Culture

Proper embryonic development of the fruit fly Drosophila melanogaster is governed by patterns of protein activity bequeathed to the fertilized egg by its mother. While the embryo is still a single cell, the maternal cells surrounding it deposit certain proteins inside it at specific locations. This establishes protein gradients that direct the development of embryonic features along its anterior-posterior and ventral-dorsal axes. Later, the embryo receives another round of maternal information, called terminal patterning, that guides the development of its head and tail.

Terminal patterning is driven by a protein called Torso that is made by the mother and deposited throughout the embryo. Torso is stimulated by binding to other proteins that are also produced by the mother, but present only at the embryo's anterior and posterior ends. Torso stimulation kicks off several signaling cascades, including one called the Ras/ERK pathway, whose activation directs the expression of genes crucial to embryonic development. Mothers lacking Torso or the proteins to which it binds are sterile because their embryos fail to develop head and tail structures and eventually die.

"At this point, most developmental patterns have been studied in great detail, so biologists know when and where they appear and disappear," notes Toettcher. "What is unknown is exactly what information is contained in such a pattern."

For instance, the level at which a patterning protein is expressed may convey information about identity or purpose (i.e., what genes should be expressed) to an embryonic cell. Alternatively, this information could be encoded by other factors, such as where or for how long the protein is expressed. Traditional approaches to studying the functions of a given protein cannot manipulate protein expression with enough spatial or temporal precision to address such questions. However, Toettcher's lab had earlier used the emerging technology of "optogenetics" to develop a new research tool: a protein called OptoSOS that, when expressed in cells, allows researchers to activate the Ras/Erk signaling pathway while OptoSOS is illuminated with blue light.

"This is great because we can produce light patterns with high precision, allowing us to draw any pattern that we would like onto the embryo," says Toettcher.

To investigate where and when Ras/Erk signaling is needed for terminal patterning, Johnson and his colleagues expressed OptoSOS in the embryos of flies that do not have Torso signaling. They then placed the embryos under a microscope and precisely stimulated the animals' anterior and posterior ends with light for long enough to mimic the natural duration of Ras/Erk signaling. Next, they watched the embryos develop.

Remarkably, whereas all embryos left in the dark died after failing to develop properly, about a third of the light-stimulated embryos developed normally. Despite the trauma of the extraction procedure and of growing in a microscope chamber, these embryos formed head and tail structures, and eventually hatched and reached adulthood. Female flies created in this way even laid eggs--although, as expected, these eggs were sterile because like their mothers, the flies lacked Torso signaling, but unlike their mothers, their eggs were not stimulated with light.

Much of terminal patterning is driven by two genes whose expression is controlled by the Ras/Erk pathway in response to Torso signaling. In normal embryos, the expression of these two genes occurs in different cells at different times. In light-stimulated OptoSOS embryos lacking Torso signaling, however, expression of the two genes overlapped more in both space and time, suggesting their precise expression patterns are not required for development.

The authors next investigated whether different aspects of the developmental program are triggered at the same or different stimulus thresholds. To do this, they monitored embryonic development after varying the intensity and duration of light stimulus in OptoSOS embryos lacking Torso signaling.

"We found that the terminal pattern appears to work as a series of switches, where successively longer light pulses trigger a predictable sequence of body parts being 'rescued' one by one," explains Toettcher.

Together, these data suggest that for terminal signaling, what appears to be a very complex developmental program is actually under the control of a relatively simple system that depends on different thresholds of Ras/Erk signaling.

"These findings demonstrate the power of using optogenetics to activate and inactivate signaling pathways in time and space," says Gertrude Schüpbach, a researcher whose work was instrumental in the early studies that identified the components of terminal patterning. "Even more amazingly, they are able to tune the strength of the signal and obtain precise quantitative information about the mechanism in the living embryo."

"We think this is the beginning of mapping when and where patterns need to be delivered to produce specific body structures," says Toettcher.

BOSTON (July 23, 2020)--A new technology that combines high throughput imaging and machine learning could speed discovery of drugs to fight tuberculosis, which for generations has killed more people worldwide than any other disease caused by a single agent--4,000 people every day.

Current treatment requires multiple drugs for at least six months and sometimes years, and antibiotic resistance is growing, increasing urgency for finding new treatments.

However, drug discovery typically requires production of hundreds of derivatives of an original compound in order to find the most effective version. The new technology--dubbed MorphEUS (Morphological Evaluation and Understanding of drug Stress)--provides a rapid, efficient, cost-effective way to determine how specific compounds act to destroy Mycobcterium tuberculosis (M. tb), the bacterium that causes tuberculosis.

"We urgently need shorter, more effective TB therapies, and MorphEUS enables us to screen through drug candidates, see how they actually affect the cell, and learn which drugs have unique ways to kill the M. tb," said Bree Aldridge, associate professor of molecular biology and microbiology at Tufts University School of Medicine and senior author on the associated paper about the new platform published online in the Proceedings of the National Academies of Sciences (PNAS) on July 17.

Aldridge and her colleagues applied MorphEUS to 34 currently available antibiotics for which modes of action were already established and three non-commercial compounds. MorphEUS categorized the drugs correctly 94 percent of the time. In the remaining instances, MorphEUS identified previously unknown target pathways.

The search for new TB treatments has been stymied by difficulties in identifying the biological activity of compounds early in the drug discovery process and the need to clarify the mechanism of action of existing therapies. Antibacterials kill pathogens via specific molecular actions, for example, by destroying the microbe's cell wall or inhibiting protein synthesis. The drugs leave clues to their particular modus operandi: characteristic physical unraveling of the bacterial cells, which may affect length, width, shape of structures like the chromosome, staining ability, and other properties. Morphological profiling to categorize drugs by these changes is well-established with pathogens such as E. coli, but Aldridge's team was the first to test it with M. tb.

"We found that conventional morphological profiling approaches didn't work with M. tb, because the bacterium's inherent response to treatment was extremely variable, and changes in morphology were much less obvious than in bacteria like E. coli," said Trever C. Smith II, co-first author on the paper and a postdoctoral researcher in the Aldridge laboratory.

MorphEUS harnesses this variation by incorporating measurements of heterogeneity itself into morphological profiles and combining this enhanced feature set with machine learning and other complex analytical tools. Network webs and matrices visualize the data analysis. For example, much of the heterogeneity in staining patterns in M. tb is due to its thick, complex cell wall. There is increased staining and less variation in staining patterns when M. tb is treated with cell-wall targeting antibiotics compared with other classes of antibiotics. "With MorphEUS, we used the distribution of staining across a large number of bacilli to learn how each drug acts on M. tb," said Aldridge. "Similarly, we looked at staining intensity and the spread of that brightness across thousands of cells to identify more subtle patterns."

MorphEUS can also determine if drugs have off-target or secondary effects that are otherwise hard to identify. Such complex mechanisms of drug action can be key in designing multidrug therapies.

"We expect that the success of MorphEUS in profiling drug action in an organism like M. tb with significant inherent heterogeneity and subtle cytological responsiveness will make it useful in other pathogens and cell types," said Aldridge, who is also a core faculty member of Tufts Center for Integrated Management of Antimicrobial Resistance, member of the immunology and molecular microbiology program faculties at Tufts Graduate School of Biomedical Sciences, and an adjunct associate professor at Tufts University's School of Engineering.

MorphEUS, like all cytological profiling techniques, is data-driven and based on classification among a pool of other profiles. It requires multiple representative profiles from M. tb treated with compounds known to target the same broad cellular target. As the drug set expands, the accuracy and resolution of MorphEUS will improve. MorphEUS is also limited in its ability to identify target pathways of compounds with novel mechanisms of action that are unlike the other profiled drugs in the reference set.

Bzz! It's mosquito season in Greenland. June and July marks the period when Arctic mosquitoes (Aedes nigripes) are in peak abundance, buzzing about the tundra. While Arctic mosquitoes serve as an important food source to other animals, they are notorious for their role as pests to humans and wildlife, including caribou, whose populations can be affected by their attacks. Yet, these mosquitoes spend most of their lives in an aquatic environment in shallow, tundra ponds. Their eggs become frozen in the winter and hatch into larvae when the ponds melt in the spring. Arctic mosquitoes spend about two to three weeks in the larval stage before they develop into pupa and then adults. Given that Arctic mosquitoes' annual abundance and ecological role remains poorly understood, Dartmouth researchers set out to understand where they are most abundant during the larval stage and why. According to the study's findings, Arctic mosquito populations appear to be driven by food quality rather than predator density. The results are published in Ecology .

As larvae, Arctic mosquitoes feed on microbial biofilms that are attached to detritus, dead organic matter in the ponds. Using a food web approach, in May and June 2018, Dartmouth researchers investigated how variation in the food quality (bottom up approach), the predaceous diving beetle (C. dolabratus) (top down approach) and other conditions such as temperature and nutrients, affected the larval population. The study sample was comprised of eight different ponds between Kangerlussuaq, Greenland and the margin of the Greenland Ice Sheet.

To measure biofilm productivity, the team used "biofilm samplers," which were left in the ponds for the microbial material to accumulate. Arctic mosquito larvae had access to some of the devices as a food source while others were intentionally blocked off, so that the biofilm could not be eaten. The researchers looked at how much biofilm the larvae consumed and conducted a lab analysis of what the microbial community was composed of.

The researchers had hypothesized that Arctic mosquitoes do not make it to the larva stage because they either do not have enough to eat or they are consumed by the diving beetle. They were surprised by the results. The ponds with the best food quality had the lowest population growth rates, as the mosquitoes tended to overcrowd these sites. These sites had the highest hatching mosquitoes, resulting in intense competition for food and poor survival. In contrast, ponds with lower food quality had higher population growth rates. "Arctic mosquito populations appear to be driven by what they are eating rather than who is eating them," explained first author, Melissa H. DeSiervo, a graduate student in the Ecology, Evolution, Environment and Society program at Dartmouth.

One pond, which is estimated to be half the size of a football field, had about 12.4 million larvae when the Arctic mosquitoes first hatched but less than 15 percent of the larvae made it until the adult stage.

"What you would expect would be the best places for Arctic mosquito larvae to grow, actually end up being the worst places for these animals because there were so many of them there," added DeSiervo.

Another way of understanding these consumer resource dynamics is to consider the following analogy. "Imagine that there's a large group of people about to eat, who have two buffets to choose from. One table features a Thanksgiving dinner and the other features a sugary snack such as Pop-Tarts®. Most people would probably be inclined to go with the former but if too many people go for the Thanksgiving dinner, not everyone will get to eat because the table is so overcrowded," explained DeSiervo.

The researchers suggest that this maladaptive strategy of the Arctic mosquitoes overcrowding the best ponds may help keep their populations in check. The larva stage is a critical life phase for Arctic mosquitoes who spend a longer time as larva than other types of mosquitoes. The shallow Arctic ponds that have these biofilms tend to dry up quickly, so Arctic mosquitoes are under intense, time constraints, as they must eat and grown enough in order to transition into adulthood. As adults, Arctic mosquitoes can be especially menacing for caribou, whose grazing can be disrupted by these pests. A swarm can be detrimental to calves, which are unable to fend off themselves. "In our rapidly warming world, gaining insight into the population dynamics of Arctic mosquitoes is fundamental to understand the ecology of the Arctic," said DeSiervo.

A team of scientists has engineered the spike protein of the SARS-CoV-2 virus - a critical component of potential COVID-19 vaccines - to be more environmentally stable and generate larger yields in the lab. By solving problems with protein instability that have held back vaccine research, the new spike protein design could accelerate the development of desperately needed vaccines and diagnostics for COVID-19. As the race for a COVID-19 vaccine continues, most researchers have focused on targeting the spike protein, the viral component that allows the SARS-CoV-2 virus to enter and infect human cells in the lungs and gut. Scientists have modified the wild-type spike protein into variants such as S-2P to improve its ability to generate immune responses, as well as to be produced in greater quantities. However, even these improved versions remain finicky for researchers, as they are still unstable and can be difficult to produce on a large scale in mammalian cells. To navigate these roadblocks, Ching-Lin Hsieh and colleagues analyzed the cryo-EM structure of the spike protein and studied the effects of various changes to the protein's chemistry, such as substituting in amino acids called prolines. After analyzing 100 spike protein designs, the authors uncovered 26 substitutions that made the protein more stable and able to be expressed in higher quantities. Hsieh et al. combined the most effective proline substitutions into a variant they named HexaPro, which was expressed 10 times higher than S-2P in human cells. HexaPro also withstood temperatures of 55°C for 30 minutes, could be stored at room temperature for 2 days, and remained stable during multiple cycles of freezing and thawing. "The high yield and enhanced stability of HexaPro should enable industrial production of subunit vaccines and could also improve DNA or mRNA-based vaccines," the team concludes.

A team of Brazilian and European scientists has determined the transmission rates and out-of-country origins of predominant SARS-CoV-2 strains currently circulating in Brazil, which harbors one of the fastest growing COVID-19 epidemics in the world. Although the researchers show that non-pharmaceutical interventions initially reduced viral transmission, the continued increases in both cases and deaths in the country suggest that these interventions remain insufficient to control SARS-CoV-2 transmission. Their findings could help inform additional strategies to address the virus' spread, including contact tracing, quarantining of new cases, rapid and accessible diagnostic screening, and coordinated social distancing measures across the country, the authors say. Reaching around 1,800,827 cases as of July 12, 2020, Brazil currently holds the second largest number of SARS-CoV-2 cases in the world. Despite these concerning numbers, the dearth of available data on real-time viral transmission - due to delays in reporting cases and inconsistent access to testing across populations - has prevented comprehensive assessment of SARS-CoV-2's spread in the country, the authors say.

Here, Darlan da Silva Candido and colleagues used data on individual mobility and reported deaths due to severe acute respiratory infections to perform model simulations on SARS-CoV-2 transmission. They showed that school and store closures in mid to late March reduced the reproduction number, or the expected number of cases arising from a single infector, from greater than 3 cases to roughly 1 case in São Paulo and Rio de Janeiro, the two largest cities in Brazil. To investigate how SARS-CoV-2 became established in the country, the authors ran PCR assays on 26,732 viral genomes taken from a network of genomic laboratories they had established using harmonized protocols. They found 29% of the samples positive for SARS-CoV-2. Sequencing 427 of these SARS-CoV-2 genomes, the researchers identified more than 100 internationally-sourced virus introductions into Brazil, estimating that more than 75% of Brazilian SARS-CoV-2 strains fell under three clades introduced from Europe between February 28 and March 11. Modeling the spread of these viral strains, the scientists discovered there were ample opportunities for SARS-CoV-2 to "export" from large urban centers to the rest of the country during the early stage of the epidemic, due an overall 25% increase in average traveled distances via domestic flights before the introduction of air travel restrictions. The authors further postulate that this increase in long-distance flights likely dispersed the virus to remote parts of Brazil, which counteracted reductions in virus transmission that may have otherwise resulted from an overall reduction in air travel after restrictions were implemented. Together, these quantifications suggest Brazil requires more extensive interventions to stifle SARS-CoV-2 transmission moving forward.

Researchers with an interest in unraveling gene regulation in human health and disease are expanding their horizons by closely looking at alternative polyadenylation (APA), an under-charted mechanism that regulates gene expression.

"APA is about modifying one of the ends, called the 3-prime end (3?end), of RNA strands that are transcribed from DNA. The modification consists of changing the length of a tail of adenosines, one of the RNA building blocks, at the 3?end before RNA is translated into proteins," said first author Dr. Hari Krishna Yalamanchili, a postdoctoral associate in the lab of Dr. Zhandong Liu at Baylor College of Medicine. "This adenosine chain helps to determine how long the messenger RNA lasts in the cell, influencing how much protein is produced from it."

The interest in APA has resulted in the development of several 3? sequencing (3?Seq) techniques that allow for precise identification on APA sites on RNA strands. But what researchers are missing is a robust computational tool that is specifically designed to analyze the wealth of 3?Seq data that has been generated.

Meet PolyA-miner

"Until now, researchers have been using traditional RNA sequencing computational tools to analyze the 3?Seq datasets. Although this approach produces results, it does not maximize the potential amount of information that can be extracted from that data," Yalamanchili said. "Here we developed a computational tool that precisely analyzes 3?Seq data. We call it PolyA-miner."

Yalamanchili and his colleagues used their new computational tool to analyze existing 3?Seq datasets. PolyA-miner not only reproduced the analyses achieved with traditional computational tools, but also identified novel APA sites that were not detected with the other analytical approaches.

"We were surprised when the PolyA-miner analysis of a glioblastoma cell line dataset identified more than twice the number of genes with APA changes than were initially reported," Yalamanchili said.

"I think that the most exciting part of this new tool is that it enables us to precisely reflect gene-level 3? changes and to identify many more APA events than before. With other analytical approaches, we underestimate the effect and number of poly-adenylation events," said Liu, associate professor of pediatrics and neurology at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Immediate applications

This development has tremendous implications for basic research and for the potential translation of scientific findings into the clinic. APA is considered a major mechanism for RNA regulation that has strong relevance both in cancer and neurological diseases. PolyA-miner can assist scientists looking to identify the genetic causes of these diseases by determining whether there are differences in APA between diseased and normal cells. With this new analysis, scientists can take a fresh look at existing genomic datasets that may provide an answer to the cause of human conditions, as well as studying newly developed datasets.

"Previously, people knew about APA changes, but did not consider them to be major contributors to gene regulation mainly because we lacked the computational tools to determine APA's overall influence on gene expression," Yalamanchili said. "PolyA-miner has shown that APA seems to play a larger role in gene regulation than we had previously thought."

BIRMINGHAM, Ala. - The thalamus is a "Grand Central Station" for sensory information coming to our brains. Almost every sight, sound, taste and touch we perceive travels to our brain's cortex via the thalamus. It is theorized that the thalamus plays a major role in consciousness itself. Not only does sensory information pass through the thalamus, it is also processed and transformed by the thalamus so our cortex can better understand and interpret these signals from the world around us.

One powerful type of transformation comes from interactions between excitatory neurons that carry data to the neocortex and inhibitory neurons of the thalamic reticular nucleus, or TRN, that regulate flow of that data. Although the TRN has long been recognized as important, much less has been known about what kinds of cells are in the TRN, how they are organized and how they function.

Now a paper published in the journal Nature addresses those questions. Researchers led by corresponding author Scott Cruikshank, Ph.D., and co-authors Rosa I. Martinez-Garcia, Ph.D., Bettina Voelcker, Ph.D., and Barry Connors, Ph.D., show that the somatosensory part of the TRN is divided into two functionally distinct sub-circuits. Each has its own types of genetically defined neurons that are topographically segregated, are physiologically distinct and connect reciprocally with independent thalamocortical nuclei via dynamically divergent synapses.

"These results provide fundamental insights about how subnetworks of TRN neurons may differentially process distinct classes of thalamic information," Cruikshank said. "The genetic distinctions add some excitement to our main findings because they will enable powerful new optogenetic and chemogenetic strategies for probing behavioral and perceptual functions of these TRN sub-circuits. A long-term goal for many of us working in this area is to learn how the TRN orchestrates information flow to and from the neocortex, guiding attention to important stimuli and suppressing distractions. If such an understanding is eventually achieved, it could help clarify how conscious awareness is lost during a form of epilepsy -- absence epilepsy -- that critically involves the TRN."

Cruikshank is an assistant professor in the University of Alabama at Birmingham Department of Neurobiology. The experimental work was done at Brown University, Providence, Rhode Island, where Cruikshank was a research track professor prior to joining UAB last November.

In some of the study details, the researchers first found that the somatosensory TRN has two sets of neurons. In a central core of the TRN are neurons that express calbindin protein and mRNA. This core is surrounded by a shell of neurons that express somatostatin protein and mRNA.

There are also two somatosensory thalamocortical nuclei -- that is, nuclei that transmit sensory information from the thalamus to the neocortex. One is the first-order ventral posterior nucleus, or VP, and the other is the higher-order posterior medial thalamic nucleus, or POM. These two nuclei send distinct information to different neocortical targets, and also send collateral axons to the TRN. So, the researchers sought to clarify the organization of those circuits, focusing on how first-order and higher-order thalamocortical nuclei communicate with the two subtypes of TRN neurons. "This is essential to understand thalamic information processing," Cruikshank said.

Cruikshank and colleagues used a channelrhodopsin-yellow fluorescent protein anterograde tracing method from either the VP or POM to map their inputs to the TRN. They found a stark anatomical segregation of projections that aligned with the segregation of TRN cell types -- VP axons made strong synaptic connections with cells in the calbindin-rich central zone of the TRN; POM axons synapsed with cells along the somatostatin-dense edges. The segregated projections were largely reciprocal -- that is, the two TRN cell types predominantly inhibited the same thalamocortical nuclei that drove them.

The researchers further showed that the TRN sub-circuits had functionally different physiological mechanisms that lead to distinct processing. "Our experiments revealed that central and edge cells differentially transform their native excitatory thalamic inputs into distinct spiking outputs through differences in both dynamics of their synaptic inputs and their intrinsic burstiness," Cruikshank said. "We were intrigued that the TRN response patterns seemed to match the types of information carried in the two sub-circuits. The primary central cells had strong but transient spiking -- ideal for processing discrete sensory events. The edge cell responses were more stable and sustained -- consistent with temporally distributed higher-order signals integrated from multiple sources.

When the researchers looked at the visual TRN, they found sub-circuits similar to the somatosensory TRN. This, in turn, suggests, the researchers say, that a primary central core -- flanked by higher-order edge neurons -- may be a widespread TRN motif.

The findings challenge a longstanding hypothesis about the way TRN implements its role as a gatekeeper of information flow. "It has been proposed that inhibitory cross-talk between distinct thalamic circuits may allow them to regulate one another locally," Cruikshank said. "However, the sharp and reciprocal segregation of sub-circuits we observed suggests that intrathalamic cross-talk may play a minor role, and perhaps we should look to other mechanisms for cross-system regulation."

"This work by Scott Cruikshank separates an otherwise jumbled bag of nerve cells into elegant sub-circuits serving distinct functions with distinct properties and projections," said Craig Powell, M.D., Ph.D., chair of Neurobiology at UAB. "The results help us better understand how different types of sensory inputs are processed by the brain. The TRN is a key brain region responsible for childhood onset seizures called absence seizures, so this work may help identify novel therapies for this childhood epilepsy that is common in neurodevelopmental disorders and is a focus of the Civitan International Research Center at UAB."

A black swan event is a highly unlikely but massively consequential incident, such as the 2008 global recession and the loss of one-third of the world's saiga antelope in a matter of days in 2015. Challenging the quintessentially unpredictable nature of black swan events, bioengineers at Stanford University are suggesting a method for forecasting these supposedly unforeseeable fluctuations.

"By analyzing long-term data from three ecosystems, we were able to show that fluctuations that happen in different biological species are statistically the same across different ecosystems," said Samuel Bray, a research assistant in the lab of Bo Wang, assistant professor of bioengineering at Stanford. "That suggests there are certain underlying universal processes that we can take advantage of in order to forecast this kind of extreme behavior."

The forecasting method the researchers have developed, which was detailed recently in PLOS Computational Biology, is based on natural systems and could find use in health care and environmental research. It also has potential applications in disciplines outside ecology that have their own black swan events, such as economics and politics.

"This work is exciting because it's a chance to take the knowledge and the computational tools that we're building in the lab and use those to better understand - even predict or forecast - what happens in the world surrounding us," said Wang, who is senior author of the paper. "It connects us to the bigger world."

From microbes to avalanches

Over years of studying microbial communities, Bray noticed several instances where one species would undergo an unanticipated population boom, overtaking its neighbors. Discussing these events with Wang, they wondered whether this phenomenon occurred outside the lab as well and, if so, whether it could be predicted.

In order to address this question, the researchers had to find other biological systems that experience black swan events. The researchers needed details, not only about the black swan events themselves but also the context in which they occurred. So, they specifically sought ecosystems that scientists have been closely monitoring for many years.

"These data have to capture long periods of time and that's hard to collect," said Bray, who is lead author of the paper. "It's much more than a PhD-worth of information. But that's the only way you can see the spectra of these fluctuations at large scales."

Bray settled on three eclectic datasets: an eight-year study of plankton from the Baltic Sea with species levels measured twice weekly; net carbon measurements from a deciduous broadleaf forest at Harvard University, gathered every 30 minutes since 1991; and measurements of barnacles, algae and mussels on the coast of New Zealand, taken monthly for over 20 years.

The researchers then analyzed these three datasets using theory about avalanches - physical fluctuations that, like black swan events, exhibit short-term, sudden, extreme behavior. At its core, this theory attempts to explain the physics of systems like avalanches, earthquakes, fire embers, or even crumpling candy wrappers, which all respond to external forces with discrete events of various magnitudes or sizes - a phenomenon scientists call "crackling noise."

Built on the analysis, the researchers developed a method for predicting black swan events, one that is designed to be flexible across species and timespans, and able to work with data that are far less detailed and more complex than those used to develop it.

"Existing methods rely on what we have seen to predict what might happen in the future, and that's why they tend to miss black swan events," said Wang. "But Sam's method is different in that it assumes we are only seeing part of the world. It extrapolates a little about what we're missing, and it turns out that helps tremendously in terms of prediction."

Forecasting in the real world

The researchers tested their method using the three ecosystem datasets on which it was built. Using only fragments of each dataset - specifically fragments which contained the smallest fluctuations in the variable of interest - they were able to accurately predict extreme events that occurred in those systems.

They would like to expand the application of their method to other systems in which black swan events are also present, such as in economics, epidemiology, politics and physics. At present, the researchers are hoping to collaborate with field scientists and ecologists to apply their method to real-world situations where they could make a positive difference in the lives of other people and the planet.

The fatal disease smallpox is older and more widespread than scientists so far have proved. A new study by an international team of researchers from the University of Copenhagen and the University of Cambridge shows that the Vikings also suffered from smallpox.

Through the ages, the highly infectious disease smallpox has killed hundreds of millions of people. But it is unclear exactly when the disease emerged. There has been found evidence of smallpox from individuals from the 17th century while written records suggest the disease is much older.

Now a new study shows that the disease dates 1,000 years further back in time than previously shown. Researchers from the University of Copenhagen (UCPH) and the University of Cambridge have found proof that smallpox also existed in the Viking Age. The new results have been published in the scientific journal Science.

"We have found the oldest evidence of smallpox. Moreover, it seems to have been surprisingly common as early as in the Viking Age," says Associate Professor Martin Sikora, Globe Institute, UCPH, and the University of Cambridge. He continues:

"Smallpox is the infection in the world that has killed most people. For that reason alone, it is very important and interesting to know how the disease developed. It gives us a unique opportunity to understand the viruses' evolution: How did it change and become the pathogen that we know of today."

Widespread in Northern Europe

The researchers have studied and analysed the DNA of 13 individuals from Northern Europe infected with smallpox. The samples are 1,000 years older than the previous oldest sample known to have been infected based on ancient DNA, and they thus push the timeline for smallpox further back in time.

The study also shows the disease has been more widespread than previously assumed. The general idea used to be that smallpox was not endemic to Northern Europe during that time period.

"We show that not only was it endemic in Europe, but it was actually quite widespread in Northern Europe already at the year 600. That means that the disease was almost certainly far more established at a much earlier age than previously thought," says Professor Eske Willerslev, Globe Institute, UCPH.

The researchers have also discovered that the viruses circulating during the Viking Age were distinct from their modern counterparts, and not directly ancestral to the viruses that caused the last big outbreak of smallpox in the 20th century.

"They share a common ancestor, but they also have unique features that differentiate them from the ones circulating later on in history. It turns out that the viruses we have found were some of these very, very early and different versions of the devastating pathogens known from the 20th century. It is the first time we can trace these early smallpox viruses and compare their genomes and mutations and see how the disease evolved over time," says Eske Willerslev.

Catalogue of Mutations

Even though the disease has been eradicated today, it is still very useful to know how it developed and mutated through the ages.

Smallpox is a so-called poxvirus, a large family of viruses with many different types infecting a diverse set of host species. One such example is monkeypox, which typically infects monkeys but has also been known to cause a disease similar to smallpox in humans. It is therefore useful to known how other types of poxviruses mutate and survive.

"When we know how the disease mutated through time, it gives us an opportunity to put together a catalogue of how these pathogens might mutate in the future: What mutations and combinations make such a pathogen viable and successful? If they had those mutations in the past, they can most likely get them again."

"It is one of a few examples where ancient genetic research has direct implications for present-day and future health," says Martin Sikora.

Smallpox:

It is the variola virus that causes smallpox. It is a so-called poxvirus.

Written records of possible smallpox infections dating at least 3,000 years back.

The disease was declared eradicated in 1980 by WHO.

Smallpox virus still exists in two laboratories in the world: one in the US and one in Russia.

New research demonstrates how two vastly different methods of measuring brain activity can provide meaningful data on brain networks simultaneously.

Functional magnetic resonance imaging and electroencephalography are used to provide information on very different aspects of neural communication between brain areas. fMRI captures very slow aspects of this communication based on neurons' energy expenditure, whereas EEG directly measures neurons' rapid communication in real time from the electrical signals of the brain. Researchers from the Beckman Institute for Advanced Science and Technology have developed a new approach to look at both types to measure brain communication simultaneously.

The study "Concurrent EEG- and fMRI-derived functional connectomes exhibit linked dynamics" was published in NeuroImage.

"Over the last two decades it has become more common to look at how different regions across the brain communicate rather than focusing on activation of individual regions. The connectome describes the entirety of connections across all the brain regions," said Sepideh Sadaghiani, an assistant professor of psychology at the University of Illinois at Urbana-Champaign, who leads the CONNECT Lab at the Beckman Institute. "Unfortunately, it has been hard to look at fMRI and EEG connectomes simultaneously."

EEG measures the electrical signals that are generated by neurons across the brain. However, the MRI scanners that are used for fMRI measurements interfere with the EEG signals because the scanners use magnetic fields that generate their own currents. As a result, artifacts are produced.

"We looked at how the fMRI connectome changes over time and whether those changes are accompanied by changes in electrophysiological connectomes, as measured by EEG," Sadaghiani said.

The researchers saw that even though fMRI-derived connectomes have been criticized in the past for noise issues, the changes in the connectome over time relate to actual changes in the neural activity, which were measured by EEG. Similarly, EEG-derived connectomes, previously criticized for spatially imprecise measurements of brain communication, are also meaningful in studying whole-brain connectomes because they correlate with the fMRI connectome changes.

"The correlation confirms that the shortcomings of both methods can be overcome and we can obtain meaningful data," Sadaghiani said.

The researchers are interested in improving the limitations of the two methods further. "fMRI is used to look at very specific regions of the brain that are a couple of millimeters in dimension. On the other hand, EEG signals can only look at large regions of the brain," Sadaghiani said. "If we need to compare connectomes obtained from both sets of data, we lose the spatial precision of fMRI. Conversely, EEG measures very rapid changes in connectomes whereas fMRI is inherently slow. Consequently, when comparing connectomes changes in EEG and fMRI we may lose the temporal resolution of EEG."

"This new finding that both modalities can reliably track changes of brain communication provides a solid foundation for future studies exploring human cognition and brain pathologies," said Jonathan Wirsich, a postdoctoral research associate in the CONNECT lab.

The researchers will conduct future studies at the Biomedical Imaging Center at Beckman to obtain higher quality data. Combined with new analytic approaches, they plan to compare the EEG and fMRI connectomes without losing the advantages of either method.

Online tools and assessments can help speed up diagnosis of autism spectrum disorder (ASD), the first comprehensive survey of research in the field has concluded.

The survey showed that using internet-based tools in healthcare - a field known as telehealth - has potential to improve services in autism care, when used alongside existing methods.

The research, published today in PLOS ONE, was conducted by a team led by experts from Swansea University Medical School. The results are timely as the Covid-19 pandemic is prompting fresh thinking about providing services online.

Currently it can sometimes take several years after someone first seeks help before ASD diagnosis is confirmed. This can be due to a shortage of expertise, to several appointments being necessary, and the fact that the process can be very stressful for individuals who might later be diagnosed with ASD. As these are specialist services, they can also require lots of travelling for families and experts alike.

Delays in diagnosis can lead to poor outcomes for both the families and individuals.

Telehealth is already used successfully in areas such as radiology, cardiology, mental health, and for monitoring patients with diabetes and hypertension. However, the new study is the first to review the existing literature on the use of telehealth to support ASD diagnostic assessment.

The research team surveyed twenty years' worth of research in fields related to autism and telehealth, narrowing down an initial sample of 3700 articles to a set of ten for close study.

They examined which telehealth approaches have been used in the diagnosis and assessment of ASD in children and adults and how they compare with face-to-face methods.

The review revealed two main approaches to using telehealth:

1 Real-Time method - for example, videoconferencing, which enables a range of health professionals in different areas to meet in real time with the family to assess the child or adult, reducing the need for travel or multiple appointments

2 Store-and-Forward method - this involves providing a way for parents/carers to upload videos of a child's behaviour to a web portal, enabling clinicians to see a child in their everyday surroundings, to better inform the assessment.

The team found evidence that these two approaches:
* are acceptable to both families and clinicians;
* have good diagnostic accuracy;
* enable families from a wider area to access professionals;
* reduce costs for accessing care;
* enable the natural behaviours in the home setting to be observed;
* may enable both parents in divorced families to contribute to the diagnostic process.

Professor Sinead Brophy of Swansea University Medical School said:

"Telehealth can potentially improve the efficiency of the diagnosis process for ASD.

The evidence reviewed in our study shows that it can reduce delays and improve outcomes, when used in conjunction with existing methods. It could be of particular benefit to those with clear autism traits and adults with ASD.

Telehealth methods allow for collaboration and the sharing of experiences between the family, education and ASD experts. They can be just as good as face-to-face methods in terms of satisfaction for the patient, family and clinician."

Manahil Alfuraydan of Swansea University Medical School, primary author of the research, said:

"They reduce the time to diagnosis, particularly for those with more severe autism where there is good agreement in terms of the diagnosis compared to the face to face methods.

Our study highlights the potential of telehealth. Larger randomised controlled trials of this technology in relation to ASD are warranted."

In a new study, researchers from Texas A&M University and industry have designed a smart technology that can help utility companies better serve communities affected by blackouts. The researchers said their single device works by improving energy delivery between home solar-power systems and the electrical grid.

"Our innovation lets solar energy consumers be less dependent on the external power grid. The same technology also allows the utility company to control energy distribution, which is particularly useful during power outages caused by storms and other natural disasters," said Dr. Le Xie, professor in the Department of Electrical and Computer Engineering. "So, It's a win-win scenario for both the consumer and the utility company."

The study was published online in the Institute of Electrical and Electronics Engineers' Journal of Emerging and Selected Topics in Power Electronics in April.

Over the last decade, a sharp drop in the cost of solar panels has encouraged more households to adopt solar power systems. In these homes, the current generated by rooftop solar panels is fed into an inverter before the electricity is ready for residential use and charging solar backup batteries. Another set of power electronics connects the solar panels and the batteries back to the grid.

These connections ensure that homes are always connected to the grid as long as the grid is functional. During the day, homes consume more solar energy, and any excess energy is supplied to the grid. At night, homes draw electricity from the grid.

The researchers noted that these conventional systems have many disadvantages. Any voltage fluctuations in the grid, due to damage to the power lines or overloading, affects connected devices in homes. Also, they said the current injected into the grid from solar-powered homes can have certain irregularities, known as harmonics, affecting the quality of the power within the grid.

The researchers said another pertinent problem is there is little that a utility company can do to limit the amount of grid electricity consumed by solar-powered homes. This drawback is particularly harmful during natural disasters where other communities or essential services, like hospitals, need energy support.

"Currently, there's no system in place to regulate or limit energy consumption," said Dr. Prasad Enjeti, TI Professor III in Analog Engineering in the Department of Electrical and Computer Engineering. "End users with solar-powered systems continue drawing electricity from the grid because utility companies have no way of controlling it."

Unlike the conventional solar-powered systems that involve many electronics to connect back and forth from the grid, the researchers put together a single device, called the power electronics intelligence at the network edge, or PINE. This device, which is installed outside a home, has three main connections: one going to the home, one to the utility grid and another to the solar panels and batteries. PINE can control the flow of electricity in any one of these directions.

"This device is like an intelligent energy router," said Enjeti. "It regulates the grid voltage, integrates solar energy, which is locally produced, and intelligently manages and routes the energy in all directions."

The researchers designed this device to also be programmable, so that an authorized external user, like the utility company, can control the amount of grid electricity reaching solar-powered homes. Enjeti said PINE systems installed at different homes can also be programmed to communicate with each other and with the distribution operator.

To test if the PINE networks will operate as envisioned, the researchers built a hardware prototype and conducted extensive computer simulations of a mixed neighborhood in which some homes had PINE systems and others did not. The hardware performance along with simulations revealed that the homes with the PINE system had a cleaner, more stable voltage. At the grid level, the injected voltage from these homes was also stable because the PINE system was regulating that as well.

"PINE systems can dynamically and in real time inject different voltage support to the utility grid. So, the utility companies need not spend millions in buying capacitor banks to support the voltage across the feeder lines," said Xie. "During power outages, PINE allows homes to be self-sufficient and use their solar power efficiently. The technology also allows the utility company to wirelessly instruct PINE systems to limit the grid current to solar-powered homes and redirect it to other affected areas."

There are many types of light -- some visible and some invisible to the human eye. For example, our eyes and brain don't have the tools to process ultraviolet light when it hits our eyes, making it invisible. But there is another type of light that is invisible simply because it never reaches our eyes. When light hits certain surfaces, part of it sticks and remains behind rather than being transmitted or scattered away. This type of light is called near-field light.

Today, near-field light is mostly used for ultra-high-resolution microscopy, known as the near-field scanning optical microscopes (NSOM). However, near-field light also has untapped potential for particle manipulation, sensing, and optical communications. But since near-field light doesn't reach our eyes like far-field light does, researchers haven't developed a comprehensive toolkit to harness and manipulate the near field.

"Today, we have a lot of tools and techniques to design what far-field light looks like," said Vincent Ginis, a visiting professor at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). "We have lenses, telescopes, prisms and holograms. All these things enable us to sculpt freely propagating light in space."

Ginis is also a professor at the Vrije University of Brussel.

Now, SEAS researchers have developed a system to mold near-field light -- opening the door to unprecedented control over this powerful, largely unexplored type of light. The research is published in Science.

"Over the years, our group has developed new powerful techniques to structure propagating light using subwavelength-patterned metasurfaces," said Federico Capasso, the Robert Wallace Professor of Applied Physics and Vinton Hayes Senior Research Fellow in Electrical Engineering, and senior author of the paper. "With this work, we show how to structure the near field at a distance, opening exciting opportunities in science and technology."

In order to manipulate near-field light, the researchers developed a device in which light confined to a waveguide bounces back and forth between two reflectors. After each bounce it changes mode, meaning it propagates with a different spatial pattern. With multiple bounces, these patterns add up to generate a complex light intensity profile along the waveguide. The near field light near the surface of the waveguide also changes. When all the different patterns of the near-field light are superimposed on each other, a specific shape is created. The researchers can pre-program that shape by tailoring the amplitude of the modes of the bouncing light.

"The coexistence of all these modes can be designed to create near-field landscapes at will on the surface of the device," said Marco Piccardo, a research associate at SEAS and co-author of the paper. "The shape of the landscape is determined by the combined properties of the cascading light."

"It's a bit like music," said Ginis. "The music that you are hearing is the superposition of many notes or modes assembled in patterns conceived by the composer. One note alone isn't much but taken together you can generate any type of music. While music operates in time, our near-field generator operates in three-dimensional space and the extra intriguing aspect of our device is that one note generates the other."

Importantly, this molding process happens remotely, meaning no part of the device directly interacts with the near-field light. This reduces interference, which is important for applications such as particle manipulation, and is a major departure from current local methods of sculpting near fields such as shining light on metallic tips and nanoparticles.

To demonstrate their design, the researchers molded near-field light into the shape of an elephant. Or, more specifically, an elephant inside a boa constrictor, an homage to the play on dimensions in Antoine de Saint-Exupéry's classic The Little Prince.

The researchers also shaped the light into a curve, a plateau and a straight line.

"This research provides a new path towards unprecedented three-dimensional control of near-field light," said Capasso. "It is a portent of the exciting discoveries and technology developments I expect to come out of this work in the future."

PHILADELPHIA (July 23, 2020) - Many Black men suffer symptoms of traumatic stress in the aftermath of traumatic injury, and they also often carry social concerns, including experiences of discrimination and stigma. Yet despite their significant needs, underserved populations often have limited access to behavioral health care as well as a lack of financial resources to pay for such care. Because of these barriers, many trauma survivors do not seek professional behavioral health care and instead rely on informal or alternative sources of care.

A new study by researchers at the University of Pennsylvania School of Nursing (Penn Nursing) and Drexel University has explored how Black male survivors of trauma articulate the factors that facilitate or hinder their help-seeking for psychological symptoms after injury. The objective was to use a novel analytic approach called Qualitative Comparative Analysis (QCA) to understand how traumatic symptoms and social factors combine in complex ways toward the outcome of psychological help-seeking.

The study revealed that severe posttraumatic symptoms create pathways to help-seeking among some Black men who survive trauma exposure, while for others, financial worry and discrimination combine in a pathway toward help-seeking even in the absence of severe psychological symptoms after trauma. Factors combine in ways that reflect a complex intersection between barriers and facilitators.

"The existence of these distinct pathways challenges the tendency to view factors individually and either as barriers or facilitators," explains lead author John A. Rich, MD, MPH, Professor of Health Management and Policy at the Dornsife School of Public Health at Drexel University. "We were able to show that various causal conditions, some classically thought to be facilitators and others thought to be barriers, may combine in different ways toward the outcome of help-seeking among the Black men in this study. This supports our view that causation is complex and often intersectional."

Using fuzzy set QCA, researchers identified three different causal pathways for psychological help?seeking among the injured Black men studied. Two pathways showed that severe psychological symptoms in the absence of financial worry were sufficient for seeking help, whereas the third showed that financial worry and discrimination in the absence of psychological symptoms were sufficient for help?seeking.

The research also identified two causal pathways which negated help-seeking, in which low posttraumatic symptom severity and low levels of discrimination or financial worry were sufficient for not seeking psychological help.

"Our study has implications for future research," said Penn Nursing's Therese S. Richmond, PhD, RN, FAAN, the Andrea B. Laporte Professor of Nursing and Associate Dean for Research & Innovation, "Understanding different pathways to help-seeking behavior may identify new approaches to aiding Black men who are victims of trauma. Somewhat akin to a precision medicine approach, future examination of these pathways may help to develop theories about the utilization of behavioral health services for Black men that are based on their experiences rather than the assumption that all Black men who are trauma survivors have a single perspective on seeking help."

The study also helps highlight that Black men bring more than their race and gender to their experience of trauma exposure, combating the tendency to see Black men only as part of a group, which is problematic from a research perspective.

"We were able to show that various causal conditions, some classically thought to be facilitators and others thought to be barriers, may combine in different ways toward the outcome of help-seeking among the Black men in this study," says co-author Theodore J. Corbin, MD, MPH, Professor of Emergency Medicine at Drexel University College of Medicine and co-director of the Drexel Center for Nonviolence and Social Justice. "Applying similar configurational methods in health research could uncover important causal pathways for health inequalities rather than focusing on race or other demographic categories that are often investigated in isolation of their socioecological context."

Florida State University researchers have new insight into the tiny packages that cells use to move molecules, a structure that is key to cellular metabolism, drug delivery and more.

Their research uncovered more about the proteins that form the outer structure of those cellular packages. The work was published in the journal Science Advances.

"Just like human mail carriers have to transport packages of different shapes and sizes, cells also have to transport a variety of materials to the right compartments within them," said Scott Stagg, associate professor of chemistry and biochemistry and a study co-author. "They need to bring in molecules from outside the cell and transport them between the different cellular compartments, and they have little molecular machines called vesicles that function like postal carriers moving microscopic packages from one compartment to another."

Scientists have previously observed cells create vesicles -- fluid-filled sacks that move materials within a cell or from one cell to another. They have also observed a protein called clathrin form a cage-like arrangement that made up the outside structure of vesicles.

But there were still questions about how exactly clathrin forms those structures and what determines the shapes it can take.

Using high-powered microscopes, the FSU researchers discovered that another protein, known as an adaptor protein, ties multiple clathrin molecules together in a way that allows those structures to take on different sizes.

They also showed that the clathrin coat could make a so-called "basket" shape, and one that scientists had thought the protein could not form, showing that clathrin assembly is more complicated than previously thought.

"We learned a lot about clathrin-coated vesicles by looking at the ones that were made by cells themselves," said Mohammadreza Paraan, a researcher at FSU's Institute of Molecular Biophysics and the study's lead author. "We found new structures and patterns that really surprised us."

The researchers found that the clathrin structures that other researchers formed in a test tube were different from the ones they saw from cells.

"This shows that there are things we don't understand about how clathrin coat assembly is regulated and progresses in cells," Stagg said. "Our hypothesis is that the cargo that vesicles carry has a role in dictating how the coats are made and that explains why we see different structures."

The ability for cells to form vesicles is essential. It is the main route by which molecules like hormones, proteins and viruses enter cells and move within them. If it stops working, cells can die, or disease can take hold in an organism.

Understanding cellular transport is also important because the process is often hijacked by viruses like influenza or the virus that causes COVID-19 to gain entry to the cell.

"Understanding the molecular mechanisms of clathrin-based transport is important because it is such a fundamental process," Stagg said. "It touches on so many cellular processes. The better we understand it, the more likely it is that we can manipulate it to do things like stop virus entry, enhance drug delivery inside cells or modulate neurotransmitter levels in the brain, just to mention a few. It's a really exciting time for clathrin research."