Culture

AMHERST, Mass. - A molecular biologist at the University of Massachusetts Amherst who has for decades studied the nightmarish group of fatal diseases caused by prions - chronic wasting disease in deer, mad cow in cattle and its human analog - credits a middle-of-the-night dream for a crucial insight, a breakthrough she hopes could lead to a cure.

In a new paper in Nature Structural and Molecular Biology by Tricia Serio, dean of the College of Natural Sciences and professor of biochemistry and molecular biology at UMass Amherst, and others, report an unanticipated role for prion nucleation seeds that enhances their ability to appear and resist curing. Nucleation seeds are molecule clusters that form when prions attach to one another and change shape. "Once that change occurs, it creates a very stable aggregate known as amyloid that was thought to be impossible to inactivate by normal means," Serio notes.

The infectious prion is an unusual pathogen, a protein without nucleic acid, she explains. Prion diseases were first described in the 1800s, and include scrapie in sheep and other neurodegenerative diseases such as mad cow disease and in humans, Creutzfeldt-Jakob disease, fatal familial insomnia and kuru from ritual cannibalism in Papua, New Guinea.

Serio says, "These diseases are always fatal," but she and colleagues including first author Janice Villali work with natural yeast prions that can't be transmitted to humans or cause disease. "It's a good model system that is not infectious, and it grows really fast."

It has been known for decades that prion protein (PrP) misfolding is a key part of the disease process, she adds. In these diseases, proteins fold into 3D shapes that cause disease. In mammals, the protein quality control system responds to folding mistakes with "chaperone" molecules that seek out misfolds and try to refold and correct mistakes.

But prions misfold so quickly that chaperones can't keep up, Serio says. "That part was known," she adds, but scientists still could not figure out what was limiting the chaperone system, allowing prions to persist. "One key factor controlling the transition from harmless protein to invincible disease menace was so hidden and obscure that it had not been previously proposed," she says.

Then, after a conference where she had talked intensely all day about prions, Serio had the crucial dream. "It came to me that the size of the aggregate nucleation seed mattered," she recalls. "So we went back and designed experiments to test the minimum size idea by mathematical modeling with co-first author Jason Dark, and it worked. That led to this investigation and why we're really excited about this paper."

The first revelation was a surprise, Serio recalls - prion aggregates come in different sizes. "Everybody knew of the nucleation seed, but no one knew they could be different sizes for the same protein." As prion proteins physically attach and the complex switches from one state to another, this minimum size is really important - but why?

It turns out, Serio says, that the seed complex must double in size for the disease to persist. It it starts with four molecules, it must reach eight. "This minimum size determines whether the chaperone can win. Four has to get to eight, but if you catch it early enough, if you pull out one side of the square, the amyloid structure can't double. Chaperones prevent the disease by preventing it from doubling in that first round."

Another discovery is that if the minimum nucleation seed starting size is 10 and it must reach 20 to create two amyloids, that complex is an easier problem for chaperones to nip, Serio points out. "In yeast, the bigger the initial seed, the more difficult it is for the disease to resist chaperones and take hold because these protein quality controls have more time to act; the smaller seed is harder to cure because it doubles more quickly."

She adds, "We realized that if we could control this transformation, we could stop the disease from arising, but we also realized that the same barrier would control going backwards and unfolding an established amyloid. The literature says that's a silly idea because prions survive and resist killing so well. But once we figured out this minimum size, we showed that it could also predict the frequency of prion curing under different growth conditions. Looking back, we can't figure out how we missed it."

Serio says she and her team now know there are at least three nucleation sizes possible, and, "I suspect that it will turn out to be an infinite number," she adds. "In fact, we have shown that we can shift the nucleation size by changing the shape of the prion or by expressing a mutant form of the protein, opening the door to therapeutic intervention to reverse this process."

A group of scientists from Sechenov University, Russia, and La Trobe University, Australia, have developed a fast and cost-effective method of detecting and identifying bioactive compounds in complex samples such as plant extracts. They successfully applied the method to examine Mediterranean and Australian native culinary herbs. Three articles on this work were published in Applied Sciences, Journal of Pharmaceutical and Biomedical Analysis and Journal of Chromatography A.

Since ancient times, people have been using herbs as food additives and medicines, though a search for useful compounds and a study of their properties remain a difficult task. It is possible to examine a compound if it is stable enough and can be separated from other substances in a sample. However, plant extracts contain hundreds of compounds. In the past, only known compounds were investigated by target analysis and most bioactive compounds were left undiscovered. Thus, the number of compounds that are yet to be explored is so huge that methods that can both screen mixtures and identify the compounds responsible for bioactivity are of greater value.

The authors of the papers used an Effect Directed Analysis (EDA) approach, which is a combination of chromatographic separation with in situ (bio)assays and physico-chemical characterisation to discover and identify bioactive compounds in complex plant samples. Thin-layer chromatography (TLC) and high performance thin-layer chromatography (HPTLC) are well established, chromatographic separation techniques ideally suited for high-throughput screening of bioactive compounds in crude samples.

To separate substances, TLC uses the fact that various compounds are transported by a solvent and absorbed by a sorbent at different speeds. A sorbent-coated plate with a studied mixture is immersed with one end in the solvent, and under the action of capillary forces, it begins to rise along the plate, taking the substances of the mixture with it. As they move upward, the compounds are absorbed by the sorbent and remain as horizontal bands that can be distinguished in visible, infrared or ultraviolet light. Using this method, crude extracts can be analysed directly with no preparation and possible loss of sample components.

Bioassays allow to determine the properties of compounds, such as toxicity, observing how model organisms (bacteria, plants or small animals) react to them. In this way, one can select extracts able to inhibit the action of individual enzymes or reactive oxygen species.

Combination of TLC chromatography with microbial (bacteria and yeast) tests and biochemical (enzyme) bioassays enables rapid and reliable characterization of bioactive compounds directly on the chromatographic plates, without isolation/extraction. The advantage of HPTLC is that plates/chromatograms can be directly immersed into enzyme solution (bioassays), incubated for up to several hours, followed by visualization of the (bio)activity profile via an enzyme?substrate reaction as bioactivity zones. This approach is more cost effective, enabling a more streamlined method to detect and characterise natural products that are suitable candidates for further investigation as potential new drug molecules.

Using this method, scientists examined the properties of bioactive compounds from culinary herbs commonly used in the Mediterranean diet: basil, lavender, rosemary, oregano, sage and thyme. Australia's native plants were added to the list: lemon myrtle (Backhousia citriodora), native thyme (Prostanthera incisa), sea parsley (Apium prostratum), seablite (Suaeda australis) and saltbush (Atriplex cinerea). Some of the secondary metabolites from these plants exhibit significant antioxidant activity and enzyme inhibition, like α-amylase inhibition. Therefore, these herbs may be preventive not only against cardiovascular diseases but also type 2 diabetes. The enzyme α-amylase breaks down polysaccharides, thereby increasing blood sugar levels. Recent studies suggest that hyperglycemia induces generation of reactive oxygen species, alteration of endogenous antioxidants and oxidative stress. It was found that patients with uncontrolled sugar levels in addition to diabetes also suffer from accelerated cognitive decline independent of their age. Although Australian native herbs are used as a substitute for related European plants, their medicinal properties are much less studied.

After preparing the extracts, the scientists began to study their composition and qualities. Rosemary and oregano extracts showed the greatest antioxidant activity, while sage, oregano and thyme were the best at slowing down reactions involving α-amylase (extracts from lavender flowers and leaves were the only ones not to show this effect). Among the studied Australian native herbs, lemon myrtle showed the strongest antioxidant properties, with the best α-amylase inhibition observed with extracts of native thyme (this property was noticed for the first time), sea parsley and saltbush.

The study of plant extracts using bioassay and thin-layer chromatography allows scientists to examine a variety of compounds, find mixtures that have the desired properties and isolate substances that exhibit them to the greatest extent. This fast and cost-effective method will be useful for finding new drug compounds.

A drug-loaded microrobotic needle effectively targets and remains attached to cancerous tissue in lab experiments without needing continuous application of a magnetic field, allowing more precise drug delivery. The details were published by researchers at DGIST's Microrobot Research Center in Korea and colleagues in the journal Advanced Healthcare Materials.

"Chemotherapeutic drugs cause a wide range of side effects due to their impacts on healthy and cancerous tissues," explains robotics engineer Hongsoo Choi of Korea's Daegu-Gyeongbuk Institute of Science & Technology (DGIST), who led the research. "To avoid these unwanted effects, scientists have been experimenting with microrobots of different shapes that deliver drugs to specific tissues."

Drug-toting microrobots usually require a magnetic field to direct them to targeted tissues and then hold them in place, otherwise they are easily flushed away by body fluids such as blood flow. Choi and colleagues wanted to design a functional microrobot that avoids impractical and prolonged use of an energy-consuming magnetic field.

They succeeded by making a microrobot shaped like a corkscrew with a needle at its end.

Choi worked with DGIST's Seungmin Lee and colleagues to fabricate the corkscrew-shaped microneedle using laser lithography. The microrobot is then layered with nickel and titanium oxide to ensure it can be magnetically manipulated and is biocompatible with the human body. Drugs can be loaded onto the porous, corkscrew-shaped scaffold and inside the needle.

The team tested the microrobots in tiny chambers filled with fluid. They successfully used a magnetic field to direct them to spear and attach to tissue. Once fixed, it took a fluid flow speed of 480 millimetres per second to flush the needle out of the tissue. For comparison, the flow rate in small arterioles is around 100 millimetres per second.

They then used a computational approach for more precise automatic, rather than manual, targeting of tissue using a magnetic field. Automatic targeting and fixation took only seven seconds, whereas manual control of the magnetic field took 55 seconds.

Finally, they loaded the microneedles with the anticancer drug paclitaxel and tested them in a microchamber containing human colorectal cancer cells. The microrobots effectively targeted and killed the cells.

Next, the team plans to improve the microrobot for more efficient drug loading and to optimize the magnetic field system for more precise control. Further tests in animals and then human trials will be needed before the microrobots can be used as a treatment strategy.

Dang robots are crummy at so many jobs, and they tell lousy jokes to boot. In two new studies, these were common biases human participants held toward robots.

The studies were originally intended to test for gender bias, that is, if people thought a robot believed to be female may be less competent at some jobs than a robot believed to be male and vice versa. The studies' titles even included the words "gender," "stereotypes," and "preference," but researchers at the Georgia Institute of Technology discovered no significant sexism against the machines.

"This did surprise us. There was only a very slight difference in a couple of jobs but not significant. There was, for example, a small preference for a male robot over a female robot as a package deliverer," said Ayanna Howard, the principal investigator in both studies. Howard is a professor in and the chair of Georgia Tech's School of Interactive Computing.

Although robots are not sentient, as people increasingly interface with them, we begin to humanize the machines. Howard studies what goes right as we integrate robots into society and what goes wrong, and much of both has to do with how the humans feel around robots.

I hate robots

"Surveillance robots are not socially engaging, but when we see them, we still may act like we would when we see a police officer, maybe not jaywalking and being very conscientious of our behavior," said Howard, who is also Linda J. and Mark C. Smith Chair and Professor in Bioengineering in Georgia Tech's School of Electrical and Computer Engineering.

"Then there are emotionally engaging robots designed to tap into our feelings and work with our behavior. If you look at these examples, they lead us to treat these robots as if they were fellow intelligent beings."

It's a good thing robots don't have feelings because what study participants lacked in gender bias they more than made up for in judgments against robot competence. That predisposition was so strong that Howard wondered if it may have overridden any potential gender biases against robots - after all, social science studies have shown that gender biases are still prevalent with respect to human jobs, even if implicit.

In questionnaires, humanoid robots introduced themselves via video to randomly recruited online survey respondents, who ranged in age from their twenties to their seventies and were mostly college-educated. The humans ranked robots' career competencies compared to human abilities, only trusting the machines to competently perform a handful of simple jobs.

Pass the scalpel

"The results baffled us because the things that people thought robots were less able to do were things that they do well. One was the profession of surgeon. There are Da Vinci robots that are pervasive in surgical suites, but respondents didn't think robots were competent enough," Howard said. "Security guard - people didn't think robots were competent at that, and there are companies that specialize in great robot security."

Cumulatively, the 200 participants across the two studies thought robots would also fail as nannies, therapists, nurses, firefighters, and totally bomb as comedians. But they felt confident bots would make fantastic package deliverers and receptionists, pretty good servers, and solid tour guides.

The researchers could not say where the competence biases originate. Howard could only speculate that some of the bad rap may have come from media stories of robots doing things like falling into swimming pools or injuring people.

It's a boy

Despite the lack of gender bias, participants readily assigned genders to the humanoid robots. For example, people accepted gender prompts by robots introducing themselves in videos.

If a robot said, "Hi, my name is James," in a male-sounding voice, people mostly identified the robot as male. If it said, "Hi, my name is Mary," in a female voice, people mostly said it was female.

Some robots greeted people by saying "Hi" in a neutral sounding voice, and still, most participants assigned the robot a gender. The most common choice was male followed by neutral then by female. For Howard, this was an important takeaway from the study for robot developers.

"Developers should not force gender on robots. People are going to gender according to their own experiences. Give the user that right. Don't reinforce gender stereotypes," Howard said.

Social is good

Some in Howard's field advocate for not building robots in humanoid form at all in order to discourage gendering and other humanization, but Howard does not take it that far.

"Robots can be good for social interaction. They could be very helpful in elder care facilities to keep people company. They might also make better nannies than letting the TV babysit the kids," said Howard, who also defended robots' comedic talent, provided they are programmed for that.

"If you ever go to an amusement park, there are animatronics that tell really good jokes."

Your house number could be the key to the safe relaxation of COVID-19-related restrictions if governments follow a new exit strategy proposal published today in the British Medical Journal.

Co-authored by Professor Adrian Barnett, a statistician with QUT's School of Public Health and Social Work, the paper suggests governments around the globe use an 'odds-and-evens' approach to allowing people to head back to work and enjoy other activities after weeks of lockdown.

"Governments in Australia and elsewhere are seeking to balance competing priorities. Social distancing has certainly been proven to reduce the rate of transmission of COVID-19 but has had a negative impact on the economy and created other health issues," said Professor Barnett.

"A major problem with relaxing restrictions too quickly is the limited evidence on how this will affect transmission of the virus and no-one wants to see another wave of infection and deaths which would lead to a return to lockdown.

"We propose an interim solution in which allowing people to return to a less-restricted life should be based on odd or even house numbers. For example, people in odd numbered houses have relaxed restrictions on odd days in the month (1st, 3rd, etc) and people in even number houses on even days (2nd, 4th, etc).

"This halves the population mixing, which reduces the risk of a new wave occurring, and it creates useful data for judging whether restrictions can be further relaxed or should be tightened."

Professor Barnett said there were precedents in place dealing with traffic pollution and congestion, with daily restrictions based on odd-or-even vehicle number plates adopted in major cities worldwide including Beijing, Rome, Paris and Mexico City.

"As for COVID-19, we are seeing similar national policies such as in Columbia where restrictions have been implemented by gender, with men allowed out some days and women on others, and in Bolivia, Honduras and Panama they are using national ID numbers to apply restrictions," he said.

"An advantage to the odds-and-evens approach is that it creates multiple randomised experiments that could be used to study how the virus spreads, because on every day we have similar groups of people who are exposed and not, creating an ideal natural experiment.

"It should also make it easier to spot a new wave of infection earlier, because there would be an alternating pattern in house numbers in people reporting symptoms."

Professor Barnett added an important factor for governments to consider with such a policy was the length of time to relax social isolation for each group.

"We have looked at it being implemented using alternate days, but governments might choose a different duration, such as by week which will have different health and economic implications. It could also start on a modest base and evolve over time," he said.

"There will also be challenges in enforcing a policy based on house number and there will always be people who choose not to obey the rules. Despite the potential problems, this approach partially re-starts the economy for a lower risk and provides valuable experimental data, so it has multiple benefits compared with relaxing restrictions en masse."

While tracing the movement of Escherichia coli, a team of French researchers noticed that near solid surfaces, the bacteria run in circles. Loop after loop, the tracing almost looks like an Olympic figure skating rink before the Zamboni irons the sheet of ice smooth. Breaking down E. coli's routine step by step, the scientists identified a signature move--surface tumbling. The work appears May 5 in the Biophysical Journal.

Bacteria can live as individuals, swimming freely around the environment, but eventually, they settle down on surfaces to form colonies and biofilms. To do so, bacteria randomly tumble to slow down and re-orientate themselves three-dimensionally, to explore and find the ideal environment.

"Tumbles are very interesting. The bacteria itself does not know where the environment is preferential for them," says first author Laurence Lemelle, a biophysicist at École Normale Supérieure de Lyon (Normal School of Lyon). "It doesn't know where to go, how to feel things. But it knows if the past environment was better or worse than the present." Bacteria use the gathered information to stop tumbling or lower the frequency of tumbling. "This means you swim more towards a direction. At the end, the population statistically swims towards the preferential conditions," she says.

Some studies claim that bacteria don't tumble and only swim when they're near a surface. But Lemelle and her colleagues say that claim sounds unlikely. Physics predicts that bacteria would get trapped, running in infinite circles on the surface if they only swam.

However, it's not easy to track these tiny creatures. Propelling forward with their several tails known as flagella, bacteria swim 20 times the length of their body in one second, and tumble happens even quicker, at one-tenth of a second. In fact, you're likely to miss the tumble even if your camera is high-res enough to film bacteria. To take a close look at how bacteria escaped from the surface, the team built a high-magnification, high-sensitivity, high-speed camera equipped with night vision.

The recording showed that when the bacteria swim near the surface, the water friction on the body near the surface causes the trajectory to bend. To prevent being trapped running in circles on the surface, the bacteria tumbles. It decelerates, and one of the flagella jiggles out of place, reorienting where it was heading. In some cases, like swimmers pushing off a pool wall, the jiggling flagella kicks on the surface, resulting in a sharper turn. The wild flagellum then returns to the bundle, accelerates the bacteria, and goes back to swimming.

"We now know that bacteria can tumble on surfaces, and these tumbles are very specific," said Lemelle. "Elucidating the strategy of surface exploration that is underlined by these tumbles is an important future step."

To the bacteria, tumbling allows them to escape from the surface, enabling them to colonize other places and optimize the exploration of the surface itself. Bacteria can swim on cell surfaces until they get in contact with a specific receptor to optimize infections. They can also swim to settle down on surfaces that are difficult to clean to form bacterial biofilms, which can be antibiotic-resistant.

"Before the pandemia, the COVID pandemic, it was difficult to convince people that we need to anticipate and develop alternative approaches to reduce the surface biocontamination," said Lemelle. "People were like, 'We have plenty of antibiotics. There's resistance, but we have time.' From a medical standpoint, understanding the near-surface tumbling events of bacteria can help limit the biocontamination of surfaces and develop antibacterial methods."

DALLAS, May 5, 2020 -- People with recent heart attacks have significantly higher activity in the amygdala, the brain area involved in stress perception and emotional response, along with greater inflammation in arteries resulting from increased bone marrow activity, a hallmark of plaque build-up -- and these are all capable of returning to near-normal, according to preliminary research presented at the American Heart Association's Vascular Discovery: From Genes to Medicine Scientific Sessions 2020. The meeting is a virtual event in 2020, to be held May 5-7, and is a premier global exchange of the latest advances in new and emerging scientific research in arteriosclerosis, thrombosis, vascular biology, peripheral vascular disease, vascular surgery and functional genomics.

"The results of this study advance our understanding of the interconnections among the brain, bone marrow and blood vessels, with activity of the brain emotional center closely linked to heart disease activity and inflammation of blood vessels which are spurred by inflammatory immune cells produced by the bone marrow," said Dong Oh Kang, M.D., lead study author and clinical instructor in the cardiovascular center of Korea University Guro Hospital in Seoul, Korea.

The researchers obtained simultaneous PET and CT scans to create 3-D images of the brain, major arteries and bone marrow of 62 study participants. The study included 45 people (84% male, average age 60 years) who had a heart attack within the previous 45 days and 17 people with no heart attack history (76% male, average age 59.6 years), the control group. All participants completed widely accepted standard screening questionnaires for depression and perceived stress.

Researchers found:

Those who had a recent heart attack had significantly higher activity in the amygdala region of the brain, which is responsible for stress perception and emotional response.

The participants who had a recent heart attack also had increased inflammation in the aorta and carotid artery (neck), which supplies blood to the brain, and increased bone marrow activity, indicating active production of inflammatory cells.

In both groups, those who reported feeling more depressed or stressed on psychological questionnaires showed higher activity in the amygdala.

Brain emotional activity and inflammation can change over time. After six months, the 10 heart attack patients who underwent follow-up imaging had near-normal PET and CT scans.

"Amygdala activity has previously been reported to be stable over time, however, the changes seen in our study suggest the possibility that stress reduction techniques may lower brain emotional activity and potentially reduce inflammation in arteries and the production of inflammatory cells, thus, potentially modifying the course of heart disease. This could become an additional strategy to prevent a second heart attack," Kang said.

Although the study found significant links between amygdala activity and artery inflammation, intervention studies are needed to investigate the possible benefits of modifying brain emotional activity on atherosclerosis. Kang also noted more research is needed to identify the most effective stress relief treatments.

Co-authors are Jae Seon Eo, M.D., Ph.D.; Eun Jim Park, M.D.; Hyeong Soo Nam, Ph.D.; Joon Woo Song, M.S.; Cheol Ung Choi, M.D., Ph.D.; Eung Ju Kim, M.D., Ph.D.; Seung-Woon Rha, M.D., Ph.D.; Hong Seog Seo, M.D., Ph.D.; Hongki Yoo, Ph.D.; and the principal investigator of this project is Jin Won Kim, M.D., Ph.D. Author disclosures are in the abstract, and no funding is reported.

The scientific presentation is at 12:05 p.m. CT, May 6, 2020; the virtual meeting link is available here.

DALLAS, May 5, 2020 -- The Vein-Chip device, a miniaturized version of a large human vein, allowed scientists to study changes in vein wall cells, blood flow and other functions that lead to deep vein thrombosis (DVT) in humans, according to preliminary research presented at the American Heart Association's Vascular Discovery: From Genes to Medicine Scientific Sessions 2020. The meeting is a virtual event in 2020, to be held May 5-7, and is a premier global exchange of the latest advances in new and emerging scientific research in arteriosclerosis, thrombosis, vascular biology, peripheral vascular disease, vascular surgery and functional genomics.

The Vein-Chip is a translucent hollow chamber which serves as a miniature version of a human vein with similar architecture and cellular function. The chip allows researchers to test various human endothelial cells to differentiate various factors - gender, race, ethnicity and more - revealing which populations may have more or less DVT risk. In the end, the technology might allow for more personalized therapies for vein diseases.

"Within the Vein-Chip, we cultured endothelial cells retrieved from human veins that line all sides of the chamber and form a venous vessel. Blood drawn from participants was perfused via a syringe pump under the same physical conditions one would expect in a patient," said Abhishek Jain, Ph.D., lead study author and assistant professor of biomedical engineering at Texas A&M University's College of Engineering in College Station, Texas. "With this micro-chip, we simulated various functions, - and we could introduce toxins and medications to make the vein diseased and cured over time. We can also observe these processes to understand changes in gene and protein expression of the cells."

Three discoveries were made in this study of the Vein-Chip. Researchers found:

Under a normal healthy state, if a DVT risk factor like slowing blood flow occurs, the body might try to adapt by releasing anti-clotting factors. This adaptation happens within the vein pocket only and suggests that medications should be locally delivered at the site most affected by the disease.

Clot dissolving medications delivered through the vein do not always easily reach the clot in the vein pocket. This suggests new strategies are needed that could enhance the local transport of drugs to the vein pockets.

Human veins have pockets of different shapes, resulting in different extents of clotting, or thrombosis. As a result, venous architecture is an important DVT contributor.

Human veins consist of pockets that are one-way, pumping valves transporting blood from the legs to the heart. "It is in these pockets where blood flow can become unstable. The living cells, that line the walls, called endothelial cells, can switch from being normal to inflammatory. The inflammation results in clots that can then break apart, reach the small vessels of the lungs and brain and block the organ's blood supply, causing death from stroke," Jain said. "Venous pockets have been largely overlooked in venous thrombosis research, even though they are the primary sites of blood clot formation."

One of the challenges of research to develop technologies such as this is human trials can be conducted only after successful animal studies, according to Jain. "This is considered by many funding agencies to be a high-risk concept. Seeing a technology like this through to human studies requires a leap of faith among basic scientists, physicians, pharmaceutical companies, the FDA and funding agencies," he said.

Navaneeth K.R. Pandian is the study's co-author. Author disclosures are in the abstract. The National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health and the Texas A&M University funded the study.

When we fall asleep, our brains are not merely offline, they're busy organizing new memories--and now, scientists have gotten a glimpse of the process. Researchers report in the journal Cell Reports on May 5 the first direct evidence that human brains replay waking experiences while asleep, seen in two participants with intracortical microelectrode arrays placed in their brains as part of a brain-computer interface pilot clinical trial.

During sleep, the brain replays neural firing patterns experienced while awake, also known as "offline replay." Replay is thought to underlie memory consolidation, the process by which recent memories acquire more permanence in their neural representation. Scientists have previously observed replay in animals, but the study led by Jean-Baptiste Eichenlaub of Massachusetts General Hospital and Beata Jarosiewicz, formerly Research Assistant Professor at BrainGate, and now Senior Research Scientist at NeuroPace, tested whether the phenomenon happens in human brains as well.

The team asked the two participants to take a nap before and after playing a sequence-copying game, which is similar to the 80s hit game Simon. The video game had four color panels that lit up in different sequences for the players to repeat. But instead of moving their arms, the participants played the game with their minds--imagining moving the cursor with their hands to different targets one by one, hitting the correct colors in the correct order as quickly as possible. While the participants rested, played the game, and then rested again, the researchers recorded the spiking activity of large groups of individual neurons in their brains through an implanted multi-electrode array.

"There aren't a lot of scenarios in which a person would have a multi-electrode array placed in their brain, where the electrodes are tiny enough to be able to detect the firing activity of individual neurons," says co-first author Jarosiewicz. Electrodes approved for medical indications, like those for treating Parkinson's disease or epilepsy, are too big to track the spiking activity of single neurons. But the electrode arrays used in the BrainGate pilot clinical trials are the first to allow for such detailed neural recordings in the human brain. "That's why this study is unprecedented," she says.

BrainGate is an academic research consortium spanning Brown University, the Providence VA Medical Center, Massachusetts General Hospital, Case Western Reserve University, and Stanford University. Researchers at BrainGate are working to develop chronically implanted brain-computer interfaces to help people with severe motor disabilities regain communication and control by using their brain signals to move computer cursors, robotic arms, and other assistive devices.

In this study, the team observed the same neuronal firing patterns during both the gaming period and the post-game rest period. In other words, it's as though the participants kept playing the Simon game after they were asleep, replaying the same patterns in their brain at a neuronal level. The findings provided direct evidence of learning-related replay in the human brain.

"This is the first piece of direct evidence that in humans, we also see replay during rest following learning that might help to consolidate those memories," said Jarosiewicz. "All the replay-related memory consolidation mechanisms that we've studied in animals for all these decades might actually generalize to humans as well."

The findings also open up more questions and future topics of study who want to understand the underlying mechanism by which replay enables memory consolidation. The next step is to find evidence that replay actually has a causal role in the memory consolidation process. One way to do that would be to test whether there's a relationship between the strength of the replay and the strength of post-nap memory recall.

Although scientists don't fully understand how learning and memory consolidation work, a cascade of animal and human studies has shown that sleep plays a vital role. Getting a good night's sleep "before a test and before important interviews" is beneficial for good cognitive performance, said Jarosiewicz. "We have good scientific evidence that sleep is very important in these processes."

The cochineal Dactylopius opuntiae 'stricta' biotype is more effective as a sustainable biocontrol in the fight against the invasive common pest pear Opuntia stricta in Laikipia County, Kenya, compared to physical and/or chemical control - CABI scientists can now reveal.

Dr Arne Witt, based at CABI's centre in Nairobi, led on research published in BioControl which shows that the D. opuntiae 'stricta' biotype - that was released in 2014 - has contributed to a 'significant reduction' in the number of cladodes, flowers and fruit of plants with cochineal.

Following a preliminary once-off survey, Dr Witt and collaborators Winnie Nunda, Fernadis Makale and Kathryn Reynolds, demonstrated that fruits that were produced on plants with the cochineal were also smaller and had fewer seeds.

Dr Witt said, "Although still preliminary, an analysis of the costs of implementing the D. opuntiae 'stricta' biotype indicate that it is the most cost-effective management intervention compared to physical and/or chemical control.

"Furthermore, while the impact of the cochineal is still fairly localized, we are confident that it will establish in much of the invaded range and reduce the impacts of the invasive cactus, consequently improving rangeland condition and livelihoods."

Since its introduction to Kenya in 1949, O. stricta is considered to be the most widespread and problematic cactus species - being most abundant in Laikipia County and Tsavo East National Park and adjacent rangelands where it forms dense stands and prevents access to homes, water resources and pasture.

"It is still too early to confirm if the agent D. opuntiae 'stricta' biotype will contribute to the complete control of O. stricta in Laikipia", Dr Witt added. "However, early indications do warrant the re-distribution of the agent to Tsavo East NP and the Serengeti-Mara ecosystem, which has some significant invasions."

Dr Witt also revealed that a biotype of O. stricta for the control of Opuntia engelmannii has also been sourced in the USA and will 'hopefully be released' in Laikipia when approval has been granted from the regulatory authorities.

Sophia Antipolis - 5 May 2020: An ingenious necklace which detects abnormal heart rhythm will be showcased for the first time on EHRA Essentials 4 You, a scientific platform of the European Society of Cardiology (ESC).

"The wearable necklace-ECG (electrocardiogram) provides a new and easy method for detecting an abnormal heart rhythm called atrial fibrillation, which is a fast-growing public health problem," said study author Mr. Elmeri Santala, a medical student at the University of Eastern Finland.

One of the major causes of stroke is unrecognised and untreated atrial fibrillation. Approximately 25% of all strokes are caused by atrial fibrillation. While it is the most common heart rhythm disturbance, atrial fibrillation is often symptomless and intermittent, making its detection and diagnosis challenging. Innovative methods for detection are therefore needed.

This study examined the diagnostic accuracy of an ECG worn around the neck (see photo). A single-lead ECG is embedded into the pendant.

To measure their heart rhythm, users start an application on their smartphone then place the necklace pendant between the palms of their hands or between the palm and the chest for 30 seconds. Data are automatically sent to a cloud service and analysed for atrial fibrillation using artificial intelligence (AI). Within a few seconds, the smartphone application displays the results of the analysis. An ECG report is also generated for physicians to confirm the diagnosis.

The study enrolled 145 adults who used the necklace to measure their own heart rhythm. Participants simultaneously underwent a three-lead ECG recording as a 'gold standard' comparison.

Two cardiologists analysed all ECG readings without knowing the initial rhythm (i.e. they were blinded to the 3-lead ECG recordings and initial 12-lead ECG). Automated AI analysis of the necklace ECG was also performed.

The necklace produced ECG recordings with excellent quality to detect and diagnose atrial fibrillation. Atrial fibrillation diagnoses made by standard ECG measurement were also picked up by the necklace device with high accuracy - both the automated AI analysis and interpretation of the ECG report by a cardiologist.

Mr. Santala said: "The necklace ECG is simple to use and allows repetitive self-monitoring of heart rhythm, thereby improving the likelihood of detecting atrial fibrillation. The ESC recommends screening for atrial fibrillation in people over 65 years of age and in those at high risk of stroke;1 automated analysis by the necklace ECG is well suited for this purpose. Diagnosis of atrial fibrillation should always be confirmed by a physician using the ECG report."

WASHINGTON, May 5, 2020 -- Electrochemical reactions that occur in processes like ethanolic fermentation include the transformation of sugars into alcohol and carbon dioxide. Similar processes occur when the human body breaks down food, drugs or other compounds.

Monitoring these metabolic processes helps in testing, studying and combating disease, but due to the small quantities of liquids involved, they are difficult to study with normal equipment.

Miniaturizing devices with environmental sensing capabilities offers promise for better testing of fermentation and other biochemical processes. The ability to operate the devices wirelessly over long periods of time increases their effectiveness.

In a paper published this week in Review of Scientific Instruments, from AIP Publishing, a miniaturized potentiostat, which controls voltage between electrodes, proved capable of quantifying molecules using voltammetric and chronoamperometric methods with an accuracy above 98%. The wireless device is compatible with most 3-electrode biosensors and can transmit its measurements via Bluetooth for 100 meters.

"One of the novelties of the potentiostat circuit is to be able to process six sensors channels simultaneously without the use of multiplexers, thereby reducing the time spent on each examination," author Saad Abdullah said. "This multichannel potentiostat can examine multiple samples of different concentrations simultaneously and transfer the data over Bluetooth in real time."

The potentiostat was tested to confirm its performance under fixed resistance and quantify the current detection limits and noise in the system, as well as its accuracy and response time. Experiments showed a current detection limit of 180 nanoamperes and a plus or minus 2% standard deviation in cyclic voltammetry measurement. They also conducted an experimental test involving six different concentrations of glucose using a chronoamperometry technique.

In the experiment, the potentiostat was equipped with screen-printed electrodes modified with the enzyme glucose oxidase, which binds with the target protein and acts as an electrochemical channel between the protein and the sensor chip. When a chronoamperometric signal is applied to the sensor chip, an output current is observed in the potentiostat that is equivalent to the concentration of glucose in the sample.

The potentiostat proved capable of operating independently and transmitting data wirelessly for 24 hours in an incubator with accuracy comparable to commercially available devices. The wireless system produced a clear data signal, 180 times stronger than the noise in the circuit. This online method has the added advantage over currently available devices that data from six different biosensors can be viewed simultaneously in real time on an external monitor.

It's said that maple syrup is Quebec's liquid gold. Now scientists at Université de Montréal have found a way to use real gold -- in the form of nanoparticles -- to quickly find out how the syrup tastes.

The new method -- a kind of artificial tongue -- is validated in a study published today in Analytical Methods, the journal of the Royal Society of Chemistry, in the United Kingdom.

The "tongue" is a colorimetric test that detects changes in colour to show how a sample of maple syrup tastes. The result is visible to the naked eye in a matter of seconds and is useful to producers.

"The artificial tongue is simpler than a human tongue: it can't distinguish the complex flavour profiles that we can detect," said UdeM chemistry professor Jean-François Masson, who led the study. "Our device works specifically to detect flavour differences in maple syrup as it's being produced."

1,818 samples tested

The artificial tongue was validated by analyzing 1,818 samples of maple syrup from different regions of Quebec. The syrups that were analyzed represented the various known aromatic profiles and colours of syrup, from golden to dark brown.

"We designed the 'tongue' at the request of the Québec Maple Syrup Producers to detect the presence of different flavour profiles," explained Simon Forest, the study's first author. "The tool takes into account the product's olfactory and taste properties."

Maple syrup has a molecular complexity similar to that of wine. Its taste is delicate, without bitterness, and it has a subtle aroma. During the production process, specialized human tasters are employed to judge which profile each batch fits into.

"The development of the artificial tongue is intended to support the colossal work that is being done in the field to do the first sorting of syrups quickly and classify them according to their qualities," said Masson.

Red for the best, blue for the rest

The researchers compare the artificial tongue to a pH test for a swimming pool. You simply pour a few drops of syrup into the gold nanoparticle reagent and wait about 10 seconds.

If the result stays in the red spectrum, it has the characteristics of a premium quality syrup, the kind best loved by consumers and sold in grocery stores or exported.

If, on the other hand, the test turns blue, the syrup may have a flavour "defect", which may be treated as an industrial syrup for use in processing.

"It doesn't mean the syrup is not good for consumption or that it has a different sugar level," Masson said of the "blue" type syrup, which the food industry uses as a natural sweetener in other products. "It just may not have the usual desired characteristics, and so can't be sold directly in bottles to consumers."

60 categories of taste

Caramelized, woody, green, smoked, salty, burnt -- the taste of maple syrup has as many as 60 categories to fit into. Maple syrup is essentially a concentrated sugar solution of 66 per cent sucrose and 33 per cent water; the remaining one per cent of other compounds determines the taste.

Like wine, the taste of maple syrup changes according to a variety of factors, including the harvest period, the region, production and storage methods and, of course, the weather. Too much variation in temperature over a weekend, for instance, can greatly affect the taste profile of the product.

The artificial tongue developed at UdeM could someday be adapted for tasting wine or fruit juice, Masson said, as well as be useful in a number of other agrifood contexts.

What The Study Did: This observational study assessed the association between the use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with the likelihood of testing positive for coronavirus disease 2019 (COVID-19).

Authors: Ankur Kalra, M.D., of the Cleveland Clinic in Akron, Ohio, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamacardio.2020.1855)

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

By manipulating the expression of one gene, geneticists can induce a form of "stress memory" in plants that is inherited by some progeny, giving them the potential for more vigorous, hardy and productive growth, according to Penn State researchers, who suggest the discovery has significant implications for plant breeding.

And because the technique is epigenetic -- involving the expression of existing genes and not the introduction of new genetic material from another plant -- crops bred using this technology could sidestep controversy associated with genetically modified organisms and food.

"One gene, MSH1, gives us access to what is controlling a broad array of plant resiliency networks," said Sally Mackenzie, professor of plant science in the College of Agricultural Sciences and professor of biology in the Eberly College of Science. "When a plant experiences a stress such as drought or prolonged extreme heat, it has the ability to adjust quickly to its environment to become phenotypically 'plastic' -- or flexible."

There are many ways to inactivate the MSH1 gene, researchers explain, and in this context they all work. In well-studied plant species, like Arabidopsis, tomato or rice, it is possible to identify mutations in the gene. In others, and for commercial testing, it is possible to design a transgene that uses "RNA interference" to specifically target MSH1 for gene silencing. Any method that silences MSH1 results in very similar outcomes, they report.

"When plants are modified epigenetically, they can modify many genes in as simple a manner as possible," Mackenzie pointed out. That includes adjusting the circadian clock -- detecting light and triggering growth and reproductive phases -- and modifying hormone responses to give them maximum flexibility, making them more resilient.

Plants that "detect" stress after the MSH1 gene is silenced can adjust their growth and change root configuration, limit above-ground biomass, delay flowering time and alter their response to environmental stimuli. Those responses are "remembered," researchers reported, and passed in selective breeding through many generations.

"In our research, we show that this memory condition is heritable by progeny but occurs in only a proportion of the progeny -- so that there are memory and non-memory full siblings," said Mackenzie, the Lloyd and Dottie Huck Chair for Functional Genomics. "That results in definable gene expression changes that impact a plant's phenotypic 'plasticity.' We suggest that all plants have this capacity, and that the condition that we describe is likely to be an important part of how plants transmit memory of their environment to precondition progeny."

By adjusting the epigenetic architecture of a plant, researchers were able to access its resiliency network, and see how genes are expressed quickly and broadly to adjust a plant's growth to adapt to the environment, noted Mackenzie, director of the Plant Institute at Penn State.

The researchers identify pathways that enhance root growth and plant vigor -- increasing yield. They present their results today (May 5) in Nature Communications. When an MSH1-modified plant is crossed or grafted, this enhanced plant vigor becomes quite pronounced.

Researchers contend that plants can be "reprogrammed" epigenetically to express genes differently without altering genotype, which constitutes a non-traditional approach to breeding. Because they can now identify gene networks that appear to be targeted by this manipulation, researchers report that plants have mechanisms designed to address stress or alter growth, and these can be accessed.

The researchers focused their efforts on the small flowering plant, Arabidopsis, or rockcress, a relative of cabbage and mustard in the Brassica family. It is one of the model organisms used for studying plant biology and the first plant to have its entire genome sequenced. Arabidopsis is useful for genetic experiments because of its short generation time and prolific seed production through self-pollination. Researchers grew five generations of Arabidopsis to study "memory" and "non-memory" plants.

In follow-up research already underway in Mackenzie’s lab, the researchers have suppressed MSH1 genes in tomato and soybean plants and grafting experiments have been field tested with excellent yield results. A large-scale experiment growing MSH1-modified canola is now in the works. This technology is part of a start-up company called EpiCrop Technologies Inc. that was co-founded on MSH1 technology and its utility in agriculture.