpredictable - like rolling a die to decide on an outcome. "We estimate the chance of a synapse between two cortical pyramidal neurons passing a chemical neurotransmitter signal can be as low as 10%," explains lead researcher Max Nolte. This uncertainty means that a neuron will hear the same message sent by connected neurons differently every time.

Secondly, when the two fundamental types of cortical neurons (excitatory and inhibitory) are interconnected in a network, small uncertainties in activity patterns become amplified. This leads to unpredictable patterns, a behavior that is called chaos.

This backdrop of noise and chaos suggests that individual cortical neurons cannot find order and fire reliable spikes, and so the brain has to 'average' the activity of many neurons for certainty - listen to the whole choir instead of individual singers.

Simulation neuroscience finds the answer

The experimental manipulations required to untangle the noise sources in the brain and evaluate their impact on neuronal activity are currently impossible to perform in a live animal in vivo, or even in separated brain tissue in vitro. "For the moment, it is simply not possible to monitor all of the thousands of brain-wide inputs to a neuron in vivo, nor to turn on and off different noise sources," says Nolte. The closest approximation of cortical tissue to date in a model is the Blue Brain Project's biologically detailed digital reconstruction of rat neocortical microcircuitry (Cell 2015). This computer model provided the ideal platform for the researchers to study to what degree the voices of individual neurons can be understood, as it contains data-constrained models of the unreliable signal transmission between neurons.

Using this model, they found that activity that is spontaneously generated from the interconnected neurons is highly noisy and chaotic, depicting very different spike times in each repetition. "We studied the origin and nature of cortical internal variability with a biophysical neocortical microcircuit model with biologically realistic noise sources," reveals Nolte. "We observed that the unreliable neurotransmitter signals are amplified by recurrent network dynamics, causing a rapidly decaying memory of the past - a sea of noise and chaos."

Reliable responses amidst noise and chaos

But, of course the mammalian brain does not have a rapidly decaying memory. In fact, perhaps the most fascinating insight from the findings is that spike times that were highly unreliable during spontaneous activity became highly reliable when the circuit received external inputs. This phenomenon was not simply a result of strong external input directly driving the neurons to reliable responses. Even weak thalamocortical input could switch the network briefly to a regime of highly reliable spiking. At that point, the interactions between the neurons that otherwise amplify uncertainty and chaos conversely amplify reliability and allow the brain to find order.

"Thalamocortical stimuli can prompt reliable spike times with millisecond precision amid noise and chaos," explains Blue Brain Founder and Director, Prof. Henry Markram. "Surprisingly, we were able to demonstrate that this effect relies on the cortical neurons working as a team. Our model thus shows that noise and chaos in networks of cortical neurons are compatible with reliable spiking, allowing the brain to find order. This finding suggests that the highly fluctuating activity of cortical neurons in a live animal is reflecting order, not noise and chaos," Markram concludes.

34 million years ago the warm ‘greenhouse climate’ of the dinosaur age ended and the colder ‘icehouse climate’ of today commenced. Antarctica glaciated first and geological data imply that the Atlantic meridional overturning circulation, the global ocean conveyor belt of heat and nutrients that today helps keep Europe warm, also started at this time. Why exactly, has remained a mystery.

"We have found a new trigger to explain the start-up of the Atlantic current system during the greenhouse-icehouse climate transition: During the warm climate, buoyant fresh water flooded out of the Arctic and prevented the ocean-sinking that helps power the conveyor. We found that the Arctic-Atlantic gateway closed due to tectonic forces, causing a dramatic increase in North Atlantic salinity. This caused warming of the North Atlantic and Europe, and kickstarted the modern circulation that keeps Europe warm today," says David Hutchinson, researcher at the Department of Geological Sciences, Stockholm University, and lead author of the article published in Nature Communications.

The team of scientists, from the Bolin Centre for Climate Research, used a combination of geophysical data and climate modelling to show that the freshwater transport through the Arctic-Atlantic gateway plays a critical role in controlling the overturning circulation.

"Not only did deep water start forming in the Atlantic Ocean, it also stopped forming in the North Pacific at the same time, which matches geological evidence. We were surprised to find that our computer simulations can explain both of these changes due to salty ocean currents connecting the Pacific to the Atlantic. Our study is the first to show that these two events are linked, which is very exciting," says Hutchinson.

The climate at this time was very warm, with atmospheric CO2 levels two to three times the present day levels, and this contributed to extremely fresh Arctic waters. The study begs the question of whether in a future warm world, in which the Arctic may again be very fresh, the sinking in the Atlantic may cease again, which may dramatically alter the climate of Europe. Without the Atlantic conveyor belt, Europe can experience both colder winters and hotter and drier summers, making a more extreme and inhospitable climate.

"Our study helps to bridge the gap between climate modelling and geological observations of the deep past. We hope this will inspire further research from both communities on the deep circulation of the ocean," says Hutchinson.

Fukuoka, Japan - The threat of explosive volcanic eruptions looms over many cities around the world. Earthquakes, another major geological hazard, are known to have some relationships with the occurrence of volcanic eruptions. Although they often precede volcanic events, the mechanisms of these relationships are not yet well understood.

Mount Aso in Kyushu, Japan, is one of the largest active volcanoes in the world and has experienced major earthquakes and eruptions as recently as 2016. Researchers at Kyushu University's International Institute for Carbon-Neutral Energy Research (I2CNER) have been investigating the relationships among these events to better understand what are happening under the surface and to help predict future disasters. In particular, for a new study published in Geophysical Research Letters, they investigated "very long period" (VLP) seismic waves, which can represent pressure changes in subsurface hydrothermal systems.

"We analyzed continuous VLP seismicity data recorded from January 2015 to December 2016, a period that includes both large earthquakes and eruptions of Mount Aso," explains lead author of the study Andri Hendriyana. "Using on this dataset, we developed a differential-time back-projection method to accurately locate VLP events, and detected over 18,000 reliable VLP events."

Using this method, two distinct clusters of these seismic events were identified in the subsurface below the caldera of Mount Aso. For most of the observation period, VLP activity was almost entirely confined to the eastern cluster. However, after the Kumamoto earthquakes on April 2016, VLP activity abruptly shifted to the western cluster for about five months. Then, in September 2016, one month before the largest eruption of Mount Aso during the study period, VLP events migrated back to the eastern cluster. After the large eruption on October 8, 2016, VLP seismicity stopped temporarily. Together, these observations show that VLP events are affected by the occurrence of earthquakes and are related to volcanic eruptions. VLP seismicity is considered to be directly related to pressure variations associated with magmatic activity.

"We interpret the migration of VLP activity after the earthquakes as a response to permeability enhancement or to fractures opening because of extension associated with the Kumamoto earthquakes," says senior author Takeshi Tsuji. He expects this method to be applied in further studies of Mount Aso as well as other volcanoes worldwide.

"The information obtained from this new monitoring approach could reveal new details about the dynamic behavior within Aso and other volcanoes after earthquakes, and could provide important information for prevention and mitigation of future disasters."