Culture

SAN FRANCISCO, CA--July 29, 2019--The Komodo dragons are the largest lizards in the world. These predators weighing up to 200 pounds can detect their prey from up to 7.5 miles away. And although they are cold-blooded, they can ramp up their metabolism to near mammalian levels, which gives them great speed and endurance. However, scientists have understood little about how the DNA of these remarkable lizards encodes such astounding characteristics.

Now, a new study from researchers at the Gladstone Institutes, in a close collaboration with scientists at UC San Francisco (UCSF) and Zoo Atlanta, provides the first high-resolution sequence of the Komodo dragon, as well as insight into how it evolved.

"We started the project 9 years ago to look at how genomes evolve, but to do so, we needed the genome sequences first," said Gladstone Senior Investigator Benoit Bruneau, PhD, a senior author of the study. "At the time, other groups had sequenced the turtle genome, snake and bird genomes, and the crocodile genome was in process, but the missing branch was the varanid lizards--the family to which Komodo dragons belong."

"I went to Komodo Island years ago as a tourist, and I saw Komodo dragons in the wild there," said Katherine Pollard, PhD, a senior investigator and the director of the Gladstone Institute of Data Science and Biotechnology, who is the other senior author of the study. "I never would have guessed then that I would one day work on their genome. We didn't even have a human genome at that time!"

The team studied the DNA of two Komodo dragons from Zoo Atlanta named Slasher and Rinca, whose blood samples were obtained as part of their scheduled annual check-ups.

"This project was a great opportunity for us to learn more about Komodo dragons using the newest and best technologies, and then be able to contribute our findings toward the general knowledge of lizard biology," said Joseph R. Mendelson III, PhD, a herpetologist and evolutionary vertebrate biologist, and the director of research at Zoo Atlanta.

The study, which was published in the journal Nature Ecology & Evolution and released on BioRxiv as a preprint with a data repository, provides an extremely high-quality sequence of the Komodo dragon genome, which can now be used as a reference in efforts to sequence other vertebrate genomes.

"Vertebrate genomes are big, and they contain many repetitive sequences," explained Pollard, who is also a professor at UCSF and a Chan Zuckerberg Biohub investigator. "Most sequencing technologies only produce short stretches of sequence at a time. When those short stretches include repetitive elements, it's impossible to know where they belong and what they connect to, making it hard to string them together."

To get around this problem, the team took a multi-pronged approach.

"We used multiple technologies, including long-range sequencing and a physical mapping technique to do the assembly," said Bruneau, who is also the director of the Gladstone Institute of Cardiovascular Disease and a professor in the Department of Pediatrics at UCSF. "As a result, we have a super deep, very high-quality sequence for the Komodo."

Once the scientists had the sequence, they used computational tools to compare it to that of other reptiles and see what makes the Komodo dragon genome unique.

Specifically, they were looking for changes in the genome that helped the Komodo dragon adapt to its environment, which have undergone an evolutionary process called positive selection. A remarkable finding was that positive selection has shaped several genes involved in the function of mitochondria, the energy powerhouses of the cell that control how well heart and other muscles function.

"Our analysis showed that in Komodo dragons, many of the genes involved in how cells make and use energy had changed rapidly in ways that increase the lizard's aerobic capacity," said Abigail Lind, PhD, a postdoctoral researcher in Pollard's lab and first author of the study. "These changes are likely key to the Komodo's ability to achieve near-mammalian metabolism."

Lizards are generally not known for their high aerobic capacity. In other words, they become exhausted quickly after physical exertions.

"However, we know from working with Komodo dragons that they're capable of sustained aerobic activity, which could be swimming, running, or walking extremely long distances," explained Mendelson, who is also an adjunct associate professor at the Georgia Institute of Technology. "Our study showed us that the secret is in these mitochondrial adaptations to increase their cardiac output. This gives us an understanding of how these animals are able to do what we had been observing."

In addition, the researchers discovered that Komodo dragons, along with some other lizards, have an unexpectedly large number of genes that encode chemical sensors known as vomeronasal receptors. These receptors are part of a sophisticated sensory system that allows animals to detect hormones and pheromones.

This type of sensing is involved in a variety of activities, including kin recognition, mate choice, predator avoidance, and hunting. In the Komodo genome, the team found over 150 copies of one class of vomeronasal receptor genes. The team also found that many of these genes are unique to each individual lizard species, raising the possibility that the Komodo dragon's vomeronasal receptors may function in Komodo-specific ways.

"It will be interesting to determine whether this explains Komodo dragons' ability to detect prey over such large distances," said Bruneau. "One of the exciting things about this project is that we didn't know what to expect. This was an opportunity to look at a genome and say, 'Tell me the story of your organism.'"

Next, Bruneau and his team are looking forward to using their findings to investigate how genes that control the formation of the vertebrate heart have changed over the course of evolution, as most reptiles have only a three-chambered heart, while mammals have four chambers.

The completed genome sequence also represents an invaluable resource for conservation biologists interested in tracking Komodo dragons to study their ecology, and for the many scientists across the world investigating vertebrate evolution.

"The significance of this study far exceeds Komodo dragons," said Mendelson. "It gives us a framework to compare other sequenced animals and understand the genetic basis for how all their characteristics have evolved. This project also brings to the forefront the importance of preserving biodiversity, and the important role zoos can play in broad-scale research without being injurious to the animals in our care."

Real and fake smiles can be tricky to tell apart, but researchers at the University of Bradford have now developed computer software that can spot false facial expressions.

By analysing the movement of the smile across a person's face, the software can determine whether or not the expression is genuine. The most significant movements detected by the software were around the eyes, supporting popular theories that a spontaneous, genuine smile is one that can be seen in a person's eyes.

"A smile is perhaps the most common of facial expressions and is a powerful way of signalling positive emotions," says Hassan Ugail, Professor of Visual Computing at the University of Bradford, who led the research. "Techniques for analysing human facial expressions have advanced dramatically in recent years, but distinguishing between genuine and posed smiles remains a challenge because humans are not good at picking up the relevant cues."

The software works by first mapping a person's face from within a video recording, and identifying the mouth, cheeks and eyes of the subject. It then measures how these facial features move through the progress of the smile and calculates the differences in movement between the video clips showing real and fake smiles.

Researchers tested the programme using two different datasets, one containing images of people expressing genuine smiles, and another in which the images portrayed posed smiles.

They found significant differences in the way the subjects' mouths and cheeks moved when comparing the real and the fake expressions. The movements around the subjects' eyes, however, showed the most striking variation, with genuine smiles generating at least 10 per cent more movement in these muscles.

"We use two main sets of muscles when we smile - the zygomaticus major, which is responsible for the curling upwards of the mouth, and the orbicularis oculi, which causes crinkling around our eyes," explains Professor Ugail. "In fake smiles it is often only the mouth muscles which move but, as humans, we often don't spot the lack of movement around the eyes. The computer software can spot this much more reliably."

He adds: "An objective way of analysing whether or not a smile is genuine could help us develop improved interactions between computers and humans - for example in biometric identification. It could also be important to social and clinical scientists aiming to gain more insight into human behaviour and emotion."

The study is published today in Advanced Engineering Informatics.

Imagine you are a farmer struggling to keep up with production demands because of the increasingly stressful climate. Or perhaps you are a producer of renewable energy struggling with dramatic heat and weather. With increasing temperatures, solar panels get too hot to function properly, and crops demand more water, problems that are exacerbated by drought and climate conditions.

Greg Barron-Gafford, associate professor at the University of Arizona, shows that combining these two systems - solar panel (photovoltaic) infrastructure and agriculture - can create a mutually beneficial relationship. This practice of co-locating the two by planting crops under the shade of solar panels is called agrivoltaics.

"In an agrivoltaic system," Barron-Gafford says, "the environment under the panels is much cooler in the summer and stays warmer in the winters. This not only lessens rates of evaporation of irrigation waters in the summer, but it also means that plants don't get as stressed out." Crops that grow under lower drought stress require less water, and because they don't wilt as easily midday due to heat, they are able to photosynthesize longer and grow more efficiently.

In the southwestern US, there is an overabundance of sunlight, and the primary means of installing solar panels is to pack them densely into a site. Barron-Gafford's study on the benefits of agrivoltaics does not change that density, but simply elevates the panels so the crops are growing in nearly full shade. "What's super interesting," he explains, "is that we can cut back about 75% of the direct sunlight hitting the plants, but there is still so much diffuse light that makes it under the panels that the plants grow really well."

Barron-Gafford and his team work with farmers through the university's extension office, as well as with community farm colleagues in the Tucson area, in designing the test plots. The current agrivoltaic trials cover about 165 square meters, but larger installations on working farms are being developed in the coming year. They also work closely with the Department of Energy's National Renewable Energy Lab (NREL) to work towards consistency in developing plans of co-location installations.

The farmers help the researchers decide on test crops as well. Every spring and fall they grow beans, tomatoes, and a couple of types of peppers. They grow high-value herbs and spices, showing the potential additional profits that can come from intentionally selecting crops that might not otherwise grow well in typical conditions, but that can now grow well in the shade of solar panels.

They also work with leafy greens like lettuces, chards, and kale, which seem to grow better in this system. Plants in high-light environments tend to have smaller leaves - an adaptation for not capturing too much sunlight and overwhelming the photosynthesis system. Plants in low-light environments grow larger leaves to spread out the light-capturing chlorophyll that let plants change light to energy. The researchers are seeing that in their trials: basil plants produce larger leaves, kale leaves are longer and wider, and chard leaves are larger. This is key for these crops because farmers harvest the leafy parts of these plants.

The solar panels themselves also benefit from the co-location. In places where it is above 75 degrees Fahrenheit when sunny, solar panels begin under-performing because they become too hot. The evaporation of water from the crops creates localized cooling, which reduces heat stress on the panels overhead and boosts their performance. In short, it is a win-win-win at the food-water-energy nexus.

When it comes time to harvest the crops, it is actually not a big hassle, explains Barron-Gafford, as farmers can use much of the same equipment. "We raised the panels so that they were about 3 meters (10 feet) off the ground on the low end so that typical tractors could access the site. This is was the first thing that farmers in the area said would have to be in place for them to consider any kind of adoption of an agrivoltaic system."

The primary drawback of an agrivoltaic system is the cost of extra steel to elevate the panels, but Barron-Gafford believes increases in the yield of food products and savings in water would offset this extra investment. "I think the primary reason more producers aren't using this system yet is lack of awareness or uncertainty about its potential," he states.

Now with evidence of the benefits of this relationship between agriculture and photovoltaics, the team is looking for even more efficient ways to co-locate. For instance, they want to experiment with solar panels that can be moved to completely vertical positions, allowing tractors to move through the rows of panels to get to the soil and crops without having to elevate the panels at all.

That said, Barron-Gafford states that farmers do not need to wait for such future plans to adopt this practice, and neither do solar companies. To profit from agrivoltaics right now, they do not need to do anything more than elevate the masts that hold the rows of panels.

"That is part of what makes this current work so exciting," he adds, "a small change in planning can yield a ton of great benefits!"

A new study coordinated by the Research Group in Developmental Biology at UPF shows that during the embryonic development of the brain, the cells that are between adjacent segments detect the mechanical forces generated during morphogenesis to regulate the balance between progenitor stem cells and differentiated neurons. The study has been published in the journal Development.

In vertebrates, the central nervous system is formed from an embryonic structure divided into three vesicles of the brain and the spinal cord. The rearmost brain vesicle will give rise to important adult derivatives such as the cerebellum and is where the cranial nerves that innervate the face derive from. During embryonic development, the hindbrain is subdivided into seven segments, called rhombomeres where neuronal progenitors are generated that will give rise to both motor and sensory neurons.

During segmentation of the hindbrain, a specific population of cells is located at the interface between successive rhombomeres. These boundary cells act as a barrier so that neighbouring cell populations do not mix, send instructions to progenitor cells of the adjacent rhombomere, and act as a source of progenitors and neurons. Although mechanical signals have been seen to be increasingly involved in directing cellular behaviour, how this happened in vivo had not yet been demonstrated.

Now, the group led by Cristina Pujades at the Department of Experimental and Health Sciences (DCEXS) at UPF has investigated how these boundary cells are able to "sense" the mechanical stimuli and transduce them into specific biological behaviours during zebrafish hindbrain segmentation.

"Using transgenic zebrafish embryos that express fluorescent markers under the control of mechanical signals, we show that boundary cells in fact act as mechanosensors, through the activity of Yap/Taz-TEAD proteins", explains Adrià Voltes, first author of the article. This activity is lost when the authors manipulate the actomyosin cytoskeleton in both whole embryos and clonal populations, indicating that the pathway responds to mechanical cues in a cell-autonomous manner.

However, the decreased activity of these proteins, either conditionally or by yap and taz mutants, decreases the number of proliferating boundary cells but does not affect their differentiation into neurons. "Therefore, the activity of Yap/Taz-TEAD is essential to maintain boundary cells as proliferating progenitors and therefore as a niche for stem cells", explains Cristina Pujades.

Taken together, these data show that the boundary cells in the hindbrain sense mechanical forces through Yap/Taz-TEAD to regulate the proliferation of progenitors during segmentation. "Based on our results, we propose that the mechanical forces generated during the process of embryonic development regulate the maintenance of the progenitors and, therefore, control the balance between the proliferation and the differentiation of neurons", concludes Cristina Pujades.

Algae take up carbon dioxide (CO2) from the atmosphere and turn the carbon into biomass while releasing the oxygen back to the atmosphere. Fast algal growth during phytoplankton blooms leads to a massive transfer of carbon dioxide into algal biomass. But what happens to the carbon next?

"Once the algae die, the carbon is remineralized by microorganisms consuming their biomass. It is thus returned to the atmosphere as carbon dioxide. Alternatively, if the dead algae sink to the seafloor, the organic matter is buried in the sediment, potentially for a very long time", explains first author Karen Krüger from the Max Planck Institute for Marine Microbiology in Bremen. "The processes behind the remineralization of algal carbon are still not fully understood."

Thus, Krüger and her colleagues investigated microorganisms during spring algal blooms in the southern North Sea, at the island of Heligoland. They specifically looked at the bacterial use of polysaccharides - sugars that make up a substantial fraction of the algal biomass. Together with colleagues from the Max Planck Institute, the University of Greifswald and the DOE Joint Genome Institute in California, Krüger carried out a targeted metagenomic analysis of the Bacteroidetes phylum of bacteria, since these are known to consume lots of polysaccharides. In detail, the scientists looked at gene clusters called polysaccharide utilisation loci (PULs), which have been found to be specific to a particular polysaccharide substrate. If a bacterium contains a specific PUL, that indicates it feeds on the corresponding algal sugar.

Low PUL diversity

"Contrary to what we expected, the diversity of important PULs was relatively low", says Krüger. Only five major polysaccharide classes were being regularly targeted by multiple species of bacteria, namely beta-glucans (such as laminarin, the main diatom storage compound), alpha-glucans (such as starch and glycogen, also algal and bacterial storage compounds), mannans and xylans (typically algal cell wall components), and alginates (mostly known as slimy stuff produced by brown macroalgae). Of these five substrates, only two (alpha- and beta-glucans) make up the majority of substrates available to the bacteria during a phytoplankton bloom. This implies that the most important polysaccharide substrates released by dying algae are made up of a fairly small set of basic components.

"Given what we know of algal and bacterial species diversity, and the enormous potential complexity of polysaccharides, it came as no small surprise to see such a limited spectrum of PULs, and in only a relatively small number bacterial clades", co-author Ben Francis from the Max Planck Institute for Marine Microbiology sums up in an accompanying comment. "This was especially unexpected because previous studies suggested something different. An analysis of more than 50 bacterial isolates - i.e. bacteria that can be cultured in the lab - that our working group carried out in the same sampling region revealed a much broader diversity of PULs", he adds.

Temporal succession of polysaccharide degradation

During the course of the algal bloom, the scientists observed a distinct pattern: In early bloom stages, fewer and simpler polysaccharides dominated, while more complex polysaccharides became available as the bloom progressed. This might be caused by two factors, Francis explains: "First, bacteria will in general prefer easily degradable substrates such as simple storage glycans over biochemically more demanding ones. Second, more complex polysaccharides become increasingly available over a blooms' course, when more and more algae die."

This study provides unprecedented insights into the dynamics of a phytoplankton bloom and its protagonists. A fundamental understanding of the bulk of glycan-mediated carbon flow during phytoplankton bloom events is now within reach. "Next, we want to dig deeper into processes underlying the observed dynamics", says Krüger. "Moreover, it will be interesting to investigate polysaccharide degradation in habitats with other carbon sources, such as the Arctic Seas or the sediment."

'Predatory journals' pose a danger that could undermine the quality, integrity, and reliability of published scientific research, a new joint statement from three leading organizations, professional in medical writing and publication planning, has warned.

The American Medical Writers Association (AMWA), European Medical Writers Association (EMWA), and International Society for Medical Publication Professionals (ISMPP) has today released a 'Joint Position Statement on Predatory Publishing', which outlines the "serious threat" that predatory journals pose - both to researchers publishing the results of their work and to the peer-reviewed medical literature itself.

If not stopped, the ultimate result of predatory journals - which as defined in the statement, are those which subvert the peer-review publication system for the sole purpose of financial gain with little evident concern for ethical behaviour - will be to "harm" scientific literature.

In seeking a resolution, the authors of the paper - published in Current Medical Research & Opinion - call for all potential medical authors to carry out due diligence by examining the reputation of the publications to which they submit, and to send their work only to those journals that provide proper peer review and that genuinely seek to contribute to the scientific literature.

"The conscious and deliberate submission of manuscripts to predatory journals is not ethical," the statement reads.

"Medical writers and editors, as well as researchers, have a responsibility to evaluate the integrity, history, practices, and reputation of the journals to which their research is submitted.

"Legitimate research carried out with the best of intentions might be lost.

"Dangers to authors also exist in that their reputations can be damaged as a result of having their work published in predatory journals or being unknowingly 'appointed' to their editorial boards. Furthermore, authors may find themselves trapped after submitting an article to a predatory journal. There is a potential risk that some journals might not return submitted manuscripts or will publish a submitted paper even after an author has protested."

The statement provides a key set of 11 identifiers, typical of predatory journals and their publishers. As well as providing a lack of information, and poorly made websites, these include:

a lack of journal indexing in a recognized citation system such as PubMed or within a legitimate online directory such as the Directory of Open Access Journals (DOAJ)

promises of unrealistically quick peer review, or no information about the process

claims made of broad coverage across multiple specialties in medicine or across multiple subspecialties in a particular discipline

a large stable of journals that have been started very recently and/or that contain no or few published articles, or are of obviously poor quality

an editorial board consisting of members from outside the specialty or outside the country in which the journal is published

Susan Krug, MS, CAE, Executive Director, AMWA states: "AMWA recognizes the serious threat that predatory publishing poses to medical and scientific literature. This position statement provides a call to action and offers guidance on how to identify and avoid predatory journals."

Barbara Grossman, President, EMWA, added: "EMWA advises that authors should not submit manuscripts to predatory journals. This statement provides support for medical communicators as they share responsibility to carry out due diligence when preparing to contribute to scientific literature."

Robert J. Matheis, PhD, MA, President and CEO, ISMPP said: "Professional medical communicators and publication planners must be aware of the serious threat predatory publishing poses to scientific literature. ISMPP's participation in this joint position statement is part of our commitment to educating our members about predatory publishing and how to address this significant issue."

Leon Heward Mills, Managing Director, Researcher Services, at Taylor & Francis added: "We have actively supported initiatives such as 'Think, Check, Submit' over a number of years, providing researchers with the tools to identify journals which do not uphold the high standards of quality and integrity that their work deserves. We wholeheartedly welcome this statement, by three such respected organisations, and hope it will further support researchers in identifying and avoiding fraudulent publications."

EAST LANSING, Mich. - What can fish teach scientists about limb regeneration? Quite a bit, as it turns out.

In the current issue of Proceedings of the National Academy of Sciences, Michigan State University scientists show that gar, a toothy, freshwater fish, can reveal many evolutionary secrets - even possible genetic blueprints for limb regeneration in people.

Scientists knew that salamanders can regrow full limbs after amputation. Ingo Braasch, MSU assistant professor of integrative biology, and his team, however, was the first to study how gar and other fish regenerate entire fins. More importantly, the researchers focused on how they rebuild the endochondral bones within their fins, which are the equivalents of human arms and legs.

"Gars are often considered 'dinosaur fish' because of their ancestor-resembling body type," Braasch said. "They're becoming a popular, new research organism for biomedical research, largely in part because the gar genome is quite similar to the human genome."

Garfish has been called a "bridge species," as its genome is similar to both zebrafish - often used as a genetic model for human medical advances - and humans, a discovery in which Braasch led. Gar evolve slowly and have kept more ancestral elements in their genome than other fish. This means that along with serving as a bridge species to people, gar also are great connectors to the deep past.

So, by studying how fish regenerate fins, Braasch's team pinpointed the genes and the mechanisms responsible that drive the regrowth. When they compared their findings to the human genome, they made an interesting observation.

"The genes responsible for this action in fish also are largely present in humans," Braasch said. "What's missing, though, are the genetic mechanisms that activate these genes in humans. It is likely that the genetic switches that activate the genes have been lost or altered during the evolution of mammals, including humans."

Evolutionary speaking, this suggests that the last common ancestor of fish and tetrapods, or four-legged vertebrates, had already acquired a specialized response for appendage regeneration, and that this program has been maintained during evolution in many fish species as well as salamanders, he added.

Continuing research into these key genes and missing mechanisms could eventually lead to some revolutionary medical advances.

"The more we study these commonalities among vertebrates, the more we can home in on prime targets for awakening this program for regenerative therapies in humans," Braasch said. "Such direct biomedical advances remain in the distant future, but studies of fin regeneration in fish will continue to reveal much about the regenerative potential of vertebrates."

Montmorency tart cherry juice has long been coveted by gout sufferers, athletes for exercise recovery, and those seeking a good night's sleep. Now there's evidence that this polyphenol-rich beverage may help improve cognitive performance in older adults.

In a new study published in the journal Food & Function, researchers at the University of Delaware found daily intake of Montmorency tart cherry juice improved memory scores among adults, ages 65 to 73 years. In this randomized-controlled trial, 34 participants were assigned to consume either 16 ounces (480 mL) of Montmorency tart cherry juice or the same amount of a placebo drink, half in the morning and half in the evening, every day for 12 weeks.

All participants were generally healthy (not heavy smokers, no prior diagnosis of heart disease, diabetes, cancer, psychiatric disorders, etc.), were not taking any medications that could affect brain function and were asked to maintain their regular diet and physical activity levels for the duration of the study. Before and after the 12-week trial, researchers analyzed cognitive function and subjective memory scores via a series of questionnaires and tests.

After 12 weeks, those drinking Montmorency tart cherry juice exhibited improved scores in both cognitive function and subjective memory. Specifically, the tart cherry group showed a 5% increase in satisfaction with their ability to remember things, a 4% reduction in movement time (a measurement of speed of response to visual stimuli) and a 23% reduction in errors made during an episodic visual memory task (which assesses visual memory and new learning) compared to placebo. They also exhibited a 3% improvement in visual sustained attention (which measures visual information processing) and an 18% reduction in errors made during a spatial working memory task (which assesses memory and strategy use) compared to baseline values.

"Cognitive function is a key determinant of independence and quality of life among older adults," said lead author Sheau Ching Chai, assistant professor of behavioral health and nutrition at the University of Delaware. "The potential beneficial effects of tart cherries may be related to the bioactive compounds they possess, which include polyphenols, anthocyanins and melanin. They may also be related to tart cherry's potential blood-pressure lowering effects, outlined in a previous study we conducted in the same population, as blood pressure can influence blood flow to the brain."

Compliance rate throughout the 12-week trial was high (94.2%), suggesting tart cherry juice twice a day was a manageable addition to these participants' daily routine.

The sample size of this study was small, and larger, longer studies are warranted to confirm its findings.

Montmorency tart cherries are the most common variety of tart cherries grown in the U.S.

Old-school Hollywood editors cut unwanted frames of film and patched in desired frames to make a movie. The human body does something similar--trillions of times per second--through a biochemical editing process called RNA splicing. Rather than cutting film, it edits the messenger RNA that is the blueprint for producing the many proteins found in cells.

In their exploration of the evolutionary origins and history of RNA splicing and the human genome, UC San Diego biochemists Navtej Toor and Daniel Haack combined two-dimensional (2D) images of individual molecules to reconstruct a three-dimensional (3D) picture of a portion of RNA--what the scientists call group II introns. In so doing, they discovered a large-scale molecular movement associated with RNA catalysis that provides evidence for the origin of RNA splicing and its role in the diversity of life on Earth. Their breakthrough research is outlined in the current edition of Cell.

"We are trying to understand how the human genome has evolved starting from primitive ancestors. Every human gene has unwanted frames that are non-coding and must be removed before gene expression. This is the process of RNA splicing," stated Toor, an associate professor in the Department of Chemistry and Biochemistry, adding that 15 percent of human diseases are the result of defects in this process.

Toor explained that his team works to understand the evolutionary origins of 70 percent of human DNA--a portion made up of two types of genetic elements, which are both thought to have evolved from group II introns. Specifically, spliceosomal introns, which make up about 25 percent of the human genome, are non-coding sequences that must be removed before gene expression. The other 45 percent is comprised of sequences derived from what are called retroelements. These are genetic elements that insert themselves into DNA and hop around the genome to replicate themselves via an RNA intermediate.

"Studying group II introns gives us insight into the evolution of a large portion of the human genome," noted Toor.

Working with the group II intron RNA nanomachine, Toor and Haack, a postdoctoral scholar at UC San Diego and first author of the paper, were able to isolate the group II intron complexes from a species of blue-green algae that lives at high temperature.

"Using a group II intron from a high-temperature organism facilitated structure determination due to the innate stability of the complex from this species," said Haack. "The evolution of this type of RNA splicing likely led to the diversification of life on Earth."

Haack further explained that he and Toor discovered that the group II intron and the spliceosome share a common dynamic mechanism of moving their catalytic components during RNA splicing.

"This is the strongest evidence to date that the spliceosome evolved from a bacterial group II intron," he said.

Additionally, the findings reveal how group II introns are able to insert themselves into DNA through a process called retrotransposition. This copy-and-paste process has resulted in selfish retroelements proliferating in human DNA to comprise a large portion of the genome.

"Replication of these retroelements has played a large role in shaping the architecture of the modern human genome and has even been implicated in the speciation of primates," noted Toor.

The researchers used cryo-electron microscopy (cryo-EM) to extract a molecular structure of the group II intron. They froze the RNA in a layer of thin ice and then shot electrons through this sample. According to the scientists, the electron microscope can magnify the image 39,000 times. The resulting 2D images of individual molecules were then put together to come up with a 3D view of the group II intron.

"This is like molecular archaeology," described Haack. "Group II introns are living fossils that give us a glimpse into how complex life first evolved on Earth."

Although psychiatric disorders can be linked to particular genes, the brain regions and mechanisms underlying particular disorders are not well-understood. Mutations or deletions of the SHANK3 gene are strongly associated with autism spectrum disorder (ASD) and a related rare disorder called Phelan-McDermid syndrome. Mice with SHANK3 mutations also display some of the traits associated with autism, including avoidance of social interactions, but the brain regions responsible for this behavior have not been identified.

A new study by neuroscientists at MIT and colleagues in China provides clues to the neural circuits underlying social deficits associated with ASD. The paper, published in Nature Neuroscience, found that structural and functional impairments in the anterior cingulate cortex (ACC) of SHANK3 mutant mice are linked to altered social interactions.

"Neurobiological mechanisms of social deficits are very complex and involve many brain regions, even in a mouse model," explains Guoping Feng, the James W. and Patricia T. Poitras Professor at MIT and one of the senior authors of the study. "These findings add another piece of the puzzle to mapping the neural circuits responsible for this social deficit in ASD models."

The Nature Neuroscience paper is the result of a collaboration between Feng, who is also an investigator at MIT's McGovern Institute and a senior scientist in the Broad Institute's Stanley Center for Psychiatric Research, and Wenting Wang and Shengxi Wu at the Fourth Military Medical University, Xi'an, China.

A number of brain regions have been implicated in social interactions, including the prefrontal cortex (PFC) and its projections to brain regions including the nucleus accumbens and habenula, but these studies failed to definitively link the PFC to altered social interactions seen in SHANK3 knockout mice.

In the new study, the authors instead focused on the ACC, a brain region noted for its role in social functions in humans and animal models. The ACC is also known to play a role in fundamental cognitive processes, including cost-benefit calculation, motivation, and decision making.

In mice lacking SHANK3, the researchers found structural and functional disruptions at the synapses, or connections, between excitatory neurons in the ACC. The researchers went on to show that the loss of SHANK3 in excitatory ACC neurons alone was enough to disrupt communication between these neurons and led to unusually reduced activity of these neurons during behavioral tasks reflecting social interaction.

Having implicated these ACC neurons in social preferences and interactions in SHANK3 knockout mice, the authors then tested whether activating these same neurons could rescue these behaviors. Using optogenetics and specfic drugs, the researchers activated the ACC neurons and found improved social behavior in the SHANK3 mutant mice.

"Next, we are planning to explore brain regions downstream of the ACC that modulate social behavior in normal mice and models of autism," explains Wenting Wang, co-corresponding author on the study. "This will help us to better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders."

Previous clinical studies reported that anatomical structures in the ACC were altered and/or dysfunctional in people with ASD, an initial indication that the findings from SHANK3 mice may also hold true in these individuals.

CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12 and targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain.

McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), described in the journal Science.

Zhang and his team, including first co-authors Omar Abudayyeh and Jonathan Gootenberg (both now McGovern Fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine -- thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang's team that changes adenine bases into inosine in RNA.

RESCUE significantly expands the landscape that CRISPR tools can target to include modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.

"To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox," says Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT. Zhang also has appointments in MIT's departments of Brain and Cognitive Sciences and Biological Engineering.

Expanding the reach of RNA editing to new targets

The previously developed REPAIR platform used the RNA-targeting CRISPR/Cas13 to direct the active domain of an RNA editor, ADAR2, to specific RNA transcripts where it could convert the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion, and evolved it in the lab until it could change cytosine to uridine, or C to U.

RESCUE can be guided to any RNA of choice, then perform a C-to-U edit through the evolved ADAR2 component of the platform. The team took the new platform into human cells, showing that they could target natural RNAs in the cell as well as 24 clinically relevant mutations in synthetic RNAs. They then further optimized RESCUE to reduce off-target editing, while minimally disrupting on-target editing.

New targets in sight

Expanded targeting by RESCUE means that sites regulating activity and function of many proteins through post-translational modifications, such as phosphorylation, glycosylation, and methylation can now be more readily targeted for editing.

A major advantage of RNA editing is its reversibility, in contrast to changes made at the DNA level, which are permanent. Thus, RESCUE could be deployed transiently in situations where a modification may be desirable temporarily, but not permanently. To demonstrate this, the team showed that in human cells, RESCUE can target specific sites in the RNA encoding β-catenin, that are known to be phosphorylated on the protein product, leading to a temporary increase in β-catenin activation and cell growth. If such a change was made permanently, it could predispose cells to uncontrolled cell growth and cancer, but by using RESCUE, transient cell growth could potentially stimulate wound healing in response to acute injuries.

The researchers also targeted a pathogenic gene variant, APOE4. The APOE4 allele has consistently emerged as a genetic risk factor for the development of late-onset Alzheimer's Disease. Isoform APOE4 differs from APOE2, which is not a risk factor, by just two differences (both C in APOE4 vs. U in APOE2). Zhang and colleagues introduced the risk-associated APOE4 RNA into cells, and showed that RESCUE can convert its signature C's to an APOE2 sequence, essentially converting a risk to a non-risk variant.

To facilitate additional work that will push RESCUE toward the clinic as well as enable researchers to use RESCUE as a tool to better understand disease-causing mutations, the Zhang lab plans to share the RESCUE system broadly, as they have with previously developed CRISPR tools. The technology will be freely available for academic research through the non-profit plasmid repository Addgene. Additional information can be found on the Zhang lab's webpage.

ROCHESTER, Minn. -- Mayo Clinic researchers have found an association between increased symptoms of burnout and heightened racial bias in medical residents. The study appears in JAMA Network Open.

"When physicians aren't operating in an optimal mental and emotional state, they may find it harder to push back against their own biases," says Liselotte Dyrbye, M.D., who led the study. "If burnout contributes to disparities in care, perhaps fighting burnout can help narrow that gap."

The results of the study suggest it can. Over 3,000 physicians from across the country who are not black were surveyed for symptoms of burnout. They were then given tests of explicit racial bias, a direct rating of how warmly they feel toward a person, and implicit racial bias, which is based on descriptive word association. Researchers conducted these surveys in the second and third years of residency to assess changes over time. Physicians experiencing high symptoms of burnout in the second year tended to respond with more racial bias, explicit and implicit. At follow-up in the third year, racial bias decreased across the board. The greatest reduction in bias, however, occurred in those physicians who experienced burnout in the second year but had recovered from burnout by the third year. This suggests that treating burnout could make a tangible improvement in racial bias in the clinic.

Health disparities between ethnic groups in the U.S. are well-documented. The Centers for Disease Control and Prevention reports a higher incidence of many health conditions among black Americans, including stroke, heart disease, infant mortality, obesity and diabetes. Many studies have investigated the ways in which differences in physician care contribute to this effect, but little previous research has explored how a physician's mental state can trigger these disparities. Rates of burnout -- a condition marked by emotional exhaustion, cynicism and negative feelings toward one's job -- are nearly doubled in physicians, compared to the general population. The researchers on this study wanted to know if burnout affects the manifestation of bias in medical residents.

While the differences in scores between the groups in the study are small, the authors suggest that further studies could better explore whether the relationship between burnout and racial bias truly is one of cause and effect and if so, foster solutions.

The study was performed in collaboration with Yale University, the University of Minnesota, Syracuse University, and Oregon Health & Science University. It was funded by the National Institutes of Health and Mayo Clinic.

Tokyo, Japan - MicroRNA (miRNA) is a type of RNA that plays an important role in various cellular processes and is also involved in developing defenses against pathogens. Increasing numbers of studies have indicated that certain human diseases are caused by altered expression and organization of miRNA.

Kotaro Yoshioka and Takanori Yokota of Tokyo Medical and Dental University (TMDU) have developed new molecules that can silence or inhibit malfunctioning miRNA, with the hope that their work could lead to new ways to treat diseases which are caused by the miRNAs. Creating a new type of antimiR, which is a molecule that inhibits miRNA, could provide the foundation for new gene therapies.

Yoshioka and Yokota recently developed a new type of antimiR with heightened efficacy against miRNA and lowered toxicity, using their original technique, hetero duplex oligonucleotides (HDO). They combined an antimiR with its complementary RNA to produce a new molecule, termed "HDO-antimiR". They then characterized HDO-antimiR--specifically, they evaluated its strength in inhibiting miRNA, assessed its biological distribution, and checked its specific action by modifying its structure in mice. They recently published their findings in Nucleic Acids Research.

"HDO-antimiR has a unique double-strand structure that is totally different from previously described antimiRs," corresponding author Yokota says. "This structure is responsible for a substantial increase in the potency of miRNA silenced by HDO-antimiR compared with the single-stranded parent antimiR."

The researchers found that compared with conventional antimiR, HDO-antimiR was 12 times as efficient in terms of binding to targeted miRNA, and had improved potency within cells. Further, HDO-antimiR produced enhanced phenotypic effects in mice, specifically increasing the expression of mRNA that targets miRNA, leading to greater miRNA inhibition.

The heightened potency of HDO-antimiR was not related to high bio-stability or an increased rate of delivery to the targeted cell. Although these are common explanations for increased potency, in this case it was a reflection of improved strength once the molecule had entered the cells. This indicates that the unique structure of HDO-antimiR enabled it to behave differently than other types of miRNA inhibitors.

* A joint survey by researchers from the Universitat Autònoma de Barcelona (UAB) and Benue State University (BSU) finds that short height and low education levels are characteristic traits of Nigerian women with type 2 diabetes showing early symptoms of dementia.

* This work points to the importance of childhood nutrition and education programmes, particularly for girls, in public health improvement strategies in Nigeria. A sustained programme addressing these problems can mitigate a future burden of dementia in the country's adult diabetic women.

Globally, DM2 in mid-life is a recognized risk factor for dementia, but this association is worse in persons of African descent, especially in women. Among African diabetics, development of dementia is more frequent and rapid, and this is associated with different factors such as lifestyle, diet, socio-economy and genetics.

This appears to be the case in Nigeria, which currently contains the largest number of persons (3 million and rising) affected by DM2 on the African continent. This makes the country a good place to study the interaction of varied factors in the development of DM and associated co-morbidities in persons of African origin. In the 1960s, the prevalence of DM in Nigeria was found to be less than 1% but this has risen to 4.6%-10%, depending on the study population within the country, in about 5 decades. Some factors implicated in this surge are ageing, obesity, hypertension, adoption of sedentary living and wide consumption of toxic diet imported from some Western countries.

Taking into account the above information, Dr. Lydia Giménez Llort (Head of the Medical Psychology Departamental Unit, representative of the Observatory for the Equality at the Faculty of Medicine, and researcher at the Institute of Neurosciences, UAB) and Dr. Efosa Kenneth Oghagbon (Department of Chemical Pathology, Faculty of Basic & Allied Medical Science, College of Health Sciences, Benue State University (BSU) and Consultant Chemical Pathologist and Metabolic Physician at the University Teaching Hospital; BSUTH, Makurdi, Nigeria) carried out a collaborative study that evaluated factors associating DM2 with dementia in a sub-Saharan population of type 2 diabetic subjects. This comprised 62 female and 47 male patients, who were compared with 53 healthy female and 46 healthy male subjects, with special attention put on the women.

Using two dementia questionnaires/scales, the mini-mental state examination (MMMS) and six item cognitive impair test (6CIT), researchers assessed the impact of anthropometric measures (body mass index, waist-hip ratio, weight and height) and other biodata (sex, age, education level and professions) on the burden of dementia.

The study results showed that diabetic women who had shorter body height and lower level of education had more severe dementia. The women afflicted with dementia had twice the level of illiteracy compared to their healthy counterparts, and this was worse compared to men who were 11 times better in literacy level. The stature or height was the most discriminating factor among the physical measures and the diabetic women in the study were generally shorter. Categorically, the two dementia scales showed that diabetic Nigerian women with shorter stature and poorer education levels had grades consistent with cognitive deterioration.

Physical height is a simple parameter that can be measured by most medical clinics in Nigeria. It should be integrated into routine assessment of diabetic patients, especially women as it can reveal increased dementia risk. The final height of adults is related to early life nutrition and thus there is the need for better feeding in childhood especially among girls and pregnant women.

Dr. Lydia Giménez-Llort emphasised that "...education augments the cognitive reserve of individuals, and this favors brain neuroplasticity and functional development". Furthermore the UAB scientist said that "...in addition to age, complications of diabetes constitutes a key predictive tool for dementia".

Dr. Efosa K. Oghagbon suggests that "an optimal nutrition at the onset of life can improve cognition and cerebral development in childhood and adolescence; key period during which to attain adequate physical and educational developments of the Nigerian child".

Both authors agree that not only is it important for government and policy makers to emphasise proper childhood nutrition in Nigerians, but should particularly focus on the girl child.

"Our results can aid the development of evidence-based public health approaches to mitigate dementia in communities in Nigeria and the sub-region. This is important as countries in the sub-region including Nigeria cannot sustain healthcare cost occasioned by dementia and associated issues", opine the two researchers.

Healthy and competitive markets - and not stringent regulations - help dial back the cost of mobile phone contacts, according to new research.

Consumers in the UK benefit from comparatively cheaper bills than many of their counterparts abroad because regulations over contract length and costs are kept to a minimum.

Instead, market competition, where companies vie to offer the best deals to customers, provides the most effective way of keeping prices down and promoting a good service.

A team of law experts from the universities of Warwick and Exeter conducted the new study by comparing the strength of regulations of several countries worldwide.

While factors such as geography can also play a role, the research team found that consumers face higher bills and costs - and have less choice over which provider to select - when contracts are tied up in greater amounts of regulation.

The experts suggest that keeping regulations to a minimum creates "friendlier markets" for both providers and consumers, which can lead to significant price decreases.

Dr Timothy Dodsworth, from the University of Exeter Law School said: "We have found competition should be a key part of the mobile phone market, as it means companies must provide the best service for consumers in order to stay in business. It is part of the reason the UK has some of the lowest bills in the world.

"Smaller businesses find it harder and more expensive to function in a highly regulated market, and strict regulations mean only a few top companies dominate it.

"This means there is very little competition, and therefore no real reason to lower prices and improve services."

Academics examined the way mobile phone contracts were regulated in Germany, Britain, USA and Canada for the study.

They found regulating mobile phone contracts can discourage new companies from entering the market, and so reduce competition and choice for consumers.

While in Europe the length of contract is now determined by the EU, Canada has introduced more regulations in an attempt to manipulate the market to be more competitive.

However, this meant that companies with no flexibility to reduce or adjust fees and costs, meaning contract prices have stagnated - compared to price falls in many other countries.

"Adverse effects can also be seen in Europe though.", Christopher Bisping from the University of Warwick explained, "Before the EU introduced a sector-wide maximum length of 24 months, there was a range of different contract lengths available, allowing consumers to to pick whatever length best suited their needs."

The USA is thought to have the least regulation of mobile phone contracts in the world, but official statistics are not kept.

In the UK the regulator Ofcom has introduced new rules around contract length but has taken the decision to not introduce other regulation because it considers there is enough competition in the market.

Dr Dodsworth said: "Ofcom are acting in a sensible way by letting the UK market balance itself, and this should remain their policy if consumers are to have the best service. Examining other countries show if you try to regulate how contracts are renewed or the initial commitment period this has a knock-on effect on the price people pay or has other unintended consequences."

In Canada prices for consumers with lower than average consumption rose by roughly 16 per cent after the introduction of the "Wireless Code" legislation in 2014. However, for average consumption users, the cost remained steady between 2013 and 2014, and higher than average consumption contracts (CAN$80 and above) dropped from an average price of CAN$93 in 2013 to CAN$80 in 2014.