Brain

Cold Spring Harbor, NY - Researchers at Cold Spring Harbor Laboratory (CSHL), working in collaboration with DepYmed Inc., a CSHL spinout company, today report that they have conducted promising preclinical experiments on a compound that could be used to treat Wilson's disease and possibly other disorders -- including certain types of cancer -- in which levels of copper in the body are elevated, causing or contributing to pathology.

Wilson's disease, affecting 1 in 30,000 people, is a severe inherited disorder that leads to profound liver and neurological damage. It is caused by mutations in a gene called ATP7B that encodes an enzyme critical in the excretion of excess copper from cells and organs.

Copper, like many other metals, is obtained mainly through the diet. Although essential in bodily function, it can be toxic when it accumulates. Normally, amounts of copper are precisely regulated both at the cellular level and in the body as a whole. In Wilson's patients, abnormal copper buildup begins in the liver, the organ that collects the metal from the gut and distributes it to other tissues via the bloodstream.

Copper toxicity can lead to liver enlargement, hepatitis, cirrhosis and even liver failure, necessitating a transplant. As the disease progresses, it can also affect the brain, with symptoms that include speech defects, cognitive impairment, psychiatric disorders, tremors, dystonia and Parkinsonian symptoms. Although Wilson's disease can't be controlled by switching to a low-copper diet, it is often manageable with drugs when treated early.

"Unfortunately, Wilson's disease may be hard to diagnose because its early symptoms are shared by other ailments, and so it is often not treated promptly" says CSHL Professor Nicholas Tonks, who, with Navasona Krishnan, Ph.D., formerly of his lab, led the research. "Moreover, currently used treatments, involving 'de-coppering' agents, have side effects and lately have become very expensive."

The team's new research confirms that DPM-1001, a small molecule, robustly reduces copper levels in cells grown in culture that were sampled from Wilson's disease patients, as well as systemically in a mouse model of Wilson's disease. It acts as a chelator - a compound that interacts with a metal to facilitate its natural removal.

The team showed that DPM-1001 is orally available -- it could be taken as a pill -- and is "exquisitely specific" for copper. Current de-coppering agents tend to affect levels of other metals in addition to copper - an undesirable feature in a drug for an illness like Wilson's. Such drugs would likely be taken for extended times, and the binding of metals other than copper may contribute to unwanted side effects.

In a mouse model of Wilson's disease, DPM-1001 ameliorated associated liver complications including enlarged cell size, irregular shape and arrangement in liver tissue. This was accompanied by dramatic lowering of tissue copper levels and reduced disease symptoms.

"It is our hope that this compound may represent the basis for an improved approach to Wilson's Disease," Tonks said. Optimization work on the compound continues in his lab in collaboration with DepYmed Inc.

A new Portland State University study suggests that universities should do more to invest in training graduate students in 21st century teaching methods, and that doing so does not mean that they would be any less prepared for a career in research.

In fact, the study found that Ph.D. students who are trained in evidence-based teaching -- methods that emphasize interactive, collaborative and hands-on learning rather than just traditional lecture -- can be just as competitive of researchers, if not better, than those who are not.

The study, published online June 25 in the journal PLOS ONE, was authored by Erin Shortlidge, an assistant professor of biology at PSU's College of Liberal Arts and Sciences, and Sarah Eddy, an assistant professor of biology at Florida International University's STEM Transformation Institute.

The authors found there was a positive relationship between increased training in evidence-based teaching and students' confidence in their preparedness for a research career, their ability to communicate their research and their research productivity, as measured by the number of papers they publish.

The findings run counter to a widespread perception that any time spent teaching, or even learning about teaching methods, will take away from research productivity for faculty and graduate students.

But Shortlidge said that amid a national push for universities to do a better job of teaching science, technology, engineering and math (STEM), it's critical that graduate students -- who as future faculty members will likely be required to teach -- learn effective teaching methods.

Evidence-based teaching can include the use of interactive tools such as clickers, small-group discussions and course-based undergraduate research experiences.

The study surveyed 338 students who were at least in their second year of a Ph.D. program in the life sciences, the STEM discipline that consistently awards the greatest number of doctorate degrees.

Shortlidge said that oftentimes graduate students who do participate in professional development opportunities in teaching have to seek them out on their own, with few receiving substantial training in student-centered teaching methods.

"There doesn't seem to be evidence that if universities invest in training graduate students in 21st century teaching methods, they're going to be harming their productivity; if anything, they could be benefiting them," Shortlidge said. "Graduate students can shift the paradigm moving forward, and take on this national push to be a better teacher as well as a cutting-edge researcher."

Princeton chemists have found a way to make a naturally occurring enzyme take on a new, artificial role, which has significant implications for modern chemistry, including pharmaceutical production. Their work appears in the journal Nature Chemistry.

"We have found a completely new way to get enzymes to do a non-natural reaction," said Todd Hyster, an assistant professor of chemistry. "A traditional perspective says that enzymes will only do one thing. This paper shows that this may not be true for all enzymes. More importantly, the strategy described in this paper can potentially be applied to other enzyme families, meaning we will be able to use this approach to invent completely new enzymatic reactions. I think this has the potential to alter the way we build molecules."

Enzymes are nature's catalysts, the keys to making critical biochemical reactions happen quickly enough to sustain life. Organic chemists have exploited this for over 100 years, but until now, their use has been limited, as individual enzymes are often only able to catalyze a single reaction.

Now, the researchers in Hyster's lab have removed an enzyme from its natural setting, added a few new ingredients, and succeeded in making it catalyze a different type of chemical reaction -- where it performed surprisingly well.

"Todd is uncovering hidden abilities in biology's vast repertoire of chemistry, some of which may not be useful to biology but will be very useful to us," said Frances Arnold, the Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry at the California Institute of Technology, who was not involved in this research.

"He is showing that enzymes are capable of many feats," said Arnold, who graduated from Princeton in 1979. "All you have to do is ask the right questions."

The key was simplifying their understanding of how an enzyme catalyzes a reaction, Hyster said.

"I think I am always surprised that our simplified approach to enzyme catalysis actually works," Hyster said. "As students, we are taught that enzymes are incredibly complicated and specific catalysts. ... Every time we find that they are capable of doing something completely new that nature never intended, it is surprising and exciting."

In their reaction, the researchers added a small amount of a carefully selected photoexcitable dye to the enzyme and flooded it with green light. In doing so, they brought together two usually unrelated branches of chemistry, noted Kyle Biegasiewicz, a postdoctoral research associate in Hyster's lab and one of two co-first-authors on the paper.

"We have discovered an incredibly exciting marriage of enzymatic catalysis (biocatalysis) and photoredox catalysis," Biegasiewicz said.

To chemists, getting more of the reaction you want and less of a reaction you don't is known as "selectivity." Enzymes are much more "selective" than most small molecule catalysts, and this new technique allows scientists to capitalize on that for their own desired reactions. "Significantly, this new transformation shows high levels of selectivity for a class of reactions that were previously very difficult to control," Hyster said.

In essence, their breakthrough allows for a new "plug-and-play" approach, using enzymes to turn on new catalytic reactivity, which has many exciting implications, Biegasiewicz said. "While I can't give away any details of ongoing projects in the group, I would inform the synthetic community to stay tuned -- the latest stuff is really cool!"

This new discovery is another aspect of the visible light photocatalysis that is transforming modern chemistry, Hyster said.

"The field of catalysis has been revolutionized in the last decade by the development of methods that use light," he said. "Princeton has really been a driver in this area. Princeton chemistry professors [David] MacMillan, [Abigail] Doyle and [Robert] Knowles all use light to do really incredible things using small molecule catalysts. We have shown that the utility of light is not limited to small molecule catalysts; it can also expand the types of things we can do with enzymes. I think that is pretty neat."

The idea for this avenue of research came from following "the bread crumbs" in previous research, said Simon Cooper, a graduate student in Hyster's lab and a co-first-author on the paper. Other scientists had demonstrated that exposure to ultraviolet light caused a significant change in the behavior of an abundant molecule, nicotinamide adenine dinucleotide phosphate (NADPH), which Hyster's team added to the enzyme along with the photosensitive dye.

"When exposed to UV light, NADPH can switch from transferring two electrons and a proton in a single step to transferring first an electron and then a hydrogen atom (an electron and a proton)," Cooper said. "We thought that if we could take advantage of this new pathway inside an enzyme, valuable new reactions awaited discovery. ... The most important aspect of the findings in this paper is controlling the transfer of a hydrogen atom to create only one of two possible mirror-image forms of a molecule. This type of selection between two mirror image forms has traditionally been very difficult to achieve for the transfer of a hydrogen atom, and the methods disclosed here are one solution to this challenge."

Cooper added: "As we advance further in the 21st century, if a growing world population is to experience the comforts of what we take for granted in the developed world, we will need more cost-effective and sustainable forms of chemical catalysis to deliver many of the products that are attributable to the modern way of life. The methods disclosed in our paper will begin to pave the way, perhaps."

"Our chemistry may seem to be niche or esoteric, but these examples only serve as proofs-of-concept for what can become powerful methods for making new molecules that can have tangible societal impact: pharmaceuticals, agrochemicals, fragrances and the list goes on," said Megan Emmanuel, a graduate student in Hyster's lab and a co-author on the paper. "The implication that our work may, one day, be used to make meaningful contributions to people's lives is exciting."

Deep inside the Earth exist pockets of water, but the liquid there isn't like the water on the surface.

When exposed to unimaginably high temperatures and pressures, water exhibits all sorts of weird phases and properties, from remaining a liquid at temperatures 10 times higher than the boiling point to existing as a liquid and a solid at the same time.

This strange world is still not fully understood, but a team of University of Chicago scientists ran quantum simulations to develop a new model of the behavior of water at extremely high temperatures and pressures. The computational measurements, published June 18 in the Proceedings of the National Academy of Sciences, should help scientists understand water's role in the makeup of the mantle and potentially in other planets.

"Subtle physics at the molecular level can impact properties of matter deep inside planets," said Viktor Rozsa, a UChicago graduate student and first author on the paper. "How water reacts and transports charge on a molecular scale affects our understanding of phenomena ranging from the movement of magma, water and other fluids to the magnetic field of the entire planet."

Under the conditions considered in the study--more than 40 times hotter than our everyday conditions and 100,000 times greater than atmospheric pressure--water is regularly ripping apart and re-forming its own chemical bonds. The result is that it can interact very differently with other minerals than it does on the surface of the earth.

Scientists have been trying to pin down exactly how these atoms interact for decades: It's extremely difficult to test experimentally, as water can react with the instrument itself. "It's surprising how little we know about water below the crust," said lead author Giulia Galli, the Liew Family Professor of Molecular Engineering and professor of chemistry at UChicago and a senior scientist at Argonne National Laboratory.

But water in these conditions exists throughout the mantle--it's possible there may be more water distributed inside the Earth than there is in the oceans--and scientists would like to know exactly how it behaves in order to understand its role in the Earth and how it moves through the mantle.

Galli's group built a model by performing quantum mechanical simulations of a small set of water molecules at extremely high pressures and temperatures--in the range of what you need to synthesize a diamond.

Their model, built with the aid of simulations performed at the Research Computing Center at UChicago, provides an explanation for some of water's more mysterious properties at such pressures, such as the connection between bizarrely high conductivity and how its molecules disassociate and re-associate.

It also predicts and analyzes a controversial set of measurements called the vibrational spectroscopic signatures of water, or fingerprints of molecular movement that lay out how molecules are interacting and moving.

In addition to furthering understanding of our own planet, Galli said, "the ability to do the kind of simulations performed in our paper could have important consequences on modeling exoplanets." Many scientists, including those at UChicago, are narrowing the conditions for distant planets that might have the conditions to create life, and much of this search revolves around water.

Galli is a member of the research team in the Institute for Molecular Engineering's water theme, led by James Skinner, the Crown Family Professor of Molecular Engineering. The team seeks to understand the physical, chemical and biological manifestations of water, and to develop applications from innovative purification filters, to new materials for desalination and lithium ion harvesting, to new catalysts for water chemistry and disinfection.

While water is everywhere and intensively important to us, Galli said, it is notoriously difficult to simulate and study: "This is one step in the long journey to understanding."

Young children are more likely to behave aggressively if they think other children want to hurt them--for example, when they interpret accidental bumps as provocations. Researchers investigated whether parents' explanations of how peers interact would help 4- to 6-year-olds interpret others' behavior with less hostility and behave less aggressively. They found that parents' explanations help young children view their peers' behavior with less hostility.

The research, conducted at Utrecht University, is published in Child Development, a journal of the Society for Research in Child Development.

"Young children may feel physically hurt, left out, or frustrated by their peers' actions, the intent of which, at this age, is frequently unclear," explains Anouk van Dijk, a postdoctoral researcher in psychology at Utrecht University, who led the research. "While most children interpret ambiguous slights as accidental, some feel they are hostile. By framing social situations in a positive way, parents can help their children perceive less hostility in their social worlds and thus, reduce their likelihood of behaving aggressively."

Young children rely primarily on their parents to help them make sense of their social worlds and many talk to their parents frequently about interactions with peers. In two studies, researchers looked at this practice to see how it affected children's views of their peers. Almost 270 Dutch middle-class parents and their 4- to 6-year-olds were given a picture book with four short stories about challenging interactions between peers, such as being hurt on the playground or being skipped over when candies were handed out.

In the first study, the researchers asked parents to discuss peer interactions in the picture book with their children as they naturally would, then observed how the discussions influenced changes in the children's tendencies to perceive the peers in the book as hostile. In the second study, researchers compared children's responses to different ways of talking about the stories by instructing some parents to discuss positive interpretations of the stories with their children (e.g., the harm was done accidentally), other parents to discuss norms and values (e.g., aggression is wrong, sharing is good), and a third group of parents to just tell the stories without any discussion (the control group).

Children made less hostile interpretations of the stories after their parents naturally discussed with them positive interpretations about the way the peers interacted, the studies found. Children also were less hostile in their interpretations when the researchers told parents to interpret the stories positively or discuss norms and values.

"Our results suggest how parents can engage with their children in constructive conversations about peer provocations to help them interpret their interactions with peers less negatively," says Astrid Poorthuis, assistant professor of psychology at Utrecht University, who coauthored the research. "Although we looked at only the short-term effects of discussing peer interactions in stories, it seems plausible that similar effects could be found if we looked at parents' day-to-day discussions about children's actual interactions with their peers."

The studies' authors caution that their findings, based on a group of mostly White and highly educated parents, may not be generalizable to more heterogeneous groups.

Drug resistance to antibiotics is on the rise and there is an urgent need to develop new drugs to treat infectious diseases that are a major threat to human health globally. Researchers from Florida Atlantic University's Harbor Branch Oceanographic Institute may have a solution to this problem using sea sponges collected from the ocean depths.

For more than 30 years, FAU Harbor Branch scientists have accumulated sea sponges and other macro-organisms from the east coast of the United States, Gulf of Mexico, Caribbean as well as European and African deep waters using manned submersibles and other methods. Many of these specimens contain large populations of microbes, some of which can be grown under laboratory conditions. The Harbor Branch Marine Microbial Collection is home to about 19,000 of these diverse micro-organisms, with 11,000 gathered from ocean depths greater than 45 meters. The collection contains more than 1,000 strains of actinobacteria, one of the most prolific microbial groups for the production of natural products. Actinomycetes produce more than half of the currently used antibiotic drugs.

In a new study published in the journal Frontiers in Microbiology, FAU Harbor Branch scientists examined 50 actinobacteria strains from these marine samples to look for new anti-infective agents. All of these strains were cultivated from marine sponges. Because they were derived from various sponge hosts collected from environmentally and geographically diverse locations, many of them can be considered to be rare actinobacteria.

Researchers screened the samples' metabolites against a panel of bacterial pathogens that are common causes of healthcare-associated infections and are listed among the most severe threats to human health. The panel of pathogens included Candida albicans, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA) and C. difficile, a cause of life-threatening diarrhea that is responsible for 453,000 cases and 29,000 deaths each year in the U.S. alone.

For the study, Guojun Wang, Ph.D., assistant research professor, Peter McCarthy, Ph.D., research professor and associate director of education, both at FAU Harbor Branch, and collaborators, used rare earth salts, an efficient and easy-to-use chemical elicitation, to trigger dormant secondary metabolic capability in the 50 actinobacteria strains they examined.

Results from the study reveal that more than half of the strains showed anti-microbial activity in at least one assay, indicating the potential of this group of actinobacteria for the production of antimicrobial natural products. Among them, several strains were identified for their potent antifungal activity, for anti-MRSA activity, and for both antifungal and antibacterial activities. A key finding from the study was the identification of a strain that produced metabolites that are more potent than the bacterial antibiotic, vancomycin, against C. difficile.

"We have found that deep-sea microorganisms, especially actinomycetes, are an attractive, untapped source for the discovery of anti-infective agents," said Wang. "In addition, the diversity of microbes we used in this study and their origins are quite novel. Most exciting is the demonstration of the importance of using an elicitor in this type of study as 50 percent of the strains showed the effect of the elicitor on antimicrobial activity."

Both the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have issued lists of priority pathogens. In 2017, the CDC listed 18 drug-resistant bacteria threats to the U.S. For the first time, WHO listed 12 families of bacteria as the greatest threat to human health.

"Marine natural products represent an increasingly attractive source of new anti-infective agents," said McCarthy. "Searching for new taxa as new sources is critical when we are looking for new agents, but equally important is finding ways to exploit the full genetic potential of these microbes. We are working to identify additional new chemicals and test their activity and mode of action with the ultimate goal to identify potent drug leads from marine microbes."

The researchers are in the process of purification and structural identification of additional bioactive chemicals and have determined the genome sequences of three of the strains they studied. They are currently analyzing and investigating the potential biosynthetic gene clusters and gene-compound relationships.

Infectious diseases remain a major threat to human health causing millions of deaths worldwide, especially in medically less-developed countries and regions. In 2016, there were an estimated 1.2 million tuberculous deaths, 1.03 million HIV/AIDS deaths, and 719,600 malaria deaths. This situation is significantly worsened by the prevalence of multi-drug resistance. While therapeutics such as vancomycin, metronidazole, fidaxomicin or nitazoxanide are available, because of drug resistance or toxicity to gut microbiome, new drugs, especially those with narrow spectrum, are desperately needed.

New Orleans, LA - Dr. Robert Zura, Professor and Chair of Orthopaedic Surgery at LSU Health New Orleans School of Medicine, was part of a research team reporting that not only may opioid use increase the risk of bone fractures, but opioids may also impair healing. The authors also question their effectiveness in controlling pain. Dr. Zura is a coauthor of the "Article in Press" available online in the journal, Injury.

The authors suggest that chronic use of certain medications may be a significant and substantial risk factor for fracture nonunion. Overall, 49.2% of opioid-naive patients receive an opioid prescription for post-operative pain control at hospital discharge after major surgery. Yet they report there is no evidence that opioids are more effective than non-opioids for acute extremity pain in the Emergency Department. The authors add that their data suggest that there is an inherent risk in use of most opioid analgesics and emphasize the importance of multimodal, non-opioid analgesic techniques at fracture.

The team studied 309,330 of the 18 most common bone fractures, as well as medication use, including antibiotics, anticoagulants, diabetes medications, osteoporosis medications, cardiac medications, diuretics, immunosuppressants, steroids, anticonvulsants, and non-opioid analgesics in addition to opioid analgesics. They found that opioid medications as a class significantly increased the risk of fracture nonunion following both acute and chronic administration.

"Chronic opioid use roughly doubled the risk of nonunion among all patients, and this effect was fairly consistent across all ages and both genders," noted Dr. Zura.

The researchers report that Schedule II opioids, as a group, create a greater nonunion risk
than non-opioid analgesics. Certain of these medications produce a significant risk, including acetaminophen/oxycodone, hydromorphone, acetaminophen/hydrocodone, oxycodone and meperidine. Of the Schedule III-V opioids, tramadol and naloxone/pentazocine were also associated with increased risk. Acetaminophen/codeine and buprenorphine were not associated with increased risk of nonunion. Prescription NSAID use also increased the risk of nonunion among chronic users.

"It is interesting that recent opioid policy discouraging the use of high-potency opioids appears to be increasing use of lower-potency opioids such as tramadol, a Schedule IV opioid," says Zura. "Our data suggest that this trend may not increase medication safety to the degree desired. It is critical that trauma surgeons and other practitioners be aware of the nonunion risk created by medication use."

The authors suggest that chronic use of certain medications may be a significant and substantial risk factor for fracture nonunion. Overall, 49.2% of opioid-naive patients receive an opioid prescription for post-operative pain control at hospital discharge after major surgery. Yet there is no evidence that opioids are more effective than non-opioids for acute extremity pain in the Emergency Department. They add that their data suggest that there is an inherent risk in use of most opioid analgesics and emphasize the importance of multimodal, non-opioid analgesic techniques at fracture.

CHAMPAIGN, Ill. -- When negative memories intrude, focusing on the contextual details of the incident rather than the emotional fallout could help minimize cognitive disruption and redirect the brain's resources to the task at hand, suggests a new study by psychologists at the University of Illinois.

"Everyone has encountered something distressing either in the recent past or the remote past. These memories can pop into our minds and distract from whatever we are doing," said study leader Florin Dolcos, a professor of psychology at Illinois. "Understanding what we can do to stay focused is important, not only for people in extreme cases where such memories can lead to difficulties in daily living - such as those with post-traumatic stress disorder, anxiety or depression - but for everyone."

In a paper published in the journal Cerebral Cortex, the researchers examined how brain activity and performance on a memory task changed when the participants were told to focus on the emotional or contextual aspects of triggered memories.

Thirty-three study participants completed detailed, lengthy surveys asking about a variety of events in their lives. One to two weeks later, participants performed cognitive memory tasks during a functional MRI scan, which is used to monitor activity in the brain. The researchers chose descriptions of negative events that the participants had written about, from sporting defeats to personal losses, and used them to trigger those memories during the tasks.

"They provided the cues themselves, so when we presented those cues in the scanner, we were sure we were triggering specific memories," said Sanda Dolcos, a professor of psychology and co-author of the study. "When they filled out the questionnaire, they did not know that we would trigger those memories when they came to do the task."

For half of the triggered memories, the participants were instructed to focus on the emotional aspects of their memories; for the other half, the participants were instructed to shift their focus away from the emotion and toward the contextual details of the memory, such as where the incident happened, who they were with, what they were wearing and other details.

"When subjects focused on the emotional aspect of their memories - how they felt, including the physical sensations - their cognitive performance was lower relative to their control tasks," said Alexandru Iordan, the first author of the paper who recently graduated from Dolcos' group with a Ph.D. and is now at the University of Michigan. "But when they were focusing on the nonemotional, contextual aspects, then their working memory performance was not impacted. They had better task performance and less negative effects when focusing on context than when focusing on emotion."

The fMRI also found changes in brain activity. When participants focused on emotion, there was increased activity in regions of the brain involving emotional processing, but reduced activity in regions involved in executive function, such as reasoning and memory. However, when the participants focused on contextual details of their memories, there was a dampening in the regions involved in distraction and emotional processing and an increase in both activity and communication among regions associated with executive function and attention.

"When regions in the brain that are involved in processing emotion are stimulated, it takes resources away from regions that are helping you stay focused on the task at hand," Florin Dolcos said. "With this shift in focus from emotion to context, you're putting resources back into the regions that are processing the task."

The researchers say the technique of focusing on context could help those who struggle with intrusive or distracting emotional memories to have a quick response ready so that when those memories are triggered, they can focus on the task at hand and then later process the memories more deeply with other techniques, such as cognitive reappraisal.

"This is important because another emotional strategy that people employ against such memories is suppression, which means bottling up your emotions. Suppression is actually associated with such clinical conditions as anxiety and depression, and it is not healthy," Florin Dolcos said. "Instead of suppressing or stifling those emotional memories, we simply shift the focus and bring to life some other aspects of the same memory. That leads to a reduction in how much those memories interfere with whatever we're doing."

The researchers are working with subjects with depression and PTSD to evaluate the effectiveness of their technique over time.

"We are also working on interventions to help people learn these strategies and apply them on a day-to-day basis," Sanda Dolcos said. "The beauty of this strategy is that it both reduces the emotional response of the intrusive memory and doesn't affect cognitive performance. Anyone can use it at any time."

A research team at the São Paulo State University's Bioscience Institute (IB-UNESP) in Rio Claro, Brazil, has identified 29 fungi with proven action against Xanthomonas citri, a bacterium responsible for citrus canker, an endemic disease in all citrus-producing countries. The origin of the fungi is surprising. They were isolated from samples of soil and marine sediment collected in Antarctica.

"These fungi live in isolated conditions and proliferate under inhospitable conditions including low temperatures and high levels of ultraviolet radiation," says Daiane Cristina Sass, a Professor at UNESP who heads a project engaged in a search for microorganisms that produce compounds with antibacterial action for use in agriculture, with support from the São Paulo Research Foundation - FAPESP.

"How have they adapted to survive in an environment so hostile to life? We wanted to see if they produced molecules with unique structures that protected them from infections and might therefore be capable of antibacterial action." Sass wrote an article published in Letters in Applied Microbiology - jointly with IB-UNESP colleagues Lara Durães Sette and Henrique Ferreira, among others - which shows some of the research's results.

More efficiency on fighting citrus canker

Although the bacterium can be combated in several ways, none is sufficient to eradicate the disease. Therefore, new chemical or biological methods of protecting citrus groves have to be pursued.

The disease is controlled directly by growers. The recommended measures include spraying trees with copper-based products and replacing infected trees with healthy new plantings derived from more resistant varieties. Control of the citrus leaf miner (Phyllocnistis citrella) is also advisable. The wounds made by larvae of this moth in feeding on the plant exacerbate citrus canker by serving as an entry point for X. citri.

"The main method for combating citrus canker consists of spraying trees with copper compounds. The downside is that when even small amounts are used for a long period, copper accumulates in the fruit, soil and water, eventually contaminating the entire environment. For this reason, we're looking for new compounds that are less aggressive to the environment and also less harmful to humans," Sass explained.

Collection and isolation of the Antarctic fungi

On the extent of the Sass-headed project and its research on biotechnology, the team came up with the idea of investigating the collection of fungi curated by Professor Sette, which resulted from Antarctic summer expeditions to the South Shetland Islands in 2013 and 2015 as part of Project Microsfera, conducted under the aegis of the Brazilian Antarctic Program (PROANTAR) and sponsored by the National Council for Scientific & Technological Development (CNPq).

Sette leads the project "Marine and Antarctic mycology: diversity and environmental application", also supported by FAPESP.

Sette isolated 33 filamentous fungi from samples collected in soil under rotten wood on Deception Island and 53 filamentous fungi from marine sediments at a depth of 20 meters in Admiralty Bay, King George Island. All fungal strains are kept at UNESP's Microbial Resource Center (CRM).

The FAPESP-funded research found that 29 of the 86 Antarctic fungi they isolated (19 of marine origin and ten terrestrial) contained compounds with proven action against X. citri.

Isolating the compounds produced by the fungi and verifying their antibacterial activity involved several stages. The process began with isolation of the fungi, which were then grown for several days in culture dishes with nutrients.

The fungi were cultured in liquid medium and shaken for 20 days at 15 °C. The solid biomass was separated from the liquid portion, and both parts were submitted to processing with solvents to obtain intracellular and extracellular extracts.

Tests

The researchers obtained 158 extracts. Each extract was diluted at several concentrations (2.10 mg/ml-0.02 mg/ml) and tested against X. citri. In the case of the soil fungi, most of the extracts with antibacterial action were intracellular in origin, while for the marine fungi, only the extracellular extracts hindered the bacterium's growth.

"We wanted to determine the lowest concentration of each extract that inhibited growth in 90% of cases," Sass said.

Some (12) of the extracts affected bacterial growth at lower concentrations than the highest tested, and ten of these inhibited growth in more than 90% of cases at concentrations of 1.5 mg/ml-1.0 mg/ml.

"At maximum concentration, one extract inhibited growth by up to 98%, and another inhibited it by about 80% at 0.52 mg/ml," Sass said. "It's important to note that we're talking about extracts [which contain varying amounts of molecules]. If an extract contains only one compound that's responsible for this bioactivity, the compound may display good antibacterial activity at much lower concentrations."

Twenty of the isolated fungi with action against X. citri belonged to the genus Pseudogymnoascus and were extracted from terrestrial and marine samples. Next came Penicillium (five), followed by Cadophora (two), Paraconiothyrium (one) and Toxicocladosporium (one), all extracted from marine sediments.

Having identified the extracts with action against X. citri, the researchers are now working to find out which chemical compounds give them this antibacterial capability.

"We expect to identify and purify some of these bioactive compounds, as well as to complete toxicology testing on them, within 18 months or less," Sass said.

The researchers plan to patent the compounds they identify. They also hope to persuade pesticide manufacturers to develop commercial products for combating citrus canker based on these compounds.

Standing guard between a cell's nucleus and its main chamber, called the cytoplasm, are thousands of behemoth protein structures called nuclear pore complexes, or NPCs. NPCs are like the bouncers of a cell's nucleus, tightly guarding exactly what goes in and out. Each structure contains about 1,000 protein molecules, making NPCs some of the biggest protein complexes in our bodies. One of the most notable clients of NPCs is a class of molecules known as messenger RNAs, or mRNAs. These are the messengers that carry genetic instructions from the nucleus to the cytoplasm, where they are then translated into proteins.

But how the NPC transports the mRNAs out of the nucleus is still a mystery.

"The mRNAs are one of the largest cargoes carried through NPCs, and the whole process occurs in just a fraction of a second," says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and a Howard Hughes Medical Institute (HHMI) Faculty Scholar. "How this works has been one of the greatest unsolved problems in biology."

NPCs are associated with several diseases. Mutations to proteins within the complex have been linked to motor neuron diseases such as amyotrophic lateral sclerosis (ALS), and people with Huntington's disease are known to have defects in the function of their NPCs.

In a new study in the June 13 issue of Nature Communications, Hoelz and his group--spearheaded by Daniel Lin (PhD '17), a former graduate student at Caltech now at Whitehead Institute for Biomedical Research at MIT, and Sarah Cai, an undergraduate student at Caltech--report the first atomic-scale look at the specific components of human NPCs responsible for dropping mRNAs off in the cytoplasm. For an mRNA to be transported through an NPC, it must be tagged with a nuclear export factor, a type of small protein. That tag is like a ticket that allows the mRNA to enter the central transport channel of the NPC. Once the mRNA reaches the cytoplasmic side, it must surrender the ticket--otherwise, the mRNA could travel back into the nucleus, and the proteins it encodes wouldn't get made.

Through a series of experiments involving X-ray crystallography, biochemistry, enzymology, and other methodologies, the researchers were able to show how this process of un-tagging the mRNA molecules works in human cells for the first time.

"It's as if we had snapshots before, and now we have a movie showing us exactly what happens at the molecular scale when mRNAs are dropped off in the cell's cytoplasm," says Lin.

The team's new findings were made possible by obtaining a series of crystal structures of a few key protein components of a human NPC. One of those components is called Gle1. The three-dimensional structure of this protein had been obtained before in yeast, but doing so for its human variant had remained a challenge. By studying the biochemical properties of yeast Gle1, the researchers were able to figure out that another protein, called Nup42, was required to stabilize Gle1. Knowing this, the team was able to purify human Gle1 from cells in high quantities for the first time, and then, using Caltech's Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource, obtain its crystal structure.

"Even with billions of years of evolution between yeast and humans, there are still aspects of our bio-machinery that remain the same," says Lin.

With the ability to purify human Gle1, the researchers set about studying how mutations affect its structure. They looked at several specific mutations of Gle1 known to be associated with a motor neuron disease called lethal contracture congenital syndrome 1 (LCCS1) and discovered that the mutated versions of the protein were not as stable.

"Gle1 is essential for life to function properly," says Hoelz, "so any mutations that cause it to be less stable are going to cause problems."

The researchers then looked at the structure of Gle1 bound to a protein called DDX19--which is responsible for un-tagging the mRNA molecules after they pass through the NPC. Gle1 is required to activate DDX19, and--until now--it was thought that a small molecule called inositol hexaphosphate (IP6) acted like a tether between Gle1 and DDX19, allowing the activation to occur.

"We found that IP6 was not required in humans, and that was a surprise because it is required in yeast, and IP6 dependence was previously believed to occur across all species," says Cai. "While there are some similarities between yeast and human proteins, there are also crucial differences."

What's more, the new research shows in atomic-level detail exactly how the un-tagging of the mRNA works. This kind of structural information could be used in the future to help in the design of therapeutic drugs for motor neuron diseases.

Hoelz says that Lin and Cai really exceeded expectations for this research. "They wanted to discover something new, and they went above and beyond with this project," he says. "They made it happen. This is a Caltech moment."

Montreal, June 12, 2018 – Michael Wright was your average high school student, juggling the responsibilities of school and friends while taking the first steps towards finding his first real job. Being diagnosed, suddenly, with type 1 diabetes was a shock. Suddenly, Michael found himself struggling with the sudden requirements that accompany treatment, from the intense monitoring of dietary habits to administering insulin – either through injections or via a cell phone-sized pump attached to the body. And, in addition to the daily struggle of staying on top of his new diagnosis, he felt stigmatized.

A team at the Research Institute of the McGill University Health Centre (RI-MUHC) report that teen and young adult (aged 14-24 years) type 1 diabetes sufferers often experience stigma, which leads them to neglect treatment and tread dangerously close to suffering medical emergencies. Michael was one of two patient partners engaged to participate in a study that is the first of its to estimate the stigma prevalence in this age group related to type 1 diabetes, which can lead to elevated HbA1c levels and severe hypoglycemia. Their findings are published in The Journal of Medical Internet Research.

“A lot of things that tend to be automatic in our bodies suddenly have to be managed, which is super stressful. Then you superimpose on this the fact that you are a young person worrying about your career, your romantic life, education, autonomy from your parents – all this stuff happening and then you get hit with this and it ticks you off,” says study senior author Dr. Kaberi Dasgupta, who is a clinician-scientist in the Metabolic Disorders and Complications Program at the RI-MUHC and internal medicine specialist at the MUHC. “They are always kind of dancing with death – constantly treading that fine line.”

Type 1 diabetes affects under 10 per cent of diabetes sufferers worldwide but accounts for 95 per cent of diabetes that starts in childhood and adolescence. It requires intensive and complex round-the-clock self-care and when vigilance dips, the risk of medical emergency is real—be it loss of consciousness and death related to low sugars or dehydration and medical emergencies related to very high blood sugars. In the longer term, blindness, renal injuries, amputation, heart disease, and strokes are all a real possibility in the absence of careful management. These constant demands mean youth with type 1 diabetes can feel stressed out while struggling with their predicament, burdened by issues with self-esteem, body image, social role definition, and peer-related issues. Two-thirds of study participants experienced stigma, with a higher proportion rate found among females compared to males.

“When I was diagnosed at 16, my friends were supportive but they could not understand – it was a shock to them as much as it was a shock to me,” Michael remembers. “I didn't expect them to understand and I didn't feel like I belonged as much anymore. And that is a common theme we discovered: a lack of social support leaving people feeling alone.”

Three hundred and eighty participants between the ages of 14 to 24 were specifically recruited via social media with the help of Diabetes Canada and diabetes clinics and organizations across the country. This has led to the creation of a Virtual Patient Network (VPN) where this type 1 age group can communicate with one another to offer a variety of health and practical tips. This ranges from managing blood sugar levels in relation to physical activity to the must-have items for a weekend camping excursion.

“The patient partners thought of the questions and helped us develop and formulate our questionnaire, and they helped interpret and analyze the data,” says Dr. Dasgupta, whose team is at the Centre for Outcomes of Evaluative Research (CORE) of the Research Institute. “The creation of the peer-to-peer network has provided those coping with stigma a platform toward the research agenda of helping to reduce stigma and live with type 1 diabetes.”

“Canada is facing a diabetes epidemic – one in three Canadians lives with diabetes or pre-diabetes and young people in their twenties have a 50 per cent chance of developing the disease in their lifetime,” said Dr. Jan Hux, president of Diabetes Canada.

“Despite the fact that type 1 diabetes is not the fault of the person affected by it – is not related to any behaviour patterns or choices – young people diagnosed with it experience a distressing level of stigma. Research and programs that raise public awareness and support around type 1 diabetes and foster resiliency in those affected by it are urgently needed. Diabetes Canada is pleased to have supported this first of its kind research in Canada.”

New York, NY - Multilingual students, who speak a language or more than one language other than English at home, have improved in reading and math achievement substantially since 2003, finds a new study published in Educational Researcher by Michael J. Kieffer, associate professor of literacy education at New York University's Steinhardt School of Culture, Education and Human Development.

This new research debunks a common myth that multilingual students and English Learners have made little progress in academic achievement in recent years, and that U.S. schools continue to fail these students.

"Educators and policymakers have been misled by traditional ways of looking at achievement data for English learners," said Kieffer. "When we look at the broader population of multilingual students, we uncover remarkable progress."

Kieffer and the study's co-author, Karen D. Thompson of Oregon State University, analyzed National Assessment of Educational Progress data from 2003 to 2015. The data demonstrated that although all students' scores improved, multilingual students' scores improved two to three times more than monolingual students scores in both subjects in grades four and eight. There is little evidence that these trends can be explained by cohort changes in racial/ethnic, socioeconomic, or regional composition.

The research also demonstrates that multilingual students are about one-third to one-half of a grade level closer to their monolingual peers in 2015 than they were in 2003. The data cannot identify the specific sources for the change in achievement, but suggests that a bundle of policy changes which occurred between 2003 and 2015 may have moved schools in the right direction in serving multilingual students.

"Despite the dominant perception that these students have made little academic progress in recent years, our findings indicate there is real evidence of progress for this population," said Thompson, the study's co-author and an assistant professor in OSU's College of Education. "Students are showing what they know."

Bartenders and cooks have long recognized the value of an orange twist, but thanks to researchers at the University of Central Florida, squeezing oranges may give us a new way to deliver medicine or to detect bridge failures before they happen.

Engineering Assistant Professor Andrew K. Dickerson and graduate student Nicholas M. Smith have figured out the mechanics of how oranges release that thin stream of fragrant oil when squeezed. They characterized the orange peels' structure and figured out the role the layers have to create the microjet dynamic. By mimicking nature's mechanism of an orange layer, pharmaceutical companies may be able to develop a less expensive and less complex way to deliver airborne medication.

"We study natural systems to mathematically characterize how creation works, and despite the ubiquity of citrus-fruit consumption, these jets had not been previously studied," Dickerson said. "Nature is our greatest inspiration for tackling real-world problems."

The team's findings are published in today's Proceedings from the National Academy of Sciences.

Florida's fruit is complex. Its hard outer layer protects the fruit, and a white spongy layer just below the skin has microscopic reservoirs of oil in hidden pockets. The spongy material absorbs impact, but when squeezed to a critical pressure it pushes up and tears open a minute section of the hard outer-layer to spray its fragrant stream. These microjets are small but fast, exiting their cavities at 22 mph on average by accelerating 5,000 Gs, which is equivalent to about 1,000 times the force astronauts feels at launch.

"There are several potential applications," Smith said. "For example, for asthmatics, you could have a small slice of material which would aerosolize emergency medication that you currently find in expensive, multi-use inhalers. This approach may be less expensive and biodegradable."

An orange peel releases an oily substance, and the dynamics should hold for other types of liquids, the researchers said.

But there's still some research needed before putting the orange peel approach to work delivering medication.

"First, we need to work out sizes and proportions," Dickerson said. "It's important to understand exactly how the microjets work and how to tune their stability for medical applications. The size of droplets and the amount of medication they carry is critical. We've got a ways to go before applications can be explored."

But when that happens, the possibilities are only limited by the imagination.

"Imagine a self-diagnosing bridge," Dickerson said. "It would have an orange-like skin layer and when you were approaching material failure, you would get a preventative warning, a color change perhaps."

Dickerson, a fluid-dynamic expert, is making a career of studying nature. He's already published several papers looking at what can be learned from the proverbial wet-dog shake and how mosquitos survive raindrop collisions. Studying the shake helps us understand how to self-dry large surfaces such as solar panels. And studying how mosquitos survive rain could help create strategies for combating the disease-carrying insects.

"Few labs nationally do this type of research," Smith said. "That's one of the reasons I came to UCF to do my graduate work. This is exciting stuff. Nature has had billions of years to get the engineering principles right and I get to look at them, figure them out and then play with them to solve problems. That's pretty exciting!"

Football referees penalize situations more severely when watching them in slow motion compared to real time, according to a study published in the open access journal of the Psychonomic Society, Cognitive Research: Principles and Implications.

Dr Jochim Spitz, Prof. W. Helsen and colleagues at University of Leuven, Belgium, studied the response of 88 elite football referees to video clips of a foul warranting a yellow card.

The researchers found no significant difference in the accuracy of a referee's decision about if a foul had occurred or not, with slow-motion videos (63% accurate) compared to the real-time videos (61% accurate). However, the judgement of intention or force behind a foul differed. More red cards were given by referees watching in slow motion compared to those watching real time video playbacks.

Dr Spitz, corresponding author of the study, said: "Our results suggest that slow motion can increase the severity of a judgement of intention, making the difference between perceiving an action as careless (no card), reckless (yellow card) or with excessive force (red card). The finding that referees were more likely to make more severe decisions following slow motion replays, is an important consideration for developing guidelines for the implementation of VAR in football leagues worldwide."

The authors concluded that although slow motion playback could be a useful tool in assessing some decisions, such as off-side and determining the exact impact of a contact, it may not be the best tool for decisions that involve judging human behaviour and intention.

Dr Spitz explained: "Slow motion video may make it clearer who initiated a foul, whether there actually was contact and whether a foul occurred either inside or outside the penalty area. However, judging human emotion, like intentionality is quite another story. It is also the reason why slow motion footage cannot be used anymore in the court room as it increases the perceived intent."

Dr Spitz added: "This is the first time that the impact of slow motion video on decision making has been studied in sports referees and it is timely given the current debate on video assistant refereeing (VAR), which will be used in the World Cup."

To investigate the impact of viewing speeds on decisions made by referees, the authors showed 88 elite football referees from 5 European countries 60 video clips of foul situations from football matches in real time or slow motion. Two independent ex-international referees that are currently acting as refereeing experts determined the correct decisions as a point of reference and then the referees who took part in the study categorised the fouls as they would in a real match by awarding a yellow card, a red card or no card.