Culture

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."

National monuments in the U.S. West increase the average number of establishments and jobs near the monument and increase the average establishment growth rate, according to a new study by Margaret Walls and colleagues. At the same time, monument designation has no effect on the number of jobs that existed before the monument, and has no effect on mining, forestry and other traditional industries that use public lands. The findings suggest that fears of local economic restriction after a national monument designation are unwarranted. It's an issue that came to light most recently in 2017, when U.S. President Donald Trump decreased the size of two Utah national monuments by more than 2 million acres. National monuments in the U.S. are protected lands that contain prehistoric, historic, scientific or cultural structures or objects of interest, and usually contain little developed infrastructure after monument designation. Walls et al. reviewed data on all business establishments within 25 kilometers (about 15.5 miles) in eight states in the U.S. Mountain West before and after designation of 14 monuments between 1900 and 2015. They then compared these data with nearby "control" communities outside the 25-kilometer zone. Monument designation appears to help more than hurt local economies, the researchers conclude. At the same time, these protected public lands provide a variety of other societal benefits from wildlife habitat to carbon sequestration.

MINNEAPOLIS - Children and teens with family members with amyotrophic lateral sclerosis, or ALS, help with bathing, dressing, eating and all types of caregiving activities, yet they may not have training or enough information about the disease, according to a study published in the March 18, 2020, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study found that children and teens age 8 to 18 spent an average of five hours per day providing care for their family member, handling an average of 12 tasks, such as helping take medication, helping get in and out of bed and cooking meals.

"With ALS, a fatal disease where people rapidly lose their ability to care for themselves, caregiving can be intense and demanding for adults, yet little attention has been paid to children and youth who are serving as caregivers," said study author Melinda S. Kavanaugh, PhD, of the University of Wisconsin-Milwaukee. "Our study found that youth are intricately involved in all areas of caregiving. They feel isolated and have little training or guidance in their care. Yet, they found ways to manage their care burden and said that helping made them feel good about themselves."

For the study, researchers used an online survey sent out through chapters of the ALS Association to identify people with ALS who had children living with them. Researchers then conducted phone interviews with the children.

A total of 38 children and teens who provide care for a family member with ALS were included in the study. The majority were providing care for a parent; 18 percent were helping with a grandparent, aunt or cousin.

The majority of the adults said they relied on children for help with care due to cost and inability to pay for outside help.

Adults and youth expressed both positive and negative feelings about the care, with adults saying they appreciate the care and are grateful, but some also felt sad or "a burden." Most of the youth said that providing care made them feel good about themselves, but also that they felt guilty when they were not helping.

Of the youth, 68% said they needed more information about ALS, 50% said they wanted to connect with other people their age to talk about ALS, 50% said it was difficult to explain ALS to their friends and 39% said they had concerns about talking about ALS with other family members.

The majority of youth said they participated in activities to help them deal with being a caregiver, such as being active, playing video games or talking with friends.

"These results really highlight the need for training and support for these young caregivers," Kavanaugh said. "Health care providers need to start asking if children are helping with care and provide them with information and access to opportunities for respite and other care services."

In addition to its small size, a limitation of the study was that all families were connected to chapters of the ALS Association, so they may be different than others who do not have access to services through the organization. Also, the majority of participants were white people, so the results may not represent other groups. Kavanaugh noted that it's possible that adults were in the room when the youth were completing the phone interview, which may have influenced their responses.

For women being treated for infertility, studies show that in-person counseling decreases anxiety, depression and stress and leads to higher rates of pregnancy.

But for a variety of reasons -- including stigma, skepticism about efficacy, cost, travel challenges and difficulty scheduling appointments -- many women in treatment don't seek additional psychological help and often give up on their dream of having a child.

In a study published March 18 in PLOS ONE, researchers at the University of Vermont demonstrated that an internet version of a highly respected clinical program achieved results similar to its in-person equivalent, both in reducing distress and in promoting pregnancy.

Women experiencing infertility issues who took the online program -- the Mind/Body Program for Fertility, developed at the Domar Center at Harvard -- experienced medium to large decreases in depression and anxiety and in stress related to sexual and social concerns, compared with a control group, and were two-and-a-half times more likely to become pregnant.

The results are comparable to studies gauging the impact of the in-person version of the Mind/Body Program.

"Offering this highly effective program online removes the barriers to counseling that prevent so many women in fertility treatment from getting the help they need," said the study's lead author, Jessica Clifton, a faculty scientist at the University of Vermont.

"It could enable women across the country, no matter where they live or what their circumstances, to reduce their distress and increase their chances of conceiving."

Clifton and her colleagues at the University of Vermont developed the online version of the Mind/Body Program over a three-year period in collaboration with the program's founder and director, Alice Domar, associate professor of Obstetrics, Gynecology and Reproductive Biology at the Harvard Medical School. Domar is a co-author of the PLOS ONE study.

The online program mirrors the in-person version, offering ten hour-long modules of instruction that include video, audio and text. Materials cover the relationship between stress, lifestyle and fertility; relaxation techniques, including diaphragmatic breathing and Hatha Yoga; mindfulness; cognitive/behavioral therapy; stress reduction strategies; listening and communication skills; strategies for emotional expression and effective coping with anger; and assertiveness training and goal-setting skills.

As with the in-person program, the online version also offers feedback from a trained therapist to participants' homework assignments. The therapist was available remotely as needed throughout the online program.

The study recruited 71 women who were experiencing infertility issues, about half took the online program right away while the other half were placed on a wait list.

Both groups took a pre- and post-assessment. Those taking the program right away reported measurable reductions in anxiety, depression and stress, while the control group reported a near-zero change. The self-reported pregnancy rate at the study's close was 53 percent for the group that took the program and 20 percent for the wait-list group. Women who took the online program also became pregnant more quickly compared to the wait-list group, in an average of 79 days compared with 97 days.

The study also demonstrated that women experiencing infertility were willing to take an online program and were largely satisfied with it, according the pre- and post-assessment.

"The results suggest we could change the way reproductive medicine is provided," Clifton said. "Medical practices could implement quick and easy screening to identify distressed patients. We could then offer a convenient, effective and affordable internet-based intervention for these patients that would measurably reduce their distress and help them achieve their dream of conceiving a child."

Brownian motion describes the random movement of particles in fluids, however, this revolutionary model only works when a fluid is static, or at equilibrium.

In real-life environments, fluids often contain particles that move by themselves, such as tiny swimming microorganisms. These self-propelled swimmers can cause movement or stirring in the fluid, which drives it away from equilibrium.

Experiments have shown that non-moving 'passive' particles can exhibit strange, loopy motions when interacting with 'active' fluids containing swimmers. Such movements do not fit with the conventional particle behaviours described by Brownian motion and so far, scientists have struggled to explain how such large-scale chaotic movements result from microscopic interactions between individual particles.

Now researchers from Queen Mary University of London, Tsukuba University, École Polytechnique Fédérale de Lausanne and Imperial College London, have presented a novel theory to explain observed particle movements in these dynamic environments.

They suggest the new model could also help make predictions about real-life behaviours in biological systems, such as the foraging patterns of swimming algae or bacteria.

Dr Adrian Baule, Senior Lecturer in Applied Mathematics at Queen Mary University of London, who managed the project, said: "Brownian motion is widely used to describe diffusion throughout physical, chemical and biological sciences; however it can't be used to describe the diffusion of particles in more active systems that we often observe in real life."

By explicitly solving the scattering dynamics between the passive particle and active swimmers in the fluid, the researchers were able to derive an effective model for particle motion in 'active' fluids, which accounts for all experimental observations.

Their extensive calculation reveals that the effective particle dynamics follow a so-called 'Lévy flight', which is widely used to describe 'extreme' movements in complex systems that are very far from typical behaviour, such as in ecological systems or earthquake dynamics.

Dr Kiyoshi Kanazawa from the University of Tsukuba, and first author of the study, said: "So far there has been no explanation how Lévy flights can actually occur based on microscopic interactions that obey physical laws. Our results show that Lévy flights can arise as a consequence of the hydrodynamic interactions between the active swimmers and the passive particle, which is very surprising."

The team found that the density of active swimmers also affected the duration of the Lévy flight regime, suggesting that swimming microorganisms could exploit the Lévy flights of nutrients to determine the best foraging strategies for different environments.

Dr Baule added: "Our results suggest optimal foraging strategies could depend on the density of particles within their environment. For example, at higher densities active searches by the forager could be a more successful approach, whereas at lower densities it might be advantageous for the forager to simply wait for a nutrient to come close as it is dragged by the other swimmers and explores larger regions of space.

"However, this work not only sheds light on how swimming microorganisms interact with passive particles, like nutrients or degraded plastic, but reveals more generally how randomness arises in an active non-equilibrium environment. This finding could help us to understand the behaviour of other systems that are driven away from equilibrium, which occur not only in physics and biology, but also in financial markets for example."

English botanist Robert Brown first described Brownian motion in 1827, when he observed the random movements displayed by pollen grains when added to water.

Decades later the famous physicist Albert Einstein developed the mathematical model to explain this behaviour, and in doing so proved the existence of atoms, laying the foundations for widespread applications in science and beyond.

Berkeley -- Like humans, cells can be easily influenced by peer pressure.

Take a neural stem cell in the brain: Whether this cell remains a stem cell or differentiates into a fully formed brain cell is ultimately determined by a complex set of molecular messages the cell receives from countless neighbors. Understanding these messages is key for scientists hoping to harness these stem cells to treat neurological conditions like Alzheimer's or Parkinson's.

With the help of photolithography and a creative use of programmable DNA, University of California, Berkeley, researchers have created a new technique that can rapidly "print" two-dimensional arrays of cells and proteins that mimic a wide variety of cellular environments in the body -- be it the brain tissue surrounding a neural stem cell, the lining of the intestine or liver or the cellular configuration inside a tumor.

This technique could help scientists develop a better understanding of the complex cell-to-cell messaging that dictates a cell's final fate, from neural stem cell differentiating into a brain cell to a tumor cell with the potential to metastasize to an embryonic stem cell becoming an organ cell.

"What's really powerful about this platform is you can create in vitro tissues that capture the spatial organization of cells in the body, from the intestinal lining of your digestive tract to the arrangements of different cell types in the liver," said Olivia Scheideler, who completed the research as a graduate student at Berkeley. "I think you could apply this technique to recreate any tissue where you want to explore how cellular interactions contribute to tissue function."

In a paper appearing today (Wednesday, March 18) in the journal Science Advances, Scheideler and her collaborators show that the new technique can be used to rapidly print intricate patterns of up to 10 different kinds cells or proteins onto a flat surface.

"Essentially, what this technique allows us to do is pattern different kinds of conditions in one shot and in a high-throughput manner," said Lydia Sohn, Chancellor's Professor of Mechanical Engineering at UC Berkeley and senior author of the paper. "It provides a whole range of options for what you could study, because it's so flexible. You can pattern many different kinds of cells or proteins."

Caught on a DNA tether

In the new technique, each cell or protein is tethered to a substrate with a short string of DNA. While similar methods have been developed that attach tethered cells or proteins one by one, the new technique takes advantage of a patterning process called photolithography to attach, or print, each type of cell protein in one quick batch, greatly speeding up the process.

"It's like color laser printing, where you print one color and then print another," Sohn said.

Like photography, photolithography works by exposing a coated surface or substrate to a pattern of light, which initiates a chemical reaction that dissolves the coating in the illuminated areas, leaving a templated substrate. In the new technique, the substrate is then bathed in strands of single-sided DNA, whose ends have been chemically altered to firmly latch on where the coating has been dissolved.

Each single-sided DNA strand is programmed have a specific sequence of the nucleotides adenine (A), thymine (T), guanine (G) and cytosine (C). Single-sided DNA strands with the complementary nucleotide sequence are embedded or attached to cells or proteins of interest.

Finally, the surface is washed with a mixture of cells or proteins attached to the complementary strands of single-sided DNA, which bond with the single-sided DNA already attached to the surface to form double-helix "tethers."

"All the cells and proteins attach exactly where they should be because of the DNA programming," Sohn said.

By repeating the process, up to 10 different kinds of cells or proteins can be tethered to the surface in an arbitrary pattern.

Conflicting messages

To demonstrate one of the many applications of the technique, Scheideler and co-author David Schaffer, Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering at UC Berkeley, used the platform to study the chemical signaling that cues neural stem cells to differentiate into mature cells.

"Stem cells have programs embedded inside their DNA that tell them (to) either stay a stem cell or to differentiate into a mature cell,'" Schaffer said. "And they receive a lot of information about what to do and which programs to activate from the environment, from other cells around them. If we could learn how to make stem cells do our bidding, how to turn them into a particular cell type, then we could harness the stem cells to mass produce specialized cell types that were lost due to disease or injury."

Neural stem cells in the brain regularly receive conflicting messages from their neighbors about how they should behave, Scheideler said. One messenger, the FGF-2 protein, tells them to make more stem cells. The other, the ephrin-B2 protein, tells them to differentiate into a mature neuron.

Scheideler used the new technique to pattern neural stem cells onto thousands of different arrays of the two proteins, FGF-2 and ephrin-B2, to see how the spatial organization of the two signals helps determine the cells' ultimate fate.

She found that many stem cells differentiated into mature neurons, even when they were primarily in contact with FGF-2, or "stay a stem cell," messengers. When she looked closer, however, she found that those cells that differentiated were more likely to have small, finger-like extensions, or "neurites," that touched the ephrin-B2 or "differentiate" messengers.

"The great thing about this patterning technology is you can easily replicate these little patterns hundreds or thousands of times across a slide," Schaffer said. "It is like running a thousand little independent experiments, each of which is a trial run to see how a stem cell listens to the cells around it. And then you can get very, very deep statistics about the various ways that it can be regulated."

The identification of an insect-specific metal-sensing receptor in the gut lining highlights a possible new way to curb populations of disease-transmitting insects such as mosquitoes.

In this new study led by the MRC London Institute of Medical Sciences, researchers discovered that removal of this nutrient-sensing receptor called Hodor was fatal in Anopheles mosquitoes as the insects did not make it past their larval stage.

The findings, published in the journal Nature, identify an attractive drug target that is easily accessible in the gut lining which can act to curb mosquito populations. It again emphasises the value of investigating insect specific biology, and not just human research, to lead to healthcare treatments and interventions.

The ability for cells in the gut to sense nutrients is essential to maintain homeostasis and their ability to adapt to a changing environment. Micronutrients, such as metal ions, are known to have important roles in growth and development, but our understanding of how metals are sensed is limited. These nutrient sensors are most commonly found in the gut lining, specifically in the enteroendocrine cells. However, Professor Irene Miguel-Aliaga, the principal investigator on this study, and colleagues were curious about enterocytes - which play more of a role in digestion and absorption of nutrients - and whether they have any ability to sense nutrients themselves.

They performed a genetic screen of over 100 candidate proteins thought to be involved in nutrient sensing. This screen uncovered a receptor that seems to regulate the development of larvae, particularly in nutrient-poor conditions that was expressed in the gut lining. Inhibiting the expression of this protein resulted in developmental delay, as referenced in the name 'Hodor' (an abbreviation for 'hold on, don't rush').

Hodor is a zinc-sensing protein that uses the metal to transport chloride within and out of cells, facilitating pathways that regulate nutrient-sensing and growth. Increasing the levels of zinc in the flies' diet led to increased feeding, which was reversed when Hodor was blocked. The authors suggest that the receptor helps to direct the animals to nutrient-rich food sources (metals such as zinc are produced by yeasts, which are found on fruit and other foods). Finally, they demonstrate that deleting the gene in mosquitoes is fatal, suggesting that such disease vectors could be targeted and controlled by using ingestible drugs and also could be harmless to humans due to its insect specificity.

Citrus greening, also called Huanglongbing (HLB), is devastating the citrus industry. Florida alone has experienced a 50 to 75 percent reduction in citrus production. There are no resistant varieties of citrus available and limited disease control measures.

Some scientists think it is possible that orange juice could one day become as expensive and rare as caviar. In an effort to prevent this, three plant pathologists at the University of California-Berkeley and United States Department of Agriculture conducted research into ways to boost citrus immunity and protect the valuable fruit against citrus greening.

Because the bacteria that causes citrus greening cannot be grown in a lab, scientists have to find novel ways to conduct experiments. The University of California-Berkeley/USDA team looked at many different strains of the bacteria that cause citrus greening to see if they could identify peptides (a compound of two or more amino acids) that would trigger immune responses.

"This was a long list, so we narrowed it down by selecting small peptides that were a bit different in their peptide sequence, which might imply that the bacterium had made those sequence changes so that they wouldn't be recognized by the plant immune system," explained Jennifer D. Lewis, group leader of the research team. "Then we further narrowed that list to peptides from strains that caused disease in citrus."

Through this research, they showed that two peptides could trigger immune responses in multiple plant species, including citrus. These peptides may play a role in preventing or reducing yield loss from citrus greening.

According to Lewis, "We thought it was particularly interesting that some of the peptides predicted to elicit a response, could actually trigger immune responses in multiple plant species. This suggests that the immune response to these peptides is conserved across species."

Last April, the Event Horizon Telescope (EHT) sparked international excitement when it unveiled the first image of a black hole. Today, a team of researchers have published new calculations that predict a striking and intricate substructure within black hole images from extreme gravitational light bending.

"The image of a black hole actually contains a nested series of rings," explains Michael Johnson of the Center for Astrophysics | Harvard and Smithsonian (CfA). "Each successive ring has about the same diameter but becomes increasingly sharper because its light orbited the black hole more times before reaching the observer. With the current EHT image, we've caught just a glimpse of the full complexity that should emerge in the image of any black hole."

Because black holes trap any photons that cross their event horizon, they cast a shadow on their bright surrounding emission from hot infalling gas. A "photon ring" encircles this shadow, produced from light that is concentrated by the strong gravity near the black hole. This photon ring carries the fingerprint of the black hole--its size and shape encode the mass and rotation or "spin" of the black hole. With the EHT images, black hole researchers have a new tool to study these extraordinary objects.

"This is an extremely exciting time to be thinking about the physics of black holes," says Daniel Kapec from the Institute for Advanced Study. "Einstein's theory of general relativity makes a number of striking predictions for the types of observations that are finally coming within reach, and I think we can look forward to lots of advances in the coming years. As a theorist, I find the rapid convergence between theory and experiment especially rewarding, and I hope we can continue to isolate and observe more universal predictions of general relativity as these experiments become more sensitive."

The research team included observational astronomers, theoretical physicists, and astrophysicists.

"Bringing together experts from different fields enabled us to really connect a theoretical understanding of the photon ring to what is possible with observation," notes George Wong, a physics graduate student at the University of Illinois at Urbana-Champaign. Wong developed software to produce simulated black hole images at higher resolutions than had previously been computed and to decompose these into the predicted series of sub-images. "What started as classic pencil-and-paper calculations prompted us to push our simulations to new limits."

The researchers also found that the black hole's image substructure creates new possibilities to observe black holes. "What really surprised us was that while the nested subrings are almost imperceptible to the naked eye on images--even perfect images--they are strong and clear signals for arrays of telescopes called interferometers," says Johnson. "While capturing black hole images normally requires many distributed telescopes, the subrings are perfect to study using only two telescopes that are very far apart. Adding one space telescope to the EHT would be enough."

"Black hole physics has always been a beautiful subject with deep theoretical implications, but now it has also become an experimental science," says Alex Lupsasca from the Harvard Society of Fellows. "As a theorist, I am delighted to finally glean real data about these objects that we've been abstractly thinking about for so long."

CAMBRIDGE, MA -- MIT biological engineers have created a multitissue model that lets them study the relationships between different organs and the immune system, on a specialized microfluidic platform seeded with human cells.

Using this type of model, sometimes called "organs-on-a-chip" or "physiome-on-a-chip," the research team was able to explore the role of circulating immune cells in ulcerative colitis and other inflammatory diseases. They also discovered that a metabolic byproduct generated by bacteria living in the human gut plays an important role under these inflammatory conditions.

"We've shown that now you can start to attack some of these really thorny, chronic inflammatory diseases by designing experiments in these organs on chips," says Linda Griffith, the School of Engineering Professor of Teaching Innovation, a professor of biological engineering and mechanical engineering, and the senior author of the study.

This approach, described today in the journal Cell Systems, could also lend itself to studying many other complex diseases, the researchers say.

"Now we have options to really decrease or increase the level of disease complexity, under controlled and systematic conditions," says Martin Trapecar, an MIT postdoc and the lead author of the paper.

Complex models

Nearly 20 years ago, Griffith's lab first began working on a model of the human liver known as the "liver chip." This system, which consists of engineered human liver tissue grown on a specialized scaffold, can be used to test drug toxicity. More recently, she has been working on small-scale replicas of many interconnected organs, also known as microphysiological systems (MPS). In 2018, she reported the development of a platform that could be used to model interactions between up to 10 organs at a time.

These kinds of devices are well-suited for analyzing complex diseases, including those that involve multiple organs, are influenced by the immune system, or cannot be accounted for by a single gene or small number of genes.

"We wanted to build technologies that would let you connect several organ systems together, so that we could start to develop new tools to combat chronic inflammatory diseases," Griffith says. "In drug development, the field really struggles with anything that's not a single-gene disease."

In the new Cell Systems study, she and Trapecar set out to model interactions between two organs, the colon and the liver. They also wanted to study how the immune system, especially T cells, influences those organs. It is already known that up to 80 percent of patients with a chronic liver autoimmune disease called primary sclerosing cholangitis also suffer from inflammatory bowel disease (IBD). And, patients with IBD have a much greater chance of developing autoimmune disorders of the liver.

The new system contains colon cells taken from patients with ulcerative colitis, along with healthy liver cells. The researchers found that when these tissues were connected, their physiological behavior completely changed as compared to when they are isolated. Inflammation in ulcerative colitis gut tissue decreased when the tissue was exposed to healthy liver cells. At the same time, genes and cellular pathways involved in metabolism and immune function became more active in both organs.

The researchers then added two types of T cells to the system: CD4+ T regulatory cells, which suppress other immune cells, and TH17 cells, which stimulate inflammation. Adding these T cells to the gut-liver interaction quickly increased inflammation and recreated certain features of both IBD and autoimmune liver diseases.

Lastly, the researchers decided to investigate the potential role of molecules called short-chain fatty acids (SCFAs) in inflammatory disease. These molecules are produced by microbes in the human gut as they feast on undigested fiber. SCFAs, which include butyrate, propionate, and acetate, are produced in large quantities and account for about 10 percent of our daily energy needs.

While these compounds have many beneficial effects in the human body, including reducing inflammation, a few studies in recent years have suggested that SCFAs can also cause harm by stimulating inflammation. The new MIT study found that adding SCFAs to the ulcerative colitis model greatly exacerbated inflammation throughout the liver and gut, but only if T cells were already present.

"The hypothesis we formed, based on these studies, is that the role of short chain fatty acids seems to depend on how much the adaptive immune system (which includes T cells) is involved," Trapecar says.

That is, in early stages of inflammation, when T cells are not heavily involved, SCFAs can help reduce inflammation. But when many effector T cells are recruited, SCFAs stimulate them to be even more inflammatory. This could be useful in cases of infection, to help the body to fend off invaders, but it can also accelerate autoimmune disorders.

Modeling brain disorders

This study grew out of a related project in which the researchers planned to look at interactions between the gut, liver, and brain. A recent study from Sarkis Mazmanian, a professor of microbiology at Caltech, showed that in a mouse model of Parkinson's, germ-free mice developed signs of the disease later than those housed under regular conditions. The study suggested that SCFAs produced by microbes might contribute to the observed phenomena and progression of the disease.

Griffith's lab is now working to use the MPS system to shed light on the connection between SCFAs and Parkinson's disease. The researchers also plan to study other complex diseases, in hopes that their results will help guide the development of new treatments for disorders that are currently difficult to treat.

"You really need very complex models," Griffith says. "You can certainly get hypotheses from animal models, but to really go forward in drug development, you need better ways to identify targets that build on samples from human patients."

The cover for issue 11 of Oncotarget features Figure 6, "Effects of AZD8186 in combination with anti-PD1 on syngeneic models," by Owusu-Brackett, et al.

In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple-negative breast cancer cell lines.

AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells.

AZD8186 significantly enhanced the antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model.

In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186.

AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro but has limited single-agent efficacy in vivo.

Dr. Funda Meric-Bernstam from the Department of Surgical Oncology, the Department of Investigational Cancer Therapeutics, the Department of Breast Surgical Oncology, as well as The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center, in Houston, Texas, USA said, "Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

"Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

- Dr. Funda Meric-Bernstam, Department of Investigational Cancer Therapeutics, the Department of Breast Surgical Oncology & The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy

Mutations, loss of copy number, epigenetic silencing and downregulation of PTEN protein by mi RNA can result in PTEN function inactivation, leading to activation of PI3K/AKT/mTOR pathway, which subsequently increases tumor growth, invasion and metastasis across a diverse set of solid tumors including breast, endometrial, prostate, renal cell, hepatocellular, glioblastoma, and colorectal cancers.

Loss of PTEN and increased PI3K signaling are associated with resistance to trastuzumab and endocrine therapy in hormone receptor-positive breast cancer and with poor prognosis in triple-negative breast cancers.

In vitro, they revealed significant growth inhibition of PTEN-deficient tumors by depleting PIK3CB which encodes PI3K, while no such growth inhibition effect was shown in corresponding PTEN-deficient tumors with downregulation of PIK3CA or PIK3CD encoding PI3K and PI3K, respectively.

Thus, PI3K isoform is the driver of abnormal proliferation in PTEN-null cancers, and as such, PI3K is a promising target for therapy in PTEN-deficient TNBC. AZD8186 is a selective and potent small-molecule inhibitor of PI3K, with additional activity against PI3K isoform.

The Meric-Bernstam Research Team concluded in their Oncotarget Research Paper, "these results provide preclinical evidence of antitumor efficacy of AZD8186 in PTEN-deficient solid tumors. AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro, with modest single-agent efficacy in vivo. Furthermore, AZD8186 enhanced the antitumor efficacy of paclitaxel but stable and progressive disease were noted with this combination in immunosuppressed models. In immunocompetent models, AZD8186 in combination with anti-PD1 resulted in tumor regression in PTEN-deficient BP tumor. We realize that while there appears to be an association of AZD8186 sensitivity to PTEN loss, a cause-effect relationship can only be speculated on. In summary, although further insights are needed into the mechanisms of activity of these combinations, the combination of AZD8186 with taxanes and with anti-PD1 agents hold promise for the treatment of PTEN-deficient solid tumors."

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DOI - https://doi.org/10.18632/oncotarget.27503

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=27503&path%5B%5D=90086

Correspondence to - Funda Meric-Bernstam - fmeric@mdanderson.org

DOI

10.18632/oncotarget.27503

ITHACA, N.Y. - Radiocarbon dating, invented in the late 1940s and improved ever since to provide more precise measurements, is the standard method for determining the dates of artifacts in archaeology and other disciplines.

"If it's organic and old - up to 50,000 years - you date it by radiocarbon," said Sturt Manning, the Goldwin Smith Professor of Classical Archaeology in the College of Arts and Sciences.

Manning is lead author of a new paper that points out the need for an important new refinement to the technique. The outcomes of his study, published March 18 in Science Advances, have relevance for understanding key dates in Mediterranean history and prehistory, including the tomb of Tutankhamen and a controversial but important volcanic eruption on the Greek island of Santorini.

Radiocarbon dating measures the decomposition of carbon-14, an unstable isotope of carbon created by cosmic radiation and found in all organic matter. Cosmic radiation, however, is not constant at all times. To account for fluctuations of cosmic radiation in the Earth's atmosphere, the radiocarbon content of known-age tree rings was measured backward in time from the 20th century, for thousands of years.

Tree-ring calibrated radiocarbon started to be widely used 50 years ago. A standard calibration curve was introduced in 1986 and is updated every few years as more data are added.

"A single Northern Hemisphere calibration curve has formed the basis of radiocarbon dating in Europe and the Mediterranean for five decades, setting the time frame for prehistory," Manning and co-authors write. "However, as measurement precision increases, there is mounting evidence for some small but substantive regional (partly growing season) offsets in the same-year radiocarbon levels."

In their study, Manning and co-authors question the accuracy of a single calibration curve for all of the Northern Hemisphere. Using data collected by only one lab to control for interlaboratory variation, they compared radiocarbon data from northern Europe (Germany) and from the Mediterranean (central Turkey) in the 2nd and 1st millennia B.C. They found that some small but critical periods of variation for Mediterranean radiocarbon levels exist. Data from two other radiocarbon labs on samples from central Italy and northern Turkey then provided consistency.

Growing seasons play a role, the paper says. The radiocarbon level on Earth varies according to the season; there's a winter low and a summer high, Manning said. The carbon in a tree ring reflects when the tree was photosynthesizing and, therefore, taking carbon out of the atmosphere.

"In northern Europe or in North America, a tree is going to be doing this in April through September. But a tree in Jordan or Israel does that October through April - almost the opposite time of the year," he said.

These variations, although small, potentially affect calendar dates for prehistory by up to a few decades, the paper concludes.

Even small date offsets - 50 years or less - are important for building the timeline of the Mediterranean region, which, in the last two millennia B.C., was a hotbed of interrelated cultures.

The adjusted dates confirm previously awkward timelines, where radiocarbon and history did not seem to agree for some historical landmarks, including the death and burial of Egyptian pharaoh Tutankhamen, which is dated around the 1320s to 1310s B.C., according to recent Egyptology.

The study also addresses a debate over the date of a massive volcanic eruption on Santorini. This much-studied event is dated around 1500 B.C. by archaeologists but earlier - 1630 to 1600 B.C. - by scientists. Manning said the new findings rule out the date of 1500 B.C., but may also modify the science. A 1630-1600 B.C. date remains possible, but a later date in the range 1600-1550 B.C. now becomes plausible, and even works better with existing archaeological and historical records, including writings from Egypt.

The study also has ramifications for understanding which culture influenced the Minoans and Mycenaeans, which led to ancient Greece.

"Getting the date right will rewrite and get our history correct in terms of what groups were significant in shaping what then became classical civilization," Manning said. "An accurate timeline is key to our history."

He predicts follow-up on this study and a future with more specific regional calibration curves within the Northern Hemisphere - as well as subsequent adjustment to historical dates.

Sounds produced by human activities--anthropogenic sounds--account for more than 90 percent of the underwater soundscape in major freshwater habitats of New England. Rodney Rountree of The Fish Listener in Massachusetts, and Adjunct Associate Professor at the University of Victoria, and colleagues present these findings in the open-access journal PLOS ONE on March 18, 2020.

Many organisms use sound to communicate or take cues from sounds in their ecosystem, including sounds produced by other organisms. For researchers, biological sounds can also serve as fingerprints of different species and behaviors. Anthropogenic sounds, such as those produced by boats, disrupt biological soundscapes. However, a lack of data on natural soundscapes hampers assessment of such threats in freshwater ecosystems.

To improve understanding of freshwater soundscapes, Rountree and colleagues recorded 2,750 minutes of underwater sounds in 173 locations across lakes, ponds, rivers, and streams representing five major river systems in New England. The scientists identified over 7,000 distinct sounds, which they categorized as anthropogenic, biological, or unknown in origin.

Most of the biological sounds recorded were from unknown sources but had acoustic features marking them as biological. The study was the first to document widespread occurrence of noises associated with movement of air within or released from fishes' bodies such as farts, burps and coughs.

The researchers identified anthropogenic sources--such as boats, planes, and fishing activities, --as accounting for over 90 percent of the recorded sounds. They noted that areas with higher overall sound levels had a lower number and diversity of biological sounds, and that the timing and acoustic features of anthropogenic sounds often overlapped those of the biological sounds.

Together, these findings suggest the potential for anthropogenic sounds to negatively impact freshwater soundscapes. Further research will be needed to identify the still-unknown components of the freshwater biological soundscape, and to fully assess anthropogenic threats.

Lead author Rountree says: "We are amazed by the widespread occurrence of sounds in different freshwater habitats including unexpectedly abundant fish farts, burps and coughs. We also found that human-caused noise dominates the freshwater soundscape, which may have detrimental impacts on animals that have evolved in otherwise relative quiet environments."

Co-author Francis Juanes adds: "Identifying biological and human-made sounds is a powerful way to study aquatic ecosystems and has important applications in conservation, fisheries management, and invasive species monitoring."

Finally, co-author Marta Bolgan notes: "I think this study represents an important call to action for increasing our understanding of freshwater soundscapes' composition and dynamics and for starting to fill the knowledge and legislative gaps regarding man-made noise monitoring and management in inland waters."