Culture

TAMPA, Fla. (December 3, 2020)- A team of researchers at the University of South Florida Department of Surgery has made a key discovery as to why we become more susceptible to heart disease as we age. The human body, especially the heart, is dependent on the mitochondria, the part of the cell responsible for producing energy to maintain organ function. The protein, Sesn2, is located inside the mitochondria and plays a pivotal role in protecting the heart from stress.

Dr. Ji Li, professor of surgery and molecular pharmacology and physiology, and his colleagues found levels of Sesn2 diminish over time, which weakens the heart and can cause it to lose functionality. His group's study published in "Redox Biology," reports that an insufficient level of Sesn2 is the reason older individuals are at greater risk of heart attack and other heart complications. This indicates stabilizing the protein could be the answer to maintaining a healthy heart.

It's common for people who've experienced cardiac arrest to have a stent inserted into a blood vessel to relieve obstruction or are prescribed medications designed to prevent blood clots. While they may offer rapid relief, these treatments can cause further injury to the heart. There are currently no known treatments available to prevent those potential side effects. Li's group, which includes the University of Louisville, found focusing on Sesn2 can keep mitochondria functional integrity, offsetting such complications.

Through biochemical analysis and high-powered microscopes, they could see Sesn2 deficiency caused cells to die in older mice, inducing heart attack. Li is now in the process of confirming their findings on human hearts provided by LifeLink, which helps facilitate organ donations for transplantation and research. Li expects to have those results available in the next couple of years.

"The age-related Sesn2 is a critical player in mitochondria," Li said. "Maintaining the cardiac Sesn2 levels could make the heart energic and against age-related heart disease."

The uncovering of Sesn2's significance helps advance the development of new therapeutic treatments. Li says the method would likely be a familiar one. Gene therapy or pharmacological approach could be considered to maintain the cardiac Sesn2 signaling pathway to strengthen the heart in aging.

Neuroscientists have provided clear visual evidence that a region of the human brain known as the ventral striatum kicks in during decision-making to weigh the costs versus the benefits of making a physical effort.

Nature Human Behavior published the research by scientists at Emory University. It gives the first detailed view of ventral striatum activity during three phases of effort-based decision-making -- the anticipation of initiating an effort, the actual execution of the effort and the reward, or outcome, of the effort.

"It's important to understand the neural mechanisms underlying motivation," says Shosuke Suzuki, first author of the study and an Emory graduate student of psychology. "Our work has wide implications for treatment of disorders related to reduced motivation, such as depression, schizophrenia and PTSD. It may also help enhance motivational programs for everything from education to athletics and public health."

"The willingness to expend effort is something crucial to our survival and something that we use every day," adds Michael Treadway, senior author of the study and Winship Distinguished Research Professor in Emory's Department of Psychology and Department of Psychiatry and Behavioral Science. "We've identified two closely overlapping, but nevertheless distinct, areas of the ventral striatum involved with different phases of effort-based decision-making. And we've provided a concrete neuroimaging tool to measure the sensitivity of signals associated with these phases that others can apply to their own data."

For example, Treadways says, the new method could provide a window into how a drug is affecting the brains of patients suffering from motivational deficits, compared to controls.

Treadway's lab focuses on understanding the molecular and circuit-level mechanisms of psychiatric symptoms related to mood disorders, anxiety and decision-making.

The ventral striatum, located deep within the brain's cerebral hemispheres, is an area associated with movement and mediating rewarding experiences and motivation.

Neuroimaging has consistently shown that the ventral striatum activates during decision-making to encode the potential value of rewards relative to costs, such as wait times and probability. The ventral striatum helps you decide whether to pay more for "next-day" delivery or choose "free, one-week" delivery to receive a package.

Neuroimaging studies had previously failed, however, to detect a strong value signal in the ventral striatum for decisions that require a physical effort. If you want more coffee, but the pot is empty, is it worth getting up and brewing some more?

"It was a mystery why this brain region encoded the value of a reward versus time and probability but did not appear to do so for physical effort," Suzuki says. "It's been a paradox in the neuroimaging literature."

Previous research on rodents showed that the ventral striatum is critical for motivating an animal to work for rewards like food. Animal research also shows evidence for two opposing signals in the ventral striatum. An activation signal prepares an animal to work and a discounting signal helps an animal select rewards that require the least effort. These signals help animals work for what they need, while also making sure they don't work more than they have to.

The presence of these signals had never been tested in humans. The Emory researchers theorized that as the physical cost to perform a task rises, the activation signal would drive an increase in activity in the ventral striatum, while the discounting signal would drive a decrease. They proposed that the simultaneous firing of these two signals -- the cost of effort versus the activation of effort itself -- is what made it harder to detect the value signal in previous studies.

An additional complication to detecting brain activation associated with physical effort is the fact that neuroimaging requires participants to lie still within a functional Magnetic Resonance Imaging (fMRI) machine while their brains are scanned.

To get around these issues, the researchers designed fMRI experiments that would allow participants to remain in a supine position and would also separate the neural signals involving effort from the one associated with the cost of the effort.

For the first set of experiments, the researchers created a virtual maze. As their brains were scanned, study participants were presented with maze navigation tasks that required different levels of effort. In one condition, the participants watched themselves move through the virtual maze passively. In another condition, they simply pressed a button on a handheld device to move through the maze. A third condition required the higher effort of repeatedly and rapidly pressing the button to move through the maze. Each maze, when successfully completed, rewarded them with a nominal dollar amount.

During a second experiment, the neural activity of participants was measured as they made a series of choices between two options, with varying amounts of reward and effort required for each option. The effort and reward amounts were presented sequentially to try to isolate the effort-activation signal during the anticipation of various effort demands.

The results showed that two distinct regions of the ventral striatum fired in response to different phases of physical effort and effort-based decision making, with some overlap. Activity in an anterior region was mainly associated with reward and effort costs, while activity in a dorsal region was mainly associated with initiation of effortful movement. And this activity related to effortful movement was distinct from activity in another region, called the putamen, which was associated with initiation of simple movement.

The researchers now hope to build upon this increased awareness for how the brain encodes signals related to motivation.

"Our current paper provides a paradigm for how to measure brain activity for effort-based decisions associated with assigned tasks," Suzuki says. "Now we're developing experiments to identify specific modes of signaling when people spontaneously initiate action. That may give us a better measure of how the brain operates when people do things because they want to do them, in real-life situations. Getting sensitive measurements for how people normally decide to expend effort may help us develop better treatments for people suffering motivational deficits related to depression or other illnesses."

A researcher at the University of Tartu described new associations between Neandertal DNA and autoimmune diseases, prostate cancer and type 2 diabetes.

Modern humans migrated out of Africa more than 60,000 years ago and met and interbred with Neandertals and other archaic human groups. As a consequence, we can find that a few percent of the genomes of people outside of Africa contain traces of archaic ancestry. Large-scale resources with genetic and medical data are needed to find out how this archaic remains affect modern human health. Most previous studies have examined European population-specific cohorts. However, the Neandertal DNA content is quite different between Europeans and Asians and our knowledge limited about non-European Neandertal DNA. A new study by Senior Research Fellow of Evolutionary and Population Genomics Michael Dannemann analyzed Neandertal associated phenotypes in an Asian cohort and compared it to those discovered in a European cohort.

This study provides evidence that the impact of Neandertal DNA on the immune system has not been population-specific. "My findings show that while the Neandertal DNA in European and Asian populations differ they both contain variants that increase the risk of autoimmune diseases like dermatitis, Graves' disease and rheumatoid arthritis," said Dannemann.

Another disease for which associations were found in both populations was prostate cancer. Dannemann said that the difference is here that this gene variant had a protective effect which means it reduces the risk for prostate cancer.

Of particular interest were the Neandertal associations with type 2 diabetes, a disease influencing many people today. The result of this study showed that Neandertal-linked associations were only found in Asians and showed evidence for an over-proportional effect on this disease given the Neandertal DNA content in this population.

However, given the different associated archaic variants in both European and Asian cohorts, the results of this study also suggest that the effects of how Neandertal DNA influences immunity might be population-specific. "This is highlighting the importance of studying a wider range of ancestries to help us to ascertain how the phenotypic legacy of Neandertals influences modern humans today," added Dannemann.

The Gaia space telescope has measured the acceleration of the Solar System when it orbits the center of our Milky Way galaxy. The Solar System motion relative to the stars agrees with the results by Finnish astronomers in the 19th century.

Moreover, the observational data by Gaia improves satellite navigation. Finnish researchers are participating in this massive endeavor, that results in three-dimensional mapping of our galaxy, to be completed in 2024.

Today, Dec. 3, 2020, the European Space Agency (ESA) released observational data from the Gaia telescope (Gaia Early Data Release 3 or EDR3), in continuation to the DR1 and DR2 releases of the years 2016 and 2018. Gaia accrues accurate knowledge about, for example, the Milky Way stars, distant extragalactic quasars, and the asteroids of our Solar System.

Quasars are bright, star-like objects that allow for the determination of planet Earth's orientation in space. With the help of their precise positions measured by Gaia, a new high-precision reference system can be constructed for defining the positions of stars, Solar System objects, and also satellites.

"The knowledge accrued by Gaia affects the precision of satellite navigation in the future. The satellite positions and Earth orientation in space are determined in a reference frame tied to the directions of quasars. The precision and state of the art of the reference frame are critical for the precision in navigation," says Professor Markku Poutanen at the Finnish Geospatial Research Institute FGI, National Land Survey of Finland.

The precise observations of quasars resulted, for the first time, in a successful computation of the acceleration of the Solar System.

"The acceleration of the Solar System towards the center of the Milky Way, as measured by Gaia, is (2.32±0.16) x 10-10 m/s2 or, roughly, two one-hundred-billionth parts of the gravitational acceleration caused by the Earth on its surface, " summarizes Astronomy Professor Karri Muinonen at the Department of Physics, University of Helsinki, also Research Professor at the Finnish Geospatial Research Institute FGI.

Gaia in the research of asteroids

Gaia's data processing is carried out within the European DPAC network (Data Processing and Analysis Consortium) with more than 300 researchers. Solar System researchers at the University of Helsinki take part in the Gaia data processing in several different ways.

"We are responsible for the daily computation of orbits for asteroids discovered by Gaia. Based on these computations, ground-based follow-up observations are organized," describes Muinonen.

"Before data releases, we take part in the validation of Gaia observations of asteroid positions, brightnesses, and spectra. Our research with Gaia data focuses on asteroid orbits, rotation periods and pole orientations, masses, shapes, and surface structural and compositional properties. In the computation of collision probabilities for near-Earth asteroids, the precision of reference frames is completely central," continues Muinonen.

Asteroid observations by Gaia were published in DR2 in spring 2018 (14 099 asteroids). In the forthcoming DR3 release in spring 2022, there will be position and brightness data for tens of thousands of asteroids and, for the first time, asteroid spectra will also be released.

Years of work and billions of stars

The EDR3 data has been collected by Gaia from the end of July 2014. The data includes, for example, position and brightness data of 1,81 billion stars and color data of 1,55 billion stars from the time period of 34 months. Furthermore, the data more than triples the number of quasars observed for precise reference frames to 1,61 million.

EDR3 is a remarkable improvement, in terms of both numbers and precisions, as compared to the earlier releases. The newest release gives hints about the gigantic nature of the forthcoming DR3 release in spring 2022 and the final DR4 release after 2024.

Gaia observes astronomical objects systematically in the so-called L2 Lagrange point some 1,5 million kilometers from the Earth in the anti-sun direction. Gaia observes about two billion stars with a precision, at best, of one hundred millionths of a degree. The result will be a three-dimensional map of our galaxy.

Stellar motion in the future

Based on the Gaia data, researchers' have modeled the motion of stars in the Milky Way. They have produced an animation for the motion of 40 000 randomly selected stars on the sky 1.6 million years into the future.

"In the animation, short and long trails describe changes in stellar positions with 80 000 years. The former are mostly related to distant stars, whereas the latter are solely due to the nearby stars. Every now and then, short trails expand into long ones, and long trails shrink into short ones. This is also related to the changing distances of the stars," says Muinonen.

In the end of the animation, stars appear to be removed from the left and collected to the right. This is due to the Solar System's motion relative to the stars. A similar phenomenon can be seen when moving from a center of a forest islet to its boundary: the trees in the front gradually disappear whereas they seem to be collected in the back.

"This shows the average motion of the Solar System with respect to the surrounding stars. From the Finnish point of view, it is intriguing that the motion documented by Gaia agrees with the pioneering research about the Solar System's motion by Friedrich Wilhelm August Argelander (1799-1875) in the 19th century at the Helsinki Observatory," concludes Muinonen.

Argelander was the first astronomer, who unequivocally calculated the direction of Solar System motion in space. He worked at the Observatory, University of Helsinki, then the Imperial Alexander University. He had made the observations at the Turku Observatory in 1827-1831 before the observatory moved to Helsinki. In Helsinki, he compiled the stellar catalog entitled "DLX stellarum fixarum positiones mediae ineunte anno 1830" that, as the title says, included the precise positions of 560 stars.

Movement of quasars is actually the movement of Solar System

More accurately, the apparent stellar streams include the information about the motion of the stars and the Solar System about the center of the Milky Way. The Gaia quasar observations allow for the determination of the acceleration related to this orbital motion.

Gaia has measured the apparent motions of quasars on the sky. These motions are tiny, about one thousandth part of the motion of stars 3000 light years from us. The apparent stream of quasars is directed toward the center of the Milky Way, that is, in the direction where the acceleration of the Solar System is pointing. Gaia has, in essence, measured the absolute motion of the Solar System relative to the distant universe. This motion derives from the gravitational forces by the Milky Way and all other objects in the universe.

What makes the elderly and people with underlying conditions more vulnerable to COVID-19? According to a new study led by McGill University researchers, clues can be found in the proteins involved in initiating infection, as the virus binds to host cells of different animals. Greater cellular oxidation with aging and sickness may explain why seniors and people with chronic illness get infected more often and more severely.

Over 60 million people have been infected and around 1.5 million have died from COVID-19. The virus is disrupting economies and food supply chains all over the world. Understanding why some animals get infected and others do not could be the key to unlocking new treatments and therapies. In a study published in Computational and Structural Biotechnology Journal, researchers analyzed available protein sequences of the virus and host cell receptors across different spices to find out why.

"We know that the virus can infect humans, cats, dogs and ferrets but not bovine and swine. Also, COVID-19 hits the elderly and people with underlying conditions more severely than the young and healthy ones. Until now reasons for this were unclear," says McGill Professor Jaswinder Singh.

The research was conducted by a multidisciplinary team of scientists led by Professor Singh. The team includes Professor Rajinder Dhindsa (McGill University), Professor Baljit Singh (University of Calgary) and Professor Vikram Misra (University of Saskatchewan).

How COVID-19 infects cells

Once inside a host cell, the virus hijacks the cell's metabolic machinery to replicate and spread. The virus's protein spikes attach to a protein receptor on the surface of the host cell called ACE2, fusing the membranes around the cell and the virus together. This process allows the virus to enter the cell and co-opt its protein-making machinery to make new copies of itself. The copies then go on to infect other healthy cells.

In analyzing the proteins and their amino acid building blocks, the researchers found that animals susceptible to the virus have a few things in common. Such animals like humans, cats, and dogs have two cysteine amino acids that form a special disulfide bond held together by an oxidizing cellular environment. This disulfide bond creates an anchor for the virus. "Our analysis suggests that greater cellular oxidation in the elderly or those with underlying health conditions could predispose them to more vigorous infection, replication and disease," says co-author Rajinder Dhindsa, an emeritus professor of biology at McGill University.

In the case of animals resistant to the virus, like pigs and cows, one of these two cysteine amino acids is missing, and the disulfide bond cannot be formed. As a result, the virus cannot anchor on to the cell.

According to the researchers, preventing the anchor from forming could be the key to unlocking new treatments for COVID-19. One strategy, they suggest, could be to disrupt the oxidizing environment that keeps the disulfide bonds intact. "Antioxidants could decrease the severity of COVID-19 by interfering with entry of the virus into host cells and its survival afterwards in establishing further infection," says Professor Singh.

In terms of next steps, the researchers say CRISPR technology could be used to edit protein sequences and test out their theory. The researchers are also looking into other proteins near the ACE2 receptor that may facilitate entry of the virus to see if they behave the same way.

DALLAS - Dec. 3, 2020 - A team led by UT Southwestern has derived a new "intermediate" embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology. A wealth of previous research has focused on developing and characterizing "naïve" embryonic stem cells (those about four days post-fertilization in mice) and "primed" epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there's been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages - largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state. Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named "XPSCs" from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution. Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation. And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

"These XPSCs have enormous potential. Our study helps open the door to each of these possibilities," says Wu, who is a Virginia Murchison Linthicum Scholar in Medical Research.

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite from those that stabilize primed PSCs. While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his colleagues placed cells from early mouse embryos into cultures containing chemicals and growth factors that activate all three pathways. These lab-grown cells were extremely stable in culture and able to multiply without developing any further for approximately two years.

Additional experiments showed that these cells met the expectations researchers have long strived to meet of contributing to chimeras and directly differentiating into primordial germ cells. Wu and his colleagues made intraspecies chimeras of mice using cells derived from mice with different coat colors by injecting the cells into early mouse embryos. They also tracked the contributions of the XPSCs by tagging the cells with a fluorescent protein and then identifying them throughout the resulting offspring's body.

Wu's team made interspecies chimeras by injecting horse XPSCs into early mouse embryos and allowing the embryos to develop in mice for several days. Surprisingly, although horses have a comparatively long gestational period - nearly a year - the researchers found that these foreign cells had contributed to mouse organ development, indicating that signals from the mouse cells determine organ developmental timelines.

Like XPSCs from other species, the human cells showed that they were capable of differentiating into a variety of tissues if culture conditions allowed them to progress in development, as well as directly form primordial germ cells in a dish.

Over a quarter of all proteins in a cell are found in the membrane, where they perform vital functions. To fulfil these roles, membrane proteins must be reliably transported from their site of production in the cell to their destination and correctly inserted into the target membrane. Researchers from the Heidelberg University Biochemistry Center (BZH) have succeeded in determining the three-dimensional structure of a molecular machine responsible for the correct placement of an important membrane protein family - the so-called "tail-anchored" membrane proteins, or TA proteins for short.

An adult human consists of an estimated 100 billion cells. Each one contains countless proteins, the architects and players in life that perform a broad range of functions. A major portion of the proteins in a cell are membrane proteins, i.e. components of the fine membranes (from the Latin membrana) that envelop every cell as well as its small organs, the organelles. Membrane proteins can form channels or pores and perform fundamental tasks such as transport of substances and signal transmission. Therefore, the correct insertion of a membrane protein is crucial for it to fulfil its biological role and, in turn, for the proper function of the cell. But what ensures that the protein ends up at the right membrane and is integrated at the right spot?

Specific signal sequences, small sections of proteins that act like "post codes", are vital for delivery to the correct location and proper insertion into the membrane. They are detected by molecular sorting machines that deliver the protein to its destination. In some proteins, the signal sequence is found at the end of the molecule, known to scientists as "tail-anchored" or TA membrane proteins. This vital membrane protein family is involved in many cellular processes, including membrane fusion and apoptosis, or programmed cell death.

BZH researchers led by Prof. Dr Irmgard Sinning recently determined the three-dimensional structure of the molecular machine that inserts the TA proteins into the membrane of the endoplasmic reticulum (ER) - an important distribution network inside the cell that is connected to all other organelles. For their structural analyses, the BZH scientists used cryo-electron microscopy (cryo-EM), a method recognised by the Nobel Prize for Chemistry in 2017. "This type of high-resolution structural information is essential to understand the final steps of the protein insertion process into the ER membrane," explains Prof. Sinning, who directs a research group at the BZH.

The GET insertion machine is responsible for the correct insertion of TA proteins into the ER membrane. GET stands for "guided entry of tail-anchored membrane proteins". This insertion machine, which has barely changed over the course of evolution from yeast to man, consists of three protein building blocks. Two are located in the ER membrane where they form a kind of cavity (Get1 and Get2). The third one (Get3) is located outside the membrane, acting as the TA protein deliverer. All three components of the GET insertion machine are essential for the correct insertion of the TA protein into the target membrane. Get2 takes the protein from the deliverer and essentially "pushes" it towards the cavity in the interior of the membrane. The Heidelberg researchers uncovered this unexpected detail concerning the interaction between Get2 and Get3 during their analysis of the protein structure. They also showed that two copies of the insertion machine always work closely together to make the integration process more efficient. "The GET insertion machine provides the TA proteins with an energetically favourable route into the membrane," states Prof. Sinning.

"Small membrane proteins like those found in the GET insertion machine are a challenge for structural biology, so our research required innovative ideas," adds structural biologist Dr Melanie McDowell. Only in recent years have technical improvements in cryo-EM allowed structures of increasingly smaller protein complexes to be identified in ever greater detail. Heidelberg University therefore established a cryo-EM network (HDcryoNet), making the structural analysis of small membrane protein complexes like the GET insertion machine possible. Prof. Sinning and Dr McDowell believe that their new data provide a crucial missing puzzle piece required to complete the picture of protein transport in the cell and protein insertion into membranes.

People with gambling problems are less likely to consider important information that could prevent them from losing, according to new research published today from the UBC's Centre for Gambling Research.

Instead, people with gambling disorder pay more attention to irrelevant information from the previous gamble to inform their next choice.

"Our research may help explain why individuals with gambling disorder continue to gamble in the face of mounting losses, and on games that have a very small chance of winning," said Eve Limbrick-Oldfield, the study's lead author and a postdoctoral research fellow at the UBC department of psychology and Centre for Gambling Research.

To conduct the study, the researchers recruited two groups of participants, 48 of whom have gambling disorder and 35 control participants. The participants were asked to complete a computerized decision-making task where they repeatedly chose between two lotteries. The two lotteries varied in prize size and chance of winning - one lottery had a smaller prize, but higher chance of winning while the other had a larger prize, but a smaller chance of winning. The participants were given all the information that was needed to make an optimal decision.

"We found control participants paid attention to both the prize size and chance of winning when choosing between the lotteries but the individuals with gambling disorder were more likely to ignore that information. Instead, they relied on whether they won or lost in the last gamble to make a decision," said Limbrick-Oldfield. "The finding can be easily translated into real-world gambling situations. For example, someone using a slot machine that hasn't paid out in a while can believe that the machine is somehow 'due' a win."

This study is the first of its kind to see whether win size and probability information have an effect on how individuals with gambling disorder make decisions. The findings support the hypothesis that individuals with gambling disorder are susceptible to irrelevant sources of information to guide gambling decisions.

The researchers do not know whether this impaired decision-making predates the gambling disorder or is a consequence of prolonged gambling but they hope to find out in future research. They are currently working on another study that uses eye-tracking to see if problem gamblers pay more attention to certain information given to them.

"These findings could help inform psychological treatments for gambling disorder that work on dismantling erroneous beliefs and enhancing financial literacy," said Luke Clark, UBC Centre for Gambling Research director and a professor in the department of psychology.

The research team also hope the findings could be used when building algorithms for online gambling websites to identify those gamblers who might be at risk of having a gambling problem.

When Terrie Williams began hearing about the wide range of symptoms experienced by patients with COVID-19, she saw a connection between the various ways the disease is affecting people and the many physiological adaptations that have enabled marine mammals to tolerate low oxygen levels during dives.

Williams, a professor of ecology and evolutionary biology at UC Santa Cruz, has spent decades studying the physiology of marine mammals and their extraordinary ability to perform strenuous activities while holding their breath for long periods under water.

"Diving marine mammals experience a lifetime of rapid physiological transitions between normal oxygenation and hypoxia [low oxygen levels]," Williams said. "They've got ways to protect themselves and allow their organs to keep functioning while holding their breath for hours at a time, but there's a whole suite of biological adaptations that had to happen for them to be able to do that."

Lacking those adaptations, humans are vulnerable to rapid damage in a wide range of tissues when oxygen levels drop due to the effects on the lungs and cardiovascular system of infection with the coronavirus SARS-CoV-2. In a review article published December 3 in Comparative Biochemistry and Physiology, Williams explores how the diving physiology of marine mammals can help us understand the effects of COVID-19.

"It really highlights why it is so important for people to protect themselves from infection with this virus," she said. "Damage to oxygen-deprived tissues happens fast and can be irreversible, which may account for the long-term effects we are beginning to see in people after coronavirus infections."

The heart and brain are especially sensitive to oxygen deprivation, and marine mammals have multiple mechanisms to protect these and other critical organs. In the first place, marine mammals have much higher oxygen carrying capacity than humans due to their greater blood volume and hemoglobin concentrations. In addition, some marine mammals contract their spleen during dives to release a store of oxygen-rich blood cells into the circulation. To avoid blood clots resulting from such high concentrations of red blood cells, many species lack a key clotting factor found in other mammals.

Other adaptations include greatly increased concentrations of oxygen-carrying proteins such as myoglobin in heart and skeletal muscles and neuroglobin and cytoglobin in the brain. In addition, numerous safety factors and biochemical buffers enable even the most oxygen-dependent tissues in marine mammals to withstand not only low oxygen but also the subsequent reperfusion of tissues with oxygenated blood. In humans, reperfusion after a heart attack or stroke often leads to additional tissue damage.

According to Williams, the solutions that marine mammals have evolved for tolerating hypoxia provide a natural template for understanding the potential for damage to oxygen-deprived tissues in humans.

"Studying marine mammals allowed me to understand what it takes to protect the body when the availability of oxygen is low," she said. "There are so many ramifications of shutting down the oxygen pathway, and I think that's what we're seeing in these COVID patients."

Williams is particularly concerned about the so-called "long-haulers" who continue to have symptoms long after they were infected with the coronavirus.

"You hear people say it's just like the flu, but COVID scares the heck out of me because of the potential for long-term damage to the heart and brain," she said. "When you think about oxygen deprivation and the tissue repair process, it makes sense that many people are having a hard time getting back to normal life, even after a mild infection."

Williams urges people to do all they can to avoid becoming infected. "Our heart and brain cells are meant to last a lifetime, and we cannot replace them once they are damaged," she said. "Dolphins and whales have natural protections that humans lack, so we are highly vulnerable to hypoxia."

"Super-spreader" events and extensive person-to-person contact propelled an outbreak of hantavirus pulmonary syndrome in a small village in Argentina from 2018-2019, according to research published today in The New England Journal of Medicine.

In the paper, an international scientific team reports the genetic, clinical, and epidemiologic features of the outbreak caused by the Andes virus, a member of the hantavirus family. The group's analysis could aid clinicians and public health officials in managing outbreaks of other viral diseases with similar transmission patterns, including COVID-19.

Andes virus is carried by wild rodents native to South America, and people can be infected through exposure to infected animals or their droppings. Like other hantaviruses, Andes virus infection can lead to a severe and often fatal respiratory disease in humans, called Hantavirus Pulmonary Syndrome (HPS). Importantly, Andes virus is the only hantavirus known to spread person to person. Those who come into direct contact with an infected individual or their body fluids, or who spend time in close proximity to an ill person, may also become infected. Currently, no licensed vaccines or drugs are available to treat the disease.

According to the study, led by scientists at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and Administracion Nacional de Laboratorios e Institutos de Salud Dr. Carlos G. Malbran (ANLIS), large social events and high viral load in infected individuals fueled person-to-person transmission of the Andes virus during the outbreak. Researchers teamed up with local health authorities to piece together a near-complete epidemiological "picture" reconstructing specific transmission events for the 34 confirmed cases. They traced the outbreak's origin to a single spillover event, and documented a 32 percent case fatality rate overall.

While person-to-person spread of Andes virus was first described in 1996, the recent outbreak had the most extensive recorded human-to-human transmission of the virus seen to date. The team's genomic analysis showed a striking similarity between the 2018-2019 and 1996 outbreak sequences. Understanding which genomic "signatures" correspond to the mechanisms necessary for person-to-person transmission may help scientists to develop new therapeutics to treat Andes virus infection.

Researchers found that droplets or aerosolized viral particles may have been routes of infection during the extensive person-to-person transmission of the 2018-2019 outbreak. They also noted that symptoms presented anywhere between 9 and 40 days after the infection took place. However, the authors pointed out that there might be a narrow window of infectiousness. Transmission often occurred on the first day of fever presentation in an infected patient. Interestingly, there was no clear association between the individuals transmitting the virus and their disease severity.

"This important observation indicates that, regardless of the severity of the disease, all HPS cases should be equally managed concerning their potential for virus transmission," said Gustavo Palacios, Ph.D., co-senior author of the paper and Division Chief of Molecular Biology at USAMRIID. "Furthermore, we need to re-evaluate the threat that this virus poses. The lack of existing medical countermeasures, super-spreading potential, and high case-fatality rate all should raise concern."

These findings could potentially help clinicians and public health officials deal with future outbreaks. As with the preventive measures currently being practiced for COVID-19, social distancing and the use of appropriate personal protective equipment were effective in controlling transmission. Moreover, widespread contact tracing and self-quarantining led to a detectable decrease in transmission.

"Although less than 10 percent of cases occurred in hospital settings, the threat to clinicians and hospital staff must not be underestimated," said Valeria Martinez, Ph.D., of ANLIS, co-first author of the study. "Doctors should remember that in the 1996 outbreak, many health care personnel got sick, and some died, when the appropriate personal protective equipment was not used."

According to the authors, the study also examined cytokines within patients to determine the types of immunological responses present in people with HPS caused by Andes virus. Cytokines are proteins that aid cell-to-cell communication in immune responses. They concluded that there was no clear mechanism, but more of a broad and dysfunctional immunologic response among patients.

"We hope that by further exploring this apparent immune dysregulation, we will expand our knowledge of how different hantavirus species cause hantavirus pulmonary syndrome," said co-author Mariano Sanchez-Lockhart, Ph.D., of USAMRIID. "Gaining a better understanding of how our immune system tackles Andes virus infection will certainly help clinicians to better manage severe cases and pave the way for new therapeutic interventions."

Based on their comprehensive data, the team confirmed the necessity to study the patterns of Andes virus emergence, super-spreading, person-to-person transmission, and pathology to improve public health response strategies. "The breadth of techniques and expertise used to piece together person-to-person transmission and super-spreading events could be applied beyond Andes virus outbreaks," said co-author Peter Larson, Ph.D., of USAMRIID. "We hope this approach serves as a model for future investigations of person-to-person transmission and for the identification of super-spreading events."

According to Palacios, the investigative foundation for this work was built and tested by USAMRIID's Center for Genome Sciences during outbreaks of Ebola virus disease in Western Africa and the Democratic Republic of the Congo, as well as the introduction of Zika virus into the United States. "While we are proud of this work and our track record, we believe this is only the beginning," said Palacios. "Having a comprehensive approach to track spillover events is a long-term goal we strive for every day."

Although separated by millions of years of evolution, plants and animals have independently alighted upon similar innate immune strategies to protect themselves against microbial infection. In both kingdoms of life, immune receptors called nucleotide-binding/leucine-rich-repeat (NLR) proteins form an important layer of defence inside cells against pathogen attack. NLRs are complex devices made up of several modules that recognize molecules from invading microbes termed effectors, and then locally activate resistance and cell death pathways to limit infection. Based on distinct structural and signalling features, plant NLRs are divided into two main classes: those that contain coiled-coiled (CC) modules (CNL proteins) and those that harbour Toll/interleukin-1 receptor/resistance (TIR) modules (TNL proteins). In a recent study, MPIPZ researchers and Humboldt Professor Jijie Chai and his team succeeded for the first time in piecing together the sequence of molecular events that convert an inactive TNL-type plant immune receptor into an active 'resistosome' complex that mediates host cell death.

Chai, who is also affiliated with the University of Cologne, joined forces with research group leader Jane Parker and MPIPZ director Paul Schulze-Lefert to determine the structural and biochemical features underlying activation of the Recognition of Peronospora parasitica 1 (RPP1) TNL-type NLR receptor, which protects the model plant Arabidopsis thaliana from infection by the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa). To understand at a molecular level how RPP1 shields plants from Hpa infection, Chai, Schulze-Lefert, Parker and colleagues expressed RPP1 together with a recognized Hpa effector ATR1 protein in insect cells, a system that allows high levels of protein expression. The ATR1-activated RPP1 receptor is an enzyme that breaks down nicotinamide adenine dinucleotide (NAD+), which is important for defence signalling.

By isolating RPP1-ATR1 oligomeric complexes and subjecting them to cryo-electron microscopy, the authors have answered two outstanding questions in NLR biology: how direct effector binding induces the conformational activation of an NLR receptor, and how organization of the TNL receptor oligomer (in this case a tetramer composed of four tightly-packed receptor molecules) creates a unique surface within a portion of the receptor, which is necessary for cleaving NAD+ to initiate defence signalling. Specifically, the tetramerization of RPP1 induced by ATR1 at one end of the receptor complex forces - at the opposite end - the four TIR modules to form two asymmetric TIR pairs, which are the sites of NAD+ breakdown (Figure 1). Thus, the RPP1 resistosome functions as a 'holoenzyme', the active form of an enzyme for NAD cleavage.

Strikingly, findings from the groups of Eva Nogales and Brian Staskawicz at the University of California, Berkeley, on another TNL-type NLR, Roq1 from the tobacco relative Nicotiana benthamiana, also show that TNL activation involves direct effector recognition and adoption of a similar tetrameric structure. The effector recognized by Roq1 is produced by a bacterial pathogen and the activated Roq1 receptor complex provides resistance to bacterial infection. Thus, the discoveries of the MPIPZ researchers seem to have a broad relevance for understanding how these critical plant immune molecules protect their hosts from infection. More generally, the oligomeric configurations adopted by active RPP1 and Roq1 resemble induced oligomeric scaffolds of other plant and mammalian NLR receptor proteins, including human receptors of the innate immune system. This suggests that these receptors rely on a common structural principle to initiate intracellular immune signalling and cell death across different kingdoms of life.

A new paper in Science Advances describes for the first time how minerals come together at the molecular level to form bones and other hard tissues, like teeth and enamel.

The University of Illinois Chicago researchers who published the paper described their experiments -- which captured high-resolution, real-time images of the mineralization process in an artificial saliva model -- and their discovery of distinct pathways that support bone and teeth formation, or biomineralization.

"Until now these pathways, particularly at the early stages when molecules are first starting to organize into a structure, have not been understood clearly," Reza Shahbazian-Yasser, UIC professor of mechanical and industrial engineering at the College of Engineering and corresponding author of the paper.

Shahbazian-Yasser and his colleagues observed that both direct and indirect formations of hydroxyapatite crystals -- the foundation of hard tissues -- can be achieved by local variations in energetic pathways for nucleation and growth.

"The control over the dissolution of amorphous calcium phosphate affects the assembly of hydroxyapatite crystals into larger aggregates," Shahbazian-Yasser said. "Using technology developed at UIC, we found evidence that these pathways coexist simultaneously -- explaining why different groups had reported seemingly different or opposite results. In addition, we now understood how hydroxyapatite materials nucleate and grow on amorphous calcium phosphate templates. The control over the nucleation and growth of hydroxyapatite will aid in developing new drugs and medical treatments to heal lost or broken bone faster or cure tooth cavities."

To capture the images, the researchers used a unique micro-device that made it possible to use electron microscopy with a liquid model. Using this method, the researchers were able to monitor chemical reactions in the model on the smallest scale.

"Our study provides clear, new evidence of how minerals organize and grow into bone materials, and this finding has many important implications for further research on bone or teeth healing," Shahbazian-Yasser said.

"By better understanding these pathways, scientists are one step closer to engineering ways to better treat dental diseases and bone injuries -- like those from traumatic injuries -- or prevent medical conditions that can develop when normal mineralization processes in the body go awry," he said.

Medical conditions caused by dysfunctional mineralization in the body can include everything from a tendency to develop cavities to osteoporosis.

"In the next step, we would like to learn how molecular modifiers can affect the process of biomineralization, which is important to develop effective drugs," Shahbazian-Yasser said.

A new study has found that a novel T cell genetically engineered by University of Arizona Health Sciences researchers is able to target and attack pathogenic T cells that cause Type 1 diabetes, which could lead to new immunotherapy treatments.

The immune system fights bacteria, viruses and other pathogens by utilizing several types of T cells, all of which have receptors that are specific to particular antigens. On killer T cells, the receptor works in concert with three signaling modules and a coreceptor to destroy the infected cell. Michael Kuhns, PhD, an associate professor in the UArizona College of Medicine - Tucson Department of Immunobiology, copied the evolutionary design to engineer a five-module chimeric antigen receptor, or 5MCAR, T cell.

"The 5MCAR was an attempt to figure out if we could build something by biomimicry, using some of evolution's natural pieces, and redirect T cells to do what we want them to do. We engineered a 5MCAR that would direct killer T cells to target autoimmune T cells that mediate Type 1 diabetes," said Dr. Kuhns, who is member of the UArizona Cancer Center, BIO5 Institute and Arizona Center on Aging. "So now, a killer T cell will actually recognize another T cell. We flipped T cell-mediated immunity on its head."

Dr. Kuhns worked with Thomas Serwold, PhD, of the Harvard Medical School-affiliated Joslin Diabetes Center, to test the 5MCAR T cells in a non-obese diabetic mouse model with promising results. The findings recently were published in the Proceedings of the National Academy of Sciences.

"When we saw that the 5MCAR T cells completely eliminated the harmful T cells that invaded the pancreas, we were blown away," Dr. Serwold said. "It was like they hunted them down. That ability is why we think that 5MCAR T cells have tremendous potential for treating diseases like Type 1 diabetes."

In 2017, the U.S. Food and Drug Administration approved two chimeric antigen receptor (CAR) T cell therapies for specific types of cancer - one for the treatment of children with acute lymphoblastic leukemia and the other for adults with advanced lymphomas. Those CAR T cells focused solely on the receptor, not the surrounding signaling modules or coreceptor.

Dr. Kuhns believes that by mimicking the form and function of a natural T cell, including its complex five-module structure, researchers will be able to more specifically target antigens with greater sensitivity in the future. This type of personalized immunotherapy is a key initiative of the UArizona Health Sciences, as well as a focus of Dr. Kuhns' lab.

"I'm generally of the belief that evolution converges on related principles to execute related tasks," Dr. Kuhns said. "Basic research from labs around the world, including ours, has helped us to understand the complex structure and function of the five-module molecular machines that have evolved to drive T cell responses. We think these results show that a biomimetic approach holds promise for CAR engineering."

Drs. Kuhns and Serwold recently received a bridge grant from the National Institute of Allergy and Infectious Diseases to continue their research into using 5MCAR T cells to prevent autoimmune disease.

"There are many things we don't yet know about this technology," Dr. Kuhns said. "What we know is that it works, and it can be very effective in a mouse model of Type 1 diabetes, so that's great. Now, we have a lot more work to do."

Accelerating tree growth in recent years has been accompanied by a reduction in tree lifespan, which could eventually neutralize part of the increase in net uptake of carbon dioxide (CO2). This trade-off between tree growth and life expectancy applies to forests worldwide, including in the Amazon and other tropical regions, as well as temperate regions and the Arctic.

Models and projections of future forest carbon uptake based on the existing system may therefore overestimate the capacity of forests to absorb greenhouse gases over time. In other words, while tree planting is important to help reduce levels of these gases in the atmosphere, it is not sufficient. Efforts to reduce carbon emissions remain essential.

These are the key points discussed in an article published in Nature Communications. It reports the findings of a study conducted by a cross-border group of researchers, including Gregório Ceccantini and Giuliano Locosselli, researchers at the University of Paulo's Institute of Biosciences (IB-USP) in Brazil. Both are supported by FAPESP (São Paulo Research Foundation).

"There's an inverse relationship between tree growth and longevity," Locosselli told Agência FAPESP. "We consistently show that this relationship exists regardless of species and location. If trees are growing faster, they're also assimilating carbon faster. The problem is that they'll live shorter lives and the carbon will be stored for less time."

Trees need large amounts of CO2 to grow and develop, so this growth acceleration has led to substantial carbon uptake. Recent studies show that about a third of the greenhouse gas emissions resulting from human activities in the past 50 years has been absorbed by terrestrial ecosystems thanks to a combination of new trees and expanding secondary forest growth.

The paper published in Nature Communications questions how far forests will continue to absorb excess atmospheric carbon in the future, arguing that this "depends not only on the growth response of trees to a changing climate and atmospheric composition but also on changes in mortality rates that ultimately release carbon back to the atmosphere. [...] This negative feedback on carbon storage via increased mortality will offset - at least to some extent - the beneficial effects of increased growth on total carbon storage of forests. Our current, incomplete knowledge of the universality and causes of the feedback hinders its representation in Earth System Models and thus is an important uncertainty in predictions of future forest carbon uptake in response to global change".

According to Locosselli, most climate change projections and models of forest biomass dynamics take into consideration tree growth but not the negative relationship with longevity. The drivers of faster growth are not entirely clear, but they may include temperature and atmospheric CO2, as well as the production and use of fertilizer and fossil fuels, which have significantly altered the amount of nitrogen in the environment.

Climate change

A report issued in 2019 by the United Nations Environment Program (UNEP) warned that global greenhouse gas emissions must fall by at least 7.6% each year over the next decade to limit the average temperature rise to 1.5°C, as promised by the Paris Agreement.

If the average temperature rise exceeds this limit, the impacts across the planet will include more intense heat waves and more frequent storms, according to the Intergovernmental Panel on Climate Change (IPCC).
Greenhouse gas emissions have risen 1.5% per year in the last decade, largely owing to fossil fuels and land-use change such as deforestation.

The G20 countries account for about 75% of total greenhouse gas emissions, led by China and the United States. Brazil ranks 14th in the world, according to the Global Carbon Atlas. Deforestation and forest fires alone account for a significant proportion of Brazil's emissions. In its Paris Agreement climate commitments, Brazil undertook to achieve a 37% reduction in emissions from the 2005 level by 2025 and a 43% reduction by 2030.

The latest study by the World Meteorological Organization (WMO) shows global CO2 fossil fuel emissions reaching a record 36.7 gigatons in 2019, for an increase of 62% compared with 1990 when climate negotiations began.
Because the pandemic has forced countries to restrict mobility for several months, CO2 emissions are set to fall 4%-7% in 2020 compared with last year, according to the WMO. Although in April daily emissions reached the lowest level seen between January and August, they were the same as in 2006, when they were rising sharply.

The means to mitigate this rise in carbon emissions include more public policies to increase the use of renewable energy sources and low-carbon transportation and to eliminate coal, as well as reducing deforestation and forest fires throughout the world.

Last year a group of 66 countries, plus 10 regions, 102 cities, 93 businesses, and 12 investors, committed to achieving net-zero CO2 emissions by 2050. Carbon pricing mechanisms under discussion entail taxing emissions and incrementing the carbon credit market so that the polluter pays if mitigation is not performed domestically. The ultimate goal is to make low-carbon production steadily more advantageous.

Methodology

To return to the relationship between tree lifespan and net carbon uptake, Locosselli explained that the study was based on an analysis of annual growth rings. The researchers compiled and analyzed tree-ring datasets for more than 210,000 trees belonging to 110 species.

When a tree grows faster, it lays down more tissue in the year, resulting in a wider growth ring, and vice-versa. The age of a tree can be calculated by counting its annual rings.

"This is how we were able to measure the dynamics of trees that are 500 or 600 years old. We extrapolated time beyond what other studies did with permanent plots," said Locosselli, who is supported by FAPESP with a Young Investigator grant for the project "Functional forests: biodiversity to benefit cities".

Forest burning also accelerates tree mortality, but this factor was not included in the study, he said. Other research has shown that when the Amazon or any other tropical forest burns, it retains 25% less carbon even after three decades of regrowth.

Stars are rather patient. They can live for billions of years, and they typically make slow transitions -- sometimes over many millions of years -- between the different stages of their lives.

So when a previously typical star's behavior rapidly changes in a few decades, astronomers take note and get to work.

Such is the case with a star known as SAO 244567, which lies at the center of Hen 3-1357, commonly known as the Stingray Nebula. The Stingray Nebula is a planetary nebula -- an expanse of material sloughed off from a star as it enters a new phase of old age and then heated by that same star into colorful displays that can last for up to a million years.

The tiny Stingray Nebula unexpectedly appeared in the 1980s and was first imaged by scientists in the 1990s using NASA's Hubble Space Telescope. It is by far the youngest planetary nebula in our sky. A team of astronomers recently analyzed a more recent image of the nebula, taken in 2016 by Hubble, and found something unexpected: As they report in a paper accepted to the Astrophysical Journal, the Stingray Nebula has faded significantly and changed shape over the course of just 20 years.

If dimming continues at current rates, in 20 or 30 years the Stingray Nebula will be barely perceptible, and was likely already fading when Hubble obtained the first clear images of it in 1996, according to lead author Bruce Balick, an emeritus professor of astronomy at UW.

"This is an unprecedented departure from typical behavior for a planetary nebula," said Balick. "Over time, we would expect it to imperceptibly brighten and expand, which could easily go unnoticed in a century or more. But here we're seeing the Stingray nebula fade significantly in an incredibly compressed time frame of just 20 years. Moreover, its brightest inner structure has contracted -- not expanded -- as the nebula fades."

Planetary nebulae form after most stars, including stars like our own sun, swell into red giants as they exhaust hydrogen fuel. At the end of the red giant phase, the star then expels large amounts of its outer material as it gradually -- over the course of a million years -- transforms into a small, compact white dwarf. The sloughed-off material expands outward for several thousand years while the star heats the material, which eventually becomes ionized and glows.

Balick and his co-authors, Martín Guerrero at the Institute of Astrophysics of Andalusia in Spain and Gerardo Ramos-Larios at the University of Guadalajara in Mexico, compared Hubble images of the Stingray Nebula taken in 1996 and 2016. Hen 3-1357 changed shape markedly over 20 years, losing the sharp, sloping edges that gave the Stingray Nebula its name. Its colors have faded overall and once-prominent blue expanses of gas near its center are largely gone.

"In a planetary nebula, the star is really the center of all the activity," said Balick. "The material around it is directly responsive to the energy from its parent star."

The team analyzed light spectra from Hen 3-1357 emitted by chemical elements in the nebula. Emission levels of hydrogen, nitrogen, sulfur and oxygen all dropped between 1996 and 2016, particularly oxygen, which dropped by a factor of 900. The resulting fade in color and the nebula's change in shape are likely connected to the cooling of its parent star -- from a peak of about 107,500 degrees Fahrenheit in 2002 to just under 90,000 degrees Fahrenheit in 2015 -- which means it is giving off less ultraviolet ionizing radiation that heats the expelled gas and makes it glow.

"Like a doused forest fire, the smoke wanes more slowly than the flames that created it," said Balick. "Even so, we were amazed when the Hubble images revealed how quickly the nebula was fading. It took a month of work to believe it."

Astronomers have yet to understand why SAO 244567 made the Stingray Nebula light up and then fade almost as quickly. One theory, posited by a team led by Nicole Reindl at the University of Potsdam, is that the star underwent a brief burst of fresh helium fusion around its core, which stirred up its outer layers and caused its surface to both shrink and heat.

If so, then as its outer layers settle back down, the star may return to a more typical transition from red giant to white dwarf. Only future observations of the star and its nebula can confirm this.

"Unfortunately, the best tool to follow future changes in the Stingray Nebula, the Hubble Space Telescope, is near the end of its life as well," said Balick. "We can hope, but the odds aren't good for Hubble's survival as its three remaining gyroscopes start to fail. It's a good race to the finish."