Brain

Natural compounds isolated from Nectandra leucantha, a neotropical tree species belonging to the laurel family (Lauraceae) and endemic to the Atlantic Rainforest biome in Brazil, where its common name is canela-seca or canela-branca, could result in new medications for the treatment of visceral leishmaniasis and Chagas disease.

In a study supported by São Paulo Research Foundation - FAPESP, researchers at Adolfo Lutz Institute (IAL) in São Paulo City found that neolignans derived from N. leucantha displayed bioactivity against parasites of the genus Leishmania and against Trypanosoma cruzi, the parasite that causes Chagas. These diseases affect millions of people in Brazil and other developing countries.

The findings are published in Scientific Reports and European Journal of Medicinal Chemistry.

"The compounds proved to be highly potent against Leishmania infantum, which causes visceral leishmaniasis, and T. cruzi," André Gustavo Tempone told. Tempone is a professor at IAL, head of its Parasitology and Mycology Center, and principal investigator for the study.

The IAL research group has spent several years seeking compounds from the Atlantic Rainforest, a biodiversity hotspot that could result in the development of new drugs to combat neglected diseases caused by infectious agents or parasites that mainly affect poor people.

The neolignans were isolated during a project conducted in collaboration with João Henrique Ghilardi Lago, a professor at the Federal University of the ABC (UFABC) also in Brazil.

Their effects on immune system cells were evaluated and demonstrated in a project conducted in collaboration with colleagues at Ohio State University in the United States and also supported by FAPESP.

Most recently, Tempone and his group synthesized 23 new neolignan derivatives as part of a project conducted in collaboration with Ed Anderson, Professor of Organic Chemistry at the University of Oxford in the United Kingdom. The project was supported by FAPESP via its program São Paulo Researchers in International Collaboration (SPRINT).

"One of the constraints on the development of new drugs to treat neglected diseases is the difficulty of finding partners to synthesize promising compounds," Tempone said. "Our collaboration with Professor Ed Anderson's group at Oxford enabled us to take this step."

The researchers evaluated the effects of the neolignan derivatives in L. infantum cells. Their analysis showed that four of the compounds reached the parasite's mitochondria, a potential molecular target for an antileishmaniasis drug.

While humans can have up to 2,000 mitochondria per cell, L. infantum cells have a single mitochondrion, Tempone explained. "We found that the compounds acted potently on the parasite's mitochondria," he said.

The compounds caused a sharp rise in intracellular calcium levels, which disrupted mitochondrial metabolism and led to cell death.

"Our hypothesis is that the compounds interfered drastically with intracellular calcium release and prevented mitochondria from producing ATP [adenosine triphosphate], the parasite's main source of energy," Tempone said.

The compounds also impaired the cell life cycle, triggering a mechanism similar to apoptosis (programmed cell death) and affecting DNA replication. Similar effects were observed in trials with T. cruzi.

"We also found that the mitochondria of T. cruzi cells underwent changes at the start of incubation of the compounds with the parasite," Tempone said.

The researchers plan to optimize the compounds to assure their adequate bioavailability in the organism. This is a key step in evaluating drug effectiveness and safety before advancing to in vivo trials. More than 90% of drug candidates tested in vitro (in cultured cells) fail to pass trials in animals, according to Tempone.

"The compounds will be optimized by means of medicinal chemistry so that we can increase the success rate in studies using an animal model," he said.

"The compounds we obtained are already highly promising prototypes, however. They combat leishmaniasis and comply with the recommendations of the Drugs for Neglected Diseases initiative [DNDi, an international non-profit organization focused on drug research and development]."

One of the DNDi's recommendations is that promising compounds for the treatment of neglected diseases should be easy to synthesize.

"Synthesis of the compounds we're studying is simple and completed in five stages. Additionally, they're inexpensive," Tempone said.

(MEMPHIS, Tenn. - July 15, 2019) Life depends on double-stranded DNA unwinding and separating into single strands that can be copied for cell division. St. Jude Children's Research Hospital scientists have determined at atomic resolution the structure of machinery that drives the process. The research appears today in the journal Nature Communications.

The process may also help to solve what the study's senior researcher called one of the greatest mysteries of biology: How double-stranded DNA separates into single strands to start the replication process. "Based on the crystal structure in this research, we propose that a rotary mechanism drives the transformation to initiate DNA replication," said Eric Enemark, Ph.D., an associate member of the St. Jude Department of Structural Biology.

Before cells divide, their DNA must be precisely copied in a process called replication. This research focused on a ring-shaped enzyme called the minichromosome maintenance or MCM complex that plays a central role. During DNA replication, the MCM complex is positioned at the fork where double-stranded DNA separates into single strands. Those strands are copied to produce a new DNA molecule.

Enemark and his colleagues have produced the first atomic resolution image of the MCM complex bound to single-strand DNA and the molecules that fuel replication.

The image captured key structural details, including the orientation of both the MCM complex and single-strand DNA. The elements illustrated how the process works like a pulley system to "pull" a single strand of DNA through the MCM complex and unwind the DNA.

The same mechanism may also explain how DNA replication begins, Enemark said. Prior to cell division, double-stranded DNA is encircled by two separate MCM complex enzymes. Based on the newly determined structure of the replication machinery, the researchers proposed that the MCM complexes begin to move in different directions, leading to separation of double-stranded DNA into single strands.

"This single event is at the heart of cell division and presents the essence of life in its most streamlined form," he said.

What The Study Did: This study of 1,600 older adults free of dementia at baseline examined whether accumulation over a lifetime of cognitive and social activities was associated with a slower rate of memory loss and a reduced risk of dementia, taking into account brain pathologies.

Authors: Xiuying Qi, Ph.D., and Weili Xu, M.D., Ph.D., of Tianjin Medical University, Tianjin, China, are the corresponding authors.

(doi:10.1001/jamaneurol.2019.2455)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

A new study from The Dartmouth Institute for Health Policy and Clinical Practice, published this week in JAMA Network Open, finds that Accountable Care Organization (ACO)-reported care management and coordination activities were not associated with improved outcomes or lower spending for patients with complex needs.

Patients with complex medical and social needs--such as older adults who are frail or suffer from multiple chronic conditions--often experience difficulty navigating the healthcare system since their care is typically fragmented across many practitioners and settings. As a result, gaps in the quality of their care and unnecessary spending occur, contributing to a disproportionate amount of Medicare-associated costs.

As they have become more widespread in healthcare, ACOs have employed a variety of care management and coordination strategies to address these issues.

To determine the impact these strategies have on improving patient outcomes and reducing healthcare costs, the researchers conducted a cross-sectional study using Medicare claims data and the National Survey of Accountable Care Organizations that included surveys from 244 Medicare Shared Savings Program ACOs.

In their analysis, the team looked at more than 1.4 million Medicare beneficiaries with complex health and social needs. They computed an index score (grouping patients by intensity of services) that measured self-reported care management and coordination activity that was then linked to Medicare claims. The primary outcomes of interest included quality of care, healthcare utilization, spending, and interactions with the healthcare system.

While the researchers found that the care management and coordination activities that were reported by ACOs were not associated with differences in spending or measured outcomes for this population of patients, the study's limitations should be considered when interpreting the results.

"The most important limitation of our study is its cross-sectional nature, which does not allow for causal interpretation," explains Carrie Colla, PhD, an associate professor at The Dartmouth Institute and senior author on the study. "Longitudinal analyses would allow for evaluation of whether or not length of exposure to care management has an effect on health outcomes."

Future efforts to care for patients with complex needs should assess whether strategies found to be effective in other settings are being used, and if so, why they fail to meet expectations.

"More research is needed to inform the field," Colla says, "particularly on other components of care management outside of the health system--such as housing, transportation, social support, and food security--and their impact on cost and health outcomes should be studied as well."

A study of up to 4.4m adult participants has shown that those who were born pre-term (under 37 weeks gestation) are less likely to form romantic relationships, have sexual relations or experience parenthood than those who were born full term

Research from the University of Warwick suggests it's partly due to pre-term birth being associated with being more often withdrawn and shy, socially excluded and less likely to take risks in adolescence

More needs to be done in schools and by parents to encourage social interactions at younger ages, so when they transition to adulthood they are more likely to meet someone and increase their wellbeing

Adults who were born pre-term (under 37 weeks gestation) are less likely to have a romantic relationship, a sexual partner and experience parenthood than those born full term. The meta-analysis by researchers at the University of Warwick with data from up to 4.4 million adult participants showed that those born preterm are 28% less likely to ever be in a romantic relationship.

A meta-analysis conducted by researchers from the Department of Psychology at the University of Warwick has published 'Association of Preterm Birth/Low Birth Weight with Romantic Partnership, Sexual Intercourse and Parenthood in Adulthood: A Systematic Review and Meta-Analysis' in JAMA Network Open today, 12th of July. They have found that adults who were born pre-term are less likely to form romantic relationships than full-term peers.

In the analysis 4.4 million adult participants those born preterm were 28% less likely to form romantic relationships and 22% less likely to become parents, when compared to those born full term.

Those studies that looked at sexual relations of pre-term children found that they were 2.3 times less likely to ever have a sexual partner when compared to full terms.

Those adults who were born very (

Close and intimate relationships have been shown to increase happiness and well-being both physically and mentally. However, studies also show that forming those relationships is harder for pre-term born adults, as they are usually timid, socially withdrawn and low in risk-taking and fun seeking.

Despite having fewer close relationships, this meta-analysis also revealed that when preterm born adults had friends or a partner, the quality of these relationships was at least as good in preterms compared to full term born adults.

First author of the paper, Dr Marina Goulart de Mendonça from the Department of Psychology at the University of Warwick comments:

"The finding that adults who were born pre-term are less likely to have a partner, to have sex and become parents does not appear to be explained by a higher rate of disability. Rather preterm born children have been previously found to have poorer social interactions in childhood that make it harder for them to master social transitions such as finding a partner, which in turn is proven to boost your wellbeing."

The senior author, Professor Dieter Wolke, from the Department of Psychology at the University of Warwick adds:

"Those caring for preterm children including parent's health professionals and teachers should be more aware of the important role of social development and social integration for pre-term children. As preterm children tend to be more timid and shy, supporting them making friends and be integrated in their peer group will help them to find romantic partners, have sexual relationships and to become parents. All of which enhances wellbeing."

MEDFORD/SOMERVILLE, Mass. (July 12, 2019) --A research collaboration between Tufts University and the Chinese Academy of Sciences has led to the development of a significantly improved delivery mechanism for the CRISPR/Cas9 gene editing method in the liver, according to a study published recently in the journal Advanced Materials. The delivery uses biodegradable synthetic lipid nanoparticles that carry the molecular editing tools into the cell to precisely alter the cells' genetic code with as much as 90 percent efficiency. The nanoparticles represent one of the most efficient CRISPR/Cas9 delivery tools reported so far, according to the researchers, and could help overcome technical hurdles to enable gene editing in a broad range of clinical therapeutic applications.

The CRISPR/Cas9 gene editing system has become a powerful research tool uncovering the function of hundreds of genes and is currently being explored as a therapeutic tool for the treatment of various diseases. However, some technical hurdles remain before it can be practical for clinical applications. CRISPR/Cas9 is a large molecular complex, containing both a nuclease (Cas9) that can cut through both strands of a targeted genomic sequence, and an engineered 'single-guide' RNA (sgRNA) that scans the genome to help the nuclease find that specific sequence to be edited. Since it is a large molecular complex, it is difficult to deliver CRISPR/Cas9 directly into the nucleus of the cell, where it can do its work. Others have packed the editing molecules into viruses, polymers, and different types of nanoparticles to get them into the nucleus, but the low efficiency of tranfer has limited their use and potency for clinical applications.

The lipid nanoparticles described in the study encapsulate messenger RNA (mRNA) encoding Cas9. Once the contents of the nanoparticles - including the sgRNA - are released into the cell. The cell's protein-making machinery takes over and creates Cas9 from the mRNA template, completing the gene editing kit. A unique feature of the nanoparticles is made of synthetic lipids comprising disulfide bonds in the fatty chain. When the particles enter the cell, the environment within the cell breaks open the disulfide bond to disassemble the nanoparticles and the contents are quickly and efficiently released into the cell.

"We are just starting to see human clinical trials for CRISPR therapies," said Qiaobing Xu, co-corresponding author of the study and associate professor of biomedical engineering at Tufts University. "There are many diseases that have long been intractable for which CRISPR therapies could offer new hope - for example sickle cell disease, Duchenne muscular dystrophy, Huntington's disease, and even many cancers. Our hope is that this advance will take us another step toward making CRISPR an effective and practical approach to treatment."

The researchers applied the new method to mice, seeking to reduce the presence of a gene coding for PCSK9, the loss of which is associated with lower LDL cholesterol, and reduced risk of cardiovascular disease. "The lipid nanoparticles are one of the most efficient CRISPR/Cas9 carriers we have seen," said Ming Wang, also co-corresponding author of the study and professor at the Chinese Academy of Sciences, Beijing National Laboratory for Molecular Science. "We can actually knock down PCSK9 expression in mice with 80 percent efficiency in the liver, suggesting a real promise for therapeutic applications."

In recent years, the idea of life on other planets has become less far-fetched. NASA announced June 27 that it will send a vehicle to Saturn's icy moon, Titan, a celestial body known to harbor surface lakes of methane and an ice-covered ocean of water, boosting its chance for supporting life.

On Earth, scientists are studying the most extreme environments to learn how life might exist under completely different settings, like on other planets. A University of Washington team has been studying the microbes found in "cryopegs," trapped layers of sediment with water so salty that it remains liquid at below-freezing temperatures, which may be similar to environments on Mars or other planetary bodies farther from the sun.

At the recent AbSciCon meeting in Bellevue, Washington, researchers presented DNA sequencing and related results to show that brine samples from an Alaskan cryopeg isolated for tens of thousands of years contain thriving bacterial communities. The lifeforms are similar to those found in floating sea ice and in saltwater that flows from glaciers, but display some unique patterns.

"We study really old seawater trapped inside of permafrost for up to 50,000 years, to see how those bacterial communities have evolved over time," said lead author Zachary Cooper, a UW doctoral student in oceanography.

Cryopegs were first discovered by geologists in Northern Alaska decades ago. This field site in Utqia?vik, formerly known as Barrow, was excavated in the 1960s by the U.S. Army's Cold Regions Research and Engineering Laboratory to explore large wedges of freshwater ice that occur in the permafrost there. Subsurface brine was eventually collected from the site in the 2000s.

"The extreme conditions here are not just the below-zero temperatures, but also the very high salt concentrations," said Jody Deming, a UW professor of oceanography who studies microbial life in the Arctic Ocean. "One hundred and forty parts per thousand -- 14% -- is a lot of salt. In canned goods that would stop microbes from doing anything. So there can be a preconceived notion that very high salt should not enable active life."

It's not fully known how cryopegs form. Scientists believe the layers might be former coastal lagoons stranded during the last ice age, when rain turned to snow and the ocean receded. Moisture evaporated from the abandoned seabed was then covered by permafrost, so the remaining briny water became trapped below a layer of frozen soil.

To access the subsurface liquids, researchers climb about 12 feet down a ladder and then move carefully along a tunnel within the ice. The opening is just a single person wide and is not high enough to stand in, so researchers must crouch and work together to drill during the four- to eight-hour shifts.

Deming describes it as "exhilarating" because of the possibility for discovery.

Samples collected in the spring of 2017 and 2018, geologically isolated for what researchers believe to be roughly 50,000 years, contain genes from healthy communities of bacteria along with their viruses.

"We're just discovering that there's a very robust microbial community, coevolving with viruses, in these ancient buried brines," Cooper said. "We were quite startled at how dense the bacterial communities are."

The extreme environments on Earth may be similar to the oceans and ice of other planets, scientist believe.

"The dominant bacterium is Marinobacter," Deming said. "The name alone tells us that it came from the ocean - even though it has been in the dark, buried in frozen permafrost for a very long time, it originally came from the marine environment."

Mars harbored an ocean of water in the past, and our solar system contains at least a half-dozen oceans on other planets and icy moons. Titan, the moon of Saturn that NASA will explore, is rich in various forms of ice. Studying life on Earth in frozen settings that may have similarities can prepare explorers for what kind of life to expect, and how to detect it.

Being able to see green spaces from your home is associated with reduced cravings for alcohol, cigarettes and harmful foods, new research has shown.

The study, led by the University of Plymouth, is the first to demonstrate that passive exposure to nearby greenspace is linked to both lower frequencies and strengths of craving.

It builds on previous research suggesting exercising in nature can reduce cravings, by demonstrating the same may be true irrespective of physical activity.

Researchers say the findings add to evidence that points to the need to protect and invest in green spaces within towns and cities, in order to maximise the public health benefits they may afford. They also suggest the causality of this link needs to be investigated further.

The study, published in the journal Health & Place, is the first to investigate the relationship between exposure to natural environments, craving for a range of appetitive substances and the experiencing of negative emotions or feelings.

It involved academics from the University's School of Psychology, with support from the European Centre for Environment and Human Health at the University of Exeter.

Leanne Martin, who led the research as part of her Master's degree in Plymouth, said: "It has been known for some time that being outdoors in nature is linked to a person's wellbeing. But for there to be a similar association with cravings from simply being able to see green spaces adds a new dimension to previous research. This is the first study to explore this idea, and it could have a range of implications for both public health and environmental protection programmes in the future."

For the research, participants completed an online survey that explored the relationships between various aspects of nature exposure, craving and negative a?ect.

Among other things, it measured the proportion of greenspace in an individual's residential neighbourhood, the presence of green views from their home, their access to a garden or allotment; and their frequency of use of public greenspaces.

The results showed that having access to a garden or allotment was associated with both lower craving strength and frequency, while residential views incorporating more than 25% greenspace evoked similar responses.

The study also measured physical activity undertaken within the same time frame that cravings were assessed, showing the reduced craving occurred irrespective of physical activity level.

Dr Sabine Pahl, Associate Professor (Reader) in Psychology, added: "Craving contributes to a variety of health-damaging behaviours such as smoking, excessive drinking and unhealthy eating. In turn, these can contribute to some of the greatest global health challenges of our time, including cancer, obesity and diabetes. Showing that lower craving is linked to more exposure to green spaces is a promising first step. Future research should investigate if and how green spaces can be used to help people withstand problematic cravings, enabling them to better manage cessation attempts in the future."

Atomic interactions in everyday solids and liquids are so complex that some of these materials' properties continue to elude physicists' understanding. Solving the problems mathematically is beyond the capabilities of modern computers, so scientists at Princeton University have turned to an unusual branch of geometry instead.

Researchers led by Andrew Houck, a professor of electrical engineering, have built an electronic array on a microchip that simulates particle interactions in a hyperbolic plane, a geometric surface in which space curves away from itself at every point. A hyperbolic plane is difficult to envision -- the artist M.C. Escher used hyperbolic geometry in many of his mind-bending pieces -- but is perfect for answering questions about particle interactions and other challenging mathematical questions.

The research team used superconducting circuits to create a lattice that functions as a hyperbolic space. When the researchers introduce photons into the lattice, they can answer a wide range of difficult questions by observing the photons' interactions in simulated hyperbolic space.

"You can throw particles together, turn on a very controlled amount of interaction between them, and see the complexity emerge," said Houck, who was the senior author of the paper published July 4 in the journal Nature.

Alicia Kollár, a postdoctoral research associate at the Princeton Center for Complex Materials and the study's lead author, said the goal is to allow researchers to address complex questions about quantum interactions, which govern the behavior of atomic and subatomic particles.

"The problem is that if you want to study a very complicated quantum mechanical material, then that computer modeling is very difficult. We're trying to implement a model at the hardware level so that nature does the hard part of the computation for you," said Kollár.

The centimeter-sized chip is etched with a circuit of superconducting resonators that provide paths for microwave photons to move and interact. The resonators on the chip are arranged in a lattice pattern of heptagons, or seven-sided polygons. The structure exists on a flat plane, but simulates the unusual geometry of a hyperbolic plane.

"In normal 3-D space, a hyperbolic surface doesn't exist," said Houck. "This material allows us to start to think about mixing quantum mechanics and curved space in a lab setting."

Trying to force a three-dimensional sphere onto a two-dimensional plane reveals that space on a spherical plane is smaller than on a flat plane. This is why the shapes of countries appear stretched out when drawn on a flat map of the spherical Earth. In contrast, a hyperbolic plane would need to be compressed in order to fit onto a flat plane.

"It's a space that you can mathematically write down, but it's very difficult to visualize because it's too big to fit in our space," explained Kollár.

To simulate the effect of compressing hyperbolic space onto a flat surface, the researchers used a special type of resonator called a coplanar waveguide resonator. When microwave photons pass through this resonator, they behave in the same way whether their path is straight or meandering. The meandering structure of the resonators offers flexibility to "squish and scrunch" the sides of the heptagons to create a flat tiling pattern, said Kollár.

Looking at the chip's central heptagon is akin to looking through a fisheye camera lens, in which objects at the edge of the field of view appear smaller than in the center -- the heptagons look smaller the farther they are from the center. This arrangement allows microwave photons that move through the resonator circuit to behave like particles in a hyperbolic space.

The chip's ability to simulate curved space could enable new investigations in quantum mechanics, including properties of energy and matter in the warped space-time around black holes. The material could also be useful for understanding complex webs of relationships in mathematical graph theory and communication networks. Kollár noted that this research could eventually aid the design of new materials.

But first, Kollár and her colleagues will need to further develop the photonic material, both by continuing to examine its mathematical basis and by introducing elements that enable photons in the circuit to interact.

"By themselves, microwave photons don't interact with each other -- they pass right through," said Kollár. Most applications of the material would require "doing something to make it so that they can tell there's another photon there."

BOSTON, MA - Patients receiving a post-surgery prescription of ibuprofen with a rescue prescription of Percocet used less opioids than a group of similar patients who were prescribed just Percocet. The research was presented by a group from the New York University Hospital for Joint Diseases in New York City today at the American Orthopedic Society of Sports Medicine's Annual Meeting.

"The current opioid epidemic demands physicians seek ways to decrease patients' requirements of narcotic medications without sacrificing their postoperative comfort level," said lead researcher Dr. Kamali A. Thompson, from New York University Hospital for Joints Diseases. "This study evaluated patients' pain following arthroscopic shoulder instability repair and compared the use of narcotic medications between patients prescribed NSAIDs with rescue opioid prescription to those prescribed opioids alone."

According to the National Institute of Drug Abuse, more than 130 people in the United States die daily after overdosing on opioids. The Centers for Disease Control and Prevention estimates that the total "economic burden" of prescription opioid misuse alone in the United States is $78.5 billion a year, including the costs of healthcare, lost productivity, addiction treatment and criminal justice involvement.

Thompson and his team randomized 40 patients who were to undergo an arthroscopic shoulder instability repair and divided the patients into two groups: one group received 600 milligrams of Ibuprofen and a 10-pill rescue prescription of Percocet 5/325mg while the other group was only given Percocet 5/325mg.

The researchers found that the total amount of opioid consumption was significantly lower in the group that received both Ibuprofen and Percocet compared to the group that received just Percocet.

"It is possible to alleviate postoperative pain with lower amounts of opioids than are currently being prescribed," said Thompson. "The public health crisis of opioid abuse requires an immediate solution beginning with the reduction of post-operative narcotics distribution."

BUFFALO, N.Y. - People who narrowly avoid disaster do not necessarily escape tragedy unharmed, and their knowledge of the victims' fate shapes how survivors respond to traumatic events, according to the results of a new paper by a University at Buffalo psychologist that explores the effects of near-miss experiences associated with the 9/11 terrorist attacks.

"There is a misfortune to being fortunate," says Michael Poulin, an associate professor of psychology at UB and lead author of the paper published in the journal Social Psychological and Personality Science.

"You would think that having a near-miss experience is unequivocally good news. That means it didn't happen to you. Although obviously that's far more preferable than having tragedy befall you, it turns out that merely being aware of that fact can be burdensome - and it's particularly true when it's vivid that others were not as fortunate."

Poulin's study, with Roxane Cohen Silver, professor of psychological science, medicine and public health at The University of California, Irvine, deepens the understanding of how large-scale trauma affects mental health.

"We tend to focus understandably on those who were affected, but our data suggest that even people who were not directly affected in any obvious way can be upset by mentally comparing what didn't happen to them in light of what actually happened to someone else, who easily could have been them."

Despite the frequency with which "survivor guilt" appears in casual conversation and popular culture, this study turns out to be among the few to directly examine near miss experiences.

"Survivor guilt is widely understood to be true, almost like a kind of clinical lore," says Poulin, an expert in stress and coping. "But in the context of near-miss experiences, there's just not much there if you go looking for empirical data on the existence of survivor guilt."

Near-miss experiences are difficult to study because of the challenges involved in finding a representative sample, but 9/11 provided Poulin and Silver with the opportunity to conduct rigorous research on the phenomenon - even though neither of the scientists were at first interested in doing so.

"This project shaped much of my graduate career," says Poulin. "Professor Silver, my co-author and advisor at the time, studies responses to trauma, in particular mass tragedies. Despite that focus, as a research team we talked it over and agreed not to go anywhere near this event. It was too raw and painful to think about a psychological study."

That conversation changed in the days after the attack when media outlets began speculating on its psychological effects with no research to support their commentary.

"What we originally considered to be exploitative suddenly appeared to be necessary," says Poulin. "This was something that needed to be studied."

The researchers used a 1,433-participant sample provided by an online research company, which assessed a near-miss experience by asking, "Did you or someone close to you experience a near miss as a result of the Sept. 11 terrorist attacks?"

Some examples include:

My brother-in-law on the 90th floor where he works called in sick.

I got a job in the World Trade Center a couple months before, and did not take it.

My son-in-law would have been on that flight, but my daughter got sick and he took her to the hospital.

The findings suggest that the near-miss participants reported higher levels of re-experiencing symptoms (sudden, traumatic memories of the event) that persisted over three years and probable post-traumatic stress disorder.

The PTSD is, not surprisingly, affected more by direct exposure, but that near-misses exist as an independent predictor suggests that their role is not related exclusively to familiarity with the victims.

"I think this study contributes to a broader debate that people are having in the world of psychology about what counts as being exposed to trauma," says Poulin. "This is also something clinicians should continue to be aware of in terms of evaluating their clients' mental health.

"It's not just 'Did this happen to you?'" "But 'Did something almost happen to you?'"
Poulin notes that these findings are based on one event of a particular magnitude and whether they can be generalized is still as yet an unanswered empirical question.

"But it would be important to find that answer," he says.

High-risk pregnancies occur frequently and may be caused by various factors. It is estimated that 10 to 20% of pregnant women miscarry during their first trimester of pregnancy. Slow fetal growth may also arise as a result of maternal infection with certain microbes, parasites or viruses (such as toxoplasmosis or infection with rubella virus, cytomegalovirus, herpes or Zika) or because of genetic or autoimmune diseases. Teams from the Institut Pasteur, the CNRS, Inserm, Necker-Enfants Malades Hospital (AP-HP) and Université de Paris have identified a new cellular mechanism that alters placental development, potentially causing serious complications during pregnancy. The mechanism is linked with the production of interferon, a molecule produced in response to infection, especially viral infection. The findings are published in Science on July 11, 2019.

The placenta is both a surface for exchange and a barrier between mother and fetus - it delivers nutrients needed for fetal growth, produces hormones and protects the fetus from microbes and the maternal immune system. The external layer of the placenta, known as the syncytiotrophoblast, is composed of cells which fuse together, forming giant cells that are optimized for the placenta's barrier and exchange functions. Cell fusion is mediated by a protein known as syncytin. If the syncytiotrophoblast fails to form correctly, it can cause placental insufficiency and hinder fetal development. An abnormal syncytiotrophoblast can be observed in conditions such as slow intrauterine growth, the lupus and in women whose fetus has Down syndrome.

Interferon is a substance produced by immune cells during infection to combat viruses and other intracellular microbes. High levels of interferon are observed in autoimmune or inflammatory diseases such as lupus, and also in some infections. In this study, the scientists demonstrated that interferon is responsible for placental abnormality and that it acts by preventing syncytiotrophoblast formation. Specifically, interferon induces the production of a family of cellular proteins known as IFITMs (interferon-induced transmembrane proteins), which block the fusion activity of syncytin.

IFITM proteins are beneficial since they prevent viral fusion with cellular membrane, thereby stopping viruses from entering and multiplying within cells. The scientists used experimental models and human cells to demonstrate that this beneficial effect can nevertheless be harmful if IFITM proteins are produced in an important level in the placenta.

"Identifying the role of IFITMs gives us a better understanding of the mechanisms involved in placental development and how it may be disrupted during infections and other diseases," comments Olivier Schwartz, Head of the Virus and Immunity Unit at the Institut Pasteur and joint last author of the paper. The scientists want to investigate whether placental pathologies of unknown etiology, such as some early spontaneous abortions and occurrences of preeclampsia, also involve IFITM proteins. In the longer term, blocking the effects of IFITMs could represent a new therapeutic strategy to prevent interferon-related placental abnormality.

Jeanette Gehrig and colleagues have designed a diet that can help digestive tracts damaged by acute childhood malnutrition develop a mature gut microbial community, necessary for proper growth and functioning. Disruption of the normal gut microbiota is common in malnutrition, and recent research suggests that without fixing this "immature" microbiota, even children given supplementary food may not be able to thrive. Using a machine-learning technique demonstrated by Arjun Raman and colleagues, Gehrig et al. were able to pinpoint the main types of bacteria present in the healthy gut of Bangladeshi children ages one to 60 months. In a series of experiments in mice and pigs with bacteria-free digestive tracts, the researchers were able to determine which sets of foods were associated with certain bacterial communities, and which could nudge an immature gut microbiota toward a mature configuration that could support a child's growth after severe malnutrition. Their findings suggest that protein-rich plant foods such as chickpeas, bananas and peanut flours support this microbial transition. Children who were fed these items as part of their nutritional recovery increased their levels of protein biomarkers related to growth, immune function, neurodevelopment and bone formation.

New research from the University of East Anglia (UEA) says there is a "clear need" for more support for young carers of parents with a mental illness as they move into adulthood.

The study argues that services need to be flexible, combining both practical support, such as the provision of additional support to the parent as they manage the transition of their child - and carer - leaving home, and emotional support for the young person and their parent to renegotiate boundaries within their relationship.

Led by Dr Kate Blake-Holmes, a lecturer in social work, the study explored the experiences of young carers who grew up with a parent with severe and long-term mental illness, and their understanding of their parent's illness from childhood to the present day.

The findings are published in the journal Advances in Mental Health, and reveal five key challenges for young adult carers: education and employment, relationships with partners, becoming a parent, making choices within their lives and maintaining boundaries with parents.

Dr Blake-Holmes, herself a social worker with experience in the field of mental health, said: "The term young carer implies that the role stops once the child reaches maturity, but care for parents often continues into adulthood. However, as young carers reach the age of 18 the acknowledgement and support for their needs falls away in many areas.

"This study extends our knowledge of young carers' experiences and support needs during the transition to adulthood and suggests the need for services to support parents so that young adult carers are able to make choices about their own lives.

"Providing care for a parent is not in itself detrimental to a child; indeed it can be a positive experience, an expression of love and a thing to be proud of. However, it can become damaging if the level of care provided and the role and responsibilities attributed to the child fall far beyond what could reasonably be expected. If the child takes on an adult role beyond their developmental years it can negatively impact their own needs, coping skills and resilience."

"While some individuals drew strength from their adversity, this study suggests that emerging adulthood may be more complex for young adult carers and they may have 'grown up fast' in certain areas while their emotional and psychological growth could have been delayed in others."

The study involved interviews with 20 people from across the UK who had cared or continued to care for their parents. They ranged in age from 19 to 54 years old. For all of the participants the complexities of their relationship with their parent and a sense of responsibility to provide care continued into their adult lives.

One participant had to leave university to care for her mother, while others were not able to follow their desired career due to their caring commitments. Several participants had difficulties forming and maintaining relationships with partners. For one, the fear of becoming ill like her mother was so great that she asked her fiancé to sign a document giving him instructions and permission to leave her and have custody of any children should she show any symptoms.

Some of the participants made an active decision not to have children based on their experiences of parental mental illness, others planned to or had gone on to have children, but worried about the difficulty of balancing their children's needs with those of their parents.

There are procedures already in place that could help young carers, such as the transition assessment, which the Care Act 2014 requires local authorities to conduct for those approaching 18. However, Dr Blake-Holmes said these are rarely carried out.

"We need to push for these assessments to be done and to be having conversations with young people," said Dr Blake-Holmes. "Everything points towards the patient, which is understandable, but we also need to include young carers in decision-making and meetings about their parents. They are the ones living with them and responding to crises, yet there is a fear of discussing issues with young carers because services feel it is inappropriate.

"A lot of these people had really traumatic childhoods, but they still love their parents and their parents love them. Not everyone will have these experiences and this isn't about saying the children or their parents should have been looked after elsewhere, but things could have been easier for these young carers and as adults it's still impacting them now.

"It's about supporting these children, who are doing an amazing job, giving them the confidence to talk about their needs and ask for help, but also to support them in achieving their own goals."

While all of the participants in the study spoke of negative experiences, several also spoke of gaining specific skills and strengths as a result. One felt her childhood had enabled her to develop a "swiss army knife" of extraordinary skills and abilities that she could use to help others within her career.

Participants who felt they were most able to manage their parent's ill health were those who felt that their relationship with their parent could be fluid, suggesting a level of resilience. They were able to draw close to their parent at times of need without fearing that they would become enmeshed and unable to move back to a point where they could focus on their own emotional needs, external commitments and aspirations. This gave them a particular mindset which enabled them to adapt, not only within their relationship with their parent but also when faced with other stresses in their adult life.

In contrast, those who described themselves as fixed in the role of either "rejecting or rescuing" appeared most consumed by their parents' mental illness and unable to manage the relationships necessary for successful transitions into adulthood.

An artificial intelligence program developed by Carnegie Mellon University in collaboration with Facebook AI has defeated leading professionals in six-player no-limit Texas hold'em poker, the world's most popular form of poker.

The AI, called Pluribus, defeated poker professional Darren Elias, who holds the record for most World Poker Tour titles, and Chris "Jesus" Ferguson, winner of six World Series of Poker events. Each pro separately played 5,000 hands of poker against five copies of Pluribus.

In another experiment involving 13 pros, all of whom have won more than $1 million playing poker, Pluribus played five pros at a time for a total of 10,000 hands and again emerged victorious.

"Pluribus achieved superhuman performance at multi-player poker, which is a recognized milestone in artificial intelligence and in game theory that has been open for decades," said Tuomas Sandholm, Angel Jordan Professor of Computer Science, who developed Pluribus with Noam Brown, who is finishing his Ph.D. in Carnegie Mellon's Computer Science Department as a research scientist at Facebook AI. "Thus far, superhuman AI milestones in strategic reasoning have been limited to two-party competition. The ability to beat five other players in such a complicated game opens up new opportunities to use AI to solve a wide variety of real-world problems."

A research paper describing this achievement in AI will be published online by the journal Science on Thursday, July 11, 2019.

"Playing a six-player game rather than head-to-head requires fundamental changes in how the AI develops its playing strategy," said Brown, who joined Facebook AI last year. "We're elated with its performance and believe some of Pluribus' playing strategies might even change the way pros play the game."

Pluribus' algorithms created some surprising features into its strategy. For instance, most human players avoid "donk betting" - that is, ending one round with a call but then starting the next round with a bet. It's seen as a weak move that usually doesn't make strategic sense. But Pluribus placed donk bets far more often than the professionals it defeated.

"Its major strength is its ability to use mixed strategies," Elias said last week as he prepared for the 2019 World Series of Poker main event. "That's the same thing that humans try to do. It's a matter of execution for humans - to do this in a perfectly random way and to do so consistently. Most people just can't."

Pluribus registered a solid win with statistical significance, which is particularly impressive given its opposition, Elias said. "The bot wasn't just playing against some middle of the road pros. It was playing some of the best players in the world."

Michael "Gags" Gagliano, who has earned nearly $2 million in career earnings, also competed against Pluribus.

"It was incredibly fascinating getting to play against the poker bot and seeing some of the strategies it chose" said Gagliano. "There were several plays that humans simply are not making at all, especially relating to its bet sizing. Bots/AI are an important part in the evolution of poker, and it was amazing to have first-hand experience in this large step toward the future."

Sandholm has led a research team studying computer poker for more than 16 years. He and Brown earlier developed Libratus, which two years ago decisively beat four poker pros playing a combined 120,000 hands of heads-up no-limit Texas hold'em, a two-player version of the game.

Games such as chess and Go have long served as milestones for AI research. In those games, all of the players know the status of the playing board and all of the pieces. But poker is a bigger challenge because it is an incomplete information game; players can't be certain which cards are in play and opponents can and will bluff. That makes it both a tougher AI challenge and more relevant to many real-world problems involving multiple parties and missing information.

All of the AIs that displayed superhuman skills at two-player games did so by approximating what's called a Nash equilibrium. Named for the late Carnegie Mellon alumnus and Nobel laureate John Forbes Nash Jr., a Nash equilibrium is a pair of strategies (one per player) where neither player can benefit from changing strategy as long as the other player's strategy remains the same. Although the AI's strategy guarantees only a result no worse than a tie, the AI emerges victorious if its opponent makes miscalculations and can't maintain the equilibrium.

In a game with more than two players, playing a Nash equilibrium can be a losing strategy. So Pluribus dispenses with theoretical guarantees of success and develops strategies that nevertheless enable it to consistently outplay opponents.

Pluribus first computes a "blueprint" strategy by playing six copies of itself, which is sufficient for the first round of betting. From that point on, Pluribus does a more detailed search of possible moves in a finer-grained abstraction of game. It looks ahead several moves as it does so, but not requiring looking ahead all the way to the end of the game, which would be computationally prohibitive. Limited-lookahead search is a standard approach in perfect-information games, but is extremely challenging in imperfect-information games. A new limited-lookahead search algorithm is the main breakthrough that enabled Pluribus to achieve superhuman multi-player poker.

Specifically, the search is an imperfect-information-game solve of a limited-lookahead subgame. At the leaves of that subgame, the AI considers five possible continuation strategies each opponent and itself might adopt for the rest of the game. The number of possible continuation strategies is far larger, but the researchers found that their algorithm only needs to consider five continuation strategies per player at each leaf to compute a strong, balanced overall strategy.

Pluribus also seeks to be unpredictable. For instance, betting would make sense if the AI held the best possible hand, but if the AI bets only when it has the best hand, opponents will quickly catch on. So Pluribus calculates how it would act with every possible hand it could hold and then computes a strategy that is balanced across all of those possibilities.

Though poker is an incredibly complicated game, Pluribus made efficient use of computation. AIs that have achieved recent milestones in games have used large numbers of servers and/or farms of GPUs; Libratus used around 15 million core hours to develop its strategies and, during live game play, used 1,400 CPU cores. Pluribus computed its blueprint strategy in eight days using only 12,400 core hours and used just 28 cores during live play.