Culture

For most people who die of cancer, the spread of the initial tumor is to blame. "Metastasis is what kills most cancer patients," says Serge Fuchs, a professor in Penn's School of Veterinary Medicine. "Yet there are not many, if any, drugs that specifically target metastatic processes."

In a paper in the journal Nature Cancer, Fuchs teamed with researchers from around campus and elsewhere to overcome that lack, studying the molecular players that foster cancer's spread and identifying a strategy to stop it. Using an inhibitor of the enzyme known as p38α kinase (p38), they successfully reduced the spread of melanoma in a mouse model, significantly prolonging survival time.

"In my opinion, this kind of therapy could be used in conjunction with surgery to remove the primary tumor or perhaps other cancer treatments, such as chemotherapy," says Fuchs.

The study emerged from conversations and collaborations that have been ongoing for years among Penn groups, including those of Penn Vet's Ellen Puré and the Perelman School of Medicine's Constantinos Koumenis, Sandra Ryeom, and Ben Stanger, as well as the nearby Wistar Institute's Dmitry Gabrilovich. All focus on different aspects of cancer biology.

Many of these conversations revolved around what are known as tumor-derived factors (TDF): the various proteins, lipids, vesicles, genetic material, signaling molecules, and other compounds that tumors secrete and which, in some cases, travel around the body. Scientists believe many of these factors help "prepare the soil," as it is often described, for the growth of metastases, making areas in the normal tissues more hospitable to tumor cells that are likewise traveling the body and disseminating to these areas.

"We kept saying how the tumors and the factors are so different and their chemical nature is so different and their receptors are different and how they're perceived by different types of normal cells," Fuchs says. "But these areas in the lung that invite disseminated malignant cells and are conducive to their growth as metastases are, generally speaking, all alike."

Aiming to focus on what united metastases, the researchers initially looked for elements that distinguished melanoma tumor cells that tended to be more metastatic from a melanoma cell line that was less so. When they introduced TDF from the more aggressive disease into normal mice, these animals developed pre-metastatic niches: areas conducive to the development of cancer metastases. Animals that received TDF from a less aggressive form of melanoma hardly developed these niches.

They also paid attention to the p38, as it is known to be activated in response to certain factors secreted by cancer cells. They observed that its activation correlated with metastasis, becoming more highly activated by the TDF from the highly metastatic melanoma and less activated by the less metastatic melanoma.

To confirm that this enzyme was important in the metastatic process, the team tried two tactics: either eliminating the enzyme using genetic manipulation or blocking the effect of the kinase's activity using an inhibitor that stopped the pathway it activates.

"By doing either of these, we didn't get a pre-metastatic niche," says Fuchs.

To give their findings a clinical context, they looked at white blood cells from patients with melanoma. Those who did not have signs of metastasis had significantly lower p38 activation than those with a diagnosis of metastatic disease.

Next they examined the lungs of mice that were given the TDF from a metastatic cancer to learn more about what p38 was doing to cultivate the pre-metastatic niche. The team found that activation of p38 by TDF in lung fibroblasts, which are connective tissue cells, increased the fibroblasts' activity and stimulated production of fibroblast activating protein (FAP), a molecule which Puré has long focused on and which has been shown to influence tumor growth and metastasis. Production of FAP then helped to recruit immune cells called neutrophils, which further acted on the pre-metastatic niche areas within lung tissue to augment their ability to trap and stimulate the growth of metastatic cells.

Hoping to prevent the formation of this niche and, ideally, metastasis, Fuchs and colleagues treated mice with two different inhibitors of p38, while also surgically removing their primary tumors. Both treatments suppressed the spread of cancer to the lung and prolonged the animals' survival.

One of the therapies they tested, ralimetinib, is an experimental cancer drug with somewhat lackluster performance at treating primary tumors. But initial trials have shown it to be relatively safe, suggesting that it could be a specialized component of the cancer-fighting arsenal, tamping down the primary tumor's ability to spread.

PITTSBURGH-- Faced with a common peril, people delay making decisions that might save lives, fail to alert each other to danger and spread misinformation. Those may sound like behaviors associated with the current pandemic, but they actually surfaced in experiments on how social networks function in emergencies.

Hirokazu Shirado, an assistant professor in Carnegie Mellon University's Human-Computer Interaction Institute, said he had expected his experiments to show that social networks, such as neighbors, work groups and extended families, would improve decision-making by giving people actionable information.

"What we found is that social networks make things worse," said Shirado, who began the research while a member of the Human Nature Lab at Yale University. A paper on their work appeared this week in the Proceedings of the Royal Society A.

Gathering data about social networks in the midst of a crisis is difficult, so Shirado devised a game in which online participants had an economic stake in making a decision whether to evacuate in the face of danger. He recruited 2,480 subjects and organized them into 108 groups, comparing how networked groups and isolated individuals compared in their decision making.

Participants received $2 at the outset of the 75-second experiment. If nothing happened, they could keep the $2 at the end. But if there was an impending disaster, they could leave the game and retain $1. If they failed to evacuate and disaster struck, they lost everything. They also received 10 cents for every other player who made a correct decision on whether to leave the game.

The participants thus had every incentive to choose correctly and were encouraged to communicate with each other. One member of each social network group also received the correct information about impending danger.

Compared with the isolated individuals, the networked players consistently tended to resist evacuation, regardless of whether the danger was real or not. Communication didn't improve decision-making so much as it delayed it, Shirado said. The networked players also generated misinformation, even though nobody had an incentive to do so.

One of the problems, he said, is that players didn't realize that they often used different strategies. A player who accepts "no news is good news," for instance, might think that all is safe simply because he hasn't heard anything. He might then send "safe" signals to other members of the group even though danger lurked. In other cases, players might be unable to learn the truth because the players adjacent to them all had bad information.

Shirado has used the same game as an educational tool in his CMU classes, including one instance just before the onset of the COVID-19 pandemic. He recalled one student was skeptical, arguing that there was no reason why the players couldn't choose correctly. But about 70 percent of the students -- including the skeptic -- erred in their decisions.

"Inside the networks, people could not understand why this was happening," he added.

Social media -- one type of social network -- was not included in the study, but might actually improve performance, Shirado said. Though individuals tend to follow like-minded people on social media, it's also easy to connect with others who might fall outside normal social networks, providing a way around some of the barriers that form within networks.

Shirado said he hopes to find ways of improving the performance of social networks.

"We cannot live without social networks," he explained. "I'm interested in how social networks can provide a benefit to individuals."

He acknowledged that one of the shortcomings of his experiment is that it was too simple and involved people who were randomly assigned into networks. Future experiments will require players to play several times with the same network of individuals, so they might learn who to trust.

May 27, 2020, NEW YORK, NY - As chromosomes go, X and Y make an unlikely pair. The X is large and contains thousands of genes critical for life. The Y, by contrast, is little more than a nub. Its main purpose is to provide the instructions for initiating male development and making sperm. Yet these two very different chromosomes must work together if they are to meet and pair up properly during meiosis -- the special form of cell division that creates sperm and egg.

How this happens has remained mysterious for decades. But scientists at the Sloan Kettering Institute have now figured it out. The answer involves some very deliberate breaking and rejoining of DNA.

Breaking is a theme of meiosis. During this process, every chromosome we got from our mothers lines up with every chromosome we got from our fathers and the two swap segments. Before this swapping can occur, the DNA in the chromosomes must be deliberately broken. The regions that are swapped are "homologous" -- they're found in the same place along the chromosome and contain the same genes (although the particular DNA sequence of each gene may be slightly different).

Homologous recombination is vastly more challenging for males because most of the X chromosome has nothing to pair with. In fact, only a very tiny portion of the already tiny Y chromosome has any homology with the X. This region is called the pseudoautosomal region (PAR), and it's critical for making sure that X and Y find their way into different sperm cells.

Scientists have known for a long time that the PAR undergoes breaking and swapping of segments at a level that far outpaces what one would expect, given its size.

"On most chromosomes, DNA double-strand breaks typically occur once every 10 million base pairs," says Scott Keeney, a molecular biologist at SKI, who studies this phenomenon. "The PAR in mice is less than 1/10 that size but it still manages to undergo frequent double-strand breaks."

In a new study published May 27 in the journal Nature, Dr. Keeney and colleagues -- including molecular biologist Laurent Acquaviva and longtime collaborator Maria Jasin -- show how this happens.

What's in a Blob?

The key to proper pairing of X and Y, they discovered, is a repeated sequence of DNA in the PAR that attracts several double-strand break-related proteins to this region. These protein clusters -- which Dr. Acquaviva dubbed "blobs" -- change the architecture of the chromosome in this region in such a way that the PAR becomes, as the authors put it, "the hottest area of double-strand break formation in the male mouse genome."

Similar blobs had been seen in images from published studies. But Dr. Acquaviva -- a postdoctoral fellow in the Keeney lab, the lead researcher on the project, and a co-corresponding author on the paper -- was the first to define what's in these blobs and connect them to the hyper-accumulation of double-strand breaks in this region.

"At first glance, the blobs just look like a mess you might see in the microscope if the experiment didn't work," Dr. Acquaviva says. "But they turned out to be completely predictable in number, timing, and location, so it became clear that in reality they are very complex structures that the cell builds on purpose."

In fact, he says, these blobs were key to understanding how the PAR DNA is tethered as short loops to the linear axis that is the structural backbone of the chromosome.

Though the X chromosome also has this same repeated DNA sequence, the two X chromosomes in female meiosis typically do not recombine at this region. Why not? The SKI scientists show that it is because pairing between other regions of the X tends to happen first and directly opposes breakage at the PAR.

This strategy of recruiting more than one's expected share of DNA-breaking proteins may not be limited to the PAR region. In a paper published earlier this month, the Keeney lab showed that small chromosomes in budding yeast resort to a similar tactic.

Groundbreaking Partnership

These new discoveries, which were made in mice, are the latest fruit of a longstanding collaboration between the Keeney and Jasin labs at SKI. "Scott and I began collaborating back in 1997 when he joined SKI," she says. "This paper will be our 40th together. It's a tribute to the collaborative atmosphere of SKI." In fact, an accompanying editorial published along with the new paper was written by a former collaborative fellow, Francesca Cole, now a faculty member at MD Anderson Cancer Center.

Drs. Jasin and Keeney are both interested in homologous recombination, but they bring complementary expertise to their collaboration. Dr. Jasin is an expert in mammalian double-strand break repair and Dr. Keeney is a specialist in how yeast does meiosis.

Last month, the team's 39th paper was published in the journal Molecular Cell. In it, they provide the most detailed look yet into how double-strand breaks are repaired. "I am hoping it will change the textbook version of how DNA strands move around during meiotic recombination," Dr. Jasin says. "But many exciting questions still remain to be tackled." In other words, stay tuned for more 'breaking' news from this team of scientists.

As the novel coronavirus spread across the globe in early 2020, hospitals worldwide scaled back medical procedures, including life-saving heart surgery, to deal with the emerging threat of COVID-19. Now, as the SARS-CoV-2 virus becomes a chronic fact of life, hospitals must find ways to resume cardiac surgeries while protecting patients and health care workers as much as possible from SARS-CoV-2.

Dr. Marc Ruel, professor in the Departments of Surgery and Cellular and Molecular Medicine at uOttawa Faculty of Medicine, and M. Pitfield Chair & Head, Division of Cardiac Surgery at the University of Ottawa Heart Institute, is the senior author of two recent articles that examine how cardiac surgery centres have been impacted by the COVID-19 pandemic, and how they can resume operations in an environment characterized by a low-grade, long-term prevalence of SARS-CoV-2.

"Cardiac surgeons, who provide lifesaving procedures, must manage two threats at the same time: obviously the threat from COVID, and that of death or complications from untreated heart disease. As such, patients with the most pressing cardiac needs have to be triaged as objectively and as reliably as possible, using predictor tools such as the one developed at the University of Ottawa by my colleague Dr. Louise Sun, from the Department of Anesthesia and Pain Medicine," Dr. Ruel said. "Every day we strive to preserve capacity for a possible COVID surge, but at the same time we must optimally manage our many patients who need heart surgery, help ease their anxieties, and safely return them to enjoying a healthy life."

In the first article, "Response of Cardiac Surgery Units to COVID-19: An Internationally-Based Quantitative Survey," published in Circulation, Dr. Ruel and his co-authors found that 60 cardiac surgery centres in 19 countries had reduced their cardiac surgeries by an average of 50 to 75% in response to the pandemic.

"The widespread interruption in cardiac surgery described herein adds to the concerning observation that excess non-COVID-19 mortality may now surpass mortality directly related to COVID-19 infections," the article noted.

The second article, "Committee Recommendations for Resuming Cardiac Surgery Activity in the SARS-CoV-2 Era: Guidance from an International Cardiac Surgery Consortium" published in The Annals of Thoracic Surgery, contains 12 recommendations developed by a consortium of experts in 19 countries. The recommendations cover topics such as: prioritizing surgeries; dealing with cardiac patients who test positive for COVID-19; and patient discharge and follow-up protocols.

DURHAM, N.C. – Small-scale gold mining in the Peruvian Amazon poses a health hazard not only to miners but also to nearby communities. Contrary to common assumption that communities closest to mining bear the brunt of exposure, new evidence shows that the highest non-occupational mercury exposures occur in native communities hundreds of kilometers away from mining.

In communities where fish is an important part of the diet, children under 12 with the highest levels of mercury in their hair (exceeding the World Health Organization guideline) have been found to have intellectual deficits amounting to a loss of 4.68 IQ points. Even children with exposure below this guideline show effects amounting to a 0.8 IQ point drop for every 1 part per million increase in hair mercury. This effect is roughly four times larger than detected in an earlier study of prenatal mercury exposure in the Republic of Seychelles.

Both findings come from a series of studies conducted by Duke University scientists in and around the Amarakaeri Communal Reserve in the Madre De Dios region of Peru. They appear in a pair of papers published May 20 GeoHealth and May 28 in the Journal of Exposure Science and Environmental Epidemiology.

The studies show that common assumptions about mercury exposure should be reexamined, and that native people in the region are more vulnerable to harm, probably because of their greater reliance on river fish, but also perhaps because their healthcare and standard of living is not as high.

“We can’t just rely on assumptions or “common sense” in science,” said lead author Caren Weinhouse, an assistant professor at Oregon Health & Science University. Many studies have looked at communities closest to the mines on the assumption that they would have the greatest mercury exposures. “We assumed that people closest to mining would have the highest exposure, but we were wrong,” she said. “The lesson is that if we only focus on the people we assume are at risk, we might end up missing the big picture.”

Artisanal and small-scale gold miners in the Peruvian Amazon use liquid elemental mercury to extract gold from soils and sediments. The mercury binds to the gold to form an amalgam, which is then extracted by burning, creating gaseous mercury that enters the atmosphere. The rest of the mercury ends up dumped on the landscape, which is ravaged and eroded by the mining. Miners are also known to simply pour excess mercury directly into surface waters.

As the mercury travels and mixes with the environment, it becomes methylmercury, which is more readily taken up by animals and tends to ‘bio-accumulate’ or add up in tissues, and then “biomagnify” as bigger fish eat contaminated little fish. Although all native communities showed high exposure, their river locations shed light on the likely exposure source. In two sampled native villages that were on tributaries of the Madre de Dios River, mercury exposure was lower than in native people living on the main stem of the river where mining runoff is concentrated, leading the scientists to conclude that fish is the likely exposure source and mining is the likely culprit.

Mercury is a neurotoxic metal that can lead to muscle weakness and problems with coordination in high doses, and neurodevelopmental delay, hyperactivity and IQ deficits in lower doses.

To gather data on hair and blood concentrations of mercury, both near mining operations and farther away, the researchers visited 1,221 Peruvian households in 23 communities in 2015 and returned to resample 900 of those households the following year.

Some of the children in a subsample of the population had higher mercury levels and were on average lower in cognitive ability. A third of the children were found to have mercury levels higher than the World Health Organization’s exposure guidelines.

“We knew going in that mercury caused IQ deficits. What we didn’t know was whether the risk was the same in this setting as it is in prior studies, which were done in “healthy, wealthy” populations,” said Duke graduate student Aaron Reuben, who led the smaller pilot study on children. Reuben explained that children in Madre de Dios are already at high risk for IQ deficits, because they have poor nutrition and socioeconomic status.

An earlier, benchmark study of prenatal mercury exposure conducted in the Republic of Seychelles reported a loss of 0.18 IQ points for every 1 part per million increase in maternal hair mercury, an effect about four times lower than those in the Peru study. Hair mercury levels in both the Seychelles and Peru studies likely reflect fetal exposure, which allows comparisons of their results.

“This study suggests that mercury may affect brain development more at the same doses in higher risk populations,” said Reuben. He noted that the group didn’t account for the effects of possible prenatal exposure in the tested children.

The researchers also found initial evidence that the higher the mercury levels in a child’s blood, the lower their hemoglobin levels, corroborating an earlier study from this research team.

“Although mercury is not generally considered a risk factor for anemia, it might be in a population with other, pre-existing risk factors for the disease,” said William Pan, the Elizabeth Brooks Reid and Whitelaw Reid associate professor of environmental sciences and policy at Duke. “Given that anemia affects over 2 billion people and mercury is a global pollutant, this is a priority research area.” Another earlier study by the Duke team found that children with higher mercury exposures were less responsive to vaccines, especially if they were also malnourished.

“Taken together, the message is that we can’t assume that we know who is exposed unless we look, and we can’t assume that health risks will translate from developed countries,” Weinhouse said. “These studies show that highest exposures happen in vulnerable, native communities and that they might be at risk for even greater harm than healthy people with the same exposures.”

ITHACA, N.Y. - Bacteria have a cunning ability to survive in unfriendly environments.

For example, through a complicated series of interactions, they can identify - and then build resistance to - toxic chemicals and metals, such as silver and copper. Bacteria rely on a similar mechanism for defending against antibiotics.

In E. coli bacterium, the inner membrane sensor protein CusS mobilizes from a clustered form upon sensing copper ions in the environment. CusS recruits the transcription regulator protein CusR and then breaks down ATP to phosphorylate CusR, which then proceeds to activate gene expression to help the cell defend against the toxic copper ions.

Cornell researchers combined genetic engineering, single-molecule tracking and protein quantitation to get a closer look at this mechanism and understand how it functions. The knowledge could lead to the development of more effective antibacterial treatments.

The team's paper, "Metal-Induced Sensor Mobilization Turns on Affinity to Activate Regulator for Metal Detoxification in Live Bacteria," published May 28 in Proceedings of the National Academy of Sciences.

"We were really interested in the fundamental mechanism," said Peng Chen, the Peter J.W. Debye Professor of Chemistry in the College of Arts and Sciences and the paper's senior author. "The broader concept is that once we know the mechanism, then perhaps we can come up with better or alternative ways to compromise bacteria's ability in defending against toxic chemicals. That will hopefully contribute to designing new ways of taming bacterial drug resistance."

The bacteria's resistance is actually a tag-team operation, with two proteins working together inside the cell. One protein (CusS), in the inner membrane, senses the presence of the chemical or metal and sends a signal to a regulator protein (CusR) in the cytosol, or intercellular fluid. The regulator protein binds to DNA and activates a gene that generates transport proteins, which purge the toxin from the cell.

Typically, scientists analyze these functions by using biochemical assays that remove the protein from the cell. However, that process prevents the scientists from observing the proteins in their native environment, and certain details, such as the spatial arrangement between proteins, have remained murky.

For a deeper analysis, Chen's team used single-cell imaging, whereby they tagged individual proteins in living E. coli with a fluorescent signal and imaged the proteins one at a time, tracking their motions. The procedure yielded millions of images and, ultimately, a finely detailed, qualitative map of the proteins' movement.

The team was specifically interested in the activities of sensor proteins, which come in two varieties - those that cluster together and those that move around the inner membrane. The researchers found that when E. coli encounters copper, the free-floating, mobile variety of the sensor proteins increase in number while the clustered faction are reduced. The mobilized sensor proteins interact with the regulator protein and initiate a complex series of steps - from binding the copper to binding and breaking down the compound ATP, which eventually lead to gene expression - that will flush the metal from the cell.

"One of the unknowns among the steps is at what point the sensor protein forms a protein-protein complex with the regulator protein," Chen said. "We found that as soon as the sensor binds copper, it already causes its recruitment of this regulator protein. This occurs really, really early in this sequence of events."

The early recruitment provides a functional advantage by initiating the sequence and quickly speeding it along before the sequence has time to decay. Chen likens this strategy to a game of hot potato.

"If I hold a hot potato and want to give it to you, I don't want to hold the potato before calling you over," Chen said. "I want you to be right next to me, so I can immediately pass it to you. Otherwise, the hot potato becomes cold. Or it's too hot, so I have to throw it away. In chemical terms, basically that species would decay or transfer to something else."

ITHACA, N.Y. - A new study examines the symbiotic relationship between two types of bacteria and spittlebugs that helps the insect live on very low-nutrient food. The bacteria use a metabolic "trick" also employed by cancer cells to create the right conditions for converting the poor food into the necessary building blocks for survival.

The study, "Syntrophic Splitting of Central Carbon Metabolism in Host Cells Bearing Functionally Different Symbiotic Bacteria," published April 29 in the journal of the International Society for Microbial Ecology.

Spittlebugs get their name from the bubbly spit they create in plant branches. The clusters of spit keeps them from drying out and allow them to hide from predators. There they feed on xylem plant sap, a very low-value food; xylem transports water and minerals from the plant's roots to its leaves.

"No animal should be able to subsist on xylem alone - it's really just water and a few nutrients," said lead author Nana Ankrah, a postdoctoral researcher in the lab of Angela Douglas, the Daljit S. and Elaine Sarkaria Professor of Insect Physiology and Toxicology in the Department of Entomology in the College of Agriculture and Life Sciences.

The answers to how these bugs survive lie in two types of bacteria that live in separate spittlebug organs, called bacteriomes; one is red, the other orange. Other similar insects that feed on plant sap have just one bacterial partner to help produce high-quality amino acids, the building blocks of proteins.

"We wanted to understand if there were any advantages to having two bacterial symbionts on this very poor diet," Ankrah said.

The researchers collected local spittlebugs, removed their red and orange bacteriomes, incubated the bacteria separately in glucose, and ran metabolic experiments and computer model simulations.

They discovered that the red bacteriome uses a process known as aerobic glycolysis to process glucose, from which the bacteria synthesize seven essential amino acids. Two byproducts of this process, pyruvate and lactate, are assimilated by the orange bacteriome to create ATP molecules, which make energy for cells. The energy boost from ATP allows the bacteria in the orange bacteriome to produce three additional essential amino acids that require a great deal of energy to produce.

Having two bacterial partners instead of one works because they have this method for exchanging products from one bacterium to the other to increase the overall energy available to them, Ankrah said.

The researchers were surprised to find aerobic glycolysis occurring in these bacteria, as cancer cells employ the same process to survive, with a subset of cancer cells undergoing glycolysis and producing pyruvate and lactate, which another subset of cancer cells consumes to create energy.

"To our knowledge," Ankrah said, "our article is the first demonstration of aerobic glycolysis as a strategy to facilitate amino acid production in symbioses."

Future studies will investigate glycolysis in other insect and bacteria partnerships, he said.

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by excessive fat accumulation in the liver. It can cause serious complications, including nonalcoholic steatohepatitis, cirrhosis, and cancer. Although prevalent, there is a dearth of drugs to treat NAFLD, with current therapies revolving around lifestyle interventions.

In a recent study published in Journal of Medicinal Chemistry, scientists from Gwangju Institute of Science and Technology, Korea, led by Prof Jin Hee Ahn, aimed to find new therapeutic options for NAFLD. Prof Ahn says, "NAFLD is a serious public health problem worldwide. However, no pharmacological agents have been specifically approved for its treatment yet."

For their study, the scientists focused on a well-known neurotransmitter called serotonin. Serotonin is widely known as the "happy" neurotransmitter, and its deficiency in the central nervous system (CNS) can cause various brain disorders. But, not many know that it is also found in the gastrointestinal tract; here, it is called "peripheral" serotonin, which has different functions altogether, such as regulating lipid metabolism in the liver.

In a previous study published in Nature Communications, Prof Hail Kim, the co-corresponding author of this study, had investigated peripheral serotonin as a drug target with knockout mice models (mice lacking functional peripheral serotonin). This study reported that these mice showed reduction in liver weight, hepatic lipid accumulation, and hepatic triglyceride content and improved NAFLD activity.

These findings formed the basis of Prof Ahn's study and prompted the research group to identify new peripheral serotonin antagonists. The scientists selected a CNS drug approved for the treatment of Parkinson's, called pimavanserin. Pimavanserin acts as an "antagonist" to serotonin, mimicking its effect in the CNS. The scientists then structurally modified this drug such that it cannot permeate the blood-brain barrier, by adding different types of molecules to it. In this way, they generated an array of novel compounds. On testing these, the scientists found one compound in particular to show promising results: it showed very low blood-brain barrier permeation and thus had the potential to target peripheral serotonin systems.

The scientists tested this compound in obese mice with impaired liver function. Interestingly, the mice showed improvement in symptoms of fatty liver disease, such as improved glucose tolerance. Additionally, their body fat decreased while lean body mass increased. Prof Ahn says, "Through the chemical optimization of an existing drug, pimavanserin, we identified a new peripheral agent for the possible treatment of NAFLD."

Although this novel compound is yet to be tested in humans, these findings show that it has remarkable potential in treating fatty liver disease. Optimistic about these findings, Prof Ahn concludes, "We hope that our novel drug candidate will offer relief to patients bearing the brunt of NAFLD."

The people who lived in the area known as the Southern Levant--which is now recognized as Israel, the Palestinian Authority, Jordan, Lebanon, and parts of Syria--during the Bronze Age (circa 3500-1150 BCE) are referred to in ancient biblical texts as the Canaanites. Now, researchers reporting in the journal Cell on May 28 have new insight into the Canaanites' history based on a new genome-wide analysis of ancient DNA collected from 73 individuals.

"Populations in the Southern Levant during the Bronze Age were not static," says Liran Carmel of The Hebrew University of Jerusalem. "Rather, we observe evidence for the movement of people over long periods of time from the northeast of the Ancient Near East, including modern Georgia, Armenia, and Azerbaijan, into the Southern Levant region.

"The Canaanites, albeit living in different city-states, were culturally and genetically similar," he adds. "In addition, this region has witnessed many later population movements, with people coming from the northeast, from the south, and from the northwest."

Carmel and colleagues came to these conclusions based on an analysis of 73 new ancient DNA samples representing mainly Middle-to-Late Bronze Age individuals from five archaeological sites across the Southern Levant. To these new data, the researchers added previously reported data from 20 individuals from four sites to generate a dataset of 93 individuals. The genomic analysis showed that the Canaanites do represent a clear group.

"Individuals from all sites are highly genetically similar, albeit with subtle differences, showing that the archaeologically and historically defined 'Canaanites' corresponds to a demographically coherent group," Carmel says.

The data suggest that the Canaanites descended from a mixture of earlier local Neolithic populations and populations related to Chalcolithic Iran and/or the Bronze Age Caucasus. The researchers documented a significant increase in the proportion of Iranian/Caucasus-related ancestry over time, which is supported by three individuals who are descendants of recent arrivals from the Caucasus.

"The strength of the migration from the northeast of the Ancient Near East, and the fact that this migration continued for many centuries, may help to explain why rulers of city-states in Canaan in the Late Bronze Age carry non-Semitic, Hurrian names," says Shai Carmi of The Hebrew University of Jerusalem. "There were strong and active connections between these regions through movements of people that help to understand the shared elements of culture."

The researchers also studied the relationship of the Canaanites to modern-day populations. While the direct contribution of the Canaanites to modern populations cannot be accurately quantified, the data suggest that a broader Near Eastern component, including populations from the Caucasus and the Zagros Mountains, likely account for more than 50 percent of the ancestry of many Arabic-speaking and Jewish groups living in the region today.

Carmel reports that they are now working to extend their sampling, both geographically and over time. "We wish to analyze Iron Age samples from different areas of the southern Levant," Carmel says. "This may shed light on the composition of the populations in the biblically mentioned kingdoms of the region, among them Israel, Judah, Ammon, and Moab."

Using the very latest wide-bore magnetic resonance imaging (MRI) scanning equipment at the University of Nottingham experts found differences in blood flow to the placenta in healthy and pre-eclampsia pregnancies, a finding which could help understand why in pre-eclampsia the baby can be born small and pre-term.

The research published today in PLOS Biology also identified a completely new phenomenon which the researchers have termed the 'uteroplacental pump'. This involves contractions of placenta and the part of the uterine wall to which it is attached.

The placenta is vital in the transfer of the right amount of nutrition and oxygen from the mother to the baby. Any disturbance to the flow of blood could affect the delivery of vital nutrients restricting fetal growth. If the placenta is not working properly this can lead to pre-eclampsia.

In the placenta the fetal blood flows in tree-like villi which are bathed in a lake of the mother's blood, so that the two different blood supplies are kept separate. Changes in blood flow and oxygenation affects fetal growth and well-being.

Unprecedented insight

The research team scanned 34 women with healthy pregnancies and 13 women diagnosed with preeclampsia, gaining an unprecedented insight how the maternal blood percolates between the villi and how this affects placental oxygenation.

Dr Neele Dellschaft, from the University of Nottingham's School of Physics and Astronomy led the research, she explains: "I am part of a team of scientists who have used MRI to look at how blood flows through the placenta to deliver oxygen to the baby. We found that in healthy pregnancies the blood flows very slowly. This seems odd at first but our other measurements suggest that this is a way in which the placenta can function efficiently. We also found that the normal patterns of flow and oxygenation were much more variable in pre eclampsia, which can help explain why babies of pre-eclamptic pregnancies tend to be smaller and often have to be delivered before term.

Most excitingly, we also identified a completely new phenomenon which we called the 'uteroplacental pump'. This is a contraction of the placenta and the part of the uterine wall to which it is attached and it is not the same as the well-known Braxton Hicks contractions in which the entire uterus contracts in practice for labour. We now want to work out the purpose of these contractions but we think it might be to stop blood stagnating in parts of the placenta."

Professor Penny Gowland added: "At present we have no clinical tools to assess the function of the placenta directly, all we can do is assess the size and growth of the baby and blood flow in the umbilical cord using ultrasound. This research demonstrates that MRI is hugely effective in providing detailed information of exactly what is happening between the baby and the mother and what is changed in a pre-eclampsia pregnancy. It's also hugely exciting to have discovered a brand new physical phenomenon that takes place during pregnancy. We hope in the future this knowledge can be built upon by clinicians to better diagnose and manage conditions like preeclampsia."

The exchange of ideas and material culture in Western Asia is well established within archaeological research. Although distinct traditions and systems of social organization emerged across Western Asia, the region from the Southern Caucasus to Anatolia and Mesopotamia had been a hub for the exchange of ideas and material culture for millennia. The extent of these exchanges, however, and the processes that lead farming communities to organize into complex societies, is still poorly understood. Was this process primarily a movement of ideas and materials, or did it also include large-scale movement of populations?

To answer this question, scientists from research institutes and universities in Europe, Asia, and North America*, led by the Department of Archaeogenetics at the Max Planck Institute for the Science of Human History (MPI SHH), analyzed genome-wide data from 110 skeletons dated approximately 7500 to 3000 years ago from archaeological sites in Anatolia, Northern Levant, and the Southern Caucasus. Their analysis indicates two influential genetic events, as well as evidence for long-distance individual movement.

A large genetic cline and a sudden genetic shift

During the late Neolithic, approximately 8,500 years ago, populations across Anatolia and the Southern Caucasus began to genetically mix, resulting in a distinct admixture that gradually spread across the entire region. This gradual change of genetic profile over a geographic region, known as a cline in genetics, could be seen millennia later in Anatolian populations from Central-North to Eastern Anatolia. Rather than indicating stationary populations, as apparent genetic continuity often does, the authors argue the spread of genetic information from North and Central Anatolia to the Southern Caucasus and the Zagros mountains in today's Northern Iran indicates ongoing human mobility and the development of a regional genetic melting pot in Anatolia.

"This far-reaching vortex of homogenization shows that ancient people within Western Asia biologically mix before their increasing connectedness and emerging sociocultural developments became visible in the archaeological record," says Johannes Krause, director of the Department of Archaeogenetics at MPI SHH, co-director at Max Planck - Harvard Research Center for the Archaeoscience of the Ancient Mediterranean (MHAAM) and senior author of the study.

In contrast to the gradual changes taking place in Anatolia, the Northern Levant experienced an introduction of new populations. "We found that the genetic makeup of Bronze Age populations from the ancient cities of Alalakh and Ebla in today's southern Turkey and northern Syria differed from preceding populations from the same area," says Eirini Skourtanioti, lead author of the study. "We detected subtle genetic changes that point to influences from external groups."

This observation could contribute to debate on human mobility between the third and second millennium BC, as there are different interpretive constructs centering on either increasing inter-regional connectivity in these periods or migration connected with a mega-drought known as the "4.2k BP event." Regarding the latter, archaeological evidence indicates an abandonment of the Khabur river valley and texts record the migration of groups such as the 'Amorites' and 'Hurrians.' Ancient Mesopotamia was likely the source of the new genetic influence observed at Alalakh and Ebla, according to material evidence and geoarchaeological research currently under study by the Alalakh excavation team; however, to date no ancient genomes have been successfully retrieved from this region.

Curious burial taps a wellspring of questions

In addition to long-term transitions at the scale of entire populations, the team also found evidence of long-distance movements at the individual level. At the Alalakh site in southern Turkey, the team found an individual whose genetic profile is most similar to Bronze Age populations in Central Asia. In addition to being a genetic outlier, the individual, who was identified as female, was unearthed at the bottom of a well which was in use at the time of her consignment.

"I was fascinated by our results for the 'lady in the well,'" says Philipp Stockhammer, co-director of MHAAM and another senior author of the study. "She provides a unique insight into individual female mobility over large distances. We know from literary sources that women travelled in this time throughout Western Asia - very often as marriage partners. However, the story of this woman of Central Asian origin will remain an enigma."

The context of this finding raises many questions, many of whose answers are beyond the resolution of modern analytical tools. How did this woman and/or her recent ancestors move from Central Asia to Northern Levant? Was she forced to leave her homeland? What was her role in the society, and was this an accident or a murder? Despite these questions, this woman demonstrates the long distances humans travelled in the past and points to the existence of migrant communities in a globalized ancient world.

DURHAM, N.C. -- Duke University researchers have developed a synthetic molecule that selectively dampen the physiological rewards of cocaine in mice. It also may represent a new class of drugs that could be more specific with fewer side effects than current medications.

In mice that were treated with the stimulant cocaine or methamphetamine, the new molecule was found to calm their drug-induced hyperactivity and interfere with the dopamine system's ability to change metabolism in the brain's rewards center.

In mice that were allowed to self-administer cocaine, the treatment slowed down their drug use in 20 minutes to an hour, and reduced the amount of drug they used by more than 80 percent, compared to a control group of mice.

The molecule, SBI-553, activates cell surface chemical receptors called G protein-coupled receptors or GPCRs, which are the target of more than 35% of all FDA-approved drugs. (The discovery and characterization of GPCRs earned the team's Duke colleague, Robert Lefkowitz, the 2012 Nobel Prize in chemistry.)

When a GPCR is activated by a signaling molecule, it transmits that signal to the inner portion of the cell via interaction with two intracellular proteins: G protein and beta-arrestin. Most GPCR drugs in use today indiscriminately activate both G protein and beta-arrestin, and sometimes activating both molecules withthe same GPCR can produce dramatically different physiological effects.

Drug developers have been trying to identify compounds that selectively activate one or the other because they have the potential to be safer drugs with fewer side effects.

In a paper appearing online May 28 in the journal Cell, the Duke researchers report the development of a new class of small molecules that may allow for just that - thereby separating the good effects from the bad.

"This kind of idea has been kicking around for 20 years or so," said senior author Marc Caron, the James B. Duke professor of Cell Biology in the School of Medicine. His work has focused on GPCR signaling involved in disorders like addiction, schizophrenia, Parkinson's Disease and depression.

For decades, researchers working on drug abuse and addiction have pursued molecules that would activate one specific GPCR called neurotensin receptor 1 (NTSR1) as a way to interrupt the actions of stimulants and treat cocaine and methamphetamine addictions.

Neurotensin is known to be involved in drug-seeking behavior and food intake in mice. "It regulates the brain's reward system and motivated behavior," said senior post-doctoral fellow Lauren Slosky, who is the lead author on the paper.

But so far, the drugs that activate NTSR1 have severe side effects for blood pressure, body temperature and motor coordination, because those are also controlled by NTSR1. "This was known, but nobody could do anything about it," Caron said.

In collaboration with the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, the Duke team screened 400,000 small molecule drugs to see if any of them could stimulate the NTSR1 beta-arrestin response.

One small molecule called SBI-553 that emerged from the screen acts at a previously unknown site on the NTSR1 and selectively activates the beta-arrestin without activating the G protein. SBI-553 can bind the NTSR1 at the same time as this receptor's natural activator, a peptide known as neurotensin, and it promotes neurotensin's ability to activate beta-arrestin while blocking its ability to activate the G protein.

"This type of activity isn't something we've seen before," said study co-author Lawrence Barak, an associate research professor who has studied GPCRs for decades and initiated the NTSR1 research program at Duke as well as the collaborative, large-scale screening effort.

Like conventional NTSR1 activators, SBI-553 was found to reduce the amount of cocaine the animals consumed and their associated drug-craving. But it did so without the usual side effects of decreased blood pressure and body temperature and motor coordination problems.

"The current findings suggest that the selective activation of the NTSR1 beta-arrestin response is sufficient to produce some of the anti-addiction effects attributed to the NTSR1, but not its effects on blood pressure and body temperature," Slosky said.

Because NTSR1 is a prototypical GPCR, molecules of this class can now be pursued for other receptors, Slosky said. "This kind of modulator may allow for the fine-tuning of receptor signaling."

Detailed seafloor mapping of submerged glacial landforms finds that Antarctic ice sheets in the past retreated far faster than the most rapid pace of retreat observed today, exceeding even the most extreme modern rates by at least an order of magnitude, according to a new study. Using an autonomous underwater vehicle (AUV) to carefully measure the delicate sets of ridges left behind in seafloor sediments by retreating ice following the Last Glacial Maximum (LGM) roughly 14,000 years ago, the authors estimate deglaciation at a rate of more than 10 kilometers per year. The findings provide a clear indication of how quickly massive ice sheets can disappear into the ocean - events that, if repeated, would have significant implications for modern sea-level rise. Antarctica's ice shelves - the waterborne fringes of tidewater glaciers - form the boundaries between the Southern Ocean and the Antarctic Ice Sheet. At the grounding-line, the place where the ice sheet no longer rests directly on the sea floor and begins to float, warm air and ocean water conspire to melt ice from above and below. As a result, these regions are prone to rapid retreat. How the fastest rates of modern ice loss stack up against the maximum possible magnitude of retreat, however, is unknown. On the Larsen continental shelf off the east coast of the Antarctic Peninsula, Julian Dowdeswell and colleagues investigated a series of ridges in the soft seafloor sediment, which they interpret as artifacts left behind during the tidal rise and fall of the ice-shelf at the grounding line. Like glacial moraines on land, the grounding-zone wedges provided a record of glacier retreat and allowed Dowdeswell et al. to estimate that the rate of ice retreat at a resolution measured in days or weeks, revealing regional post-LGM deglaciation rates of 40-50 meters per day. "Perhaps most importantly, Dowdeswell et al. demonstrate the immense value of high-resolution seafloor mapping in unraveling the complex history of glacial dynamics. Only fractions of the seafloor in the hard-to-access ice-covered polar regions are mapped, and much is left to discover and learn," writes Martin Jakobsson in a related Perspective.

As the intensity and frequency of the strongest cyclones east of Taiwan have increased, so has the strength of the Kuroshio current, a Pacific current responsible for redistributing heat throughout the western North Pacific Ocean. According to a new study, intensifying tropical cyclones have increased the amount of energy in the ocean eddies that feed into the Kuroshio, accelerating the current. The results reveal a positive feedback between tropical cyclones (TCs) and potentially significant increased warming at higher latitudes. Climate models that overlook this and similar mechanisms may misrepresent the magnitude and pattern of warming in future climate predictions, say the authors. Similar to the Atlantic's Gulf Stream, the Kuroshio current is responsible for transporting vast amounts of warm water from the tropics to higher latitudes, retributing tropical heat to cooler latitudes. The speed of the Kuroshio (and the rate of heat transfer) is largely controlled by the wind and the mesoscale ocean eddies that feed into the larger current. Here, Yu Zhang and colleagues show that the increasing frequency and intensity of TCs in the region - a product of Pacific warming - has had the overall effect of increasing the strength of cyclonic mesoscale ocean eddies that feed the Kuroshio. At the same time, it has decreased the strength of anticyclonic ones. The result is a northward acceleration of the current, resulting in the transfer of more heat energy into the mid- and high-latitude ocean water. The results illustrate how larger tropical cyclones related to increased climate warming can influence large-scale ocean circulation by modifying underlying eddy fields that feed currents - further enhancing climate warming in regions farther afield. "For a proper representation of eddies in climate models, more theoretical and modeling studies are needed to improve our understanding of the physical processes involved in the interactions among eddies, TCs and large-scale ocean circulation, write Zhang et al.

What The Study Did: Symptoms of posttraumatic stress disorder, depression, anxiety and insomnia among health care workers in Italy during the COVID-19 pandemic are reported in this observational study.

Authors: Rodolfo Rossi, M.D., of the University of Rome Tor Vergata in Italy, is the corresponding author.

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(doi:10.1001/jamanetworkopen.2020.10185)

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