Culture

It isn't easy being a loner -- someone who resists the pull of the crowd, who marches to their own drummer.

But loners exist across the natural world, and they might just serve a purpose, said Corina Tarnita, an associate professor of ecology and evolutionary biology. She ticked off examples of loners who sit out their species' collective actions: the small herd that skips the great wildebeest migration, the locusts that peel off from the swarm and revert to calm grasshopper behaviors, the handful of bamboo that flower a few days before or after the rest of the species, and the slime molds that hang back from forming the swaying towers studied by Princeton luminary John Bonner.

"Now that we're starting to look for it, we realize that a whole lot of systems are not perfectly synchronized -- and it's tantalizing to think that that there may be something to this imperfect synchronization," Tarnita said. "Individuals that are out-of-sync with the majority of a population exist in humans, too. We call them misfits or geniuses, contrarians or visionaries, very much depending on how the rest of the society feels about their behavior, but they certainly exist."

To Tarnita, the problem with collective systems like wildebeest migrations and locust swarms is that they do not easily lend themselves to experimental manipulation, to testing whether loners are random or a predictable quantity, possibly subject to natural or cultural selection. But she and her collaborators found an ideal system in which to test these questions: the cellular slime mold, Dictyostelium discoideum. In the March 19 issue of PLoS Biology, they demonstrated that evolution could indeed select for loner behavior in slime molds. Loners are both an ecological and an evolutionary insurance plan, a way to diversify a genetic portfolio to ensure the survival of the social, collective behavior.

Consider the humble slime mold. As seen in the many videos Bonner made over his seven-decade career, when they are threatened by starvation, the tiny amoebae coalesce into slug-like creatures that then aggregate into a large, swaying tower that grows upward with a burgeoning slimy top -- until that top sticks to an unwitting passing insect, the starvation-resistant spores hitchhiking out into the world, while all the individuals making up the base and stalk die. In other words, the collective phase is necessary for survival and dispersal.

"Whenever a system has a collective behavior, it's so eye-catching, and so awesome -- and as humans, we tend to look at what's eye-catching," said Fernando Rossine, a graduate student in Tarnita's lab and one of two co-first authors on the paper.

But what caught Tarnita's eye were the slime mold loners, the amoebae that resist the biochemical call to form the tower. She first noticed them the week before she started her faculty job at Princeton in 2013.

"I was at a conference, and a speaker was showing videos of slime molds doing this very complex collective behavior, all determined to reach the center of aggregation," Tarnita said. "All but some, I noticed: Here and there, some scattered cells on the plate just didn't seem to react at all to this aggregation process."

She inquired about these lonely cells, and the speaker dismissed them as "mistakes." "In other words, how could we even expect millions of cells to aggregate without a few chance stragglers being left behind?" explained Tarnita.

When she got to Princeton, Tarnita connected with Allyson Sgro, who was then a postdoctoral researcher in the lab of Thomas Gregor, a professor of physics and biophysics. Sgro is now an assistant professor of biomedical engineering and physics at Boston University.

Together, Tarnita and Sgro "just started to poke at the loners a little bit," Tarnita said. They tested the loners to see if they were flawed in some way, but they couldn't find anything wrong with them. The loners would eat if given food, and they could divide and make offspring and do everything a healthy slime mold does. And when they starved, their progeny could assemble into the reproductive tower that their parents had resisted previously. But they, too, left behind some loners.

As a theoretical ecologist, Tarnita is drawn to these naturally occurring puzzles, which she tackles with mathematical models. This time, she started with some fundamental questions: What if having some loners stay out of the tower is not just a mistake? What if this is actually part of the strategy of this organism? How might that work?

In a previous paper, Tarnita and her co-authors -- which included Sgro and Ricardo Martinez-Garcia, Tarnita's then-postdoc who is now an assistant professor in biological physics at the South American Institute for Fundamental Research, in Brazil -- theorized that it could make sense for some fraction of the slime mold population to remain behind in order to take advantage of any resources that might return in the environment while the rest of the cells are aggregating. They showed that this was theoretically feasible, but the dream was to eventually fully characterize the loner behavior experimentally.

Over several years, multiple graduate students tackled the problem, but the challenges appeared insurmountable. For example, the very first step towards characterizing these loners required being able to rigorously and precisely count them. But amoebae have a non-descript, formless shape, which makes it hard to distinguish a single cell from a tiny group of two or three cells.

In came Rossine, whom Tarnita describes as "extraordinarily creative, both conceptually and experimentally." With guidance from Sgro, as well as from Gregor, in whose lab all the experimental work was performed, Rossine began to master the system.

First, he was surprised to find that loners are more numerous than anyone had imagined. When he began trying to replicate the slime mold experiments of other researchers, Rossine discovered that those scientists had carefully optimized conditions to encourage the maximum number of slime molds to join the tower, but even then, a few loners held back. "Even in these very, very idealized conditions, you couldn't exclude loners, because you just can't -- they're part of the process," he said. When Rossine did experiments with slime molds collected from the wild, he was startled to see that up to 30% chose the loner life over collective action.

Then came the second surprise: Tarnita's initial proposal for the nature of these loners turned out to be only half right. When Rossine accurately counted the loners, he confirmed Tarnita's hypothesis that they are decidedly not random mistakes, but a heritable trait. However, they were not a constant fraction of the initial population of starving cells, as she had theorized. Instead, their number depended on the density of the population. In other words, loners were not flipping a coin and deciding, by themselves, to stay back, as Tarnita had first assumed.

In the smallest populations, they found, all the cells remain loners. Above a certain threshold, there is indeed a steady fraction of amoebae that avoid tower-building -- but with a large enough starting population, the number of loners plateaued.

"This was exhilarating because it meant that we had originally been right that the loners were far from boring, but it also meant that, theoretically, we needed to go back to the drawing board," said Tarnita. Led by Martinez-Garcia (who shares first author honors), with constant input from Rossine, the modeling effort took a couple of years to develop and begin to give insight into the experimental findings.

Their combination of experimentation and theoretical modeling sets this work at the "frontier of our understanding," said Silvia De Monte, a modeler of eco-evolutionary population dynamics with CNRS, IBENS, Paris and the Max Plank Institute, who was not involved in this research. "This interdisciplinary approach sheds new light on the processes underlying the formation and evolution of aggregative multicellularity," she said. "Tarnita and her colleagues provide evidence that the proportion of solitary cells in the social amoeba Dictyostelium discoideum is not simply determined by each cell individually tossing a coin. It results instead from interactions between the [organism] and the environment."

Collective actions provide huge benefits but they often come with risks, whether it is cheaters undermining the cooperation necessary to build a slime mold tower or rinderpest -- an infectious disease also known as cattle plague -- spreading aggressively through the dense wildebeest migrants. The loners who hang back might therefore serve as a bet-hedging strategy, ensuring that damage to the majority doesn't wipe out the entire population or its ability to be social. In other words, and counterintuitively, the loners might be the key to preserving the social aspect of these systems -- they themselves are not social, which makes them invulnerable to the kinds of threats that collectives face, but their offspring retain the ability to be social under the right conditions, so sociality is preserved.

"It's a social bet-hedging," said Rossine. "And a fascinating conclusion that follows from our findings is that, at least for slime molds, the decision not to become part of the collective is, in fact, taken collectively. All the cells kind of talk to each other chemically: 'Oh, you're going? I guess I'm staying.' There's communication involved in becoming a loner."

The work was successful only because of the remarkable cross-disciplinary spirit that characterizes the Princeton campus, said Tarnita. "The high density of really smart people who are all primed to think interdisciplinarily makes it very easy to start collaborations and even to produce these kinds of papers, where all the authors are from Princeton," she said.

CLEVELAND, Ohio (March 18, 2020)--Nearly one-third of women who choose to have their ovaries removed before the natural age of menopause are susceptible to negative mood and executive dysfunction. A new study shows that a woman's risk for such disorders may be linked with the degree of childhood adversity she experienced. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Women with mutations in BRCA1 and BRCA2 susceptibility genes are more likely to undergo a risk-reducing salpingo-oophorectomy in order to help lower their risk of breast and ovarian cancers. The premature loss of ovarian hormones caused by the procedure has been shown to increase the risk of central nervous system impairment and an overall decline in quality of life. Previous studies have shown that women who have their ovaries removed before natural menopause are at increased risk of dementia and cognitive dysfunction. More specifically, the largest declines in cognitive performance after oophorectomy occur in the executive functioning domains.

This new study of cognitive function in BRCA1 and BRCA2 mutation carriers who underwent risk-reducing salpingo-oophorectomy examined the association between childhood adversity and executive function as well as the role of mood. Women with higher levels of childhood adversity reported more symptoms of dysfunction and also performed worse on executive function tasks.

These results could provide valuable insights to healthcare providers when they are counseling women who would benefit from risk-reducing salpingo-oophorectomy. Assessment of childhood adversity may help identify women who are more likely to experience executive function difficulties and mood symptoms after surgery and provide an opportunity to treat these difficulties before symptoms negatively affect quality of life.

Study results appear in the article "Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter?"

"Assessment of childhood adversity and mood symptoms in women undergoing risk-reducing salpingo-oophorectomy in the setting of high-risk mutations in the BRCA1 and BRCA2 genes may help identify women who are more likely to experience difficulty with executive function and allow for management of mood symptoms before they negatively affect quality of life," says Dr. Stephanie Faubion, NAMS medical director.

Are we the best at judging our own attractiveness?

New research out in Frontiers in Robotics and AI shows that we might not be after all. Researchers from the Experimental Virtual Environments (EVENT) Lab at the University of Barcelona examined the difference between how we believe we look, and how we view our own body from an outsider's perspective.

What they found was that people rate their own body more negatively when embodied in it, compared to viewing their exact same body except as an outsider. So, how exactly do we view our own body as an outsider?

The researchers set out to answer this by recruiting 11 men and 12 women from the University of Barcelona. Participants filled out one questionnaire on eating disorders and one on body shape perception.

The team used virtual reality to create three virtual bodies ("avatars") for each participant: one based on how participants indicated measurements of their own body as their own image of it, one based on their ideal body shape, and one based on their real body measurements. Once these computer models were created, participants were immersed in virtual reality to view these three avatars from two different perspectives - first-person (like how we see our own bodies day to day) or third-person (how others in public would see us). They were then asked to rate the attractiveness of each of these virtual bodies.

"Our results suggest that a change in perspective affected the evaluation of the attractiveness of a virtual body. For female participants, when the same virtual body was perceived from a third person perspective, it was evaluated as more attractive than when it was perceived from a first-person perspective," says lead author Dr. Solène Neyret.

"Importantly, we also observed that the internal representation that people create of their own body is highly inaccurate."

The researchers found that individuals' prior beliefs about 'the self' may be responsible for this effect and could prevent people from accurately judging their real appearance. Interestingly, the researchers also noted that the "ideal body" described by participants often had similar physical attributes one to another. This points towards the predominance of an 'ideal body shape' within the study's cultural environment.

By using virtual reality, the researchers were able to give participants a new perspective on themselves - in more than just a physical sense. The gap between the reality of how we look versus how we perceive how we look can often be at the root of many body perception disorders, and the techniques described here may have future applications for treatment.

"By showing their real body to our female participants from a third person perspective, it appeared more attractive to them than when the same body was seen from a first-person perspective. We believe that this method can be particularly efficient for increasing body satisfaction in patients with eating disorders", states Neyret.

"This method could help patients to understand the biased representation they have of their own body. This knowledge could re-orientate their attention to the real features of their body shape in a more accurate and objective way, that isn't affected by the negative prior beliefs they have about themselves", says Neyret.

By being able to see ourselves as from an outside perspective, we might learn to get a more objective perception of our bodies, and start to live with a healthier and more accurate body image.

Korea Brain Research Institute (KBRI, President: Pann-Ghill Suh) announced on February 10 that its research team led by Dr. Ja Wook Koo and Dr. Sukwon Lee proved that the posterior parietal cortex (PPC) of the cerebrum plays a role in fear renewal occurring in a novel context.

Posterior parietal cortex (PPC): The posterior parietal cortex is a part of the parietal lobe located in the upper-rear part of the brain and is related to high-level cognitive functions of the brain, including spatial reasoning and decision-making.

The findings were published in the February issue of the international scientific journal Molecular Brain. The title of the paper and its authors are as below.

Title: Posterior parietal cortex mediates fear renewal in a novel context
*

Authors: Bitna Joo (first author), Ja Wook Koo, and Sukwon Lee (corresponding authors)

Posttraumatic stress disorder (PTSD) is a mental health condition 'where' a person exposed to traumatic events such as severe accidents and violence repeatedly suffers from mental or physical distress. PTSD patients experience chronic distress because a mere visit to a place that reminds them of their trauma can result in relapse. For instance, some survivors of national disasters, such as the Sewol ferry incident and the Daegu subway fire, can no longer board a ship or are reluctant to use the subway in another city.

A KBRI research team has discovered, for the first time in the world, that PPC is associated with fear renewal in a novel context.

In this study, fear memory was produced in the form of associative memory through the simultaneous use of auditory and electric stimuli. This memory was a conditioned memory as shown in Pavlov's dogs salivate in response to bell ringings after several repetitions of being fed while bell ringing.

The research team exposed mice simultaneously to sound and electric shock in order to create an auditory fear memory, and then exposed them again to the same sound in a novel context.

Control mice that received no treatment exhibited the same fear response in both novel and familiar contexts, 'where'as experimental mice whose PPC was inactivated via drug treatment or light stimulation showed no fear response in a novel context. (Still, in a familiar context, their fear relapse could not be prevented.)

? The present study has proved that fear renewal in a novel context requires the activation of the PPC. The findings also suggest that, among regions of the cerebral cortex that perform high-level cognitive tasks (e.g. perception, thinking and memorizing), the PPC plays a crucial role in spatial reasoning and decision-making.

Dr. Ja Wook Koo and Dr. Sukwon Lee of KBRI stated that the research team "discovered a new role for the PPC that had previously not been fully understood" and that they hoped to "help researchers develop treatment strategies needed to prevent fear renewal from occurring in patients with PTSD and fear-related disorders."

In 2016, KBRI established the Co-operative Cerebral Cortex Research Group to study the PPC of the cerebrum. This group has been researching animal models associated with socialization and cognitive behavior, and aims to complete, by 2026, the creation of a PPC-centered functional brain map.

Researchers working towards understanding the brain in high-definition, single-cell level of detail have designed a new computer program to identify each nerve cell in fluorescent microscope images of living worms. Previous attempts to automate the identification of individual nerve cells have been thwarted by the fact that the same cell can be in vastly different locations in different worms.

The worms are C. elegans, tiny roundworms common in soil and research labs around the world. Each of the 959 cells in the animals' transparent, 1 millimeter-long bodies has been identified, named and mapped, including their 302 nerve cells.

Scientists completed the first map of the C. elegans nervous system in 1986 and have been improving it ever since. More recent projects include OpenWorm, an ongoing global effort to design a cell-by-cell and behaviorally accurate virtual C. elegans - a research-worthy version of a Tamagotchi pet.

Despite their value, generalized brain atlases, so-called connectome maps, are still no help for identifying neurons in individual, live, wriggling worms.

"Imagine if you knew the names of all the cities on a map, but the cities moved each time you looked. That is what it's like, trying to compare current brain atlases to living organisms," said Professor Yuichi Iino from the University of Tokyo, co-last author of the recent research paper published in BMC Biology.

Iino's research group wants to identify and map each nerve cell in living C. elegans so that they can chart the pathways of electrical impulses that make behaviors, learning and memory possible.

C. elegans brain neurons are not trapped in a skull, but just form a loosely packed group of 150 neurons in the head region of the animal.

"The neurons are tiny, and in the head of C. elegans they are surrounding this large bulb that's part of the digestive system, so they get pushed and pulled around a lot as the animal moves or eats," explained Iino.

Researchers began by finding unique combinations of genes that, when artificially attached to fluorescent protein tags, would cause 35 different small groups of neurons to glow under a microscope.

These new genetically modified strains of C. elegans made all of the researchers' subsequent image studies and computer programming work possible.

Researchers identified individual neurons in 311 worms in total, about 10 worms for each of the 35 neuron groups, and measured the distances and relative positions between pairs of neurons in the microscopy images.

Although neurons were known to shift within each worm, no one expected the neurons to have different "home base" locations in different individuals. The positions of the central cell body of some neurons can vary by more than 0.02 millimeter between different animals, a significant distance for an animal only 1-millimeter long.

"Individual C. elegans are thought to be uniform because they all have almost the same cell lineages and a stereotyped neural circuit. It was really surprising, though, how large the positional differences are between individual animals," said Assistant Professor Yu Toyoshima, a co-first author of the recent research paper and member of the Iino lab.

The research team then used their new position variation data and the C. elegans connectome brain atlas to develop a computer program to automatically identify neurons. The program uses a mathematical algorithm to analyze a microscopy image of the C. elegans brain and assign the statistically most likely identity to each neuron based on that neuron's position in relation to other neurons.

"The algorithm is only 60 percent accurate, which is too low for fully automatic cell identification, but it speeds up our work enough to make other projects possible to understand neural networks based on whole-brain imaging data," said Toyoshima.

Part of what made this project possible in C. elegans is that every neuron was already known and named. Using a similar technique in other animals would require fine-tuned genetic manipulation to cause groups of neurons to glow under a microscope and knowing how many neurons need to be identified.

"The human brain has billions of neurons, so understanding our own brains at the single-cell level would be extremely difficult. C. elegans have small brains, but they can still learn and change behaviors, so they could allow us to understand how networks of neurons create behavior," said Iino.

Negligence claims against the NHS due to failure to inform patients before they consent to procedures have spiralled up since a landmark legal ruling in 2015, a new study has found.

The research, conducted by Queen Mary University of London, found that while the rate of increase of other claims has remained steady, cases relating to consent have risen fourfold overall since March 2015 - and where failure to inform was added as a contributory claim, the rise was nearly ten-fold.

The change follows a landmark Supreme Court judgement - known as Montgomery - that changed the legal test for determining what is sufficient disclosure before consent is given to treatment, by moving away from asking what a reasonable doctor would warn about and asking instead what a reasonable patient would expect to know.

Study lead, David Wald, Professor of Cardiology at Queen Mary University of London, says: "Although the Supreme Court case in 2015 was reasonable in overturning the judgement in favour of the claimant, Nadine Montgomery, our research shows that the broader implications of the ruling have had serious, unintended consequences for the NHS. By blurring the requirements for what doctors should tell patients and changing how negligence is determined, it has made it harder for hospitals to defend allegations of failing to properly inform patients before consent. The Supreme court believed their ruling would reduce litigation but the opposite has happened."

The team obtained the data through a Freedom of Information request on the claims settled by the NHS between 2005 and 2019. Of 70,000 cases, just over 2300 were linked to failure to inform, with a total value of nearly £400m. For some of these cases, failure to inform was the primary claim against the NHS. For others, it was a secondary claim - an extra claim added and unrelated to the primary reason for litigation.

Although failure to inform cases are a small percentage of overall claims against the NHS, they still have substantial - and rising - financial implications. The researchers found that between 2011 and 2015, costs for settling these types of cases rose from £25m per year to £28m per year. From 2015 to 2019 costs rose to £62m per year. The rise was purely due to the increase in numbers of claims, as the cost per claim remained steady.

"Claims involving failure to inform are normally invisible in the overall numbers of negligence claims, but the rise we've identified is striking and shows no sign of stopping," says Professor Wald. "The data support concerns that lawyers are adding consent-related claims to other allegations which on their own may not be successful in court. The Montgomery ruling now makes these cases much easier to win, and the NHS is paying the bill."

Professor Wald believes that there's an urgent need for hospitals to improve communication before consent - and for lawmakers to consider revising the legal framework to provide a fairer and less costly system.

"One of the problems for the NHS is the subjectivity of determining exactly what constitutes a material risk to a patient," he says. "This may differ considerably between patients undergoing the same procedure, based on lifestyles and hobbies which may not always be disclosed to doctors in the discussion before consent."

The researchers highlight the need to consider alternative legal frameworks for failure to inform cases, such as the no-fault compensation scheme that exists in New Zealand or the UK Criminal Injuries Compensation Authority Scheme. This would mean patients wouldn't need to bring legal claims to get compensation in the event of a complication. The study found that lawyers' fees accounted for about 40 per cent (£155million) of costs paid by the NHS in settled claims due to failure to inform.

Professor Wald believes the NHS can do more to improve the situation for both clinicians and patients. He has developed multilingual animations for medical and surgical procedures which are made available to patients to give them time to consider the benefits, risks and alternatives and prepare any questions prior to treatment, to support the discussion before consent (see http://www.explainmyprocedure.com).

"Seeking consent is often rushed and people may not speak English fluently," says Professor Wald. "Patients can feel under pressure to go ahead with treatment without really feeling in control of the decision. Improving communication before consent and making better use of the time available, helps doctors focus on what matters to patients and helps patients take responsibility for the ultimate choice."

An investigation by The BMJ has uncovered links between groups and individuals campaigning for wider access to cannabis for medical reasons and those pushing for the legalisation of cannabis for recreational use.

It also explores how a research collaboration that includes Oxford University is taking funding from the tobacco industry for research into the medicinal properties of cannabis.

In a two-part special report, investigative journalist Jonathan Gornall asks if industry support for wider patient access is motivated by promises of a lucrative recreational market for the drug in the UK.

By 2024, the UK's medicinal cannabis market is predicted to be worth nearly $1.3bn, while the recreational market is estimated to be even greater - roughly $1.7bn.

In the first part, Gornall focuses on the links between commercial organisations who are seeking new markets for recreational cannabis and patient groups and individuals lobbying for wider patient access to cannabis for medical use.

For example, he describes the case of Billy Caldwell, a boy with severe epilepsy, who made headlines after his mother Charlotte flew to Canada to get cannabis oil for her son, which was seized at customs on her return.

Steve Moore, former CEO of David Cameron's Big Society initiative, helped to organise Charlotte Caldwell's trip and promote her cause.

But Moore's interest in cannabis is not limited to the drug's medicinal use, writes Gornall.

Moore is strategic counsel for the Centre for Medicinal Cannabis, an industry body for businesses and investors in cannabis medicinal products, and co-founder and strategic counsel of Volteface, an advocacy group set up in 2017 to lobby for legalisation of cannabis for recreational use.

Moore is also strategic counsel for another trade body, the Centre for Medicinal Cannabis, whose members include the Canadian based Supreme Cannabis Company, which has invested in several cannabis brands in Canada and Europe.

Ian Gilmore, director of the Liverpool Centre for Alcohol Research and chair of Alcohol Health Alliance UK, told The BMJ that he is sympathetic to patients who feel that cannabis and its extracts are useful for their medical condition and are frustrated that it is not legally available to them.

But, he says: "We must not drift into the situation we found ourselves in with tobacco and alcohol, where global companies seeking to maximise their markets distorted the arguments, often through third parties. We must protect patients from having groups with conflicts of interest building up unrealistic hopes."

Stephen Murray, executive director of Prohibition Partners, a UK private investment group "with a mission to make cannabis more accessible and acceptable" told The BMJ that the debate about the medical use of cannabis was "normalising the conversation around cannabis, bringing it into social circles where it wouldn't have been debated previously," and that major corporate investors were becoming increasingly interested in the broad range of cannabis opportunities.

But psychiatrist Marta Di Forti, a member of the government taskforce appointed to review evidence for the safety and efficacy of cannabis for the treatment of pain, which is due to report this spring, is concerned about the engagement of cannabis companies with patient groups and the "big jump" that medicinal cannabis should be made more widely available to treat a range of conditions for which evidence was still lacking.

In the second part of his investigation, Gornall looks at the involvement of the tobacco industry in funding research into medicinal cannabis, and the complex web of connections linked to both medicinal and recreational use of cannabis.

He describes Gavin Sathianathan as "typical of the new breed of cannabis entrepreneur."

He is founder and main shareholder of Alta Flora, a private limited London based company specialising in "wellness products from natural sources."

He is also a trustee of the United Patients Alliance (UPA), a patient led medical cannabis support group, chief executive of cannabis investment fund, Forma Holdings, and a co-founder and director of Oxford Cannabinoid Technologies, part of a research collaboration that includes Oxford University.

Funders of Oxford Cannabinoid Technologies include Casa Verde Capital, a US venture capital firm co-founded in 2015 by Snoop Dogg, the US rap artist and high profile exponent of recreational cannabis use, and tobacco company Imperial Brands (formerly Imperial Tobacco).

A spokesperson for Oxford Cannabinoid Technologies told The BMJ that the company "would not look to enter the recreational market" should restrictions in the UK be eased and added that Imperial's investment was "modest and represents a small percentage of the total value of OCT."

But Marta Di Forti called for more independent funding for cannabis research. "It is always very dangerous to forget history and we are now seeing the sort of connections that we have seen happening before," she said - and the involvement of tobacco company Imperial was "dreadful and shocking."

"We are lacking in funding for cannabis research from independent organisations such as the Wellcome Trust or the Medical Research Council. The result will be that more and more you are going to see even prestigious and reputable academic institutions accepting money from some of these companies."

Findings from a phase 2 clinical trial show that the drug selumetinib improves outcomes for children with the genetic disorder neurofibromatosis type 1 (NF1). In the trial, selumetinib shrank the inoperable tumors that develop with NF1 called plexiform neurofibromas, and children experienced reduced pain, improved function, and better overall quality of life after receiving the treatment.

The trial was led by intramural researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health. Results of the trial were published March 18, 2020, in the New England Journal of Medicine.

"Until now, no effective medical therapies have existed for children with NF1 and plexiform neurofibromas, and it's been a long journey to find a drug that can help them," said Brigitte Widemann, M.D., lead author of the study, and chief of CCR's Pediatric Oncology Branch, which developed and coordinated the trial. "While this is not yet a cure, this treatment is shrinking tumors and it's making children feel better and have a better quality of life."

The trial was sponsored by the NCI Cancer Therapy Evaluation Program (CTEP) and conducted by the NIH intramural program. Drugmaker AstraZeneca provided the study drug under a Cooperative Research and Development Agreement with NCI and supported correlated studies that were part of the trial. The company worked closely with the researchers on the New Drug Application to gather the data that has been submitted by the company to the U.S. Food and Drug Administration (FDA). In addition, the Neurofibromatosis Therapeutic Acceleration Program (NTAP) provided funding to support patient enrollment at participating sites.

The trial enrolled 50 children ages 3 to 17 years with NF1-related plexiform neurofibromas in 2015 and 2016. The most common symptoms from the tumors were disfigurement, limitations on strength and range of motion, and pain. The children received selumetinib orally twice a day in 28-day cycles continuously, and assessments were performed at least every four cycles. The researchers used a novel approach to assess outcomes tailored to each patient's specific tumor-related symptoms, something no prior clinical trial directed at NF1 neurofibromas had done before.

As of March 2019, 35 children, or 70%, had a confirmed partial response (? 20% volumetric tumor shrinkage), and most of them maintained that response for more than a year. After a year on the treatment, children and parents reported lower levels of pain and clinically meaningful improvement in interference of pain in daily function, overall quality of life, strength, and range of motion.

"One of the most surprising findings of this trial was the impact the treatment had on pain," said Andrea M. Gross, M.D., of CCR, first author of the study. "It even helped patients who had been living with chronic, debilitating pain come off pain medications, which was not something we anticipated. So that was a really exciting finding."

Five children stopped receiving selumetinib because of side effects possibly related to the drug, and six children had disease progression. The most frequent side effects included nausea and vomiting, diarrhea, and rashes.

The new study confirmed results of an earlier phase 1 trial that demonstrated for the first time that the drug could shrink large tumors. Dr. Widemann and her team have been studying selumetinib for NF1 since 2011. The drug works by blocking a protein called MEK that is part of the RAS signaling pathway, which is overly active in patients with NF1, leading to the growth of tumors. FDA granted orphan drug designation to selumetinib for the treatment of NF1 in 2018, and in 2019, the drug received FDA breakthrough therapy designation.

Plexiform neurofibromas have proven hard to treat. The tumors can grow quickly and become very large--up to 20% of a child's body weight. Surgery to remove the tumors is often not feasible because the tumors can be intertwined with healthy nerves and tissue. Tumors that have been partially removed by surgery also tend to grow back, especially in young children.

Dr. Widemann had been doing trials with different medications for NF1 since 2001 and was excited when she saw the first tumors shrink. She and her team are grateful to the many different groups and programs that have worked together to reach this point, including the NCI intramural and extramural programs, NTAP, and the Children's Tumor Foundation, all of which she said made this work possible. Most of all, however, the researchers want to thank the children and families who participated in the trial.

"There's a lot more to be done. Even though these children have tumor shrinkage, many still have disabling tumors," Dr. Widemann said. "But these findings are a big step forward and inspire us to work even harder towards additional progress in NF1 therapies."

The trial was conducted at the NIH Clinical Center in Bethesda, Maryland, as well as three participating sites: Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, and Children's National Hospital in Washington, D.C. Both the Children's Hospital of Philadelphia and Cincinnati Children's Hospital received additional funding for the trial from NTAP.

Scientists using sophisticated genetic analysis techniques have found that some fish are better than others at coping with heatwaves.

A world-first study tracked how wild fish populations responded to a severe marine heatwave, focussing on the 2016 event that killed a third of the Great Barrier Reef corals.

"Our study shows that reef fishes are directly affected by heatwaves, but their responses vary greatly between species," said co-author Dr Jodie Rummer, Associate Professor from the ARC Centre of Excellence for Coral Reef Studies at James Cook University (Coral CoE at JCU).

Dr Rummer was part of an international team that tracked changes in the expression of thousands of different genes in five species of coral reef fishes collected at different time points before, during, and after the 2016 heatwave.

"Changes in gene expression can tell us how an animal responds physiologically to an environmental shock, such as a heatwave," said one of the co-lead authors, Dr Celia Schunter from the University of Hong Kong.

Regulating gene expression is critical to an organism's performance and survival.

It is analysed by tracking RNA, which is responsible for converting the genetic information in DNA into a format used to build proteins.

Essentially, RNA controls when proteins are made and in what amount, dictating how cells will function. This can give us clues of how an organism is responding.

The scientists identified species-specific responses to the heightened temperatures, with some fish struggling more than others.

"Spiny damselfish responded to the warmer conditions with changes in the expression of thousands of genes, suggesting it is particularly sensitive to heatwaves," said co-lead author Dr Moisés Bernal, Assistant Professor at Auburn University. "Other species appear to be more tolerant, with fewer changes in gene expression."

The results also suggest that fish populations are influenced by both the intensity of a heatwave and how long it lasts.

"Marine heatwaves are becoming more frequent, more severe, and are further exacerbated by climate change," Dr Rummer said.

"We found the physiological mechanisms the fish used to cope with the warmer waters changed as the heatwave progressed," she said.

The study provides a possible approach for predicting which fish species are most at risk under repeated heatwave conditions, said co-author Professor Timothy Ravasi, from the Marine Climate Change Unit at the Okinawa Institute of Science and Technology Graduate University (OIST).

"Our results are important because they show that when scientists do experiments, or target commercial species, they cannot generalise based on geography or from one or two species that have been studied in the laboratory," he said.

"This has ramifications for policy makers and for the fishing industry, because not all species will be equally affected. We need to screen a large number of species to predict which will be sensitive and which will be more tolerant to warming waters and heatwaves."

"Over time, the fish may adapt to rising temperatures, or even migrate to cooler waters," Dr Rummer said.

"But these heatwaves are happening now, and it's necessary to understand and consider the immediate consequences."

A puzzling modification of DNA that is common in bacteria is not present in humans or other mammals. This has been shown in a new study by scientists at Linköping University in Sweden, published in Science Advances. The study shows that detection of the epigenetic mark 6mdA in animals was probably the result of limitations of the technology used and bacterial contamination of samples.

A few years ago, some studies were published that aroused considerable interest among researchers in genetics. These studies had examined a particular epigenetic mark, or modification of the DNA that influences how the DNA sequence is used in different cells. This mark had not previously been observed in multicellular organisms. The mark, known as "6mdA", is, in contrast, common in bacteria, where it plays an important role in protecting the bacteria against viruses. Reports from numerous research groups stating that they had found 6mdA in various animal species, and even in human cells, stimulated not only major interest among the research community, but also some questions. One of these concerned the levels of 6mdA detected, which were so low that scientists wondered whether such a rare epigenetic signal could truly have a function. Following these initial reports, some other published studies were unable to detect 6mdA in animals.

Just as many other research groups, Colm Nestor's group at Linköping University started to study this puzzling epigenetic signal. They were, however, unable to detect it in human or mouse cells. Eventually, they detected 6mdA in two samples of human cells, but it turned out that both of the samples were contaminated with mycoplasma bacteria. The researchers suspected that the epigenetic mark came from the bacteria and not the human cells. They treated the cells with antibiotics against mycoplasma and saw the 6mdA signal disappear.

The LiU researchers believe that contamination with mycoplasma bacteria is an underestimated problem in epigenetic research. The particular strain of mycoplasma they found is common in healthy people and typically does not cause any negative health effects. Since mycoplasma bacteria can exist not only outside cells but also inside cells in the body, it may be that this bacterium is present, but undetected, in human samples. For most types of bacteria, researchers can easily detect if cells cultured in the laboratory are contaminated. However, this is not the case for mycoplasma contamination, which requires special testing.

The LiU researchers soon discovered that it is not only mycoplasma bacteria that cause problems for researchers studying the 6mdA mark. They also found problems with several methods used to detect this epigenetic modification.

"We realised that the 6mdA 'signals' detected by these techniques were simply noise. However, as a consequence of several complex technical problems the background noise in several of the methods was not random, but appeared to be a true signal. Now we can say without a doubt that 6mdA is not present in mammals", says Colm Nestor, research fellow in the Department of Biomedical and Clinical Sciences at Linköping University, and leader of the study.

Colm Nestor maintains that the reports of 6mdA in mammals are from well-executed studies published in reputable scientific journals. It is extremely unusual that several methods give similar misleading results as a result of completely different artefacts.

"When we analyse very rare phenomena, we must be extremely careful and consider whether we truly can measure them using the methods we have chosen. With respect to 6mdA, a lot of time and money can be saved, and a lot of disappointment avoided, if researchers stop studying something that is simply not there", says Colm Nestor.

WASHINGTON, DC--A groundbreaking study by Resources for the Future (RFF) researchers, to be published in Science Advances March 18, 2020 at 2:00 pm EDT, shows that national monuments have had mostly positive effects on local economies in the American West.

Study authors Margaret Walls, Patrick Lee, and Matthew Ashenfarb highlighted the following key findings:

After the monuments were designated, the number of nearby business establishments and jobs increased by an average of 10 percent and 8 percent, respectively, compared to "control" areas.

The boost in businesses and jobs was detected in several service industries, including business services and financial services, as well as the construction industry.

Natural resource industries that rely on public lands--mining, forestry, and livestock grazing--showed no effect, positive or negative, from the designations. Average wage incomes in areas near monuments were also unaffected.

Monument detractors often argue that protecting public lands harms local communities by restricting extractive industries and by replacing high-income jobs with low-income ones. The study finds strong evidence to suggest otherwise.

The study examined 14 monuments--protected public lands that contain historic landmarks, historic and prehistoric structures, or objects of historic or scientific interest--established in the eight Mountain West states since 1990. Using a unique set of data and state-of-the-art statistical methods, the authors determined how the monument designations affected nearby jobs, wage income, businesses, and industries. A new article in Resources magazine provides an accessible overview of the study and findings.

"Rural communities in the US are changing and their economies transitioning away from a reliance on resource-dependent industries," the authors state. "Our results suggest that protecting some of these public lands as national monuments does not exacerbate these trends, but rather could even be reversing them and creating a new set of economic forces oriented around the historic, cultural, and scenic amenities these public lands provide."

A recent study in mice led a team of researchers in Japan to believe that psychosis may be caused by problems with specialized nerve cells deep within the brain, as well as a certain kind of learning behavior. The researchers hope this could provide insight into the emergence of delusions in patients with psychosis or schizophrenia with the aim of finding ways to help them.

Psychosis is a debilitating psychological condition with a long history. Described in the medical writings of Hippocrates as early as the 4th century B.C., the psychotic state of hallucinations, delusions and disordered thought represent an existential threat to an afflicted human mind. Now, a team of researchers from the International Research Center for Neurointelligence (IRCN) and the Graduate School of Medicine at the University of Tokyo, and the Graduate School of Informatics at Kyoto University, proposes that psychosis involves defective neural signaling in a deep brain area called the ventral striatum during a behavior called discrimination learning.

Led by Lecturer Sho Yagishita and Professor Haruo Kasai, the researchers studied the way mice predict future rewards in their environment, a behavior known as reward learning, which is shared by us humans and other mammals, too. Reward learning involves the release of a chemical messenger dopamine to a receptor protein in the brain called dopamine D1 receptor (D1R) to signal the anticipation of a reward. Specifically, the team searched for a second dopamine signal that occurs only when the anticipated reward fails to materialize -- reward omission.

The researchers suspected this signal for reward omission existed in neurons of the ventral striatum area of the brain that contain a counterpart to D1R, dopamine D2 receptor (D2R). Coincidentally, D2R is the major brain receptor for nearly every antipsychotic medication used to date. The team showed that reward omission triggers a signal in these neurons called the dopamine dip, a drop in dopamine levels, which lasts less than a second.

These dips seem to contribute to the process of discrimination learning, which includes how all animals, including humans, judge previously learned rewards and punishments. To explore the connection between dips and discrimination learning, the researchers used sophisticated optogenetic technologies to artificially increase or decrease the dips for the first time and measured their effects on how the mice estimated rewards. Optogenetics is a way to activate artificial light-sensitive proteins with finely controlled laser light to turn neuronal activity on or off.

"We initially observed that dips caused certain synaptic structures called spines to expand and send signals within D2R neurons," said Yagishita. "We searched for several years before we discovered that discrimination learning was the cognitive process that refines reward learning following dopamine dips."

To establish a link to psychosis, the authors administered a well-known psychosis-inducing drug, methamphetamine, and showed that both discrimination learning and dopamine dips were impaired. As a result, mice showed exaggerated behavioral and dopamine responses even when no reward was presented, as is the case in human psychosis. These deficits could be prevented with an antipsychotic compound that blocks D2R activity.

"If D2R signaling and discrimination learning is impaired, subjects may be unable to assign an appropriate significance to objects or people in their environment, and their fears or insecurities may fill in the gap," said Yagishita. "For example, persecutory delusions arise from mistakenly assigning malevolent intent to strangers who pose no threat."

The authors propose that these findings open a previously unknown window into psychosis. Their data show that an antipsychotic D2R drug can reverse effects of a psychosis-inducing one by specifically restoring the dopamine dips and discrimination learning to normal levels. Their hypothesis is that an impairment in discrimination learning can result in an inability to predict the environment accurately, leading to overt symptoms of psychosis or schizophrenia.

"The brain seems to have an intrinsic capacity for fantasy or delusional thinking, but there are built-in controls like D2R discrimination learning that help us to correct our misjudgments," commented Kasai. "Our study raises the possibility that when these corrective controls break down, we can risk losing contact with reality and may enter a downward spiral of pathology."

Looking ahead, Kasai concluded, "We hope to build a general learning model to accommodate clinical disorders of cognition that can also lead to new principles for next-generation AI (artificial intelligence)."

This research is a peer-reviewed experimental study in mice.

The oldest fossil of a modern bird yet found, dating from the age of dinosaurs, has been identified by an international team of palaeontologists.

The spectacular fossil, affectionately nicknamed the 'Wonderchicken', includes a nearly complete skull, hidden inside nondescript pieces of rock, and dates from less than one million years before the asteroid impact which eliminated all large dinosaurs.

Writing in the journal Nature, the team, led by the University of Cambridge, believe the new fossil helps clarify why birds survived the mass extinction event at the end of the Cretaceous period, while the giant dinosaurs did not.

Detailed analysis of the skull shows that it combines many features common to modern chicken- and duck-like birds, suggesting that the 'Wonderchicken' is close to the last common ancestor of modern chickens and ducks. The fossil was found in a limestone quarry near the Belgian-Dutch border, making it the first modern bird from the age of dinosaurs found in the northern hemisphere.

The fossil doesn't look like much on first glance, with only a few small leg bone fragments poking out from a piece of rock the size of a deck of cards. Even those small bones attracted the researchers' interest, since bird fossils from this point in Earth's history are so rare.

Using high-resolution X-ray CT scans, the researchers peered through the rock to see what was lying beneath the surface. What they saw, just one millimetre beneath the rock, was the find of a lifetime: a nearly complete 66.7-million-year-old bird skull.

"The moment I first saw what was beneath the rock was the most exciting moment of my scientific career," said Dr Daniel Field from Cambridge's Department of Earth Sciences, who led the research. "This is one of the best-preserved fossil bird skulls of any age, from anywhere in the world. We almost had to pinch ourselves when we saw it, knowing that it was from such an important time in Earth's history.

"The ability to CT scan fossils, like we can at the Cambridge Biotomography Centre, has completely transformed how we study palaeontology in the 21st century."

"Finding the skull blew my mind," said co-author Juan Benito, also from Cambridge, who was CT scanning the fossils with Field when the skull was discovered. "Without these cutting-edge scans, we never would have known that we were holding the oldest modern bird skull in the world."

The skull, despite its age, is clearly recognisable as a modern bird. It combines many features common to the group that includes living chickens and ducks - a group called Galloanserae. Field describes the skull as a kind of 'mash-up' of a chicken and a duck.

"The origins of living bird diversity are shrouded in mystery -- other than knowing that modern birds arose at some point towards the end of the age of dinosaurs, we have very little fossil evidence of them until after the asteroid hit," said co-author Albert Chen, a PhD student based at Cambridge. "This fossil provides our earliest direct glimpse of what modern birds were like during the initial stages of their evolutionary history."

While the fossil is colloquially known as the Wonderchicken, the researchers have given it the slightly more elegant name of Asteriornis, in reference to Asteria, the Greek Titan goddess of falling stars.

"We thought it was an appropriate name for a creature that lived just before the end-Cretaceous asteroid impact," said co-author Dr Daniel Ksepka from the Bruce Museum in Greenwich, Connecticut. "In Greek mythology, Asteria transforms herself into a quail, and we believe Asteriornis was close to the common ancestor that today includes quails, as well as chickens and ducks."

The fact that Asteriornis was found in Europe is another thing which makes it so extraordinary. "The late Cretaceous fossil record of birds from Europe is extremely sparse," said co-author Dr John Jagt from the Natuurhistorische Museum Maastricht in the Netherlands. "The discovery of Asteriornis provides some of the first evidence that Europe was a key area in the early evolutionary history of modern birds."

"This fossil tells us that early on, at least some modern birds were fairly small-bodied, ground-dwelling birds that lived near the seashore," said Field. "Asteriornis now gives us a search image for future fossil discoveries -- hopefully it ushers in a new era of fossil finds that help clarify how, when and where modern birds first evolved."

The announcement of the Wonderchicken find coincides with a new exhibit at Cambridge's Sedgwick Museum of Earth Sciences, where visitors can learn more about Asteriornis and see the fossil up close. "Dawn of the Wonderchicken" runs from 19 March to 15 June. Admission is free.

Dr Daniel Field is funded by a UKRI Future Leaders Fellowship. He is a University Lecturer in the Department of Earth Sciences at the University of Cambridge, and a Fellow of Christ's College Cambridge.

Two new studies from Karolinska Institutet in Sweden underscore health risks associated with childhood obesity. Children with obesity have a three times higher risk of mortality in early adulthood compared with children in the general population and are more likely to suffer from anxiety and depression. The findings, published in PLOS Medicine and BMC Medicine, highlight the need to identify specific risk factors for children with obesity and find preventative tools, according to the researchers.

The prevalence of children with obesity has increased in recent decades and the World Health Organization currently ranks childhood obesity as one of the most serious public health challenges of the 21st century. Prior studies have linked childhood obesity with an increased risk of premature mortality from middle adulthood.

In the current studies, the researchers wanted to find out if children with obesity also have a higher risk of premature death in early adulthood as well as if children with obesity are more likely to suffer from anxiety and depression than other children.

In the study published today in PLOS Medicine, the researchers showed that people with obesity in childhood have a three times higher risk of dying in early adulthood than a comparison group from the general population. The study included about 7,000 individuals who received obesity treatment at some point between the ages of 3 and 17. They were matched with some 34,000 people of the same age, gender and area of residence. A total of 39 people (0.55 percent) in the childhood obesity group died during the average follow-up period of 3.6 years compared with 65 (0.19 percent) in the control group. The average age at the time of death was 22 years.

"Our study shows that children with obesity have a significantly higher risk of premature mortality already as young adults," says Emilia Hagman, researcher at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and one of the study's authors. "Both the risk of death from somatic diseases, of which more than a quarter were directly related to obesity, and the risk of suicide were increased for this group. We did not, however, see an increased risk of mortality from injuries or external causes such as criminal acts."

Possible explanations for the findings may be that childhood obesity has been linked to somatic diseases such as diabetes, liver disease and high blood pressure. Children and adolescents with obesity are also more exposed to discrimination, which could lead to psychological problems. However, the underlying causality between the associations will need to be evaluated in future studies, according to the researchers.

Another study by the same research group recently published in BMC Medicine found that obesity was linked to an increased risk of anxiety and depression in children and adolescents. Girls with obesity had a 43 percent higher risk of anxiety and depression than girls from the general population while boys with obesity had a 33 percent higher risk than their peers. The study included more than 12,000 children between the ages of 6-17 who were treated for obesity and compared with a matched group of 60,000 children from the general population. The associations remained after the researchers adjusted for other risk factors such as Nordic background, neuropsychiatric disorders, family history of anxiety or depression and socioeconomic status.

"Taken together our studies highlight the vulnerable situation that children with obesity are in," says Louise Lindberg, researcher at the Department of Clinical Science, Intervention and Technology and another of the study's authors. "Anxiety and depression cause emotional and physiological stress and suffering and may also hinder obesity treatment. It is important that children with obesity are offered adequate and long-term treatment early in life to reduce these risks. It is deeply unethical that children with obesity do not receive any form of treatment in some regions in Sweden."