Culture

LA JOLLA--(September 10, 2019) During high stress situations such as making a goal in soccer, some athletes experience a rapid decline in performance under pressure, known as "choking." Now, Salk Institute researchers have uncovered what might be behind the phenomenon: one-way signals from the brain's emotion circuit to the movement circuit. The study, which was published online on September 6, 2019, in eLife, could lead to new strategies for treating disorders with disrupted movement, such as obsessive-compulsive disorder, anxiety and depression, along with aiding in recovery from spinal cord injuries or physical performance under pressure.

"This finding is very exciting as it is the first time that a comprehensive circuit mechanism has been found showing how emotional states can influence movement through connections in an area of the brain called the basal ganglia, a region involved in guiding behavior," says Associate Professor Xin Jin, senior author on the paper. "We did not previously know much about this pathway, so it brings about a whole new paradigm for examining psychiatric disorders as well as spinal cord injury."

It was previously believed that the brain's emotion and movement loops worked like parallel closed circuits, operating independently to relay important information. However, researchers suspected that there could be some influence of emotion on movement due to the observation that, in neuropsychiatric conditions such as depression, decreased physical movement is a symptom and could be linked to disrupted emotional processing and reduced motivation. Yet, scientists did not know much about the connections within each circuit or how the circuits might interact.

"We wanted to explore how emotion information reaches the movement circuitry in the brain by using a combination of cutting-edge viral and optogenetic techniques," says Sho Aoki, co-first author and postdoctoral fellow in the Jin lab.

The scientists sought to trace these circuits in rodent models to better understand each step of neuronal communication. They focused on the emotion and movement brain loops, starting from a region involved in emotion (the medial prefrontal cortex) and a region involved in movement (the primary motor cortex). They used multiple genetic and viral tracing tools, including a technique developed by Salk Professor Ed Callaway's lab, to observe how each loop was organized in the brain.

To the researchers' surprise, they found a one-way communication pathway from the emotion loop to the movement loop through an area located deep in the brain called the basal ganglia. The basal ganglia, which includes structures involved in guiding behavior, essentially acts as a crossroads for the emotion circuit to directly influence the movement circuit to control action. To confirm their results, the authors used optogenetics, a technique that uses light to control cells, to investigate the precise function of the neurons in this region. They also studied each neural circuit in isolation from the rest of the brain and confirmed the novel pathway.

"Psychiatric diseases such as depression and anxiety can alter actions in a dramatic way by either decreasing or increasing movement. This mechanism represents a likely way that emotional states are related to changes in action control in psychiatric diseases," says Jin.

Additionally, this unidirectional communication may be relevant for recovery from spinal cord injury. Researchers previously focused on movement centers of the brain because spinal cord injury is a movement issue; however, since these results suggest emotional states can influence brain movement centers, experiencing positive emotions such as motivation may aid patients in the recovery process. Activating emotion centers could likewise stimulate movement centers and facilitate recovery, according to the Salk co-first authors Jared Smith, a postdoctoral fellow, and Hao Li, a senior research associate. Further, these results suggest that emotional states could directly influence sports performance. So, Jin advices, maybe the next time you feel anxious during a game, just calm down and let the action take care of itself.

The majority of marketing authorizations granted through two expedited assessment pathways in Europe are based on non-validated surrogate endpoints rather than clinical outcomes, according to a study published September 10 in the open-access journal PLOS Medicine by Patricia McGettigan of Queen Mary University of London, and colleagues.

The approval of new pharmaceutical products addressing an unmet need or public interest may be speeded up if medicine regulators at the European Medicines Agency agree to assess them through expedited assessment pathways, including conditional marketing authorization (CMA) and accelerated assessment (AA). In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints (e.g., those based on a blood test or a radiological change) reduce drug development time compared with waiting for the intended clinical outcomes (i.e., benefits in how patients feel or function or how long they survive). However, it is not known how often regulatory approval is based on a surrogate endpoint instead of a clinical outcome, or how accurately the surrogate endpoints used in pivotal trials correspond to improvement in clinical outcomes. To address this gap in knowledge, McGettigan and colleagues used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorized through CMA or AA pathways from 2011 through 2018.

Most of the expedited approvals studied (46/51, 90%) were based on surrogate endpoints, none of which has been shown to reliably predict clinical outcomes (i.e., non-validated surrogate endpoints). Among a total of 49 products with surrogate endpoints reported, most were rated as being reasonably likely (n=30, 63%) or of having biological plausibility (n=45, 94%) to predict clinical outcomes. The information provided by the regulator for prescribers and patients did not consistently explain that the approval for the product was based on trials that reported surrogate endpoints rather than clinical outcomes.

The authors note that these findings apply to just two expedited pathways and may not be generalizable to products authorized through the standard pathway. Still, according to the authors, EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorizations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by non-validated surrogate endpoints, postauthorisation measures to confirm clinical benefit should be imposed by the regulator on the marketing authorisation holders.

ATHENS, Ohio (Sept. 10, 2019) - The parasite that causes Chagas disease, which had largely been thought to be asexual, has been shown to reproduce sexually after scientists uncovered clues hidden in its genomic code.

That's the finding of new research, published by a team of scientists from an international group of institutions that includes the Infectious and Tropical Disease Institute at the Ohio University Heritage College of Osteopathic Medicine.

Trypanosoma cruzi is the single-celled parasite responsible for Chagas disease, which is found mostly in Latin America. Around 8 million people are infected by the disease, which can cause irreversible damage to the heart and digestive tract.

Chagas is primarily spread by insects known as Triatominae, or "kissing bugs," but can also be transmitted by food contaminated with T. cruzi. While some medication can cure patients if given early enough, medication is less effective once the disease is established.

In new research published Sept. 3 in Nature Communications, scientists have sequenced the whole genome of Trypanosoma cruzi and resolved 30 years of heated debate to show that it can indeed be sexually active. This could have important implications for treating the disease and controlling its spread.

Institutions involved in the study, "Meiotic sex in Chagas disease parasite Trypanosoma cruzi," included the University of Glasgow, Pontifical Catholic University of Ecuador, the Infectious and Tropical Disease Institute at Ohio University's Heritage College of Osteopathic Medicine, the London School of Hygiene and Tropical Medicine, the Institute of Tropical Medicine Antwerp and Karolinska Institutet Biomedicum Stockholm.

"Chagas Disease in Ecuador is a killer, destroying lives and livelihoods," said Mario Grijalva, Ph.D., director of ITDI and the lead investigator in Ecuador for the research. "Our study is an important step toward understanding how to control infections and limit spread."

By studying a large group of parasites found in a small area in Ecuador and sequencing the whole genome of those they found, the researchers were able to spot the tell-tale signatures sexual activity leaves in the genes.

Lead author of the research, Dr. Philipp Schwabl from the University of Glasgow, said: "There has been a lot of argument among scientists about whether T. cruzi is sexual or not. It turns out people weren't looking in the right places.

"We sampled and analysed, in unprecedented detail, the parasites found in a small geographic area in Ecuador. Remarkably, we discovered that some groups of parasites can be highly sexual. However, it also seems other groups of parasites from very nearby sites can behave very differently - seemingly completely abstinent.

"At the moment, we have no idea why"

Dr. Martin Llewellyn, UK senior scientist on this study, said: "Through analyzing the genetic code, we now know that these parasites do have sex; however, we still can't pinpoint the exact stage of their life that this happens in. Our hypothesis is that this is happening when the parasites are inside the insect that spreads Chagas disease. Confirming that is the next step."

WASHINGTON, D.C.-- The Physicians Committee for Responsible Medicine praised an Environmental Protection Agency (EPA) decision to phase out animal testing of chemical products. EPA Administrator Andrew Wheeler announced today that animal testing will be substantially reduced in six years and phased out by 2035.

The change comes after years of work by the Physicians Committee, first to pass a 2016 bill that mandated reductions in EPA animal use, and then to help regulators and product manufacturers to implement nonanimal research methods. “This measure will mean a safer environment as well as scientific methods that are technically better and more humane,” said Kristie Sullivan, MPH, Physicians Committee vice president for research policy. Ms. Sullivan and Esther Haugabrooks, PhD, also of the Physicians Committee, joined Administrator Wheeler at the EPA for today’s announcement .

In today’s action, the EPA announced its intent to end its reliance on mammalian animal tests to assess chemical and pesticide risks and to invest in computer-based and in vitro tissue models. The EPA also announced awards of $4.2 million in grants for research into new test methods.

Currently, hundreds of thousands of animals are killed every year to test chemicals, pesticides, cleaning products, and other substances that are regulated by the EPA. Results from animal tests are often not relevant to human health, due to the significant differences across species. Additionally, tests using animals take much longer to conduct than most nonanimal methods, so new, more reliable methods will allow for the introduction of safe products on a faster timeline and will help rule out dangerous chemicals earlier.

In addition to the Physicians Committee, scientists from the People for the Ethical Treatment of Animals and the Humane Society of the United States have worked hard to replace animal use in environmental tests.

UNIVERSITY PARK, Pa.--A new way of measuring how relationships in a network change over time can reveal important details about the network, according to researchers at Penn State and the Korean Rural Economic Institute. For example, when applied to the world economy, the method detected the greatest amount of network change during 2008-2009, the time of the global financial crisis.

"Most existing approaches only capture relationship changes in a network one network member at time," said Stephan Goetz, professor of agricultural and regional economics, Penn State, and director of the Northeast Regional Center for Rural Development (NERCRD). "Our measure allows us to see how these relationships change over time across the entire network, which will give us potential new insights into how networks behave, as well as the impacts of those changes."

According to Goetz, networks of all types are represented visually by individual nodes connected to one another by lines, or links. The familiar airline hub-and-spoke map is one example. Each node represents an entity in a network -- an airport, a person, a business, or a country, for example. The links between two nodes represent their connection or relationship.

"Think about your own network of relationships, with each person in your network represented by a node and your connection to them represented by a link. Over time, some people might drop out, others might come in, some relationships get stronger, others weaken," Goetz said. "Because most networks change over time, this configuration of nodes and links also changes."

This change from one period to the next is represented by a change in the angles formed by the nodes and links, and these angles are the focus of the study, which was published on July 24 in PLOS ONE.

Goetz and his co-author, Yicheol Han, a research fellow at the Korea Rural Economic Institute in Nasu-si, South Korea, and formerly a research associate at NERCRD, turned to a familiar mathematical measure called the cosine similarity, which is traditionally used to measure the orientation of the angles between points and lines radiating from the points. When applied to network science, cosine similarity allowed the researchers to measure the size of the change in any given relationship, both relative to itself and to the overall network.

To test their new measure, the researchers applied it to several real-world networks, including the World Input-Output (I/O) Table, which documents economic transactions on a yearly basis both across and within nations. Focusing on the years 2000-2014, they found that the greatest amount of network change, which they refer to as "rewiring," occurred during 2008-2009. This was not unexpected, due to the Global Financial Crisis which occurred during those years.

"Rewiring is another way of thinking about reorganization, in this case," Goetz said. "Our findings show what a tremendous shock the world financial crisis was. It's interesting that the measure picked this up so strongly, and that it can be used as a new way of quantifying how the economy adjusted after the shock."

Their measure also showed a pronounced downward trend in rewiring after 2010, which they hypothesize may have contributed to the unusually slow recovery from the recession.

Next, the team looked at three individual countries -- the U.S., Germany and China -- to see how the rewiring in these countries' economies compared. While the U.S. and Germany followed a similar pattern as the overall world economy, China exhibited a significantly different pattern, with a spike in its rewiring occurring both before and after the financial crisis. However, to Goetz's surprise, they found that the financial crisis was not the most significant shock to the Chinese economy during this time period.

"The rewiring measure shows that joining the World Trade Organization in 2003 was a bigger shock to the Chinese economy than the Great Recession," Goetz said. "I'm not aware that anybody has shown this using any other measure."

Goetz and Han also looked at how rewiring in several nations' economic I/O tables affected their compound annual income growth rate per capita, the "holy grail" of economic measures, according to Goetz.

"We found that whether countries belonging to the Organization for Economic Cooperation and Development rewired a lot or a little didn't make much difference to their compound annual growth rate," said Han. "On the other hand, former Soviet Union nations really benefitted from rewiring. The more they rewired, the more their annual growth rate increased. We think it's because they only recently became market economies and lack mature institutions and other adjustment mechanisms to recession, so rewiring has more of an impact on their growth."

Future research will look at how the measure can be applied to rural economies, to see how these areas may or may not benefit from rewiring.

"That has the potential to lead to new ways of looking at how rural areas in the U.S. can develop and adjust to emerging shocks and other structural challenges," Goetz said.

Alzheimer's disease (AD) begins to alter and damage the brain years -- even decades -- before symptoms appear, making early identification of AD risk paramount to slowing its progression.

In a new study published online in the September 9, 2019 issue of the Neurobiology of Aging, scientists at University of California San Diego School of Medicine say that, with further developments, measuring how quickly a person's pupil dilates while they are taking cognitive tests may be a low-cost, low-invasive method to aid in screening individuals at increased genetic risk for AD before cognitive decline begins.

In recent years, researchers investigating the pathology of AD have primarily directed their attention at two causative or contributory factors: the accumulation of protein plaques in the brain called amyloid-beta and tangles of a protein called tau. Both have been linked to damaging and killing neurons, resulting in progressive cognitive dysfunction.

The new study focuses on pupillary responses which are driven by the locus coeruleus (LC), a cluster of neurons in the brainstem involved in regulating arousal and also modulating cognitive function. Tau is the earliest occurring known biomarker for AD; it first appears in the LC; and it is more strongly associated with cognition than amyloid-beta. The study was led by first author William S. Kremen, PhD, and senior author Carol E. Franz, PhD, both professors of psychiatry and co-directors of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine.

The LC drives pupillary response -- the changing diameter of the eyes' pupils -- during cognitive tasks. (Pupils get bigger the more difficult the brain task.) In previously published work, the researchers had reported that adults with mild cognitive impairment, often a precursor to AD, displayed greater pupil dilation and cognitive effort than cognitively normal individuals, even if both groups produced equivalent results. Critically, in the latest paper, the scientists link pupillary dilation responses with identified AD risk genes.

"Given the evidence linking pupillary responses, LC and tau and the association between pupillary response and AD polygenic risk scores (an aggregate accounting of factors to determine an individual's inherited AD risk), these results are proof-of-concept that measuring pupillary response during cognitive tasks could be another screening tool to detect Alzheimer's before symptom appear," said Kremen.

"Hot and dry" are the watchwords for large fires. In just seconds, a spark in hot and dry conditions can set off an inferno consuming thick, dried-out vegetation and almost everything else in its path. While every fire needs a spark to ignite and fuel to burn, hot and dry conditions in the atmosphere play a significant role in determining the likelihood of a fire starting, its intensity and the speed at which it spreads. Over the past several decades, as the world has increasingly warmed, so has its potential to burn.

Since 1880, the world has warmed by 1.9 degrees Fahrenheit, with the five warmest years on record occurring in the last five years. Since the 1980s, the wildfire season has lengthened across a quarter of the world's vegetated surface, and in some places like California, fire has become nearly a year-round risk. 2018 was California's worst wildfire season on record, on the heels of a devasting 2017 fire season. In 2019, wildfires have already burned 2.5 million acres in Alaska in an extreme fire season driven by high temperatures, which have also led to massive fires in Siberia.

Whether started naturally or by people, fires worldwide and the resulting smoke emissions and burned areas have been observed by NASA satellites from space for two decades. Combined with data collected and analyzed by scientists and forest managers on the ground, researchers at NASA, other U.S. agencies and universities are beginning to draw into focus the interplay between fires, climate and humans.

"Our ability to track fires in a concerted way over the last 20 years with satellite data has captured large-scale trends, such as increased fire activity, consistent with a warming climate in places like the western U.S., Canada and other parts of Northern Hemisphere forests where fuels are abundant," said Doug Morton, chief of the Biospheric Sciences Laboratory at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "Where warming and drying climate has increased the risk of fires, we've seen an increase in burning."

A Hotter, Drier World

High temperatures and low humidity are two essential factors behind the rise in fire risk and activity, affecting fire behavior from its ignition to its spread. Even before a fire starts they set the stage, said Jim Randerson, an Earth system scientist at the University of California, Irvine who studies fires both in the field and with satellite data.

He and his colleagues studied the abundance of lightning strikes in the 2015 Alaskan fire season that burned a record 5.1 million acres. Lightning strikes are the main natural cause of fires. The researchers found an unusually high number of lightning strikes occurred, generated by the warmer temperatures that cause the atmosphere to create more convective systems -- thunderstorms -- which ultimately contributed to more burned area that year.

Hotter and drier conditions also set the stage for human-ignited fires. "In the Western U.S., people are accidentally igniting fires all the time," Randerson said. "But when we have a period of extreme weather, high temperatures, low humidity, then it's more likely that typical outdoor activity might lead to an accidental fire that quickly gets out of control and becomes a large wildfire."

For example, in 2018 sparks flying from hammering a concrete stake into the ground in 100-degree Fahrenheit heat and sparks from a car's tire rim scraping against the asphalt after a flat tire were the causes of California's devastatingly destructive Ranch and Carr Fires, respectively. These sparks quickly ignited the vegetation that was dried out and made extremely flammable by the same extreme heat and low humidity, which research also shows can contribute to a fire's rapid and uncontrollable spread, said Randerson. The same conditions make it more likely for agricultural fires to get out of control.

A warming world also has another consequence that may be contributing to fire conditions persisting over multiple days where they otherwise might not have in the past: higher nighttime temperatures.

"Warmer nighttime temperature allow fires to burn through the night and burn more intensely, and that allows fires to spread over multiple days where previously, cooler nighttime temperatures might have weakened or extinguished the fire after only one day," Morton said.

Climate Systems at Work

Hot and dry conditions that precede fires can be tempered by rain and moisture circulating in the atmosphere. On time scales of months to years, broader climate patterns move moisture and heat around the planet. Monitoring these systems with satellite observations allows researchers to be able to begin to develop computer models for predicting whether an upcoming fire season in a given region will be light, average or extreme. The most important of these indicators are sea surface temperatures in the Pacific Ocean that govern the El Niño Southern Oscillation (ENSO).

"ENSO is a major driver of fire activity across multiple continents," Randerson said, who along with Morton and other researchers have studied the relationship between El Niño events and fire seasons in South America, Central America, parts of North America, Indonesia, Southeast Asia and equatorial Asia. "The precipitation both before the fire season and during the fire season can be predicted using sea surface temperatures that are measured by NASA and NOAA satellites."

An ongoing project, said Randerson, is to now extend that prediction capability globally to regions that are affected by other ocean-climate temperature changes and indicators.

The Human Factor

In studying the long-term trends of fires, human land management is as important to consider as any other factor. Globally, someplace on Earth is always on fire -- and most of those fires are set by people, either accidentally in wildlands, or on purpose, for example, to clear land or burn agricultural fields after the harvest to remove crop residues.

But not all fires behave the same way. Their behavior depends on the fuel type and the how people are changing the landscape. While fire activity has gotten worse in northern latitude forests, research conducted by Randerson and Morton has shown that despite climate conditions that favor fires, the number of fires in grassland and savanna ecosystems worldwide are declining, contributing to an overall decline in global burned area. The decline is due to an increased human presence creating new cropland and roads that serve as fire breaks and motivate the local population to fight these smaller fires, said Morton.

"Humans and climate together are really the dual factors that are shaping the fires around the world. It's not one or the other," Randerson said.

Fire Feedbacks

Fires impact humans and climate in return. For people, beyond the immediate loss of life and property, smoke is a serious health hazard when small soot particles enter the lungs, Long-term exposure has been linked to higher rates of respiratory and heart problems. Smoke plumes can travel for thousands of miles affecting air quality for people far downwind of the original fire. Fires also pose a threat to local water quality, and the loss of vegetation can lead to erosion and mudslides afterwards, which have been particularly bad in California, Randerson said.

For the climate, fires can directly and indirectly increase carbon emissions to the atmosphere. While they burn, fires release carbon stored in trees or in the soil. In some places like California or Alaska, additional carbon may be released as the dead trees decompose, a process that may take decades because dead trees will stand like ghosts in the forest, decaying slowly, said Morton. In addition to releasing carbon as they decompose, the dead trees no longer act as a carbon sink by pulling carbon dioxide out of the atmosphere. In some areas like Indonesia, Randerson and his colleagues have found that the radiocarbon age of carbon emissions from peat fires is about 800 years, which is then added to the greenhouse gases in that atmosphere that drive global warming. In Arctic and boreal forest ecosystems, fires burn organic carbon stored in the soils and hasten the melting of permafrost, which release methane, another greenhouse gas, when thawed.

Another area of active research is the mixed effect of particulates, or aerosols, in the atmosphere in regional climates due to fires, Randerson said. Aerosols can be dark like soot, often called black carbon, absorbing heat from sunlight while in the air, and when landing and darkening snow on the ground, accelerating its melt, which affects both local temperatures -- raising them since snow reflects sunlight away -- and the water cycle. But other aerosol particles can be light colored, reflecting sunlight and potentially having a cooling effect while they remain in the atmosphere. Whether dark or light, according to Randerson, aerosols from fires may also have an effect on clouds that make it harder for water droplets to form in the tropics, and thus reduce rainfall -- and increase drying.

Fires of all types reshape the landscape and the atmosphere in ways that can resonate for decades. Understanding both their immediate and long-term effects requires long-term global data sets that follow fires from their detection to mapping the scale of their burned area, to tracing smoke through the atmosphere and monitoring changes to rainfall patterns.

"As climate warms, we have an increasing frequency of extreme events. It's critical to monitor and understand extreme fires using satellite data so that we have the tools to successfully manage them in a warmer world," Randerson said.

University of Maryland researchers have discovered that seemingly identical cells can use different protein molecules to carry out the same function in an important cellular process. The scientists named this newly discovered variability "functional mosaicism," and it has significant implications for the development of therapeutic treatments, which are often designed to target a specific molecule, or a gene that produces a specific molecule.

By showing that individual cells within the same tissue can use different molecules to carry out the same functions, the new findings may help explain the persistence of some infected cells after drug treatment and relapses in complex diseases such as cancer. The research paper describing the work was published in the September 10, 2019, issue of the journal Nucleic Acids Research.

"Functional mosaicism introduces a cautionary message," said Antony Jose, senior author of the paper and associate professor of cell biology and molecular genetics at UMD. "It means that if you're developing a drug therapy that targets a certain process within cells, you can no longer assume that all cells of the same type use the same molecule or molecules to carry out that process. If you do, you may miss a few cells where things work differently."

Although scientists have long known about biological redundancy--when cells can carry out important functions in multiple ways--they typically assume consistency and the same redundancies among all cells of the same type. Functional mosaicism, on the other hand, means that within a group of seemingly identical cells, some of the individual cells can use an alternate path for certain functions.

"With biological redundancy, if you're developing a drug to target a particular function and the cells have an alternative way to accomplish the function, your drug will fail because all cells will use the alternative," Jose explained. "Functional mosaicism is different, and it can fool you. Your drug may appear to work because it works in some cells - even most cells, but there may be a few cells that persist because they can use an alternative you're not aware of."

Jose and his team of UMD researchers discovered functional mosaicism while studying RNA interference (RNAi), an important biological process that helps cells fight infection. Although they have not looked for functional mosaicism in other cellular processes yet, their findings represent a previously unknown and unexpected level of variability that, according to Jose, is likely to exist in many other cellular processes.

In the study, Jose and his team were investigating how RNA moves from one tissue type to another to turn off genes. Like DNA, RNA is a string of coded instructions that guide various functions in living cells. Unlike DNA, RNA usually occurs in single strands, except in some viruses, which introduce double strands of RNA into cells. One common defense that living cells have developed against viral infection is that they recognize double-stranded RNA and turn off genes with matching DNA sequences. This gene-silencing process is called RNAi.

RNAi relies on a group of protein molecules, or enzymes, called RNA-dependent RNA polymerases (RdRp), which replicate strands of RNA that can find and silence their matching genes. Many different RdRp enzymes exist, but researchers assumed they were tissue specific and that all cells from the same tissue used the same RdRp enzyme to carry out RNAi.

Jose and his colleagues first genetically modified nematode worms to fluoresce green. Next, they genetically modified the worms to make double-stranded RNA in neurons with the sequence matching the gene for green fluorescence. The double-stranded RNA moved throughout the worms' bodies and turned off the gene for green fluorescence in many cell types, including intestinal cells.

The researchers then removed the RdRp enzyme thought to be responsible for a critical step in RNAi gene silencing in intestinal cells. Only some of the cells fluoresced green, meaning that something continued to silence the fluorescent gene in some of the other intestinal cells. The RdRp they removed is called RRF-1, but there are three other RdRp's in the species of worm Jose and his colleagues studied (C. elegans).

Next, the scientists turned to the other three RdRp enzymes present in the nematode and eliminated one at a time to determine which turned off the green fluorescent gene in the worms' intestines. The culprit: EGO-1, which was thought to aid in RNAi only in reproduction-related germline cells.

Repeating their experiments in multiple individuals revealed that some cells required the RdRp called RRF-1 for silencing, but others did not because they could use EGO-1. Additionally, which intestinal cells used EGO-1 appeared to be random.

"We found that which enzyme gets used varies from cell to cell, and which cells use which enzyme varies from worm to worm," Jose said. "You can't tell from looking at them which cells use the alternative molecule, and from the cell's perspective, it doesn't matter which molecule it uses."

According to Jose, functional mosaicism could explain the persistence of some bacterial cells and cancer cells after treatment. If some cells persist by using a different mechanism than the one targeted by therapy, those cells may be the underlying cause of some instances of cancer relapse or antibiotic resistance.

"It may not be that these diseases are developing some new mechanism to survive," Jose said. "It may be that they already had more than one way of doing the same thing, and the alternates step in to replace whatever the therapeutic treatments knock out."

Current research into cellular processes is often conducted at the level of body tissues. Scientists combine multiple cells from a given tissue and examine them as a whole with the assumption that cellular processes are the same for all of the cells. According to Jose, therapeutic approaches should now consider the possibility of functional mosaicism, which requires closely examining what's going on at the single-cell level both before and after treatment.

Jose and his team suggest that functional mosaicism may also provide insight into the evolution of similar traits that develop using different mechanisms.

"Imagine starting off with two equally good ways of doing one thing, and as populations separate and begin to speciate, a mutation could cause one population to get stuck doing that thing one way, and the other population could get stuck doing it the alternative way," Jose said. "You could end up with two completely different ways of doing the same thing."

For example, although vision exists throughout the animal kingdom, eyes develop differently between animal groups. Functional mosaicism in a biological process responsible for sensing light in an early ancestor could have led to the divergence in visual systems that exists today among modern animals.

"Now that we know about functional mosaicism, we can go looking for it," Jose said. "It doesn't exist in every process to be sure, but it is something we have to be aware of."

Bottom Line: A new liquid biopsy test could detect microsatellite instability (MSI) and tumor mutational burden (TMB), indicating that it could help determine which patients are likely to respond to immune checkpoint inhibitors.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research.

Authors: Andrew Georgiadis, MS, scientist at Personal Genome Diagnostics in Baltimore, and Dung Le, MD, associate professor of oncology at the Sidney Kimmel Cancer Center at Johns Hopkins.

Background: In May 2017, the U.S. Food and Drug Administration (FDA) approved the immune checkpoint inhibitor pembrolizumab (Keytruda) for patients with unresectable or metastatic tumors that tested high for MSI (MSI-H or MSI-high) or mismatch repair deficiency (dMMR). This marked the FDA's first "site-agnostic" drug approval.

However, detecting MSI-H and dMMR status is often challenging, explained the study's lead author, Georgiadis. Currently, MSI is detected using tissue biopsies and technologies such as PCR-based amplification or next-generation sequencing. These processes are complicated and have sensitivity limitations, and certain tumor samples lack enough tissue for accurate testing, he added.

"A liquid biopsy test assessing MSI could reach a larger subset of patients, such as those where tissue is limited or where there are safety concerns around additional surgical intervention," Georgiadis said.

How the Study Was Conducted and Results: In this study, researchers sought to evaluate the sensitivity and specificity of a liquid biopsy approach developed by Personal Genome Diagnostics. They developed a 98 kb pan-cancer 58-gene panel, then employed a multifactorial error-correction method and a novel peak-finding algorithm to identify MSI frameshift alleles in cell-free DNA (cfDNA). The study was based on 61 patients with advanced cancer and 163 plasma samples from healthy individuals.

The authors explained that MSI can be detected by measuring the length of altered microsatellite sequences in tumor DNA as compared with normal DNA. In this study, the researchers flagged certain sequence data for error correction, then subjected the data to a peak-finding algorithm that identified instability in the loci. If 20 percent or more of the loci were determined to have MSI, the samples were classified as MSI-high.

For TMB, next-generation sequencing data were processed, and variants were identified using the VariantDx software. The researchers set five mutations in the targeted plasma panel as the threshold for identifying tumors as having exceptionally high mutational burden.

For MSI, the test produced a specificity of greater than 99 percent, and a sensitivity of 78 percent. For TMB, the test produced a specificity of greater than 99 percent, and a sensitivity of 67 percent.

The researchers also obtained plasma from 29 patients with metastatic cancers, including colorectal, ampullary, small intestine, endometrial, gastric, and thyroid. Among these, archival tissue-based analysis classified 23 cases as MSI-high and six cases as microsatellite stable. The VariantDx test detected high MSI in 18 of the 23 MSI-high patients (78.3 percent), and correctly identified the six microsatellite stable cases.

The researchers found that direct detection of MSI in baseline cfDNA was associated with progression-free survival of patients who were being treated with immune checkpoint blockade. Improvements in overall survival were not statistically significant.

Author's Comments: "Our data also demonstrate that liquid biopsy analysis of MSI and TMB may be more predictive of immunotherapy response than archival tissue, given that it is both a real-time and global measurement and resolves the inherent sampling bias of tissue biopsy," Georgiadis said.

Fellow author Le said that if results of this study are further validated and the test becomes commercially available, more patients could benefit from immune checkpoint inhibitors.

"A majority of patients with advanced incurable cancers who have an MSI-high tumor should be given the option to be treated with immunotherapy," she said. "If the tests become more accessible, less expensive, and require fewer resources such as tissue acquisition and pathology resources, more patients could be tested."

Study Limitations: The authors noted that this study was limited to a small population of cancer patients. Further research, conducted across a broader range of tumor types, will be necessary to confirm the study results.

Using your feet like hands can cause organised 'hand-like' maps of the toes in the brain, never before documented in people, finds a new UCL-led study of two professional foot painters.

These findings, published in Cell Reports, demonstrate an extreme example of how the human body map can change in response to experience.

"For almost all people, each of our fingers is represented by its own little section of the brain, while there's no distinction between brain areas for each of our toes," said the study's lead author, PhD student Daan Wesselink (UCL Institute of Cognitive Neuroscience and University of Oxford).

"But in other non-human primate species, who regularly use their toes for dextrous tasks like climbing, both the toes and fingers are specifically represented in their brains. Here, we've found that in people who use their toes similarly to how other people use their fingers, their toes were represented in their brains in a way never seen before in people."

The two study participants are among three professional foot painters in the UK who paint holding paintbrushes between their toes. They also use their toes regularly for everyday tasks such as dressing themselves, using cutlery and typing. To do what most people would do with their two hands, both artists typically use one foot for highly dextrous tasks while using the other foot to stabilise.

Their distinctive experiences extend beyond behaviour; by not regularly wearing enclosed footwear, the foot painters get more complex touch experiences on their toes. This may also have impacted brain development of these organised toe maps.

For the study, funded by Wellcome and the Royal Society, the foot painters (as well as 21 people born with two hands, who served as a control group) completed a series of tasks testing their sensory perception and motor control of their toes.

The participants then underwent ultra high-resolution fMRI brain scanning of the brain's body area - the somatosensory cortex. While inside the scanner, a researcher tapped the toes of the study participants, first looking for activity in the foot area of the body map.

In the foot painters, specific sections of the brain's foot area clearly reacted to their toes being touched. Brain maps comprised of individual toes were seen for the artists' dextrous foot, with a similar but less pronounced pattern showing in their stabilising foot. The two-handed controls showed no such maps. Other analyses showed the foot painters' feet were represented in the brain in a 'hand-like' way, but not the control participants' feet.

The researchers also found that the foot painters' toes were additionally represented in the part of their brain that would otherwise have served their missing hands. This corresponds with another study from the same lab finding that the brain's hand area gets used to support body parts being used to compensate for disability, such as the lips, feet or arms of people who were born with only one hand.

Perhaps surprisingly, motor tasks showed the foot painters were not any better than controls at wiggling one toe at a time, but they did have heightened sensory perception for their toes compared to controls.

Peter Longstaff, one of the foot painters who took part in the study, said he was fascinated to learn about how his brain developed differently due to how he has used his feet. Longstaff, who ran his own pig farm for 20 years, turned to foot painting in 2002.

"I've enjoyed helping science by demonstrating how most people's feet are not used to their full potential, and I hope the results will encourage other people to consider unconventional ways to get by without the use of hands," he said.

The researchers say the findings reveal that all people may have an innate capacity for forming these ordered maps of each toe in the brain - similar to our monkey relatives. Most people's brains don't develop as such, however, probably due to a lack of necessary experience.

"The body maps we have in our brains are not necessarily fixed - it appears as such because they are very consistent across almost all people, but that's just because most people behave very similarly," said co-lead author Dr Harriet Dempsey-Jones (UCL Institute of Cognitive Neuroscience).

"Our study demonstrates an extreme example of the brain's natural plasticity, as it can organise itself differently in people with starkly different experiences from the very beginning of their lives," said the study's senior author, Dr Tamar Makin (UCL Institute of Cognitive Neuroscience).

Dr Makin leads the Plasticity Lab at UCL, seeking to further our understanding of how our brains are malleable in order to develop ways to tap into the brain's innate plasticity, which may inform new rehabilitation approaches or treatments for phantom limb pain.

New work from Finland has been able to link mammalian behavior to its underlying neural code. The work examined how mammals' brains interpret signals from the eyes at low light levels.

The new study shines light on a route to solve the two broad goals of neuroscience. The first goal is to read nerve signals and interpret what they mean to our brains, and the second is to work out how our brain takes these signals and decides what to do - predicting how we behave based on what we see.

Secret to interpreting neural code found in pitch-dark maze

All the information the body sends to the brain - like what we can see, hear, smell and feel - gets sent through nerves as electrical impulses called spike trains.

The rulebook for how the brain decodes spike trains is unknown, and working it out is made harder by the fact that the nervous system often carries the same message in many different ways. When the different versions of the same message reach the brain, it interprets all these signals together to decide how to behave. Professor Petri Ala-Laurila and his teams at Aalto University and the University of Helsinki have now been able to link behaviour in a mouse to specific spike-trains originating in its eyes.

The mice had been trained swim towards an extremely faint light in a pitch-dark maze, and the team measured how effective the mice were at finding it. Darkness had to be used because it critically reduces the number of relevant spike trains to the two most sensitive ones to dim light: one called the ON channel and one called the OFF channel. By creating a scenario where there are a limited number of spike trains getting sent for a specific input, the team were able to isolate which individual spike train controlled behaviour.

It is very difficult to carry out precise science experiments in complete darkness, so the team developed a unique repertoire of state-of-the-art techniques. They had to design ways to measure electrical signals originating from single photons through the neural tissue of the eye - the retina - and linked these signals to mouse behavior in the maze. One of the breakthroughs is that the team can track mice in the dark using night-vision cameras and their deep-learning based software so accurately that they are able to predict with unprecedented resolution where photons land on each mouse's retinas.

The light the mouse was trying to find was made dimmer each time, to the point that in the last few attempts only a few photons at a time were entering the mouse's eyes.

The team compared two types of mice. The first group of mice that did the task were ordinary laboratory mice. The second group had been genetically modified so that their most sensitive ON channel needs 10 times more light to send a spike train than the most sensitive OFF channel. These modified mice turned out to be 10 times worse at seeing the light than their unmodified cousins. Therefore, the researchers were able to prove their important discovery: individual spike trains going through the ON channel were responsible for the mouse seeing the light.

Result relevant to all neuroscientists studying perception

This result is the first time anyone has linked visual behavior with this resolution to precise spike-codes coming from the retina. "This is like trying to translate a language," Professor Petri Ala-Laurila explains. "Previously we were using a phrasebook: we knew what whole sentences meant but not the meaning of individual words. Now that we can link precise codes consisting of individual nerve impulses to behavior, we are getting closer to understanding individual 'words'."

The result is highly relevant to researchers working on vision, but also broadly relevant to all neuroscientists working on perception, because of a surprising aspect of the result that overturned previously held beliefs in neurology. For 70 years, researchers have been using information theory to model how the brain handles different signals. One of the assumptions was that if the brain has to choose between two competing codes, it will rely on the signal that contains more information. In the case of the ON and OFF channels in vision in the genetically modified mice, the ON channel - which the team showed was key in controlling behavior - contains less information. The ON channel increases the amount of nerve impulses it sends to the brain when it detects photons, whereas the OFF channel decreases its impulse rate, and the researchers show that behaviour relies only on messages that are encoded in increased impulse rate rather than decreased impulse rate. "This discovery is really exciting for all of neuroscience because it's experimental proof of the brain prioritizing information encoded in spikes rather than in the absence of spikes" says Lina Smeds, the PhD student at University of Helsinki who is first author of the paper.

The next steps for the Finnish groups are to measure if the same principles apply to more neural circuits and behavioral paradigms and to see if they also follow the same rules. Professor Ala-Laurila compares the discovery to that of the Rosetta Stone in terms of its applicability. "When the Rosetta Stone was discovered, it didn't mean we could immediately understand Ancient Egyptian: but it gave researchers a tool that they used over the next 2 decades to finally translate Hieroglyphics. Likewise, this discovery doesn't mean we can immediately predict behavior from sensory nerve signals, but it will mean we can now start to study what individual signals mean to the brain".

Despite having lived about 300,000 years ago, the oldest ancestor of all members of Homo sapiens had a surprisingly modern skull--as suggested by a model created by CNRS researcher Aurélien Mounier of the Histoire Naturelle de l'Homme Préhistorique laboratory (CNRS / Muséum National d'Histoire Naturelle) and Cambridge University professor Marta Mirazón Lahr. After comparing the virtually rendered skull to those of five African fossil specimens contemporaneous with the first appearance of Homo sapiens, the two researchers posit that our species emerged through interbreeding of South and East African populations. Their findings are published in Nature Communications (10 September 2019).

Our species, Homo sapiens, arose in Africa roughly 300,000 years ago. But how and where exactly? Because few African fossils less than 500,000 years old have been discovered to date, we're missing pieces to complete the puzzle of the history of our species. In this new study, the researchers wanted to expand the pool of available fossils ... by creating virtual ones.

Accordingly, they took exhaustive measurements of 263 skulls of fossil and modern hominins (1) from 29 different populations,(2) to prepare 3D models.

Mounier and Mirazón Lahr demonstrated there was a close connection between the average cranial dimensions for each of the 29 populations and the respective positions of these populations in a phylogenetic tree largely constructed using genetic data.(3) This relationship allowed the researchers to calculate the likely skull dimensions of the most recent ancestor of all Homo sapiens groups. The virtual 300,000-year-old fossil has relatively modern features: its round cranium, relatively high forehead, and slight brow ridges and facial projection make it similar in morphology to some fossils that are only 100,000 years old.

The researchers compared their virtual fossil skull to five real fossil skulls from African members of the genus Homo who lived 130,000 to 350,000 years ago and are occasionally thought to have been our ancestors. Their analysis suggests our species arose through the hybridization of populations from South and East Africa. On the other hand, North African populations--possibly represented by the Jebel Shroud fossil--are believed to have interbred with Neanderthals after migration into Europe, accounting to a lesser extent for the makeup of our species.

This study also sheds light on the history of our species outside of Africa. It supports the hypothesis, advanced by others on the basis of genetic evidence,(4) that after an initial exodus from Africa that only left its mark in Oceania, a second migration allowed Homo sapiens to successively populate Europe, Asia, and finally, the Americas.

A USC scientist and colleagues have identified a new species of giant flying reptile that once soared over what is now North America.

The creature is similar to the largest pterosaurs known, yet key characteristics gleaned from a cache of bones unearthed in Canada show it's actually part of a new genus and species. The scientists call it Cryodrakon boreas, or Frozen Dragon of the North.

"These are among the most popular and charismatic of all fossil animals," said Michael Habib, assistant professor of Integrative Anatomical Sciences at the Keck School of Medicine of USC and research associate at the Dinosaur Institute of the Natural History Museum of Los Angeles County. "They have been inspiration for countless movie monsters, they were critical parts of global ecosystems worldwide during the Age of Dinosaurs, so they are key to understanding the ecology and extinctions of that time, and, just like flying animals today, they could carry important clues about how animals at the time responded to major changes in climate."

The findings are reported today in Journal of Vertebrate Paleontology.

Paleontologists have been collecting pterosaur bones from Dinosaur Provincial Park in southern Alberta since 1972. Typically, those bones date to the late Cretaceous epoch between 76.9 and 75.8 million years ago and represent azhdarchid (as-DAR-kid) pterosaurs. They included the biggest flying creatures ever, with a wingspan of 30 feet and weighing 500 pounds, capable of sailing across continents and oceans. Even the smallest species had wingspans of the largest living albatross.

Yet, azhdarchids are known primarily from limited and fragmentary remains, which makes them difficult to classify or understand their behavior and biology. Sometimes they are grouped as Quetzalcoatlus or Zhejiangopterus, giant flying reptiles found in Texas and China, respectively, and beyond.

Amid this uncertainty, the researchers behind the new study identified a new species, which they say could account for some of the previous discrepancies in pterosaur remains coming from the Canadian badlands and around the world.

Habib and colleagues from Canada and the United Kingdom examined a collection of bones comprising much of a skeleton. The fossils are better preserved than other azhdarchid fossils. The scientists noted key differences in the shape of vertebrae, cervical bones and leg bones. These would have affected the spinal column, shape of the legs and size of the creature, the study says.

"This type of pterosaur (azhdarchids) is quite rare, and most specimens are just a single bone. Our new species is represented by a partial skeleton. This tells us a great deal about the anatomy of these large flyers, how they flew, and how they lived," Habib said.

From these findings, the scientists conclude that Cryodrakon was about the same size, and looked similar to Quetzalcoatlus, but was likely heavier and more robust. That's an important finding because it challenges classic reconstructions of these animals as ultralight soaring specialists. Instead, Cryodrakon may have been extra-muscular ground hunter that used flight to burst away from danger.

"This particular group of pterosaurs includes the largest flying animals of all time. Their anatomy holds important clues about the limits of animal flight and may be important in the future for biologically inspired mechanical design for flight," Habib said.

Did you know that the DNA in any cell of the human body - or any organism for that matter - contains the genetic information required to develop every possible type of cell within that organism? Yet cell types differ markedly from each other both structurally and functionally. This is manifest through the production of different proteins encoded in the genetic information of the cell.

How is the information in DNA expressed as different proteins in diverse cells, such as those in a human liver, brain, heart or, maybe more pressing to ask, in a cancerous tumour?

This kind of fundamental question is the focus of molecular biologists, particularly those with an evolutionary bent, who seek to understand how life evolved and how gene expression and cell development occur.

Dr. Jeffrey Fillingham, an associate professor in the Department of Chemistry and Biology at Ryerson University, and Dr. Ronald Pearlman, University Professor Emeritus in the Department of Biology at York University, are just the sort of molecular biologists who ask these basic questions. Among their areas of interest, the two researchers study transcription and gene expression.

"Transcription is the process by which the information contained in DNA is turned into RNA, which carries the messages that direct the synthesis of proteins involved in making a particular cell," says Pearlman. "The question is, 'how, when, why and where are genes activated so they can be transcribed into cell-specific proteins?'"

Recently, a team based at Fillingham's Ryerson research lab in the MaRS Discovery District explored this question, working with researchers in Pearlman's group at York University and supported by others in Dr. Jack Greenblatt's research group at the University of Toronto, as well as contributions from the SciNet HPC Consortium at the University of Toronto, along with Université Laval.

The team studied protein complexes involved in transcription using two experimental techniques: affinity purification and mass spectrometry. To do so, they looked at transcription in a single-cell eukaryotic (contains organelles such as the nucleus bounded by a membrane) model organism called Tetrahymena, which is an ideal system to study because it is easy to work with and manipulate molecularly, biochemically, and genetically, and grows quickly. Its genome has more evolutionary similarity to humans than other non-mammalian model research organisms.

The objective of the study was to better understand the function of a protein complex called Mediator, which plays a central role in gene expression through transcription, with particular focus on a protein called Med31, a subunit of the Mediator complex.

Med31 is interesting to molecular biologists because it has been conserved through millennia of evolutionary change, which means that highly similar versions of the protein are found in organisms as divergent as Tetrahymena and human beings. (Tetrahymena Med31 has approximately 42% sequence identity with human Med31.) Previous studies have demonstrated Med31 has ancient roots, is present in almost all organisms alive today, and plays a central role in cell development regulation in mammals.

These aspects of Med31 - and Mediator - lead to some interesting questions.

"The fact that Med31 is so conserved in evolution indicates that it plays some key fundamental role in transcription," says Fillingham. "What is it doing? What is its role? Those are questions the answers to which nobody has really got at yet."

The team's investigation shed some light on the functioning of Mediator and Med31 in Tetrahymena by suggesting some ways that Mediator may function in developmental regulation for organisms. The findings were published in an article called "The Med31 Conserved Component of the Divergent Mediator Complex in Tetrahymena thermophila Participates in Developmental Regulation" in the highly-regarded journal Current Biology, one of several in the prestigious Cell Press stable of journals.

Current Biology's decision to publish the article is notable because it focuses on publication of research with a broad general interest, which means the journal editors and reviewers believe the findings of the Fillingham-led team are of interest and value to the wide biology community. What's also interesting is that another paper using the same Tetrahymena model system published in the same journal issue reached similar conclusions to this study by asking different research questions, which amplifies the veracity of the team's findings.

"In the field of transcription and gene expression, our findings are very interesting," says Fillingham. "People will be interested to know how Tetrahymena Mediator is functioning in gene regulation and what this tells us more generally about transcription and regulation of gene expression."

Enteroviral infections are common viral infections with usually rather few symptoms and also believed to be linked to the onset of type 1 diabetes. Type 1 diabetes is a disorder in which the pancreatic insulin-producing beta-cells are destroyed, and it is more common in Finland than anywhere else in the world. A new study by the University of Turku and Tampere University in Finland supports the link between enteroviral infections and type 1 diabetes.

The goal of the new study by the research groups of Academy Professor at Turku Bioscience Centre Riitta Lahesmaa and Professor at Tampere University Heikki Hyöty was to understand the mechanisms that control the development of chronic enteroviral infection in the pancreas. The study also aimed at creating a comprehensive picture on the alterations caused by enteroviral infection that could possibly have adverse health effects.

In the study, cutting-edge proteomic methods were utilised to measure how the infection influences the expression and secretion of thousands of different proteins in the cellular models of chronic pancreatic enteroviral infection.

Having persisted for almost a year, the chronic enteroviral infections modified the cellular expression of numerous proteins that are key to cellular functions, such as proteins regulating energy metabolism. The infections also caused alterations in the secretion of several proteins.

"For example, the levels of proteins in the regulated secretory pathway participating in the secretion of hormones such as insulin in the beta-cells decreased with the chronic infection. The infections also clearly affected the levels of other proteins that are involved in the function and survival of beta-cells," says Dr Niina Lietzén from the Turku Bioscience Centre.

"Interestingly, chronic infections that had been developed by using two different virus strains triggered partly very different responses. For example, major differences in the activation of immune responses were discovered between these two models. This indicates that the viruses have different kinds of abilities to manipulate the cellular defence systems," adds Hyöty.

Published in the iScience journal, the study revealed several mechanisms through which chronic enteroviral infections can impact pancreatic functioning and possibly the development of type 1 diabetes. The report is part of the ongoing doctoral studies of Doctoral Candidates Anni Honkimaa from Tampere University and Karoliina Hirvonen from the University of Turku.