Culture

UCLA life scientists have identified six "words" that specific immune cells use to call up immune defense genes -- an important step toward understanding the language the body uses to marshal responses to threats.

In addition, they discovered that the incorrect use of two of these words can activate the wrong genes, resulting in the autoimmune disease known as Sjögren's syndrome. The research, conducted in mice, is published this week in the peer-reviewed journal Immunity (Cell Press).

"Cells have evolved an immune response code, or language," said senior author Alexander Hoffmann, the Thomas M. Asher Professor of Microbiology and director of the Institute for Quantitative and Computational Biosciences at UCLA. "We have identified some words in that language, and we know these words are important because of what happens when they are misused. Now we need to understand the meaning of the words, and we are making rapid progress. It's as exciting as when archaeologists discovered the Rosetta stone and could begin to read Egyptian hieroglyphs."

Immune cells in the body constantly assess their environment and coordinate their defense functions by using words -- or signaling codons, in scientific parlance -- to tell the cell's nucleus which genes to turn on in response to invaders like pathogenic bacteria and viruses. Each signaling codon consists of several successive actions of a DNA binding protein that, when combined, elicit the proper gene activation, in much the same way that successive electrical signals through a telephone wire combine to produce the words of a conversation.

The researchers focused on words used by macrophages, specialized immune cells that rid the body of potentially harmful particles, bacteria and dead cells. Using advanced microscopy techniques, they "listened" to macrophages in healthy mice and identified six specific codon-words that correlated to immune threats. They then did the same with macrophages from mice that contained a mutation akin to Sjögren's syndrome in humans to determine whether this disease results from the defective use of these words.

"Indeed, we found defects in the use of two of these words," Hoffmann said. "It's as if instead of saying, 'Respond to attacker down the street,' the cells are incorrectly saying, 'Respond to attacker in the house.'"

The findings, the researchers say, suggest that Sjögren's doesn't result from chronic inflammation, as long thought, but from a codon-word confusion that leads to inappropriate gene activation, causing the body to attack itself. The next step will be to find ways of correcting the confused word choices.

Many diseases are related to miscommunication in cells, but this study, the scientists say, is the first to recognize that immune cells employ a language, to identify words in that language and to demonstrate what can happen when word choice goes awry. Hoffman hopes the team's discovery will serve as a guide to the discovery of words related to other diseases.

The immune system at war: Words and codes

How are immune cells so effective at mounting a response that is specific and appropriate to each pathogen? The answer, Hoffman says, lies in "signaling pathways," the communication channels that link immune cells' receptor molecules -- which sense the presence of pathogens -- with different kinds of defense genes. The transcription factor NFκB is one of these signaling pathways and is recognized as a central regulator of immune cell responses to pathogen threats.

"The macrophage is capable of responding to different types of pathogens and mounting different kinds of defenses. The defense units -- army, navy, air force, special operations -- are mediated by groups of genes," he said. "For each immune threat, the right groups of genes must be mobilized. That requires precise and reliable communication with those units about the nature of the threat. NFκB dynamics provide the communication code. We identified the words in this code, but we don't yet fully understand how each defense unit interprets the various combinations of the codon-words."

And of course, calling up the wrong unit is not only ineffective, Hoffmann notes, but may do damage, as vehicles destroy roads, accidents happen and worse, as in the case of Sjogren's and, possibly, other diseases.

Algorithms, computers and calculus: Identifying the six words

For the study, the scientists analyzed how more than 12,000 cells communicate in response to 27 immune threat conditions. Based on the possible arrangement of temporal NFκB dynamics, they generated a list of more than 900 potential "words" -- analogous to all combinations of three-letter words with a vowel for the second letter.

Then, using an algorithm originally developed in the 1940s for the telecommunications industry, they monitored which of the potential words tended to show up when macrophages responded to a stimulus, such as a pathogen-derived substance. They discovered that six specific dynamical features, or "words," were most frequently correlated with that response.

An analogy would be listening to someone in a conversation and finding that certain three-letter words tend to be used, such as "the," "boy," "toy," and "get," but not "biy" or "bey," said lead author Adewunmi Adelaja, who earned his Ph.D. in Hoffmann's laboratory and is now working toward his M.D. at UCLA.

The team then used a machine learning algorithm to model the immune response of macrophages. If they taught a computer the six words, they asked, would it be able to recognize the stimulus when computerized versions of cells were "talking?" They confirmed that it could. Drilling down further, they explored what would happen if the computer only had five words available. They found that the computer made more mistakes in recognizing the stimulus, leading the team to conclude that all six words are required for reliable cellular communication.

The scientists also used calculus to study the biochemical molecular interactions inside the immune cells that produce the words.

Hoffmann and his colleagues revealed in the journal Science in 2014 how and why the immune system's B cells respond only to true threats. In a study published in Cell in 2013, his team showed for the first time that it was possible to correct a cellular miscommunication involving the connection of receptors to genes during inflammation without severe side effects.

The immune system's main job is identifying things that can make us sick. In the language of immunology, this means distinguishing "self" from "non-self": The cells of our organs are self, while disease-causing bacteria and viruses are non-self.

But what about the billions of bacteria that live in our guts and provide us with benefits like digesting food and making vitamins? Are they friend or foe?

This isn't only a philosophical question. An immune system that mistakes our good gut bacteria for an enemy can cause a dangerous type of inflammation in the intestines called colitis. An immune system that looks the other way while gut microbes spill past their assigned borders is equally dangerous. Understanding how the immune system learns to make a brokered peace with its microbial residents, called the microbiota, is therefore an important area of research.

"Right now, each of us has immune cells in our body that can recognize and attack specific members of our gut microbiota," says Gretchen Diehl, an immunologist in the Sloan Kettering Institute. "So, it's a puzzle why more of us don't have colitis caused by these cells attacking our gut microbes."

To try to solve that puzzle, Dr. Diehl and her colleagues, including SKI postdoctoral researcher Daniel Zegarra-Ruiz and immunologist Matthew Bettini at the University of Utah, recently conducted a study using lab mice to explore what happens to microbe-specific T cells (a type of immune cell) when mice are exposed as young pups to a common gut microbe.

"We thought that maybe T cells specific for this microbe would be eliminated from the mice, or perhaps the mice would develop anti-inflammatory T cells that would protect them from developing colitis," Dr. Diehl says. In other words, they hypothesized the bacteria would be seen as self.

Surprisingly, that wasn't the case. Not only were the microbe-specific T cells not deleted, they actually grew in number. The results, which were published May 12, 2021, in Nature, document a previously unknown way that gut microbes interact with the immune system and raise yet more questions about what goes awry in autoimmune disease.

Hidden Highway

The scientists focused their attention on an immune system organ called the thymus, which is located in the upper chest behind the breastbone. The thymus's main role is "educating" T cells about which markers, or antigens, in the body are self versus non-self. T cells that recognize self are actively culled while those that do not recognize self are spared. The non-self-recognizing T cells are then released into the circulation where they patrol for viruses, bacteria, and other invaders.

The education process is thought to be primarily about protecting the body from self-attacking T cells that could cause trouble in the form of autoimmunity. Dr. Diehl and her colleagues were taken aback to find that rather than eliminating T cells that recognize gut bacteria, the thymus was giving them the green light.

"We were very, very surprised that when we colonized mice with gut bacteria, instead of seeing the development of regulatory T cells that calm immune reactions or loss of microbe-specific T cells, we saw an expansion of them," she says. "As far as we are aware, this is the first time anyone has shown the thymus playing this role in the expansion of microbe-specific T cells."

Next they asked: How is information about gut bacteria making its way to the thymus?

Using standard gut microbiota detection techniques, they could see that bacterial DNA was showing up in the thymus, suggesting that the gut is somehow in communication with this organ via DNA. But that only raised the further question of how this DNA was getting there.

One possible explanation is that bacterial DNA is carried there by immune cells called dendritic cells, whose main job is, in fact, to carry suspicious antigens from tissues to lymph nodes. Traveling from the gut to the thymus hadn't been seen, but the scientists couldn't rule out that possibility.

To track the movement of dendritic cells, Dr. Diehl and her colleagues took advantage of a hi-tech lab mouse developed by Kat Hadjantonakis's lab at MSK. The mouse had been engineered to make a fluorescent marker called green fluorescent protein (GFP) in its cells. When GFP-containing cells are hit with light from a laser, they change from emitting green fluorescence to emitting red. By shining the laser in the intestine of the mouse, the scientists could turn gut dendritic cells red and then watch and see if red cells turned up in the mouse thymus. Sure enough, they did.

"The dendritic cells are clearly migrating that whole way, which is kind of crazy," Dr. Diehl says.

A Temporary Window

The gut-to-thymus journey only happens in very young animals. When the scientists looked at older animals, they didn't see the red cells turning up. Nor did they find any gut microbe DNA in the thymus or expansion of gut-specific T cells.

What might be the purpose of this gut-to-thymus traffic that only happens during a specific developmental window in the mice?

"What we think is happening is a kind of templating on the immune system," Dr. Diehl says. "In that timeframe, the mouse immune system is very underdeveloped and the most relevant thing for it to recognize is microbes. So, it brings gut antigens to the thymus to educate the T cells about these and related dangers."

As evidence for this possibility, they showed that the T cells that recognize the introduced bacteria also afford protection against pathogens the mice hadn't yet seen. But because they recognize gut microbes, these T cells can also cause inflammation that can lead to colitis.

What the scientists next want to understand is whether this process differs in people who are more susceptible to colitis.

Dr. Diehl wonders: "Do you have this happening for a more extended period of time in people with colitis? Do you have it happening for less? Does it restart in someone with colitis? These are all questions we want to explore."

Our body's relationship with bacteria is complex. While infectious bacteria can cause illness, our gut is also teaming with "good" bacteria that aids nutrition and helps keep us healthy. But even the "good" can have bad effects if these bacteria end up in tissues and organs where they're not supposed to be.

Now, research published in Nature reveals insights into how the body maintains this balance. Investigations with mice demonstrate that early life is a critical time when the immune system learns to recognize gut bacteria and sets up surveillance that keeps them in check. Defects in these mechanisms could help explain why the immune system sometimes attacks good bacteria in the wrong place, causing the chronic inflammation that's responsible for inflammatory bowel disease, the study's authors say.

"From the time we are born, our immune system is set up so that it can learn as much as it can to distinguish the good from the bad," says Matthew Bettini, Ph.D., associate professor of pathology at U of U Health and co-corresponding author with Sloan Kettering Institute immunologist Gretchen Diehl, Ph.D. "Our studies make clear that there is a window in which gut microbiota have access to the immune education process. This opens up possibilities for designing therapeutics that can influence the trajectory of the immune system during this early time point."

Setting Boundaries

In seeking to understand how the body maintains a healthy relationship with bacteria, Bettini, Diehl, and colleagues discovered ways in which the resident gut microbiota shape the developing immune system. They found that specialized immune cells capture pieces of bacteria and carry them over long distances, from the gut to the thymus. Located in the chest, above the heart, the thymus is a gland responsible for "educating" immune T cells. Delivery of the cargo prompts the thymus to produce T cells that are targeted to the microbiota. Then, the T cells exit the thymus to surveil lymph nodes, the gut, and other sites in order to keep the bacteria under control.

The scientists identified these steps by seeding the intestines of mice with a certain type of bacteria. In response, the thymus produced T cells that specifically recognized those bacteria. However, the scientist didn't know how this occurred.

Finding DNA from the bacteria in the thymus and lymph nodes was the first clue that microbiota migrated to those sites. To trace their journey, the researchers used specially engineered mice whose cells fluoresced red after being exposed to a laser. In the two days following photoactivation, red gut cells eventually made their way to the thymus, lymph nodes, and spleen.

These processes were robust within the first weeks of life but waned significantly by the time the mice reached adulthood.

"Our study challenges previous assumptions that potential pathogens have no influence on immune cells that are developing in the thymus," Bettini explains. "Instead, we see that there is a window of opportunity for the thymus to learn from these bacteria. Even though these events that shape which T cells are present happen early in life, they can have a greater impact later in life."

Bad Education

This notion was made apparent by the finding that T cells programmed to target beneficial bacteria could double as defense against closely related "bad" bacteria. Mice populated with E.coli at a young age were more than six times as likely to survive a lethal dose of Salmonella later in life. The results suggest that building immunity to microbiota also builds protection against harmful bacteria the body has yet to encounter.

Delving into these early communications between the body and microbiota demonstrates just how important it is to prime the immune system right from the start, Bettini says. "This early education of immune T cells is absolutely necessary to quickly develop a broad repertoire of cells to protect us."

"We believe that our findings may be extended to areas of research where certain bacteria have been found to be either protective or pathogenic for other conditions, such as Type 1 and Type 2 diabetes," Bettini says. "Now we're wondering, will this window of bacterial exposure and T cell development also be important in initiating these diseases?"

If you did not catch the flu this year — and there is an overwhelming chance that you did not — you have COVID-19 to thank.

It’s a small consolation, given the enormously disruptive scope of the pandemic. But it’s the focus of a new paper published in the journal Frontiers in Public Health by two Concordia researchers and their colleagues that studies the 2020 influenza figures from Canada, the United States, Australia and Brazil. The authors show there is a clear relationship between the implementation of COVID-mitigation measures such as hand-washing, masking and social distancing and the spread of the annual flu.

They write that these preventive measures all but eliminated the flu in countries where it can kill tens of thousands of people a year, even as cases of COVID-19 soared.

“With the introduction of COVID-19 mitigation measures, we saw a steep decline in influenza cases in the northern hemisphere,” says Jovana Stojanovic, a postdoctoral fellow in the Department of Health, Kinesiology and Applied Physiology and the lead author of the paper.

“Then we also observed that as COVID-19 cases went up and down in different ways, influenza was basically annulled across both the north and south hemispheres. That speaks volumes about how contagious COVID-19 is compared to influenza.”

Simon Bacon, a professor of health, kinesiology and applied physiology, co-authored the paper, along with Vincent Boucher and Kim Lavoie at UQAM as well as Jacqueline Boyle and Joanne Enticott of Monash University in Australia.

No peaks, all valleys

The researchers initially had two objectives. The first involved using data from FluNet, the World Health Organization’s influenza virological surveillance tool. They wanted to see how the epidemiological pattern of the 2019-20 influenza tracked onto the evolution of the COVID-19 pandemic after the introduction of public mitigation measures were introduced in Canada, the United States, Australia and Brazil.

The second was to combat the misleading statements and disinformation being circulated worldwide that COVID-19 was similar to influenza. Their graphs below clearly show the stark differences in transmissibility between the influenza and novel coronavirus.

“In the northern hemisphere, we initially had overlapping flu and COVID-19 cases,” Bacon says. “When we introduced basic measures like hand-washing, social distancing and wearing masks, the flu was almost totally obliterated while COVID kept going.”

The researchers note that the first two graphs, looking at Canada and the United States, show significant reduction of influenza cases compared with the averages of the four previous years after mitigation efforts were introduced (indicated by the solid black line). Flu season, which usually runs from October to May, effectively ended a month earlier in Canada and almost two months earlier in the United States. Cases remained close to nil at the start of the 2020 flu season in both countries, which roughly coincided with the second COVID-19 wave.

The next set of graphs, showing figures from Brazil and Australia, reveal similar figures. Flu season in the southern hemisphere lasts from May to November but in these cases, there was no traditional mid-year spike for flu, though COVID-19 was nearing its second-wave high. Flu cases remained near zero through the end of the year.

Easy steps

These findings offer lessons for public health authorities as we eye a post-COVID future, Bacon explains.

“We know the flu is particularly problematic for older individuals and those with respiratory conditions and so on,” he says. “When we interact with people in those high-risk brackets, we should maintain some measures like handwashing, mask-wearing and social distancing. We’re used to them now, so maintaining them moving forward is probably a good idea.”

DURHAM, N.H.-- A national report from the University of New Hampshire shows close to one and a half million children each year visit a doctor, emergency room or medical facility as a result of an assault, abuse, crime or other form of violence. This is four times higher than previous estimates based only on data from U.S. emergency rooms for violence-related treatment.

In their study, recently published on JAMA Network Open, researchers from UNH's Crimes against Children Research Center (CCRC) used survey information from a representative sample of 8,503 children and youth from across the country, ages two to 17 years, as part of a series of nationwide studies in 2011 and 2014. They found that while the majority of those needing medical attention for violence exposure were teens, one third were under the age of 10. The rate of past-year medical visits due to violence exposure was 1.9% which is equivalent to a national estimate of 1.4 million children and teens. Previous estimates based on data obtained only from emergency rooms were 340,000 visits, which reflects a severe undercount of violence related medical treatment for children.

"This flood of visits to medical authorities each year by young crime victims means that our medical professionals need to know more about how to help, not only treating the injuries but how to counsel children and their families about how to stay safe and how to get appropriate help from schools, therapists and child protection agencies," said David Finkelhor, director of the CCRC and lead author.

Most of the medical visits were to treat injuries but some were to document harms and others to seek supportive help for problems like bullying and sibling victimization. The violence responsible for these visits included gang violence, aggravated assault by peers, dating violence, sexual assault and parental abuse with the largest category being simple assault by other peers. Researchers say that children are the most crime exposed segment of the population, experiencing serious assaults at twice the rate as adults.

"We should not be treating assaults as just a rite of passage for children," said Finkelhor. "We need to build interpersonal safety into our education systems, our environments and prepare practitioners to provide resources on prevention and safety skills."

The 1949 letter by the physicist and Nobel laureate discusses bees, birds and whether new physics principles could come from studying animal senses.

It's a position still being realised within physics to this day, with a growing body of research and understanding of how animals such as birds and bees find their way around.

Now a study led by RMIT University in Melbourne, Australia, discusses how recent discoveries in migratory birds back up Einstein's thinking 72 years ago.

The previously unpublished letter was shared with researchers by Judith Davys - Einstein had addressed it to her late husband, radar researcher Glyn Davys.

RMIT's Associate Professor Adrian Dyer has published significant studies into bees and is the lead author of the new paper on Einstein's letter, published in the Journal of Comparative Physiology A.

Dyer said the letter shows how Einstein envisaged new discoveries could come from studying animals.

"Seven decades after Einstein proposed new physics might come from animal sensory perception, we're seeing discoveries that push our understanding about navigation and the fundamental principles of physics," he said.

The letter also proves Einstein met with Nobel laurate Karl von Frisch, who was a leading bee and animal sensory researcher.

In April 1949, von Frisch presented his research on how honeybees navigate more effectively using the polarisation patterns of light scattered from the sky.

The day after Einstein attended von Frisch's lecture, the two researchers shared a private meeting.

Although this meeting wasn't formally documented, the recently discovered letter from Einstein provides insight into what they might have talked about.

"It is thinkable that the investigation of the behaviour of migratory birds and carrier pigeons may someday lead to the understanding of some physical process which is not yet known," Einstein wrote.

Professor Andrew Greentree, a theoretical physicist at RMIT, said Einstein also suggested that for bees to extend our knowledge of physics, new types of behaviour would need to be observed.

"Remarkably, it is clear through his writing that Einstein envisaged new discoveries could come from studying animals' behaviours," Greentree said.

More than 70 years since Einstein sent his letter, research is revealing the secrets of how migratory birds navigate while flying thousands of kilometres to arrive at a precise destination.

In 2008, research on thrushes fitted with radio transmitters showed, for the first time, that these birds use a form of magnetic compass as their primary orientation guide during flight.

One theory for the origin of magnetic sense in birds is the use of quantum randomness and entanglement. Both of these physics concepts were first proposed by Einstein.

PROVIDENCE, R.I. [Brown University] -- Researchers with the BrainGate collaboration have, for the first time, used an implanted sensor to record the brain signals associated with handwriting, and used those signals to create text on a computer in real time.

In a study published in the journal Nature, a clinical trial participant with cervical spinal cord injury used the system to "type" words on a computer at a rate of 90 characters per minute, more than double the previous record for typing with a brain-computer interface. This was done by the participant merely thinking about the hand motions involved in creating written letters.

The research team is hopeful that such a system could one day help to restore people's ability to communicate following paralysis caused by injury or illness.

The new study is part of the BrainGate clinical trial, directed by Dr. Leigh Hochberg. Hochberg is a critical care neurologist and a professor at Brown University's School of Engineering and Carney Institute for Brain Science. Frank Willett, a research scientist at Stanford University and the Howard Hughes Medical Institute (HHMI), led the study, which was supervised by Krishna Shenoy, a Stanford professor and HHMI investigator, and Dr. Jaimie Henderson, a professor of neurosurgery at Stanford.

"An important mission of our BrainGate consortium research is to restore rapid, intuitive communication for people with severe speech or motor impairments," said Hochberg, who also directs the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital and the VA RR&D Center for Neurorestoration and Neurotechnology at the Dept. of Veterans Affairs Providence Healthcare System. "Frank's demonstration of fast, accurate neural decoding of handwriting marks an exciting new chapter in the development of clinically useful neurotechnologies."

The BrainGate collaboration has been working for several years on systems that enable people to generate text through direct brain control. Previous incarnations have involved trial participants thinking about the motions involved in pointing to and clicking letters on a virtual keyboard. That system enabled one participant to type 40 characters per minute, which was the previous record speed.

For this latest study, the team wanted to find out if asking a participant to think about motions involved in writing letters and words by hand would be faster.

"We want to find new ways of letting people communicate faster," Willett said. "This new system uses both the rich neural activity recorded by intracortical electrodes and the power of language models that, when applied to the neurally decoded letters, can create rapid and accurate text."

The trial participant, a 65-year-old (at the time of the study) man, was paralyzed from the neck down by a spinal cord injury. As part of the clinical trial, Henderson placed two tiny electrodes about the size of a baby aspirin in a part of his brain associated with the movement of his right arm and hand. Using signals the sensors picked up from individual neurons when the man imagined writing, a machine learning algorithm recognized the patterns his brain produced with each letter. With this system, the man could copy sentences and answer questions at a rate similar to that of someone the same age typing on a smartphone.

The system is so fast because each letter elicits a highly distinctive activity pattern, making it relatively easy for the algorithm to distinguish one from another, Willett says.

The new research is the latest in a series of advances in brain-computer interfaces (BCIs) made by the BrainGate collaboration, which includes researchers from Brown University, Massachusetts General Hospital, Harvard Medical School, the Providence VA Medical Center, Stanford University, and Case Western Reserve University.

In 2012, the team published landmark research in which clinical trial participants were able, for the first time, to operate multidimensional robotic prosthetics using a BCI. That work has been followed by a steady stream of refinements to the system, as well as new clinical breakthroughs that have enabled people to directly control tablet apps and even move their own paralyzed limbs. Most recently, the team demonstrated the first human use of a wireless intracortical BCI that can transmit neural data at full bandwidth.

Hochberg said he's grateful to clinical trial participants for making these breakthroughs and future ones possible.

"The people who enroll in the BrainGate trial are amazing," Hochberg said. "It's their pioneering spirit that not only allows us to gain new insights into human brain function, but that leads to the creation of systems that will help other people with paralysis."

Scientists have for the first time revealed the structure surrounding important receptors in the brain's hippocampus, the seat of memory and learning.

The study, carried out at Oregon Health & Science University, published today in the journal Nature.

The new study focuses on the organization and function of glutamate receptors, a type of neurotransmitter receptor involved in sensing signals between nerve cells in the hippocampus region of the brain. The study reveals the molecular structure of three major complexes of glutamate receptors in the hippocampus.

The findings may be immediately useful in drug development for conditions such as epilepsy, said senior author Eric Gouaux, Ph.D., senior scientist in the OHSU Vollum Institute, Jennifer and Bernard Lacroute Endowed Chair in Neuroscience Research and an Investigator with the Howard Hughes Medical Institute.

"Epilepsy or seizure disorders can have many causes," he said. "If one knows the underlying cause for a particular person's seizure activity, then you may be able to develop small molecules to modulate that activity."

Working with a mouse model, the OHSU researchers made the breakthrough by developing a chemical reagent based on monoclonal antibodies to isolate the receptor and the complex of subunits surrounding it. They then imaged the assemblage using state-of-the-art cryo-electron microscopy at the Pacific Northwest Cryo-EM Center, housed in OHSU's South Waterfront campus in Portland.

Gouaux anticipates the technique will transform structural biology.

"It really opens the door to specifically target the molecules that need to be targeted in order to treat a particular condition," he said. "A great deal of drug development is structure-based, where you see what the lock looks like and then you develop a key. If you don't know what the lock looks like, then it's much harder to develop a key."

Previously, scientists had to rely on mimicking the actual receptors by artificially engineering receptors by combining DNA segments in tissue culture. However, that technique has obvious shortcomings.

"It doesn't work perfectly because the real receptors are surrounded by a constellation of additional, sometimes previously unknown, subunits," Gouaux said.

The new monoclonal antibody reagents, also developed at OHSU, enabled scientists to isolate actual glutamate receptors from the brain tissue of mice. They then were able to image those samples in near-atomic detail using cryo-EM, which allowed them to capture the entire assemblage of three types of glutamate receptors along with their auxiliary subunits.

"Previously, it's been impossible to do this because we had no good way to isolate molecules and no way to see what they looked like," Gouaux said. "So this is a super exciting development."

Stanford scientists' software turns 'mental handwriting' into on-screen words, sentences

Call it "mindwriting."

The combination of mental effort and state-of-the-art technology have allowed a man with immobilized limbs to communicate by text at speeds rivaling those achieved by his able-bodied peers texting on a smartphone.

Stanford University investigators have coupled artificial-intelligence software with a device, called a brain-computer interface, implanted in the brain of a man with full-body paralysis. The software was able to decode information from the BCI to quickly convert the man's thoughts about handwriting into text on a computer screen.

The man was able to write using this approach more than twice as quickly as he could using a previous method developed by the Stanford researchers, who reported those findings in 2017 in the journal eLife.

The new findings, to be published online May 12 in Nature, could spur further advances benefiting hundreds of thousands of Americans, and millions globally, who've lost the use of their upper limbs or their ability to speak due to spinal-cord injuries, strokes or amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, said Jaimie Henderson, MD, professor of neurosurgery.

"This approach allowed a person with paralysis to compose sentences at speeds nearly comparable to those of able-bodied adults of the same age typing on a smartphone," said Henderson, the John and Jene Blume -- Robert and Ruth Halperin Professor. "The goal is to restore the ability to communicate by text."

The participant in the study produced text at a rate of about 18 words per minute. By comparison, able-bodied people of the same age can punch out about 23 words per minute on a smartphone.

The participant, referred to as T5, lost practically all movement below the neck because of a spinal-cord injury in 2007. Nine years later, Henderson placed two brain-computer-interface chips, each the size of a baby aspirin, on the left side of T5's brain. Each chip has 100 electrodes that pick up signals from neurons firing in the part of the motor cortex -- a region of the brain's outermost surface -- that governs hand movement.

Those neural signals are sent via wires to a computer, where artificial-intelligence algorithms decode the signals and surmise T5's intended hand and finger motion. The algorithms were designed in Stanford's Neural Prosthetics Translational Lab, co-directed by Henderson and Krishna Shenoy, PhD, professor of electrical engineering and the Hong Seh and Vivian W. M. Lim Professor of Engineering.

Shenoy and Henderson, who have been collaborating on BCIs since 2005, are the senior co-authors of the new study. The lead author is Frank Willett, PhD, a research scientist in the lab and with the Howard Hughes Medical Institute.

"We've learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements," Willett said. "And we've learned that complicated intended motions involving changing speeds and curved trajectories, like handwriting, can be interpreted more easily and more rapidly by the artificial-intelligence algorithms we're using than can simpler intended motions like moving a cursor in a straight path at a steady speed. Alphabetical letters are different from one another, so they're easier to tell apart."

In the 2017 study, three participants with limb paralysis, including T5 -- all with BCIs placed in the motor cortex -- were asked to concentrate on using an arm and hand to move a cursor from one key to the next on a computer-screen keyboard display, then to focus on clicking on that key.

In that study, T5 set what was until now the all-time record: copying displayed sentences at about 40 characters per minute. Another study participant was able to write extemporaneously, selecting whatever words she wanted, at 24.4 characters per minute.

If the paradigm underlying the 2017 study was analogous to typing, the model for the new Nature study is analogous to handwriting. T5 concentrated on trying to write individual letters of the alphabet on an imaginary legal pad with an imaginary pen, despite his inability to move his arm or hand. He repeated each letter 10 times, permitting the software to "learn" to recognize the neural signals associated with his effort to write that particular letter.

In numerous multi-hour sessions that followed, T5 was presented with groups of sentences and instructed to make a mental effort to "handwrite" each one. No uppercase letters were employed. Examples of the sentences were "i interrupted, unable to keep silent," and "within thirty seconds the army had landed." Over time, the algorithms improved their ability to differentiate among the neural firing patterns typifying different characters. The algorithms' interpretation of whatever letter T5 was attempting to write appeared on the computer screen after a roughly half-second delay.

In further sessions, T5 was instructed to copy sentences the algorithms had never been exposed to. He was eventually able to generate 90 characters, or about 18 words, per minute. Later, asked to give his answers to open-ended questions, which required some pauses for thought, he generated 73.8 characters (close to 15 words, on average) per minute, tripling the previous free-composition record set in the 2017 study.

T5's sentence-copying error rate was about one mistake in every 18 or 19 attempted characters. His free-composition error rate was about one in every 11 or 12 characters. When the researchers used an after-the-fact autocorrect function -- similar to the ones incorporated into our smartphone keyboards -- to clean things up, those error rates were markedly lower: below 1% for copying, and just over 2% for freestyle.

These error rates are quite low compared with other BCIs, said Shenoy, who is also a Howard Hughes Medical Institute investigator.

"While handwriting can approach 20 words per minute, we tend to speak around 125 words per minute, and this is another exciting direction that complements handwriting. If combined, these systems could together offer even more options for patients to communicate effectively," Shenoy said.

What The Study Did: Researchers describe overdose deaths in San Francisco before and after the initial COVID-19 shelter-in-place order to try to make clear whether characteristics of fatal overdoses changed during this time in an effort to guide future prevention efforts.

Authors: Luke N. Rodda, Ph.D., of the Office of the Chief Medical Examiner for the city and county of San Francisco, is the corresponding author.

To access the embargoed study:  Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.10452)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Researchers used registry data to examine the number, characteristics and outcomes of patients with sunburns severe enough to warrant admission to specialist burn services in Australia and New Zealand.

Authors: Lincoln M. Tracy, Ph.D., of Monash University in Melbourne, Australia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamadermatol.2021.1110)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Delayed localized injection-site reactions to the Moderna COVID-19 vaccine for 16 patients are described in this report.

Authors: Alicia J. Little, M.D., Ph.D., of the Yale University School of Medicine in New Haven, Connecticut, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamadermatol.2021.1214)

Editor's Note: The article includes conflicts of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

LA JOLLA, CALIF. - May 12, 2021 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have taken a deep dive into a previously overlooked family of proteins and discovered that they are essential to maintaining the energy that cells need to grow and survive. The proteins, known as lipid kinases, produce messengers that help balance cellular metabolism and promote overall health. The findings, published in Developmental Cell, provide further support to pursue lipid kinases as promising therapeutic targets for diseases that demand excess energy, such as cancer.

"Cancer cells are hungry--they grow faster than most cell types and need energy to support their aggressive attempts to metastasize," says Brooke Emerling, Ph.D., assistant professor in the Cell and Molecular Biology of Cancer Program at Sanford Burnham Prebys and corresponding author of the study. "Our study is one of the first to look at how PI5P4Ks--lipid kinases with known links to sarcomas and certain types of breast cancer--facilitate communications within the cell and maintain an energy balance to support cell growth."

For years scientists have tried to halt cancer by blocking nutrients from reaching tumor cells. But these attempts have been disappointing because cancer cells are tricky and create back up routes to source food to sustain their growth. Emerling's approach is to find and attack metabolic vulnerabilities within cells, which would deprive them of energy even in an abundance of nutrients and special tactics.

Using a combination of cell lines, imaging technology and mouse tumor models, Emerling's team revealed that PI5P4Ks produce an active messenger that coordinates communications between peroxisomes and mitochondria--two organelles intimately involved in making and using fuel to support cellular growth. In the absence of the messenger, the interplay between the organelles breaks down, mitochondria become overworked, and cells starve and die.

"Mitochondria are the powerhouses of the cell, says Archna Ravi, Ph.D., a postdoctoral researcher in Emerling's lab and first author of the paper. "They play an essential role in generating energy to drive cellular function and basically all biological processes. This research supports targeting PI5P4Ks as a cancer treatment strategy because it would deprive tumors of the one thing they can't live without: energy."

Emerling's team previously discovered the essential role of PI5P4K in tumor formation. The new study indicates a role for PI5P4Ks not only in tumor establishment, but for the first time in tumor maintenance.

"We use sarcomas as a tumor model because PI5P4Ks are highly expressed in high grade sarcomas, and their expression correlates with patient survival," says Emerling. "Sarcomas are a rare group of cancers that affect the body's connective tissues, and about half of all cases can be cured, but for the other half, better therapies are desperately needed."

Targeting PI5P4K may also be valuable for other tumor types that have developed profound metabolic alterations to source nutrients, such as triple negative breast cancer. Like sarcomas, triple negative breast cancer therapies remain woefully inadequate.

"Our goal is to develop drugs in the near future that inhibit PI5P4K and test the drugs in mice. If successful, we hope to advance to human clinical trials. I think the future for our research is very bright now," concludes Emerling.

Social anxiety disorder can cause considerable suffering in children and adolescents and, for many with the disorder, access to effective treatment is limited. Researchers at Centre for Psychiatry Research at Karolinska Institutet and Region Stockholm in Sweden have now shown that internet-delivered cognitive behavioural therapy is an efficacious and cost-effective treatment option. The study is published in the journal JAMA Psychiatry.

Social anxiety disorder (SAD, previously known as social phobia) has a typical onset during childhood and is characterised by an intense and persistent fear of being scrutinised and negatively evaluated in social or performance situations.

The fear typically leads to avoidance of such anxiety triggering situations or are endured under great distress, resulting in an impaired ability to function in everyday life.

The disability can lead to underperformance in school, social isolation from peers and, inability to partake in leisure activities.

As one of the most common anxiety disorders among youth, the disorder affects 5 to 10 percent of the youth population and without effective treatment it has been linked to long-term psychosocial adversity and persistence into adulthood.

Despite known evidence-based treatments for SAD, such as cognitive behavioural therapy (CBT), the access to effective treatment is very limited.

As a means to increase access, researchers at Centre for Psychiatry Research at Karolinska Institutet and the Child and Adolescent Mental Health Services in Region Stockholm have now developed and evaluated a 10-week internet-delivered CBT (ICBT) programme for young people with SAD.

The study was conducted between 2017 and 2020, and included 103 youths aged 10 to 17 along with their parents. Participants were randomly assigned to either internet-delivered CBT or an active control group, internet-delivered supportive therapy.

Both interventions included ten online treatment modules with weekly therapist support and, three video sessions with the therapist. Parents parallelly received five online modules with therapist support.

The results showed that ICBT was significantly more effective than supportive therapy in reducing social anxiety and comorbid psychiatric symptoms, as well as in increasing the level of global functioning.

The superiority of ICBT was shown in assessments of participants' symptoms made by masked assessors as well as in ratings by participants themselves and their parents.

According to the researchers, the digital format can also increase access to evidence-based treatment for children and adolescents with SAD.

"Offering treatment digitally means that children and parents don't have to take time off school and work to travel to a health care facility," says the study's first author Martina Nordh, psychologist and researcher at the Centre for Psychiatry Research, part of Karolinska Institutet's Department of Clinical Neuroscience, and Region Stockholm. "We also believe it may lower the threshold to seeking treatment, as young people with SAD can find it too challenging to meet with unfamiliar people and to be in a new setting."

The total time spent by the therapists in ICBT was about a quarter of the time normally required by face-to-face CBT for SAD.

"Shorter therapist time enables each therapist to treat more patients and may lead to reduction of waiting times," says principal investigator Eva Serlachius, child and adolescent psychiatrist and adjunct professor at the Centre for Psychiatry Research, part of Karolinska Institutet's Department of Clinical Neuroscience, and Region Stockholm. "This also makes digital CBT less costly for the healthcare services and resources can be redistributed to those with greater need of more intensive treatment."

The acidity of the atmosphere is increasingly determined by carbon dioxide and organic acids such as formic acid. The second of these contribute to the formation of aerosol particles as a precursor of raindrops and therefore impact the growth of clouds and pH of rainwater. In previous atmospheric chemistry models of acid formation, formic acid tended to play a small role. The chemical processes behind its formation were not well understood. An international team of researchers under the aegis of Forschungszentrum Jülich has now succeeded in filling this gap and deciphering the dominant mechanism in the formation of formic acid. This makes it possible to further refine atmosphere and climate models. The results of the study have now been published in the peer-reviewed journal Nature.

In Germany, we are familiar with acid rain, particularly from our experience in the 1980s. The cause of it was that nitrogen oxides and sulfur oxides released into the atmosphere by human beings reacted with the water droplets in the clouds to form sulfuric acid and nitric acid. Acid rain has a pH of about 4.2-4.8, lower than that of pure rainwater (5.5-5.7), which results from the natural carbon dioxide content of the atmosphere.

However, the chemical process that forms the bulk of the formic acid present in the atmosphere was unknown up to now. Dr. Bruno Franco and Dr. Domenico Taraborrelli from Jülich's Institute of Energy and Climate Research - Troposphere have now deciphered it: Formaldehyde is formed naturally by photo-oxidation of volatile organic compounds. Formaldehyde reacts in cloud droplets with water molecules to form methanediol. The majority of this is outgassed and reacts with OH radicals, sometimes called the "detergent of the atmosphere", in a photochemical process to form formic acid. A smaller portion reacts with the liquid phase of the water droplets to also form formic acid that is spread by rain.

"According to our calculations, the oxidation of methanediol in the gas phase produces up to four times as much formic acid as what is produced in other known chemical processes in the atmosphere," says Domenico Taraborrelli. This amount reduces the pH of clouds and rainwater by up to 0.3, which highlights the contribution of organic carbon to the natural acidity in the atmosphere.

As a first step, the two scientists tested their theory using MESSy, a global atmospheric chemistry model, and compared the results with remote sensing data. To carry out the modelling, they used the Jülich supercomputer JURECA. Subsequent experiments in Jülich's SAPHIR atmosphere simulation chamber confirmed the results. "We assume that the mechanism demonstrated is also active in aqueous aerosols and applies to other organic acids such as oxalic acid, which are not adequately accounted for in atmospheric chemistry models to date," says Taraborrelli. One of the effects of this could be an improved understanding of the growth of aerosol particles and the development of clouds.