Culture

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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Many insects process visual information to make decisions about controlling their flying skills and movements- flies must decide whether to pursue prey, avoid a predator, maintain their flight trajectory or land based on their perceptions.

Why is understanding this process important? We move every day and perceive the world differently as a result.

For example, if you're driving on the freeway your visual system adapts to high speed, and after a while 50km/h feels very slow. In contrast, when running or walking you are able to maintain a more steady velocity.

New research published in journal Current Biology describes the firing of descending neurons in hoverflies to examine the important link between neural processing in the central brain and their normal behaviour in flight.

These neurons correspond to descending neurons in our human spinal cord.

"As the spinal cord is very inaccessible in humans, flies become an excellent comparison model," says Professor Karin Nordström, a neuroscientist at Flinders University who studies how insects perceive the world while moving.

"The responses of these descending neurons help explain how and where this discrepancy between adaptation to motion and the ability to maintain more constant movement takes place."

"We found that these descending neurons continue to respond to visual motion, which is fascinating, as sensory neurons typically adapt." says Professor Nordström.

The researchers investigated these significant observations in hoverflies by using test-adapt-test protocols, which are commonly used in visual science to quantify the effect adaptation has on responses to subsequent stimuli.

Flinders University Research Officer Sarah Nicholas says descending neurons haven't been studied enough and provide an important insight into the link between the brain and the resulting behaviour of hoverflies, and ultimately all vertebrates, including humans.

"These descending neurons show sensory properties (by adapting) as well as pre-motor properties (persistent firing), which is quite a unique integration of neuronal responses."

"As motion vision, and adaptation, in flies show many similarities to those described in vertebrate cortical areas, and as persistent firing has been shown in both invertebrate and vertebrate central pattern generators, our findings are broadly appealing."

Users of high-potency cannabis are four times more likely to report associated problems, and twice as likely to report anxiety disorder, than users of lower-potency strains, according to new research from the University of Bristol.

Published today on JAMA Psychiatry the research uses data from Children of the 90s, a long-term health study that recruited more than 14,000 pregnant women and their babies born in and around Bristol in the early 1990s and has been following their health and development ever since.

This is the first research of its kind to look at data from a general population sample, with previous research into the links between cannabis potency and mental health only looking at clinical and self-selecting samples of people who use drugs. Added to this, the nature of the data available from the Children of the 90s health study enabled the research team to take into account whether mental health symptoms were present before the individual started using cannabis.

Frequency of cannabis use, which is also often associated with increased mental health problems, was also taken into account in order to determine whether this would explain the relationship between higher-potency usage and mental health conditions.

Lead author Dr Lindsey Hines, Senior Research Associate from Bristol Medical School explained: "We know that people who use cannabis are more likely to report mental health problems than those who don't use cannabis, but we don't fully understand how recent increases in the strength and potency of cannabis affects this. This study gives us an estimate of the increased likelihood of mental health problems from use of high-potency cannabis, compared to use of lower-potency cannabis, and we are able to account for the effect that people's early adolescent mental health symptoms may have on this relationship."

The research looked at data collected from participants aged 24 years who had reported using cannabis in the previous year, of which 13 per cent reported use of high-potency cannabis. Participants were also asked about their usage, and those who self-reported two or more of the Cannabis Abuse Screening Test (CAST) items within the past year were classified as having recently experienced problems as a result of their cannabis use. Researchers were then able to compare this data to reported mental health symptoms at age 24 as well as early symptoms of mental health collected when participants were younger.

Dr Hines continued: "People who use cannabis are more likely to report mental health problems than those who don't use cannabis, but reducing the potency and regularity of their cannabis use may be effective for lessening likelihood of harms from use. In countries where cannabis is sold legally, limiting the availability of high-potency cannabis may reduce the number of individuals who develop cannabis use disorders, prevent cannabis use escalating to a regular behaviour, and reduce impacts on mental health. In countries like the UK, where we are not able to limit the availability of high-potency cannabis, we should make sure there is good treatment and support for those who develop problems from cannabis use."

The Near East was a crossroad for the ancient world's greatest civilizations, and invasions over centuries caused enormous changes in cultures, religions and languages. However, a new study of the DNA of ancient skeletons spanning 4,000 years has revealed that most of these changes had no lasting effect on the genetics of the local population of Beirut.

Whilst the invasions and conquests may have been revolutionary for the elite rulers, researchers at the Wellcome Sanger Institute, University of Birmingham, French Institute of the Near East in Lebanon and their collaborators found only three time periods that had any impact on the long-term genetics of the ordinary people. These were the beginning of the Iron Age, the arrival of Alexander the Great, and the domination of the Ottoman Empire.

Reported today (28 May) in the American Journal of Human Genetics, the study shows the value of using genetics alongside archaeology to help understand what could be happening in the lives of ordinary people throughout history.

Over the centuries, the Levant has had many different rulers, including the Egyptians, Babylonians, Assyrians, Persians, Greeks, Romans, Crusaders, Arabs, and Ottomans. Most of these had permanent cultural effects on the local population, including changes to religion and even languages, as shown by the historical records and archaeological findings.

However, despite this, previous research showed that present-day local people in Lebanon were mainly descended from local people in the Bronze Age (2100-1500 BCE)*, with 90 per cent of their genetic make-up coming from around 4,000 years ago, and very few lasting traces of even the Crusaders invasion around the 11th-13th Century**.

To understand this potential contradiction and build a picture of the genetic history of ordinary people in the region, the researchers studied the DNA of ancient skeletons through 4,000 years. The team sequenced the genomes of 19 ancient people who lived in Lebanon between 800BCE and 200CE, and by combining with previous ancient and modern data, created an 8-point time line across the millennia.

Scientists detected lasting genetic changes in the local people from just three time periods - during the beginning of the Iron Age (about 1,000 BCE), the arrival of Alexander the Great (beginning 330 BCE), and the domination of the Ottoman Empire (1516 CE) - but not from the other times.

Dr Marc Haber, first author from the University of Birmingham and previously from the Wellcome Sanger Institute, said: "We revealed a genetic history of the area across 4,000 years, with a time-point approximately every 500 years. This showed us that despite the huge cultural changes that were occurring during this period, there were only a few times that the genetics of the general population changed enough to affect the ordinary people."

The study revealed that some people did mix and form families with people from other cultures. One burial site was found to contain the remains of an Egyptian mother, and her son whose father had Egyptian and Lebanese ancestry. However, this cosmopolitan mixing did not seem to be widespread.

Historical evidence is based on archaeological findings and written records, but these are biased towards the elite rulers and people with money and influence, as they have far more resources and write the history. It can be difficult to understand the lives of the ordinary people.

Dr Joyce Nassar, an author on the paper and archaeologist from the French Institute of the Near East, Lebanon, said: "This study is really exciting, as the genetic evidence is helping us to interpret what we find. Some people might think that when a land was invaded, that the population would change. But this study shows it isn't that simple, and reveals there was only limited biological mixing, despite the cultural and political influence of the invasions."

The skeletons came from four archaeological excavation sites in Beirut, which were discovered during building projects in the Lebanese capital city and rescued by the Directorate General of Antiquities***. The archaeologists and researchers then worked together to transfer the bones to a laboratory in Estonia dedicated to ancient DNA, where the surviving ancient DNA was extracted from the temporal bone in the skulls. The DNA was then sequenced and analysed at the Sanger Institute. Recent advances in DNA extraction and sequencing technology made studying the ancient and damaged DNA possible.

Dr Chris Tyler Smith, senior author on the paper and previously from the Wellcome Sanger Institute, said: "We see that people like the Egyptians and the Crusaders came to Lebanon, lived, raised families and died there. Their DNA sequences reveal this, but a little while later, there may be no trace of their genetics in the local population. Our study shows the power of ancient DNA to give new information about the human past, that complements the available historical records, and reveals the benefits of archaeologists and geneticists working together to understand historical events."

CAMBRIDGE, MA -- Many proteins are useful as drugs for disorders such as diabetes, cancer, and arthritis. Synthesizing artificial versions of these proteins is a time-consuming process that requires genetically engineering microbes or other cells to produce the desired protein.

MIT chemists have devised a protocol to dramatically reduce the amount of time required to generate synthetic proteins. Their tabletop automated flow synthesis machine can string together hundreds of amino acids, the building blocks of proteins, within hours. The researchers believe their new technology could speed up the manufacturing of on-demand therapies and the development of new drugs, and allow scientists to design artificial proteins by incorporating amino acids that don't exist in cells.

"You could design new variants that have superior biological function, enabled by using non-natural amino acids or specialized modifications that aren't possible when you use nature's apparatus to make proteins," says Brad Pentelute, an associate professor of chemistry at MIT and the senior author of the study.

In a paper appearing today in Science, the researchers showed that they could chemically produce several protein chains up to 164 amino acids in length, including enzymes and growth factors. For a handful of these synthetic proteins, they performed a detailed analysis showing their function is comparable to that of their naturally occurring counterparts.

The lead authors of the paper are former MIT postdoc Nina Hartrampf, who is now an assistant professor at the University of Zurich, MIT graduate student Azin Saebi, and former MIT technical associate Mackenzie Poskus.

Rapid production

The majority of proteins found in the human body are up to 400 amino acids long. Synthesizing large quantities of these proteins requires delivering genes for the desired proteins into cells that act as living factories. This process is used to program bacterial or yeast cells to produce insulin and other drugs such as growth hormones.

"This is a time-consuming process," says Thomas Nielsen, head of research chemistry at Novo Nordisk, who is also an author of the study. "First you need the gene available, and you need to know something about the cellular biology of the organism so you can engineer the expression of your protein."

An alternative approach for protein production, first proposed in the 1960s by Bruce Merrifield, who was later awarded the Nobel Prize in chemistry for his work on solid-phase peptide synthesis, is to chemically string amino acids together in a stepwise fashion. There are 20 amino acids that living cells use to build proteins, and using the techniques pioneered by Merrifield, it takes about an hour to perform the chemical reactions needed to add one amino acid to a peptide chain.

In recent years, Pentelute's lab has invented a more rapid method to perform these reactions, based on a technology known as flow chemistry. In their machine, chemicals are mixed using mechanical pumps and valves, and at every step of the overall synthesis they cycle through a heated reactor containing a resin bed. In the optimized protocol, forming each peptide bond takes on average 2.5 minutes, and peptides up to 25 amino acids long can be assembled in less than an hour.

Following the development of this technology, Novo Nordisk, which makes several protein drugs, became interested in working with Pentelute's lab to synthesize longer peptides and proteins. To achieve that, the researchers needed to improve the efficiency of the reactions that form peptide bonds between amino acids in the chain. For each reaction, their previous efficiency rate was between 95 and 98 percent, but for longer proteins, they needed it to be over 99 percent.

"The rationale was if we got really good at making peptides, we could expand the technology to make proteins," Pentelute says. "The idea is to have a machine that a user could walk up to and put in a protein sequence, and it would string together these amino acids in such an efficient manner that at the end of the day, you can get the protein you want. It's been very challenging because if the chemistry is not close to 100 percent for every single step, you will not get any of the desired material."

To boost their success rate and find the optimal recipe for each reaction, the researchers performed amino-acid-specific coupling reactions under many different conditions. In this study, they assembled a universal protocol that achieved an average efficiency greater than 99 percent for each reaction, which makes a significant difference when so many amino acids are being linked to form large proteins, the researchers say.

"If you want to make proteins, this extra 1 percent really makes all the difference, because byproducts accumulate and you need a high success rate for every single amino acid incorporated," Hartrampf says.

Using this approach, the researchers were able to synthesize a protein that contains 164 amino acids -- Sortase A, a bacterial protein. They also produced proinsulin, an insulin precursor with 86 amino acids, and an enzyme called lysozyme, which has 129 amino acids, as well as a few other proteins. The desired protein has to be purified and then folded into the correct shape, which adds a few more hours to the overall synthesis process. All of the purified synthesized proteins were obtained in milligram quantities, making up between 1 and 5 percent of the overall yield.

Medicinal chemistry

The researchers also tested the biological functions of five of their synthetic proteins and found that they were comparable to those of the biologically expressed variants.

The ability to rapidly generate any desired protein sequence should enable faster drug development and testing, the researchers say. The new technology also allows amino acids other than the 20 encoded by the DNA of living cells to be incorporated into proteins, greatly expanding the structural and functional diversity of potential protein drugs that could be created.

"This is paving the way for a new field of protein medicinal chemistry," Nielsen says. "This technology really complements what is available to the pharmaceutical industry, providing new opportunities for rapid discovery of peptide- and protein-based biopharmaceuticals."

The researchers are now working on further improving the technology so that it can assemble protein chains up to 300 amino acids long. They are also working on automating the entire manufacturing process, so that once the protein is synthesized, the cleavage, purification, and folding steps also occur without any human intervention required.