Culture

OKLAHOMA CITY - In the field of addiction research, one question looms large: Why do some people face a higher risk than others for alcoholism and drug abuse?
A researcher at the OU College of Medicine, William R. Lovallo, Ph.D., recently published one of the field's few studies focused on how a person's genes contribute to addiction. Lovallo's research showed that a tiny genetic mutation can put people at higher risk for alcohol or drug addiction. His research was published in the world's leading journal on alcoholism, Alcoholism: Clinical and Experimental Research.

Many people ask whether addiction is caused by person's genes or their family environment. The short answer is that it's both. However, Lovallo's research zeroes in on specific gene and how it responds to a person's environment.

COMT is the name of a gene that helps the body manage dopamine, a chemical that is released when a person drinks alcohol or takes a drug like amphetamine. Lovallo's research focused on a small mutation of COMT. What he discovered demonstrates the interplay between a person's genetic makeup and adversity during childhood. People with this mutation of the COMT gene are more vulnerable to the effects of stress in their early lives, such as divorce or emotionally distant parents. That heightened vulnerability often leads to consumption of alcohol and drugs younger than age 15, which is one of the biggest independent predictors of addiction.

"Early-life adversity doesn't make everyone an alcoholic," Lovallo said. "But this study showed that people with this genetic mutation are going to have a higher risk for addiction when they had a stressful life growing up."

Because the COMT gene is involved with how well dopamine works in the brain, the behavior of the genetic mutation is especially revealing.

"This one random mutation makes a difference in how the COMT gene works fine in one person but not as well in another person," Lovallo said. "There is no such thing as a gene for addiction, but there are genes that respond to our environment in ways that put us at risk. You have to have the right combination to develop the risk factors."

Lovallo's discovery is a top achievement in his 20 years of well-funded research in this area. As a senior research career scientist at the VA Medical Center, he has conducted studies on veterans with alcohol addiction. However, those studies, like many others, concentrated on people after they became addicted to a substance. He knew he wanted to shift his research toward understanding the causes of addiction and how to prevent it.

"Many of us know people who drink alcohol moderately and never have any problems. And we know people who drink a little and then go down the path toward alcoholism," he said. "What's the difference between going down that path and not going down that path? Now we have a better understanding that it's not just exposure to alcohol or drugs that leads to problems; there is a genetic component.

"Addiction is a real health problem, and to be making progress toward understanding it is one of the most exciting and worthwhile things I've ever done," he said.

WASHINGTON, Aug. 16, 2019 -- On April 26, 1986, the Soviet Union's Chernobyl Power Complex nuclear reactor 4 exploded. This week on Reactions, we talk about the chemistry behind this catastrophic event: https://youtu.be/uvpS2lUHZD8.

CAMBRIDGE, Mass. - Stock market investors often rely on financial risk theories that help them maximize returns while minimizing financial loss due to market fluctuations. These theories help investors maintain a balanced portfolio to ensure they'll never lose more money than they're willing to part with at any given time.

Inspired by those theories, MIT researchers in collaboration with Microsoft have developed a "risk-aware" mathematical model that could improve the performance of cloud-computing networks across the globe. Notably, cloud infrastructure is extremely expensive and consumes a lot of the world's energy.

Their model takes into account failure probabilities of links between data centers worldwide -- akin to predicting the volatility of stocks. Then, it runs an optimization engine to allocate traffic through optimal paths to minimize loss, while maximizing overall usage of the network.

The model could help major cloud-service providers -- such as Microsoft, Amazon, and Google -- better utilize their infrastructure. The conventional approach is to keep links idle to handle unexpected traffic shifts resulting from link failures, which is a waste of energy, bandwidth, and other resources. The new model, called TeaVar, on the other hand, guarantees that for a target percentage of time -- say, 99.9 percent -- the network can handle all data traffic, so there is no need to keep any links idle. During that 0.01 percent of time, the model also keeps the data dropped as low as possible.

In experiments based on real-world data, the model supported three times the traffic throughput as traditional traffic-engineering methods, while maintaining the same high level of network availability. A paper describing the model and results will be presented at the ACM SIGCOMM conference this week.

Better network utilization can save service providers millions of dollars, but benefits will "trickle down" to consumers, says co-author Manya Ghobadi, the TIBCO Career Development Assistant Professor in the MIT Department of Electrical Engineering and Computer Science and a researcher at the Computer Science and Artificial Intelligence Laboratory (CSAIL).

"Having greater utilized infrastructure isn't just good for cloud services -- it's also better for the world," Ghobadi says. "Companies don't have to purchase as much infrastructure to sell services to customers. Plus, being able to efficiently utilize datacenter resources can save enormous amounts of energy consumption by the cloud infrastructure. So, there are benefits both for the users and the environment at the same time."

Joining Ghobadi on the paper are her students Jeremy Bogle and Nikhil Bhatia, both of CSAIL; Ishai Menache and Nikolaj Bjorner of Microsoft Research; and Asaf Valadarsky and Michael Schapira of Hebrew University.

On the money

Cloud service providers use networks of fiber optical cables running underground, connecting data centers in different cities. To route traffic, the providers rely on "traffic engineering" (TE) software that optimally allocates data bandwidth -- amount of data that can be transferred at one time -- through all network paths.

The goal is to ensure maximum availability to users around the world. But that's challenging when some links can fail unexpectedly, due to drops in optical signal quality resulting from outages or lines cut during construction, among other factors. To stay robust to failure, providers keep many links at very low utilization, lying in wait to absorb full data loads from downed links.

Thus, it's a tricky tradeoff between network availability and utilization, which would enable higher data throughputs. And that's where traditional TE methods fail, the researchers say. They find optimal paths based on various factors, but never quantify the reliability of links. "They don't say, 'This link has a higher probability of being up and running, so that means you should be sending more traffic here," Bogle says. "Most links in a network are operating at low utilization and aren't sending as much traffic as they could be sending."

The researchers instead designed a TE model that adapts core mathematics from "conditional value at risk," a risk-assessment measure that quantifies the average loss of money. With investing in stocks, if you have a one-day 99 percent conditional value at risk of $50, your expected loss of the worst-case 1 percent scenario on that day is $50. But 99 percent of the time, you'll do much better. That measure is used for investing in the stock market -- which is notoriously difficult to predict.

"But the math is actually a better fit for our cloud infrastructure setting," Ghobadi says. "Mostly, link failures are due to the age of equipment, so the probabilities of failure don't change much over time. That means our probabilities are more reliable, compared to the stock market."

Risk-aware model

In networks, data bandwidth shares are analogous to invested "money," and the network equipment with different probabilities of failure are the "stocks" and their uncertainty of changing values. Using the underlying formulas, the researchers designed a "risk-aware" model that, like its financial counterpart, guarantees data will reach its destination 99.9 percent of time, but keeps traffic loss at minimum during 0.1 percent worst-case failure scenarios. That allows cloud providers to tune the availability-utilization tradeoff.

The researchers statistically mapped three years' worth of network signal strength from Microsoft's networks that connects its data centers to a probability distribution of link failures. The input is the network topology in a graph, with source-destination flows of data connected through lines (links) and nodes (cities), with each link assigned a bandwidth.

Failure probabilities were obtained by checking the signal quality of every link every 15 minutes. If the signal quality ever dipped below a receiving threshold, they considered that a link failure. Anything above meant the link was up and running. From that, the model generated an average time that each link was up or down, and calculated a failure probability -- or "risk" -- for each link at each 15-minute time window. From those data, it was able to predict when risky links would fail at any given window of time.

The researchers tested the model against other TE software on simulated traffic sent through networks from Google, IBM, ATT, and others that spread across the world. The researchers created various failure scenarios based on their probability of occurrence. Then, they sent simulated and real-world data demands through the network and cued their models to start allocating bandwidth.

The researchers' model kept reliable links working to near full capacity, while steering data clear of riskier links. Over traditional approaches, their model ran three times as much data through the network, while still ensuring all data got to its destination. The code is freely available on GitHub.

Washington, DC - August 16, 2019 - Researchers have shown that three genes from a probiotic Lactobacillus species, used in some commercial probiotic vaginal capsules, are almost certainly involved in mediating adhesion to the vaginal epithelium. This is likely critical to how this species benefits vaginal health.

"These results could help us screen for better probiotic candidates in the future," said principal investigator Harold Marcotte, PhD. The research is published this week in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

"An imbalance of the normal microbiota, and particularly a loss of lactobacilli, predisposes women to urogenital infections such as bacterial vaginosis," said Dr. Marcotte, who is Associate Professor, Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. In such cases, "administration of selected probiotic lactobacilli that adhere more strongly to the vaginal walls might help to restore a healthy microbiota." That, he explained, could prevent pathogens from infecting those tissues.

Despite a wealth of clinical data showing health benefits from probiotic capsules containing these bacteria, "there is still a lack of understanding of the molecular mechanisms underlying their probiotic activities," said Dr. Marcotte. "Recently, we developed a new tool that allows us to edit the genome of lactobacilli, enabling us to inactivate genes." Inactivating genes can reveal their function.

Inactivating the three genes from the probiotic strain Lactobacillus gasseri resulted in a 30-40 percent reduction in the strength of the mutant L. gasseri's adherence to vaginal epithelial cells as compared to the wild-type strain. That is powerful evidence that the proteins these genes encode, which include a novel adhesion factor, are all involved in adhesion to vaginal epithelial cells," said Dr. Marcotte.

"We chose Lactobacillus gasseri DSM 14869 as a model organism since this strain, contained in the commercial probiotic vaginal capsules, called EcoVag, was initially selected as a probiotic due to its high adherence capacity and was subsequently shown to colonize the vagina following capsule administration," said Dr. Marcotte.

"We are planning to functionally analyze other Lactobacillus genes that are potentially involved in probiotic activity such as those involved in the synthesis of antimicrobial compounds," said Dr. Marcotte.

A new fruit fly model that mimics diseases associated with high uric acid levels, such as gout and kidney stones, has revealed new targets for developing treatments for these diseases. Pankaj Kapahi of Buck Institute and colleagues report these findings in a new study published 15th August in PLOS Genetics.

Consuming too much alcohol, red meat and sugary beverages all contribute to high levels of uric acid in the blood or urine, which increases the risk of gout, kidney stones, metabolic syndrome, obesity, diabetes and early death. Alarmingly, more than 20 percent of the United States population has elevated uric acid levels, and existing drug treatments frequently have adverse side effects, contraindications or interactions with other drugs. To better understand how the body accumulates this compound, researchers developed a strain of fruit fly that builds up uric acid in its body when triggered by a high-purine diet. They discovered that the insulin-like signaling pathway, a pathway which animals use to sense nutrients, plays a role in regulating uric acid levels. Furthermore, they demonstrated that they could lower uric acid levels in the fly by suppressing this pathway. The investigators also found that they could reduce the effects of uric acid accumulation and improve fruit fly survival by inhibiting free radicals--unstable atoms that cause damage to cells--using antioxidants like Vitamin C or by suppressing a gene called NOX.

The researchers showed that three genes are associated with uric acid levels in the fruit fly model, and these potentially could be pursued as new targets for drug development. Previous research in humans has identified several genes associated with high uric acid levels, however their causal role in altering uric acid pathologies is not well understood. This fruit fly model could be used to investigate their role further and could help identify new drugs for the numerous diseases linked to uric acid accumulation. A person's uric acid levels often increase with age, and so such therapies have the potential not only to prevent an early death, but also to increase a person's healthy years.

"Uric acid is important for longevity," said Kapahi. "Gout, the most common inflammatory arthritis, is associated with premature mortality. Conversely, many centenarians are genetically predisposed to have lower levels of uric acid. We think this work could help establish uric acid as a biomarker of aging."

From within the genetic diversity of wild teosinte – the evolutionary ancestor of modern maize –valuable traits lay hidden. In searching the ancestral genome, researchers report the discovery of UPA2, a rare allele long-lost to the selective pressures of domestication in modern maize, which can be used to directly increase the crop yields of densely planted maize by altering the angle of the plants leaves. “The work suggests that re-domesticating crops may identify other useful traits hidden in our crop’s ancestors,” writes Sarah Hake in a related Perspective. The ability to grow ever-increasing amounts of food to meet global demand relies on our ability to reap more from limited agricultural land. Increasing the density of planted crops can improve yields; however, for many crops, maize included, crowded plantings impose competition between plants for water, sunlight and soil nutrients. By adapting new varieties of maize with more upright leaves, the planting density of maize has been drastically increased. However, human selection comes at the cost of genetic diversity, which can limit the adaptive potential and genetic health of future generations. Recognizing the breadth of genetic variation within wild teosinte, Jinge Tian and colleagues created recombinant inbred lines between modern maize and teosinte and revealed a molecular regulatory network controlling the UPA2 allele. According to the results, UPA2 confers upright and narrow plant growth in teosinte, but the gene is absent in maize. Introgression of the lost allele into modern maize resulted in hybrids with significantly increased yield under high-density planting, the authors say. Tian et al. suggest the advantage of these traits have only recently become relevant and could explain why the gene was not conserved over domestication.

The host range of the influenza A virus (IAV) is restricted by dysregulated expression of the M viral gene segment, according to a study published August 15 in the open-access journal PLOS Pathogens by Anice Lowen and John Steel of Emory University School of Medicine, and colleagues.

IAV pandemics arise when a virus adapted to a non-human host overcomes species barriers to successfully infect humans and sustain human-to-human transmission. To gauge the adaptive potential and therefore pandemic risk posed by a particular IAV, it is critical to understand the mechanisms underlying viral adaptation to human hosts. To address this question, Lowen and Steel examined the role of one of IAV's eight gene segments, the M segment, in host adaptation. The authors compared the growth of IAVs with avian- and human-derived M segments in avian and mammalian systems.

The avian, but not the human, M segment restricted viral growth and transmission specifically in mammalian cells. This host-specific restricted growth was associated with excess production of the M2 protein resulting from transcription of the avian IAV M segment in mammalian cells. Excess production of the M2 protein interfered with cellular functions on which the virus relies. The results suggest that control of M segment gene expression is a critical aspect of IAV host adaptation. According to the authors, the findings could lead to the development of effective strategies for monitoring IAV pandemic risk.

The authors add, "The results reveal that careful regulation of viral gene expression is achieved through species-specific interactions with the host cell, and thereby point to this aspect of the viral life cycle as a restriction on avian influenza A virus emergence in humans."

GAINESVILLE, Fla. --- Scientists have recovered the first genetic data from an extinct bird in the Caribbean, thanks to the remarkably preserved bones of a Creighton's caracara from a flooded sinkhole on Great Abaco Island.

Studies of ancient DNA from tropical birds have faced two formidable obstacles. Organic material quickly degrades when exposed to heat, light and oxygen. And birds' lightweight, hollow bones break easily, accelerating the decay of the DNA within.

But the dark, oxygen-free depths of a 100-foot blue hole known as Sawmill Sink provided ideal preservation conditions for the bones of Caracara creightoni, a species of large carrion-eating falcon that disappeared soon after humans arrived in the Bahamas about 1,000 years ago.

Florida Museum of Natural History postdoctoral researcher Jessica Oswald extracted and sequenced genetic material from a 2,500-year-old C. creightoni femur from the blue hole. Because ancient DNA is often fragmented or missing, Oswald had modest expectations for what she would find - maybe one or two genes. But instead, the bone yielded 98.7% of the bird's mitochondrial genome, the set of DNA that most living things inherit only from their mothers.

"I was super excited. I would have been happy to get that amount of coverage from a fresh specimen," said Oswald, lead author of a study describing the work and also a postdoctoral researcher at the University of Nevada, Reno. "Getting DNA from an extinct bird in the tropics is significant because it hasn't been successful in many cases or even tried."

The mitochondrial genome showed that C. creightoni is closely related to the two remaining caracara species alive today: the crested caracara, Caracara cheriway, and the southern caracara, Caracara plancus. The three species last shared a common ancestor between 1.2 and 0.4 million years ago.

At least six species of caracara once cleaned carcasses and picked off small prey in the Caribbean. But the retreat of glaciers 15,000 years ago and the resulting rise in sea levels triggered extinctions of many birds, said David Steadman, Florida Museum curator of ornithology.

C. creightoni managed to survive the sweeping climatic changes, but the arrival of people on the islands ultimately heralded the species' demise, as the tortoises, crocodiles, iguanas and rodents that the caracara depended on for food swiftly disappeared.

"This species would still be flying around if it weren't for humans," Steadman said. "We're using ancient DNA to study what should be modern biodiversity."

Today, the islands host only a fraction of the wildlife that once flourished in the scrubland, forests and water. But blue holes like Sawmill Sink can offer a portal into the past. Researchers have collected more than 10,000 fossils from the sinkhole, representing nearly 100 species, including crocodiles, tortoises, iguanas, snakes, bats and more than 60 species of birds.

Sawmill Sink's rich store of fossils was discovered by cave diver Brian Kakuk in 2005 in his quest for horizontal passages in the limestone. The hole was not a popular diving spot: Thirty feet below the surface lay a 20-foot-thick layer of saturated hydrogen sulfide, an opaque mass that not only smells of rotten egg, but also reacts with the freshwater above it to form sulfuric acid, which causes severe chemical burns.

After multiple attempts, Kakuk, outfitted with a rebreather system and extra skin protection, punched through the hydrogen sulfide. His lamp lit up dozens of skulls and bones on the blue hole's floor.

Soon after, Kakuk and fellow cave diver Nancy Albury began an organized diving program in Sawmill Sink.

"This was found by someone who recognized what it was and never moved anything until it was all done right," Steadman said.

Though the hydrogen sulfide layer presented a foul problem for divers, it provided excellent insulation for the fossils below, blocking UV light and oxygen from reaching the lower layer of water. Among the crocodile skulls and tortoise shells were the C. creightoni bones, including an intact skull.

"For birds, having an entire head of an extinct species from a fossil site is pretty mind-blowing," Oswald said. "Because all the material from the blue hole is beautifully preserved, we thought at least some DNA would probably be there."

Since 2017, Oswald has been revitalizing the museum's ancient DNA laboratory, testing methods and developing best practices for extracting and analyzing DNA from fossils and objects that are hundreds to millions of years old.

Ancient DNA is a challenging medium because it's in the process of degradation. Sometimes only a minute quantity of an animal's original DNA - or no DNA at all - remains after bacteria, fungi, light, oxygen, heat and other environmental factors have broken down an organism.

"With ancient DNA, you take what you can get and see what works," Oswald said. "Every bone has been subjected to slightly different conditions, even relative to other ones from the same site."

To maximize her chance of salvaging genetic material, Oswald cleans a bone, freezes it with liquid nitrogen and then pulverizes it into powder with a rubber mallet.

"It's pretty fun," she said.

While previous studies required large amounts of bone, Oswald's caracara work showed ancient DNA could be successfully recovered at a smaller scale.

"This puts an exclamation point on what's possible with ancient DNA," said Robert Guralnick, Florida Museum curator of bioinformatics. "We have new techniques for looking at the context of evolution and extinction. Beyond the caracara, it's cool that we have an ancient DNA lab that's going to deliver ways to look at questions not only from the paleontological perspective, but also at the beginnings of a human-dominated planet."

Steadman, who has spent decades researching modern and extinct biodiversity in the Caribbean, said some questions can only be answered with ancient DNA.

"By understanding species that weren't able to withstand human presence, it helps us better appreciate what we have left - and not just appreciate it, but understand that when these species evolved, there were a lot more things running and flying around than we have today."

Between walking at a leisurely pace and running for your life, human gaits can cover a wide range of speeds. Typically, we choose the gait that allows us to consume the least amount of energy at a given speed. For example, at low speeds, the metabolic rate of walking is lower than that of running in a slow jog; vice versa at high speeds, the metabolic rate of running is lower than that of speed walking.

Researchers in academic and industry labs have previously developed robotic devices for rehabilitation and other areas of life that can either assist walking or running, but no untethered portable device could efficiently do both. Assisting walking and running with a single device is challenging because of the fundamentally different biomechanics of the two gaits. However, both gaits have in common an extension of the hip joint, which starts around the time when the foot comes in contact with the ground and requires considerable energy for propelling the body forward.

As reported today in Science, a team of researchers at Harvard's Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), and the University of Nebraska Omaha now has developed a portable exosuit that assists with gait-specific hip extension during both walking and running. Their lightweight exosuit is made of textile components worn at the waist and thighs, and a mobile actuation system attached to the lower back which is controlled by an algorithm that can robustly detect the transition from walking to running and vice versa.

The team first showed that the exosuit worn by users in treadmill-based indoor tests, on average, reduced their metabolic rates of walking by 9.3% and of running by 4% compared to when they were walking and running without the device. "We were excited to see that the device also performed well during uphill walking, at different running speeds and during overground testing outside, which showed the versatility of the system," said Conor Walsh, Ph.D., who led the study. Walsh is a Core Faculty member of the Wyss Institute, the Gordon McKay Professor of Engineering and Applied Sciences at SEAS, and Founder of the Harvard Biodesign Lab. "While the metabolic reductions we found are modest, our study demonstrates that it is possible to have a portable wearable robot assist more than just a single activity, helping to pave the way for these systems to become ubiquitous in our lives," said Walsh.

The hip exosuit was developed as part of the Defense Advanced Research Projects Agency (DARPA)'s former Warrior Web program and is the culmination of years of research and optimization of the soft exosuit technology by the team. A previous multi-joint exosuit developed by the team could assist both the hip and ankle during walking, and a medical version of the exosuit aimed at improving gait rehabilitation for stroke survivors is now commercially available in the US and Europe, via a collaboration with ReWalk Robotics.

The team's most recent hip-assisting exosuit is designed to be simpler and lighter weight compared to their past multi-joint exosuit. It assists the wearer via a cable actuation system. The actuation cables apply a tensile force between the waist belt and thigh wraps to generate an external extension torque at the hip joint that works in concert with the gluteal muscles. The device weighs 5kg in total with more than 90% of its weight located close to the body's center of mass. "This approach to concentrating the weight, combined with the flexible apparel interface minimizes the energetic burden and movement restriction to the wearer," said co-first-author Jinsoo Kim, a SEAS graduate student in Walsh's group. "This is important for walking, but even more so for running as the limbs move back and forth much faster." Kim shared the first-authorship with Giuk Lee, Ph.D., a former postdoctoral fellow on Walsh's team and now Assistant Professor at Chung-Ang University in Seoul, South Korea.

A major challenge the team had to solve was that the exosuit needed to be able to distinguish between walking and running gaits and change its actuation profiles accordingly with the right amount of assistance provided at the right time of the gait cycle.

To explain the different kinetics during the gait cycles, biomechanists often compare walking to the motions of an inverted pendulum and running to the motions of a spring-mass system. During walking, the body's center of mass moves upward after heel-strike, then reaches maximum height at the middle of the stance phase to descend towards the end of the stance phase. In running, the movement of the center of mass is opposite. It descends towards a minimum height at the middle of the stance phase and then moves upward towards push-off.

"We took advantage of these biomechanical insights to develop our biologically inspired gait classification algorithm that can robustly and reliably detect a transition from one gait to the other by monitoring the acceleration of an individual's center of mass with sensors that are attached to the body," said co-corresponding author Philippe Malcolm, Ph.D., Assistant Professor at University of Nebraska Omaha. "Once a gait transition is detected, the exosuit automatically adjusts the timing of its actuation profile to assist the other gait, as we demonstrated by its ability to reduce metabolic oxygen consumption in wearers."

In ongoing work, the team is focused on optimizing all aspects of the technology, including further reducing weight, individualizing assistance and improving ease of use. "It is very satisfying to see how far our approach has come," said Walsh, "and we are excited to continue to apply it to a range of applications, including assisting those with gait impairments, industry workers at risk of injury performing physically strenuous tasks, or recreational weekend warriors."

"This breakthrough study coming out of the Wyss Institute's Bioinspired Soft Robotics platform gives us a glimpse into a future where wearable robotic devices can improve the lives of the healthy, as well as serve those with injuries or in need of rehabilitation," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS, the Vascular Biology Program at Boston Children's Hospital, and Professor of Bioengineering at SEAS.

Extraterrestrial scientists landing in a football stadium would be struck by the sight of the crowd suddenly standing up and shouting in unison. In a similar manner, since the nineties, researchers have observed a special pattern of neuronal activity in rodents: tens of thousands of nerve cells firing in unison in a part of the brain called the hippocampus. But, like an alien scientist, the researchers have not been able to understand the "language" of the rodents' minds when these mysterious synchronous bursts occurred. Recently Weizmann Institute scientists succeeded in recording these rapid bursts of activity - called "hippocampal ripples" - in the human brain, and they were able to demonstrate their importance as a neuronal mechanism underlying the engraving of new memories and their subsequent recall. These findings appear today in Science.

"The ripple is an amazing event in its intensity and timing. It is an orchestrated burst of synchronous activation by about 15% of hippocampal neurons - all firing together within about a tenth of a second. It's a nerve-cell fireworks display," explains Prof. Rafi Malach of the Institute's Neurobiology Department. It was first revealed that they emerge during mental states of sleep and rest, and that they play an important role in rodents' spatial navigational memory. Only recently it was found that such synchronous electrical activity in large groups of neurons also occurs in the primate hippocampus during the awake state. However, until now, scientists have been kept in the dark as to the roles the ripples play in human cognition and mental activity.

Humans can, of course, communicate their thoughts, but most research methods do not give scientists a detailed view of what happens at the same time within the brain. Yitzhak Norman, a PhD student in Malach's lab, who led the current research in collaboration with the group of Prof. Ashesh Mehta from the Feinstein Institute for Medical Research in the US, recruiting patients who undergo invasive recordings in the course of their medical diagnosis. In this clinical procedure, patients suffering from intractable epilepsy get electrodes implanted in multiple brain regions to locate the epileptic focus and surgically remove it. These patients freely volunteered to participate in the memory experiments while they waited in the hospital between seizures.

During the experiment, the patients were presented with pictures, rich in color and visual detail, of either faces of famous people (e.g., Barack Obama, Uma Thurman) or famous monuments (e.g., the Statue of Liberty, the Leaning Tower of Pisa). The patients were asked to try to remember these pictures in as much detail as possible. After this picture-viewing stage, and following a short distraction task, they were asked, with their eyes covered, to freely recall the pictures and describe them in detail. Throughout the experiment, the talking of the patients was recorded simultaneously with their corresponding brain activity, which was revealed through the electrodes implanted both in the hippocampus, as well as other regions in the cerebral cortex.

Correlating the brain's activity and the patient's verbal reports revealed a number of striking observations. First, it was found that ripple-bursts had a critical role in the free recall process: about a second or two before the patients recalled and began describing a new picture, there was a significant increase in the ripple rate anticipating their recall. Importantly, the hippocampal ripples re-expressed the content of the pictures: pictures that elicited a higher number of ripples during the viewing stage also elicited a higher number of ripples during the subsequent recall.

Since brain activity was recorded simultaneously in the hippocampus and the cerebral cortex, the researchers were able to demonstrate that the ripples were synchronized with cortical activation, specifically in the visual centers of the brain where the detailed visual information is likely to be stored. Furthermore, high-level visual centers are known to be specialized in representing specific visual categories - for example, faces are represented in one cortical region and monuments in another region. Accordingly, when patients recalled a face, for example, Barack Obama, or alternatively, a monument, such as the Eiffel Tower, cortical activity was selectively enhanced in the corresponding visual centers. Norman explains: "An orchestrated action across a number of centers is revealed during free recall, with the hippocampus playing the role of the conductor."

The findings substantially expand our understanding of the function of the hippocampus. They emphasize the importance of synchronized neuronal group activity. The hippocampal burst, it should be remembered, involves the synchronous activation of hundreds of thousands of nerve cells. "This constitutes a major advance in our understanding of neuronal mechanisms underlying human memory," summarizes Malach. "Engraving memories, their storage and their recall are naturally dependent on a complex set of processes. However, the 'neuronal drama' of such synchronized hippocampal bursts clearly points to their central role in memory formation and recall."

Countries that relax regulations for regenerative medicines could be causing a downward spiral in international standards, according to new research published today.

Researchers warn that if just one country decides to relax regulations in the field, a heightened sense of competition can spur others to do the same.

It's unclear whether this deregulation best serves competition, science or the patients.

Regenerative medicine focuses on developing therapies to regenerate or replace injured, diseased or defective cells, tissues or organs, like stem cell 'treatments'.

Due to the use of living cells, it can be hard to set regulations in the same way as for other drugs so differences in the rules can occur.

But, according to Professor Margaret Sleeboom-Faulkner from the University of Sussex and Douglas Sipp, from the RIKEN Centre for Developmental Biology (CDB), Kobe, Japan, one thing that should always be maintained is efficacy - the ability to reliably produce a certain therapeutic result.

Professor of Social & Medical Anthropology, Margaret Sleeboom-Faulkner said: "Regenerative medicine contains a lot of economic promise, and there's already been enormous investments into it.

"While this is good in terms of focusing on new and innovative treatments to improve healthcare, it also leaves the field particularly vulnerable to regulatory brokerage. When one country relaxes their regulations, others are tempted to do the same in order to 'keep up'.

"Competition is the last way we want medicine to be progressing."

The paper, published today in the journal Science, uses the example of South Korea as the first country to give preferential regulatory treatment to stem cell medicine. Their decision to issue a flurry of three stem cell-based medical products between 2011-12, and a fourth in 2014, attracted international scepticism for sacrificing clinical data standards in exchange for speed to market.

Yet Japan, who had launched a multi-billion dollar initiative to lead the world in regenerative medicine, instead began to see South Korea as a competitor. This resulted in a change of the law in 2013, to allow regenerative medicine products a faster entry to the market.

Professor Sleeboom-Faulkner explained: "The International Society for Stem Cell Research has published general guidelines around regenerative medicines but countries regulate it in different.

"At the moment, Britain has the safety net of the EU stamp on its regulations. While we're not expecting to lose that, with Brexit looming, we could see new interpretations of the existing guidelines and find ourselves starting to compete with other countries too.

"The UK has a reputation for high standards in medicines regulation and should continue to uphold this and to be vigilant in the face of political pressures for eye-catching innovation."

Professor Sleeboom-Faulkner also notes that strict regulations can have a negative impact too, making things hard for developing countries who have to import equipment and resources. As a result, strict regulations can cause some lower income countries to relax the implementation of their regulations and take measures to be able to catch up. Of late, however, it is the wealthy countries that have become more permissive.

Professor Sleeboom-Faulkner said: "What's needed is a greater awareness that the regulations of one country can have cascading effects internationally.

"Regenerative medicines are often trialled on patients with a terminal illness, so it's hard to know the precise effect of all of this. With less stringent clinical trials and the fast-tracking of 'treatment', we'd assume standards are slipping and risks increase, but it's hard to prove that.

"Ideally, regulations should be internationally coordinated and there should be a collaborative global approach in order to maintain basic standards."

Professor Sleeboom-Faulkner is cautioning countries to be vigilant when it comes to developing treatments particularly in the face of deviant ventures such as the recent case of gene-edited foetuses in China, and the current trend of increasing flexibilities in regulations internationally.

Worcester, Mass. - August 15, 2019 - A biologist at Worcester Polytechnic Institute (WPI) has shown that a key biological component in a worm's communication system can be repurposed to take on a different job, a critical finding about the workings of evolution that could one day affect research into drug interactions, agricultural bio-engineering, and a better understanding of genetic inheritance through multiple generations.

Jagan Srinivasan, associate professor of biology and biotechnology at WPI, and his research team published their findings in Nature Communications, a highly regarded, peer-reviewed scientific journal. The paper, "Co-option of neurotransmitter signaling for inter-organismal communication in C. elegans," focuses on the evolution of the chemical communication components involved in inter-organismal signaling, which is essential for animals to navigate and survive in their natural environment.

"Evolution is intelligent, complicated, and opportunistic," said Srinivasan. "This was an old protein that the worm used for one thing and then, when a new need arose, used it for a novel function. It's more energy efficient to take something it already has and use it for a new function instead of creating something wholly new. Scientists had hypothesized about this kind of biological repurposing, but no one had shown it. We believe we are the first to show this repurposed receptor in the signaling system."

Neurotransmitters and neuroreceptors play a central role in biology, enabling cell-to-cell and animal-to-animal communication. For instance, in C. elegans, which are transparent nematodes widely used in biological and biomedical research, a neurotransmitter-sensing receptor, called TYRA-2, is needed for the worm's avoidance response to osas#9, a specific pheromone created during times of starvation. If a worm is starving, it will secrete osas#9, signaling to other worms to avoid the area because there's no food. Osas#9 and TYRA-2 work together for this avoidance response.

Funded in part by a $1.6 million National Institutes of Health grant received in 2017, Srinivasan's team has discovered that the nematodes repurpose the TYRA-2 receptor to bring about an aversive response, not between cells but among worms. This represents an inter-organismal communication pathway that evolved from inter-cellular neurotransmitter signaling via co-option of a neurotransmitter and its cognate receptor.

Other scientists had previously discovered that amino acid receptors can be re-purposed but Srinivasan's team is the first to show the repurposing of a neurotransmitter receptor. He will be studying whether other types of receptors can be repurposed, as well.

"This is not the end of the story. This is the tip of the iceberg," said Srinivasan. "This repurposing tells you how neurotransmitter signaling can evolve and how it affects the organism, whether it be humans, worms, or flies."

Over the course of more than four years of research that culminated in this Nature Communications paper, Srinivasan worked with Christopher Chute '18, PhD in Biology and Biotechnology; Douglas Reilly, PhD candidate in Biology and Biotechnology; and Veronica Coyle '16, undergraduate Biology and Biotechnology major; and with Elizabeth DiLoreto, research associate in his lab.

His team's discovery is now leading Srinivasan and his research lab to focus on three different, but related, areas that could be greatly affected by his re-purposing discovery.

The team is investigate how their finding about re-purposing could affect our understanding of drug interactions. A medication, for example, might have been created to target a specific disorder, like diabetes but by better understanding how someone's body might utilize the same neuroreceptor to use that same medication for a different function, scientists may better be able to determine the potential utility of off-target effects in the treatment of infectious diseases.

The WPI researchers also will study parasitic nematodes that attack plants, causing disease and crop and financial loss in the agricultural industry. For example, a report in Western Farm Press, a news site that focuses on agricultural production in California and Arizona, noted that soybean cyst nematodes are considered to be the most serious pathogenic threat to soybeans, and are estimated to reduce returns to U.S. soybean producers by close to $1 billion annually. Srinivasan is researching whether plants can be engineered to produce osas#9 as an adversive agent, sending out avoidance signals to cause nematodes to leave the plants alone, so farmers wouldn't need to use pesticide.

Srinivasan also is applying his findings to epigenetic research, the fairly new and quickly growing field of studying studying intergenerational (heritable) effects. Srinivasan, who has been working on research around how gene changes caused by environment and life changes are passed down through generations, now is studying how many generations of nematodes are affected by these changes.

"It looks like this receptor could cause epigenetic inheritance when you expose the mother to osas#9. Six generations of kids are sensitized to that," said Srinivasan. "Why does that happen? This data on repurposing is a big piece of that puzzle. We're putting pieces of the puzzle together."

Srinivasan worked with Frank Schroeder, professor of chemistry and chemical biology at Cornell University, to discover the osas#9 neurotransmitter in 2013.

Caenorhabditis elegans (C. elegans), which are used in Srinivasan's research, are transparent nematode worms that have a short lifespan, enabling scientists to conduct numerous observations and experiments in a relatively short period of time. Because the biological structures and processes being studied are common in all animals, work with C. elegans has implications for human health, aging and neurodegeneration.

A Dartmouth-led research team has identified a non-verbal, neural marker of autism. This marker shows that individuals with autism are slower to dampen neural activity in response to visual signals in the brain. This first-of-its kind marker was found to be independent of intelligence and offers an objective way to potentially diagnose autism in the future. The results are published in Current Biology.

"Autism is hard to screen for in children, when the first signs are present. A trained clinician may be able to detect autism at 18-months or even younger; yet, the average age of a diagnosis of autism in the U.S. is about four years old," explains lead author Caroline Robertson, an assistant professor of psychological and brain sciences at Dartmouth, and director of the Dartmouth Autism Research Initiative. "We need objective, non-invasive screening tools that don't depend on assessing a child's behavior. One of the big goals of the field is to develop objective neural markers of autism that can work with non-verbal individuals. This neural marker is just that," she added.

People with autism have long been thought to have differences in inhibiting the neural signals in the brain. This is thought to underpin symptoms in autism, such as hypersensitivity to sensory input, which includes differences in processing visual information.

When the human brain is presented with two different images at the same time, the images rock back and forth in awareness, toggling between the left and right eye. Prior research led by Robertson has demonstrated that the autistic brain is slower in switching from one image to the next (also known as slower binocular rivalry) due to differences in inhibitory neural transmission in the brain. In the autistic brain, the neurotransmitter, GABA, has difficulty filtering and regulating sensory signals, including in this case, suppressing one of the images.

The new study used brain imaging to measure the slower rate of binocular rivalry in individuals with autism. With these results, the research team was able to accurately determine if participants had autism and predict the severity of autism symptoms, which were measured using traditional clinical assessments.

To obtain the neural data, the study measured brain signals from a single electroencephalography (EEG) electrode that was placed on a participant's head, over the visual region of the brain. Participants were presented with one of two visual images: red checkerboards in the left eye and green checkerboards in the right eye that flickered back and forth at different rates.

The research revealed that neural data could be used to predict whether or not an individual had autism with 87 percent accuracy. The findings were striking and tracked with clinical measures of autism: participants with a higher level of autism had a slower rate of binocular rivalry, where the brain was slower in switching from one image to the next.

The research offers new promise for the way autism is diagnosed. "This visual test may be a non-verbal marker of autism in adults. Our next steps are to learn whether this test could potentially be used to detect autism in pre-verbal children and non-verbal adults and develop it into a screening tool for the condition. In the meantime, this result gives us new insight into the brain in autism, showing that visual regions of the brain are affected" says Robertson. The researchers also note that the visual sensitivities individuals with autism experience differ significantly among people on the autism spectrum, so while measuring these differences in visual processing may not detect autism in all individuals, it might help to better understand the autism spectrum.

What The Study Did: This study of 1,400 elementary and junior high school students in Tokyo estimated the rate of nearsightedness.

Authors: Toshihide Kurihara, M.D., Ph.D., and Kazuo Tsubota, M.D., Ph.D., of the Keio University School of Medicine in Tokyo, are the corresponding authors.

(doi:10.1001/jamaophthalmol.2019.3103)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Finnish researchers have found cellular components in the epithelial tissue of the eye, which have previously been thought to only be present in electrically active tissues, such as those in nerves and the heart. A study at Tampere University found that these components, voltage-gated sodium (Nav) channels, are involved in the renewal of sensory cells in the adjacent neural tissue, the retina. The research results are highly significant considering both the basic research of the eye and incurable retinal diseases because a clear understanding of the mechanisms of many diseases is still lacking.

"The research project focused on the retinal pigment epithelium (RPE), a tissue that is critically important to the functioning of the retina. The project revealed proteins in the RPE whose function is essential for neural tissue, but whose prevalence or activity in epithelial tissue has not been previously reported," says Academy of Finland Research Fellow Soile Nymark from Tampere University.

"These proteins, voltage-gated sodium channels, are typically responsible for generating electrical signals in the nerve cells," says Nymark.

"Therefore it is exciting to think of what they could do in the epithelial tissue, which is traditionally considered electrically inactive," Nymark continues.

In order for our vision to work properly, retinal sensory cells need to be constantly renewed, and this renewal requires the operation of a strictly controlled and multistep phagocytosis process in the RPE. In this process, part of the retinal sensory cell is detached and enclosed within the adjacent epithelium. The epithelial tissue then metabolises these detached parts of the sensory cells in a controlled manner and thus maintains normal functioning of the retina.

The present discovery reveals how the ion channel proteins responsible for the electrical signalling of neurons influence the phagocytosis process. This process is impaired in many retinal degenerative diseases, the most important example being age-related macular degeneration (AMD). The mechanisms and causes of these diseases can now be studied in the light of the new findings, which creates opportunities for the development of curative treatments.

Our present understanding on the functioning of epithelial tissues is strongly based on cell biological studies. In this study at Tampere University, the researchers investigated the epithelial tissue of the eye by utilizing techniques that have traditionally been used to determine the electrical communication of nerve cells.

"This perspective enabled our new observation and highlights that the major role of electrical phenomena and the underlying ion channels in the functioning of epithelial tissue may not yet be fully understood," Nymark points out.

In the future, the multidisciplinary project will focus in particular on the role of the newly discovered ion channels in the communication between epithelial cells.