Culture

In years to come, our personal memories of the COVID-19 pandemic are likely to be etched in our minds with precision and clarity, distinct from other memories of 2020. The process which makes this possible has eluded scientists for many decades, but research led by the University of Bristol has made a breakthrough in understanding how memories can be so distinct and long-lasting without getting muddled up.

The study, published in Nature Communications, describes a newly discovered mechanism of learning in the brain shown to stabilise memories and reduce interference between them. Its findings also provide new insight into how humans form expectations and make accurate predictions about what could happen in future.

Memories are created when the connections between the nerve cells which send and receive signals from the brain are made stronger. This process has long been associated with changes to connections that excite neighbouring nerve cells in the hippocampus, a region of the brain crucial for memory formation.

These excitatory connections must be balanced with inhibitory connections, which dampen nerve cell activity, for healthy brain function. The role of changes to inhibitory connection strength had not previously been considered and the researchers found that inhibitory connections between nerve cells, known as neurons, can similarly be strengthened.

Working together with computational neuroscientists at Imperial College London, the researchers showed how this allows the stabilisation of memory representations.

Their findings uncover for the first time how two different types of inhibitory connections (from parvalbumin and somatostatin expressing neurons) can also vary and increase their strength, just like excitatory connections. Moreover, computational modelling demonstrated this inhibitory learning enables the hippocampus to stabilise changes to excitatory connection strength, which prevents interfering information from disrupting memories.

First author Dr Matt Udakis, Research Associate at the School of Physiology, Pharmacology and Neuroscience, said: "We were all really excited when we discovered these two types of inhibitory neurons could alter their connections and partake in learning.

""It provides an explanation for what we all know to be true; that memories do not disappear as soon as we encounter a new experience. These new findings will help us understand why that is.

"The computer modelling gave us important new insight into how inhibitory learning enables memories to be stable over time and not be susceptible to interference. That's really important as it has previously been unclear how separate memories can remain precise and robust."

The research was funded by the UKRI's Biotechnology and Biological Sciences Research Council, which has awarded the teams further funding to develop this research and test their predictions from these findings by measuring the stability of memory representations.

Senior author Professor Jack Mellor, Professor in Neuroscience at the Centre for Synaptic Plasticity, said: "Memories form the basis of our expectations about future events and enable us to make more accurate predictions. What the brain is constantly doing is matching our expectations to reality, finding out where mismatches occur, and using this information to determine what we need to learn.

"We believe what we have discovered plays a crucial role in assessing how accurate our predictions are and therefore what is important new information. In the current climate, our ability to manage our expectations and make accurate predictions has never been more important."

"This is also a great example of how research at the interface of two different disciplines can deliver exciting science with truly new insights. Memory researchers within Bristol Neuroscience form one of the largest communities of memory-focussed research in the UK spanning a broad range of expertise and approaches. It was a great opportunity to work together and start to answer these big questions, which neuroscientists have been grappling with for decades and have wide-reaching implications."

PHILADELPHIA -- An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein's buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic. Results were published in Science Translational Medicine.

The work shows, for the first time, how toxic poly(GR) (glycine-arginine repeat) proteins produced by the mutated C9orf72 gene stimulate the clumping of TDP-43 found in ALS, also known as Lou Gehrig's disease, and FTD patients. In a mouse model, the researchers also show that treatment with a pipeline drug known as an antisense oligonucleotide (ASO) reduced the levels of poly(GR), TDP-43 clumps, and neurodegeneration along with it.

"A common genetic cause of ALS and FTD is a repeat expansion in the C9orf72 gene, which somehow leads to TDP-43 aggregation in degenerating neurons, but what remained unclear until now was how those two were connected," said co-senior author James Shorter, PhD, a professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania. "We found that TDP-43 aggregates much more rapidly if these toxic poly(GR) proteins are around, suggesting a direct link between the mutation, poly(GR), and TDP-43."

ALS is the progressive degeneration of motor neurons that control people's muscles, speech, and ability to breathe. FTD, the most common form of dementia in people under 60, results in damage to the anterior temporal and/or frontal lobes of the brain; as it progresses, it becomes increasingly difficult for people to function and even care for oneself.

"This finding presents an exciting potential therapeutic target to treat these debilitating diseases by lowering poly(GR) levels," added Hana Odeh, PhD, a post-doctoral fellow in the Shorter lab and co-first author.

After researchers in the Shorter lab demonstrated the role of poly(GR) proteins in TDP-43 accumulation at the protein level, their colleagues at Mayo Clinic in Jacksonville, Fla., studied the interactions in both human cells and mice to support the initial bench side finding at Penn. Co-senior authors from Mayo Clinic include Yongjie Zhang, PhD, an assistant professor of Neuroscience, and Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic College of Medicine and Science.

They showed in a series of complementary experiments, including immunofluorescence staining and immuno-electron microscopy, that poly(GR) in human cells alone can sequester TDP-43 proteins, and in doing so induce the formation of dense protein clumps. This same mechanism was then demonstrated in a mouse model.

It's worth noting, the researchers said, that the burden of both TDP-43 and poly(GR) correlate with neurodegeneration in patients observed in past studies: the higher the protein levels, the worse the neurological function, providing further evidence that the two proteins are conspiring.

Next, the team delivered an ASO drug known as c9ASO, which is being investigated in clinical trials, into the brains of three-month old mice expressing the ALS/FTD-causing repeat-expansion and found that it had diminished the levels of both poly(GR) and TDP-43 aggregates. c9ASO has been shown to switch off the repeat expansions in the C9orf72 gene and reduce poly(GR), but this is the first time it's been shown to reduce TDP-43 clumping.

To assess the drug's neuroprotective ability, the researchers examined the amount of neurons and plasma neurofilament light (NFL), a known biomarker of neurodegeneration in patients, in treated mice. The drug prevented the reduction of cortical neurons and decreased levels of plasma NFL, they found, suggesting the drug helped confer neuroprotection. "If that extends to patients, the plasma NFL level provides a way to track how effective your therapeutic is," Odeh said.

The researchers plan to study in more detail how TDP-43 and poly(GR) and other similar toxic proteins associated with the mutated C9orf72 interact, and conduct further studies with ASO drugs to better understand their role in stopping the clumping of TDP-43.

"This exciting collaborative study sets the stage for continued teamwork in this space, which I see as being of great interest to the ALS and FTD community," Shorter said.

ORLANDO, Sept. 8, 2020 - Storm surges sometimes can increase coastal sea levels 10 feet or more, jeopardizing communities and businesses along the water, but new research from the University of Central Florida shows there may be a way to predict periods when it's more likely that such events occur.

In a study published recently in the Journal of Geophysical Research: Oceans, researchers developed models to predict extreme changes in sea level by linking storm surges to large-scale climate variability that is related to changes in atmospheric pressure and the sea surface temperature, such as El Niño.

El Niño is a periodic warming of sea surface temperatures in the Pacific Ocean between Asia and South America that can affect weather around the globe.

"If we were capable to predict in advance when we go through periods of relatively higher flood risk, that would be very useful information to have, for example in order to make available and deploy resources way in advance," says Mamunur Rashid, the study's lead author and a postdoctoral research associate in UCF's Department of Civil, Environmental and Construction Engineering.

"Our analysis was only the first step in this direction, and while we show that there is some capability in predicting storm surge variability over inter-annual to decadal time scales, we are not at the point yet where such a modeling framework can be used in an operational way or for making important decisions based on the results," he says.

The study was supported by the National Oceanic and Atmospheric Administration's Climate Program Office, Climate Observations and Monitoring Program.

The study builds on previous research that showed storm surge is a major factor in extreme sea level variability, which is when water level thresholds are higher or lower than normal conditions. In addition to storm surge, factors behind extreme sea level variability also include mean sea level and low frequency tides.

Coastal flood risk assessments often omit the role of extreme sea level variations, ignoring that flood risk is higher in some periods than others, and instead focus on long-term sea level rise, says Thomas Wahl, study co-author and an assistant professor in UCF's Department of Civil, Environmental and Construction Engineering.

"Knowing how the extreme sea level variations we are investigating modulate the potential losses can help better plan and adapt to mitigate these impacts," he says.

To develop the models, the researchers linked large-scale climate variability events, such as El Niño, to variability in storm surge activity. Then they tested the models by having them predict past storm surge variability and then compared their predictions with what actually occurred.

The results indicated that the models matched the overall trends and variability of storm surge indicators for almost all coastal regions of the U.S during both the tropical and extra-tropical storm seasons.

For Florida, the models reflect the difference in the variability of storm surge on the west coast compared to the east, Wahl says.

"It's a little bit larger on the west coast, and the highs and lows along the two coastlines are also not in phase," he says.

The researchers say they will continue to improve their models as the global climate models they employ continue to improve in accuracy.

AMHERST, Mass. - Farmers and fruit growers are reporting that climate change is leading to increased ozone concentrations on the soil surface in their fields and orchards - an exposure that can cause irreversible plant damage, reduce crop yields and threaten the food supply, say materials chemists led by Trisha Andrew at the University of Massachusetts Amherst.

Writing in Science Advances, co-first authors Jae Joon Kim and Ruolan Fan show that the Andrew lab's method of vapor-depositing conducting polymer "tattoos" on plant leaves can allow growers to accurately detect and measure such ozone damage, even at low exposure levels. Their resilient polymer tattoos placed on the leaves allow for "frequent and long-term monitoring of cellular ozone damage in economically important crops such as grapes and apples," Andrew says.

They write, "We selected grapes (Vitis vinifera L.) as our model plant because the fruit yield and fruit quality of grapevines decrease significantly upon exposure to ground level ozone, leading to significant economic losses." Ground-level ozone can be produced by the interaction between the nitrates in fertilizer and the sun, for example.

UMass Amherst viniculturist Elsa Petit, who advised the chemistry team, says the sensor tattoo could be especially useful to the grape industry. "With climate change, ozone will increase and this new sensor might be extremely useful to help farmers act before the damage is recognizable by eye," she says. Ground-level ozone can be mitigated by early detection and treating the soil surface with charcoal or zeolite powders.

As Andrew explains, her lab, funded by the National Science Foundation, adapted the electrode vapor-deposition method they had developed earlier to coat fabrics for medical sensing devices for a new use - on living plants. The conducting polymer film, poly(3,4-ethylenedioxytiophene), PEDOT, is just 1 micron thick so it lets sunlight in and does not hurt leaves. Non-metal, carbon-based polymers that act as conducting electrodes are increasingly used in soft materials design since they were invented in the 1970s, she adds.

"Ours acts like a temporary tattoo on a human," Andrew says. "It doesn't wash away and the polymer's electrical properties don't degrade, even over a long time. We have some tattooed plants in a greenhouse on campus and a year later they are still growing fine, putting out roots and leaves as normal."

To test for early ozone damage, she and colleagues use a hand-held impedance spectrometer adapted from human medical practice. When it touches the electrode tattoo, a read-out reports the electrical resistance vs frequency relationship. This voltage value changes in the presence of various factors, including oxidative damage from ozone.

Andrew says, "You get a wave-form image; a software program fits the wave so we can extract certain tissue parameters. We can recognize patterns for different kinds of damage. It's consistent and remarkably accurate. If you use it on the same plant over a year, as long as the plant is healthy the signal doesn't really change over that time."

"The problem scientifically is that visual ozone damage looks exactly the same as if you watered the plant too little or it got too much sun. This project became intellectually interesting to us when we looked at the ozone signature of our read-outs and it was very different from drought or UV damage. Ozone produces a unique change in the high-frequency electrical impedance and phase signals of leaves."

The scientists hope their invention could be used by farmers and fruit growers who could place a few "reporter plants" among crops to periodically monitor soil ozone levels. "It gives you a picture of what is going on in your soil," Andrew suggests. "You can be alerted if the fertilizer level is wrong, for example. This can happen, especially with food crops that need a lot of sun and fertilizer to produce, like melons, grapes and orchard fruits. Some plants are very sensitive to it."

HOUSTON - (Sept. 8, 2020) - If you're looking for an unconventional approach to doing business, select a CEO with an uncommon name, according to new research co-authored by an expert at Rice University's Jones Graduate School of Business.

"Using 19 years of data on 1,172 public firms, we show that firms' distinctive strategies are systematically linked to their CEOs' uncommon names," wrote co-authors Yan Anthea Zhang, the Fayez Sarofim Vanguard Professor of Strategy at the Jones School, and Yungu Kang and David H. Zhu of Arizona State University's W.P. Carey School of Business.

Past studies have examined how organizational outcomes are associated with leadership personalities, values, experiences and demographic characteristics, but not CEO's names -- "one of the most fundamental attributes," the authors argue. A person's name influences their behavior, cognition and sense of self, according to the paper.

"Studies suggest that individuals with uncommon names tend to have a self-conception of being different from their peers," they wrote. "Although many people may not have the confidence to exhibit how unique they believe themselves to be, CEOs do -- they are generally confident individuals."

CEOs who have uncommon names are motivated to differentiate themselves from other CEOs, they argue, which influences strategic distinctiveness, or the degree that a business' strategy differs from industry peers.

"This is consistent with findings from psychological research that successful professionals who have uncommon names tend to view themselves as more special, unique, interesting and creative," they wrote.

Developing and implementing unique business strategies is "critical for firms to obtain competitive advantage and achieve superior performance," according to the authors. They argue that CEOs with uncommon names tend to adopt strategies that deviate from the industry norm, leading to distinctive strategies.

"Our findings can help all stakeholders to better understand and predict a CEO's strategic decisions, they wrote. "Because CEOs with uncommon names tend to pursue distinctive strategies, boards that seek to enhance the distinctiveness of their firms' strategies may want to hire CEOs with uncommon names."

"Other top executives, middle-level managers and employees can also expect a higher likelihood of implementing distinctive strategies when their CEOs have more uncommon names," the authors continued. "Competitors can expect a firm to engage in unusual competitive moves when the CEO has an uncommon name."

Research conducted by the Computational Neuroscience Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) has shown for the first time that a computer model can replicate and explain a unique property displayed by a crucial brain cell. Their findings, published today in eLife, shed light on how groups of neurons can self-organize by synchronizing when they fire fast.

The model focuses on Purkinje neurons, which are found within the cerebellum. This dense region of the hindbrain receives inputs from the body and other areas of the brain in order to fine-tune the accuracy and timing of movement, among other tasks.

"Purkinje cells are an attractive target for computational modeling as there has always been a lot of experimental data to draw from," said Professor Erik De Schutter, who leads the Computation Neuroscience Unit. "But a few years ago, experimental research into these neurons uncovered a strange behavior that couldn't be replicated in any existing models."

These studies showed that the firing rate of a Purkinje neuron affected how it reacted to signals fired from other neighboring neurons.

The rate at which a neuron fires electrical signals is one of the most crucial means of transmitting information to other neurons. Spikes, or action potentials, follow an "all or nothing" principle - either they occur, or they don't - but the size of the electrical signal never changes, only the frequency. The stronger the input to a neuron, the quicker that neuron fires.

But neurons don't fire in an independent manner. "Neurons are connected and entangled with many other neurons that are also transmitting electrical signals. These spikes can perturb neighboring neurons through synaptic connections and alter their firing pattern," explained Prof. De Schutter.

Interestingly, when a Purkinje cell fires slowly, spikes from connected cells have little effect on the neuron's spiking. But, when the firing rate is high, the impact of input spikes grows and makes the Purkinje cell fire earlier.

"The existing models could not replicate this behavior and therefore could not explain why this happened. Although the models were good at mimicking spikes, they lacked data about how the neurons acted in the intervals between spikes," Prof. De Schutter said. "It was clear that a newer model including more data was needed."

Testing a new model

Fortunately, Prof. De Schutter's unit had just finished developing an updated model, an immense task primarily undertaken by now former postdoctoral researcher, Dr. Yunliang Zang.

Once completed, the team found that for the first time, the new model was able to replicate the unique firing-rate dependent behavior.

In the model, they saw that in the interval between spikes, the Purkinje neuron's membrane voltage in slowly firing neurons was much lower than the rapidly firing ones.

"In order to trigger a new spike, the membrane voltage has to be high enough to reach a threshold. When the neurons fire at a high rate, their higher membrane voltage makes it easier for perturbing inputs, which slightly increase the membrane voltage, to cross this threshold and cause a new spike," explained Prof. De Schutter.

The researchers found that these differences in the membrane voltage between fast and slow firing neurons were because of the specific types of potassium ion channels in Purkinje neurons.

"The previous models were developed with only the generic types of potassium channels that we knew about. But the new model is much more detailed and complex, including data about many Purkinje cell-specific types of potassium channels. So that's why this unique behavior could finally be replicated and understood," said Prof. De Schutter.

The key to synchronization

The researchers then decided to use their model to explore the effects of this behavior on a larger-scale, across a network of Purkinje neurons. They found that at high firing rates, the neurons started to loosely synchronize and fire together at the same time. Then when the firing rate slowed down, this coordination was quickly lost.

Using a simpler, mathematical model, Dr. Sungho Hong, a group leader in the unit, then confirmed this link was due to the difference in how fast and slow firing Purkinje neurons responded to spikes from connected neurons.

"This makes intuitive sense," said Prof. De Schutter. He explained that for neurons to be able to sync up, they need to be able to adapt their firing rate in response to inputs to the cerebellum. "So this syncing with other spikes only occurs when Purkinje neurons are firing rapidly," he added.

The role of synchrony is still controversial in neuroscience, with its exact function remaining poorly understood. But many researchers believe that synchronization of neural activity plays a role in cognitive processes, allowing communication between distant regions of the brain. For Purkinje neurons, they allow strong and timely signals to be sent out, which experimental studies have suggested could be important for initiating movement.

"This is the first time that research has explored whether the rate at which neurons fire affects their ability to synchronize and explains how these assemblies of synchronized neurons quickly appear and disappear," said Prof. De Schutter. "We may find that other circuits in the brain also rely on this rate-dependent mechanism."

The team now plans to continue using the model to probe deeper into how these brain cells function, both individually and as a network. And, as technology develops and computing power strengthens, Prof. De Schutter has an ultimate life ambition.

"My goal is to build the most complex and realistic model of a neuron possible," said Prof. De Schutter. "OIST has the resources and computing power to do that, to carry out really fun science that pushes the boundary of what's possible. Only by delving into deeper and deeper detail in neurons, can we really start to better understand what's going on."

BOSTON - Patients hospitalized with severe COVID-19 infections who have high levels of the blood clotting protein factor V are at elevated risk for serious injury from blood clots such as deep vein thrombosis or pulmonary embolism, investigators at Massachusetts General Hospital (MGH) have found.

On the other hand, critically ill patients with COVID-19 and low levels of factor V appear to be at increased risk for death from a coagulopathy that resembles disseminated intravascular coagulation (DIC), a devastating, often fatal abnormality in which blood clots form in small vessels throughout the body, leading to exhaustion of clotting factors and proteins that control coagulation, report Elizabeth M. Van Cott, MD, investigator in the deparment of pathology at MGH and colleagues.

Their findings, based on studies of patients with COVID-19 in MGH intensive care units (ICUs), point to disturbances in factor V activity as both a potential cause of blood clotting disorders with COVID-19, and to potential methods for identifying at-risk patients with the goal of selecting the proper anticoagulation therapy.

The study results are published online in the American Journal of Hematology.

"Aside from COVID-19, I've never seen anything else cause markedly elevated factor V, and I've been doing this for 25 years," Van Cott says.

Patients with severe COVID-19 disease caused by the SARS-CoV-2 virus can develop blood clots in medical lines (intravenous lines, catheters, etc), and in arteries, lungs, and extremities, including the toes. Yet the mechanisms underlying coagulation disorders in patients with COVID-19 are still unknown.

In March 2020, in the early days of the COVID-19 pandemic in Massachusetts, Van Cott and colleagues found that a blood sample from a patient with severe COVID-19 on a ventilator contained factor V levels high above the normal reference range. Four days later, this patient developed a saddle pulmonary embolism, a potentially fatal blood clot occurring at the junction of the left and right pulmonary arteries.

This pointed the investigators to activity of factor V as well as factor VIII and factor X, two other major clotting factors. They studied the levels of these clotting factors and other parameters in a group of 102 consecutive patients with COVID-19, and compared the results with those of current critically ill patients without COVID-19, and with historical controls.

They found that factor V levels were significantly elevated among patients with COVID-19 compared with controls, and that the association between high factor V activity and COVID-19 was the strongest among all clinical parameters studied.

In all, 33 percent of patients with factor V activity well above the reference range had either deep vein thrombosis or a pulmonary embolism, compared with only 13 percent of patients with lower levels. Death rates were significantly higher for patients with lower levels of factor V (30 percent vs. 12 percent), with evidence that this was due to a clinical decline toward a DIC-like state.

Van Cott and colleagues also found that the clinical decline toward DIC was foreshadowed by a measurable change in the shape or "waveform" of a plot charting light absorbance against the time it takes blood to coagulate (waveform of the activated partial thromboplastin time, or aPTT).

"The waveform can actually be a useful tool to help assess patients as to whether their clinical course is declining toward DIC or not," Van Cott explains. "The lab tests that usually diagnose DIC were not helpful in these cases."

Importantly, the MGH investigators note that factor V elevation in COVID-19 could cause misdiagnosis of some patients, because under normal circumstances factor V levels are low in the presence of liver dysfunction or DIC. Physicians might therefore mistakenly assume that patients instead have a deficiency in vitamin K.

"This investigation was spurred by the surprising case we encountered, and was conducted rapidly by an interdisciplinary pathology team at MGH during the peak of the pandemic," said Jonathan Stefely, MD, PhD, one of the study's co-authors.

From the Rocky Mountains to the Alps, the question of whether a deer population migrates can be answered by how springtime comes to the landscapes they occupy.

That's the key finding of a first-of-its-kind study produced by a cross-continental team of researchers working with lead author Ellen Aikens, a recent doctoral student of the U.S. Geological Survey's Wyoming Cooperative Fish and Wildlife Research Unit at the University of Wyoming. The paper was published today (Sept. 7) in Current Biology, a leading journal in the field.

The researchers found that the dynamics of springtime plant growth, specifically whether green-up progresses like a wave or not, explains where migration occurs in many ecosystems. A slow and long spring green-up correlates to a resident strategy.

In contrast, migratory behavior often is found in places where the green-up is shorter in any one place but progresses up in elevation. Migratory behavior emerges as a means for animals to track food in landscapes where pulses of the best forage actually move across the landscape as the spring season unfolds. This wave-like green-up is fleeting, and animals make the most of it by moving sequentially across large landscapes in a behavior that scientists call "green-wave surfing."

The analysis combined vegetation data from satellites with GPS-tracking data from 1,696 individuals across 61 populations of four ungulate species: roe deer and red deer in Europe, and mule deer and elk in North America.

Few other studies have combined movement and vegetation data at this large of a scale to get at the root of what makes deer migrate. This work was made possible through the collaboration of 36 biologists spread out across North America and Europe. The EuroDeer project contributed some of the most crucial datasets on roe deer and red deer movement.

Intriguingly, researchers found that at the species level, migrants and residents received equal foraging benefits regardless of which movement strategy they employed. This finding suggests that the movement tactics of deer populations are fine-tuned to the dynamic way that forage resources move across the landscapes they inhabit.

An important implication is that management and conservation of deer species are best tailored to local patterns of plant growth, and the particular behavioral adaptations that have arisen in each area.

For example, roe deer don't have to move to secure the food they need due to the long springtime season in France or Belgium. However, in the Rocky Mountains or the Alps, to stay put is to be hungry and miss out on the best forage.

"This new research shows that ungulate movement is influenced by altered patterns of forage availability," Aikens says. "Migrations can be lost when changes in the underlying habitat eliminate the need to migrate over long distances."

For example, shortened migrations or increased residency have been caused by food subsidies such as agriculture and supplemental feeding. In such altered landscapes, a switch to a resident strategy may be adaptive in a changing world.

On the other hand, in less-developed areas where animals depend on migration to survive, climate-induced changes in the green wave -- or new barriers to movement such as highways or housing -- can reduce food availability. These changes might be early warning signals of future population declines.

"This research has global implications for the field of animal ecology and should help drive future conservation work," says Matthew Kauffman, director of the Wyoming Cooperative Fish and Wildlife Research Unit and a senior author of the study. "It allows us to understand more fully the types of landscapes where migration is required by ungulates and where conservation of corridors is thus paramount."

COLUMBUS, Ohio - While acetaminophen is helping you deal with your headache, it may also be making you more willing to take risks, a new study suggests.

People who took acetaminophen rated activities like "bungee jumping off a tall bridge" and "speaking your mind about an unpopular issue in a meeting at work" as less risky than people who took a placebo, researchers found.

Use of the drug also led people to take more risks in an experiment where they could earn rewards by inflating a virtual balloon on a computer: Sometimes they went too far and the balloon popped.

"Acetaminophen seems to make people feel less negative emotion when they consider risky activities - they just don't feel as scared," said Baldwin Way, co-author of the study and associate professor of psychology at The Ohio State University.

"With nearly 25 percent of the population in the U.S. taking acetaminophen each week, reduced risk perceptions and increased risk-taking could have important effects on society."

The study extends a series of studies led by Way that have shown acetaminophen - the main ingredient in the pain-reliever Tylenol and nearly 600 other medicines - has psychological effects that most people don't consider when they take it.

Previous research by Way and his colleagues has shown that acetaminophen reduces positive and negative emotions, including hurt feelings, distress over another's suffering and even your own joy.

Way conducted the current study with Alexis Keaveney, a former doctoral student at Ohio State, and Ellen Peters, a former professor at Ohio State who is now at the University of Oregon. The study was published online in the journal Social Cognitive and Affective Neuroscience.

In one study, 189 college students came to a lab and took either 1,000 mg of acetaminophen (the recommended dosage for a headache) or a placebo that looked the same. After waiting for the drug to take effect, the participants rated on a scale of 1 to 7 how risky they thought various activities would be.

Results showed that those under the influence of acetaminophen rated activities like bungee jumping, walking home alone at night in an unsafe area of town, starting a new career in your mid-30s, and taking a skydiving class as less risky than those who took the placebo.

The effects of acetaminophen on risk-taking were also tested in three separate experimental studies.

Across these studies, 545 undergraduate students took part in a task developed in 2002 that is often used by researchers to measure risk-taking behavior. Other researchers have shown that taking more risk on this task predicted risky behaviors outside the laboratory, including alcohol and drug use, driving without a seatbelt and stealing.

In the task, participants click a button on the computer to inflate a balloon on their computer screen. Each time they inflate it they receive virtual money. They can stop at any time and add the money to their "bank," and move on to the next balloon. But there is risk involved.

"As you're pumping the balloon, it is getting bigger and bigger on your computer screen, and you're earning more money with each pump," Way said.

"But as it gets bigger you have this decision to make: Should I keep pumping and see if I can make more money, knowing that if it bursts I lose the money I had made with that balloon?"

For those who took the acetaminophen, the answer was: Keep on pumping. Results showed that those on the drug pumped more times than those on the placebo and had more burst balloons.

"If you're risk-averse, you may pump a few times and then decide to cash out because you don't want the balloon to burst and lose your money," he said.

"But for those who are on acetaminophen, as the balloon gets bigger, we believe they have less anxiety and less negative emotion about how big the balloon is getting and the possibility of it bursting."

The results have a variety of real-life implications, Way said.

For example, acetaminophen is the recommended treatment by the CDC for initial COVID-19 symptoms.

"Perhaps someone with mild COVID-19 symptoms may not think it is as risky to leave their house and meet with people if they're taking acetaminophen," Way said.

Even everyday activities like driving presents people with constant decisions involving risk perception and assessment that could be altered by use of the painkiller.

"We really need more research on the effects of acetaminophen and other over-the-counter drugs on the choices and risks we take," he said.

DALLAS - Sept. 8, 2020 - A program that asks patients to mail in stool samples to screen for colon cancer is an effective way to expand screenings to underserved and underinsured communities and offers an alternative to in-person testing during the pandemic, according to a study conducted by UT Southwestern.

In an article published recently in CA: A Cancer Journal for Clinicians, UT Southwestern physicians identified nine best practices for effective mail-in screening campaigns, which can take the place of invasive, unpopular colonoscopies.

While doctors say that mail-in stool samples bring new meaning to the phrase "dropping something in the mail," they also note that this program is a way to continue cancer screenings while keeping people out of clinics and hospitals during the COVID-19 pandemic.

It's also cost-effective and just as capable of detecting cancer as a colonoscopy.

"This project is succeeding in making cancer screenings less invasive and more widely available. Serendipitously, it now has the added benefit of being yet another way to keep people out of hospitals and clinics during pandemic shutdowns," says Amit Singal, M.D., an author of the study, professor of internal medicine and population and data sciences, medical director of the Liver Tumor Program, and clinical chief of hepatology at UT Southwestern.

More than 53,200 Americans are expected to die of colon cancer in the United States in 2020, according to the National Cancer Institute.

The best practices identified in the article are:

1. Reach out to recipients with texts, telephone calls, and printed mailings before sending them the fecal immunochemical testing kit, or "FIT kit."

2. Ensure the invitation letters are brief and easy to read.

3. Keep instructions simple and address challenges that may lead to failed laboratory processing.

4. Send reminders to recipients who do not return their tests.

5. Use data infrastructure to track each step of the outreach process.

6. Have protocols and procedures, such as patient navigation, in place to promote a colonoscopy if a FIT test shows abnormal results.
7. Use high-quality FIT tests.

8. Ensure the program has a champion, organizational support, and sufficient funding.

9. Push for wide implementation to increase the program's efficacy and efficiency.

The best practices were learned from mailed FIT campaigns throughout the United States, including one that reached more than 108,000 people in 25 North Texas counties including Tarrant County. Another campaign reached more than 15,000 persons at Parkland Health & Hospital System, the Dallas County safety-net health system. Nearly a third of the FIT kits were returned by recipients, and approximately 5 percent of them returned positive.

"What the test enables you to do is say you can do this in the privacy of your own home. A lot of people prefer that," says Keith Argenbright, M.D., director of UT Southwestern's Moncrief Cancer Institute in Fort Worth and a professor in the Harold C. Simmons Comprehensive Cancer Center.

Returned stool samples were tested for a blood antigen associated with colon cancer, and patients who tested positive were told they needed to schedule a diagnostic colonoscopy. Follow-up with patients from Dallas County was performed by UT Southwestern staff, and follow-up with patients from other counties was handled by staff from the Moncrief Cancer Institute, which is part of the Simmons Cancer Center.

Argenbright said oncologists nationwide fear cancer deaths will spike several years from now because many cancers will go undetected as people put off colonoscopies and other screenings during the pandemic.

"We think this is an extremely timely solution to the current pandemic," he says. "Even though screening efforts restarted, patients are still afraid to come in."

Spending long periods of time in space can wreak havoc on space traveler health, including negative effects on metabolism, bone and muscle health, gastrointestinal health, immunity and mental health. This could prevent us pursuing long-distance missions, such as a Mars landing. However, a new review in open-access journal Frontiers in Physiology highlights that promoting a healthy gut microbiome could protect space travelers from the rigors of space travel. Finding out which microbes provide the most benefit and the best way to use them could be key to reaching the red planet in one piece.

If humans are to ever walk on Mars, they will need to endure a long space flight, but space travel can have negative impacts on health, potentially limiting how far we can go. The microgravity environment can result in muscle breakdown and reduced bone mass. It can cause nausea, meaning that sometimes space travelers struggle to eat enough (space food isn't all that nice either). The change in diet aboard a spaceship can disrupt the gut microbiome, leading to further health issues.

These factors can contribute to malnourishment and gastrointestinal problems, such as infection and inflammation. Space travelers can also experience metabolic disturbances, including decreased sensitivity to insulin. Other issues include immune system deficits, mental illness and cognitive decline.

A growing number of studies have focused on gut microbes, and their role in space-related health, prompting Prof. Silvia Turroni of the University of Bologna and Prof. Martina Heer of the University of Bonn to write this latest review.

Their review discusses a variety of studies suggesting that disruptions in the gut microbiome occur during space travel. For instance, one study found that the microbiomes of space travelers on the same mission became more similar to each other during the journey. There was also an increase in bacteria associated with intestinal inflammation and a decrease in those with anti-inflammatory properties.

"Changes in the microbiome are likely to lead to the breakdown of the balanced and complex relationship between microbes and their human host, with potentially severe repercussions on the functionality of body systems," said Turroni.

However, the review reveals that manipulating the gut microbiome may be a powerful way to maintain health on board a spacecraft. "The literature suggests that nutritional countermeasures based on prebiotics and probiotics hold great promise to protect space travelers," said Turroni.

So, what would these microbial treatments involve? They may be as simple as nutritionally balanced meals, with lots of fiber to kickstart microbial metabolism in the gut. Other options could be more targeted, including microbial supplements, such as bacteria that secrete immune-boosting substances, or those that synthesize vitamins required for bone growth.

In fact, there is a huge variety of pro-biotics and nutritional options to protect space travelers from specific issues they may encounter in space. However, there is still plenty of work required to figure out which treatments are most effective and how best to use them for each space traveler.

"The well-being of the gut microbiome of space travelers should be among the primary goals of long-duration exploratory missions," said Heer. "To ensure the success of the mission, we must not overlook the myriad of microorganisms that reside in our gastrointestinal tract and make sure they are in balance."

While future missions to Mars will undoubtedly look for evidence of microbial life on the red planet, this review suggests that it may be our homegrown microbes that get us there.

New research provides insights on the potential causes of racial disparities in deaths following prostate cancer surgery. The findings are published early online in CANCER, a peer-reviewed journal of the American Cancer Society (ACS).

Black men not only have a higher rate of developing prostate cancer compared with white men, but they're also more than twice as likely to die from the disease. Meanwhile, Asian American and Pacific Islanders (AAPIs) have the lowest rates of death from prostate cancer among all races.

To investigate the potential causes behind such disparities, Wanqing Wen, MD, MPH, of Vanderbilt University School of Medicine in Nashville, Tennessee, and his colleagues examined information from the National Cancer Database, which includes cancer registry data from more than 1,500 US facilities. The team sought to quantify the contributions of tumor-related and treatment-related characteristics, as well as factors related to access to care and disparities in prostate cancer survival among different groups.

The analysis included 432,640 white, 63,602 Black, 8,990 AAPI, and 21,458 Hispanic patients who underwent prostate removal between 2001 and 2014. The median follow-up time was 5.5 years, and the 5-year survival rates were 96.2 percent, 94.9 percent, 96.8 percent, and 96.5 percent for whites, Blacks, AAPIs, and Hispanics, respectively.

When the researchers adjusted for age and year of diagnosis, they observed that Blacks had a 51 percent higher death rate than whites, while AAPIs and Hispanics had 22 percent and 6 percent lower rates, respectively. After adjusting for all clinical factors and non-clinical factors, the Black-white survival disparity narrowed to being 20 percent higher for Blacks, while the AAPI-white disparity increased to being 35 percent lower for AAPIs. Adjusting for these factors had little effect on survival disparities between Hispanics and whites.

Of the factors included in the team's adjustments, education, median household income, and insurance status contributed the most to racial disparities. For example, if Blacks and whites had similar education levels, median household income, and insurance status, the survival disparity would decrease from 51 percent to 30 percent.

"Socioeconomic status and insurance status are all changeable factors. Unfortunately, the socioeconomic status inequality in the United States has continued to increase over the past decades," said Dr. Wen. "We hope our study findings can enhance public awareness that the racial survival difference, particularly between Black and white prostate patients, can be narrowed by erasing the racial inequities in socioeconomic status and health care. Effectively disseminating our findings to the public and policy makers is an important step towards this goal."

The hormone, ghrelin, may help protect the elderly population from muscle loss, according to a study being presented at e-ECE 2020. The study found that administering a particular form of ghrelin to older mice helped to restore muscle mass and strength. As muscle-related diseases are a serious health concern in the elderly population, these findings suggest a potential new treatment strategy for muscle loss to enable the aging population to remain fit and healthy.

Age-related skeletal muscle mass loss, in absence of any underlying disease, is defined as sarcopenia, which leads to deterioration of elderly people's quality of life. It causes a decline in muscle mass and functionality, often resulting in poor balance, higher risk of falls or fractures, immobilisation and loss of independence.

Ghrelin is a hormone involved in metabolic regulation and energy balance through activation of appetite, but also plays an important role in protecting against muscle wasting. Both acylated (AG) and unacylated (UnAG) forms are present in the body, but UnAG does not bind to the AG receptor (GHSR-1a), so does not increase appetite. A growing body of evidence indicates that UnAG is acting at an unidentified receptor, which also mediates some common AG and UnAG biological activities, including a strikingly protective effect against muscle wasting. Ghrelin levels decline as we age and may be involved in the development of sarcopenia, but the role of AG versus UnAG in this process has not been investigated previously.

Dr Emanuela Agosti, and her team at the University of Piemonte Orientale in Italy, investigated how unAG affected age-related decline of muscle mass and function, by either deleting the ghrelin gene in mice, or overexpressing unAG. Muscle function as they aged was assessed through a wire hanging test, during which "falling" and "reaching" scores were recorded, to assess whole body strength and endurance. Both the deletion of the ghrelin gene and the lifelong overexpression of UnAG reduced age-associated decline in muscle mass and function. Despite both groups of animals displaying similar aging tendencies in body weight and muscle mass, the mice overexpressing UnAG maintained better muscle structure, performance and metabolism, more typical of muscle in younger mice.

"Understanding the causes and effects of sarcopenia will improve our ability to prevent, detect, and hopefully manage this disease. These findings provide novel understanding and point to UnAG, or analogues, as a possible therapeutic target for future treatment," Dr Agosti comments.

The study indicates that UnAG, or possibly drugs that mimic it, can preserve muscle function and reduce the risk of age-related sarcopenia, without causing weight gain and obesity.

"Due to the worldwide increase in the elderly population, sarcopenia has an important social impact greatly affecting both aged people's quality of life and government health care costs. Therefore, therapeutic strategies aimed at preventing and/or reducing sarcopenia are of pivotal importance." Dr Agosti adds.

Dr Agosti and her colleagues now plan to identify the receptor mediating UnAG biological activities. This will help better define the molecular pathways involved in AG/UnAG actions and to design treatments that may reduce loss of muscle mass in sarcopenia and other similar conditions.

LA JOLLA--(September 8, 2020) Salk scientists have used skin cells called fibroblasts from young and old patients to successfully create blood vessels cells that retain their molecular markers of age. The team's approach, described in the journal eLife on September 8, 2020, revealed clues as to why blood vessels tend to become leaky and hardened with aging, and lets researchers identify new molecular targets to potentially slow aging in vascular cells.

"The vasculature is extremely important for aging but its impact has been underestimated because it has been difficult to study how these cells age," says Martin Hetzer, the paper's senior author and Salk's vice president and chief science officer.

Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. So, most knowledge about how blood vessel cells age comes from observations of how the blood vessels themselves change over time: veins and arteries become less elastic, thickening and stiffening. These changes can contribute to blood pressure increases and a heightened risk of heart disease with age.

In 2015, Hetzer was part of the team led by Salk President Rusty Gage to show that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells' aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age.

In the new work, Hetzer and his colleagues applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.

"We are among the first to use this technique to study the aging of the vascular system," says Roberta Schulte, the Hetzer lab coordinator and co-first author of the paper. "The idea of developing both of these cell types from fibroblasts was out there, but we tweaked the techniques to suit our needs."

The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging.

The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation. In patients with HGPS, some genes reflected the same expression patterns usually seen in older people, while other patterns were unique. In particular, levels of BMP-4 protein, which is known to play a role in the calcification of blood vessel, were slightly higher in aged cells compared to younger cells, but more significantly higher in smooth muscle cells from progeria patients. This suggests that the protein is particularly important in accelerated aging.

The results not only hinted at how and why blood vessels change with age, but confirmed that the direct-conversion method of creating vascular endothelial and smooth muscle cells from patient fibroblasts allowed the cells to retain any age-related changes.

"One of the biggest theoretical implications of this study is that we now know we can longitudinally study a single patient during aging or during the course of a treatment and study how their vasculature is changing and how we might be able to target that," says Simone Bersini, a Salk postdoctoral fellow and co-first author of the paper.

To test the utility of the new observations, the researchers tested whether blocking BMP4--which had been present at higher levels in smooth muscle cells developed from people with HGPS--could help treat aging blood vessels. In smooth muscle cells from donors with vascular disease, antibodies blocking BMP4 lowered levels of vascular leakiness--one of the changes that occurs in vessels with aging.

The findings point toward new therapeutic targets for treating both progeria and the normal age-related changes that can occur in the human vascular system. They also illustrate that the direct conversion of fibroblasts to other mature cell types--previously successful in neurons and, now, in vascular cells--is likely useful for studying a wide range of aging processes in the body.

"By repeating what was done with neurons, we've demonstrated that this direct reprogramming is a powerful tool that can likely be applied to many cell types to study aging mechanisms in all sorts of other human tissues," says Hetzer, holder of the Jesse and Caryl Philips Foundation Chair.

The team is planning future studies to probe the exact molecular mechanisms by which some of the genes they found to change with age control the changes seen in the vasculature.

African wild dogs have a vestigial first digit and muscular adaptations for life on the run

Anatomists identify a vestigial first digit in the forelimb of the African wild dog and document anatomical adaptations to its unique lifestyle of long-distance running and exhaustive predation

African wild dogs (Lycaon pictus) are known for their unique hunting style, often referred to as "exhaustive predation", in which they chase their prey to exhaustion, rather than hunting using speed, strength, or stealth. They are also unique among the dog clade in having only four full digits on their front paws. Until recently, it was unclear how these unique behavioral and anatomical features would affect their forelimb morphology.

The African wild dog, also known as the African painted dog or Cape hunting dog, is native to southern and eastern Africa, and classified as Endangered by the International Union for the Conservation of Nature (IUCN). They use sophisticated, coordinated hunting behaviors in which some packs decide as a group to hunt and communicate their vote via "sneezing". They also have a nomadic lifestyle with packs traveling up to 50 km per day and geographically extensive home ranges of 560 to 3000 km2. African wild dogs also differ from other canid (dog) species in the absence of a fully formed first digit (tetradactyly), which may allow for increased speed and stride length, facilitating long-distance pursuit of prey.

In a recent study published in PeerJ, a team of anatomists discovered a small, vestigial first metacarpal deep to the skin of the African wild dog. Surprisingly, this species is not fully tetradactyl as previously thought, but instead has a rudimentary digit 1. Prior to this study, the vestigial first digit of the African wild dog had never been described. The unexpected reduced digit results in a reconfiguration of some of the associated forelimb muscles to assist with proprioceptive functions (the body's perception of its own position and movement). According to Heather F. Smith, the study's lead author, "We now not only know that this vestigial digit exists, but how its presence completely reorganizes and repurposes the muscles typically associated with the first digit."

The authors have also discovered a stout ligament in the wrist which may act as a strut, assisting with passive flexion and rebound of the forefoot. This taut ligament provides non-muscular propulsion during push-off of the forepaw, which may help sustain endurance running and prevent the wrist muscles from tiring. This morphology is similar in function to the suspensory ligaments of the horse "spring foot", which provides passive "spring" action by absorbing and transferring forces experienced during locomotion.

Several other muscular adaptations to long-distance endurance running in the forelimb muscles have also been identified, including relatively reduced wrist rotator muscles and thick ligaments binding the radius and ulna (the two forearm bones), resulting in greater wrist and forearm stability. Several muscles associated with joint stability elastic energy storage during locomotion are also expanded compared to other species.

According to Smith, "This is the first in-depth study of African wild dog forelimb anatomy, and it demonstrates multiple adaptive mechanisms of endurance running, including reconfiguration of forelimb muscles, ligaments, and even bones, which function synchronously to facilitate the highly cursorial lifestyle of this fascinating species".