First image of antigen-bound T-cell receptor at atomic resolution

The cryo-EM structure of the fully assembled T-cell receptor (TCR) complex with a tumor-associated peptide/MHC ligand provides important insights into the biology of TCR signaling. These insights into the nature of TCR assembly and the unusual cell membrane architecture reveal the basis of antigen recognition and receptor signaling. 
Credit: Robert Tampé | Goethe University Frankfurt

T cells are our immune system's customized tools for fighting infectious diseases and tumor cells. On their surface, these special white blood cells carry a receptor that recognizes antigens. With the help of cryo-electron microscopy, biochemists and structural biologists from Goethe University Frankfurt, in collaboration the University of Oxford and the Max Planck Institute of Biophysics, were able to visualize the whole T-cell receptor complex with bound antigen at atomic resolution for the first time. Thereby they helped to understand a fundamental process which may pave the way for novel therapeutic approaches targeting severe diseases.

The immune system of vertebrates is a powerful weapon against external pathogens and cancerous cells. T cells play a crucial role in this context. They carry a special receptor called the T-cell receptor on their surface that recognizes antigens – small protein fragments of bacteria, viruses and infected or cancerous body cells – which are presented by specialized immune complexes. The T-cell receptor is thus largely responsible for distinguishing between “self" and “foreign". After binding of a suitable antigen to the receptor, a signaling pathway is triggered inside the T cell that “arms" the cell for the respective task. However, how this signaling pathway is activated has remained a mystery until now – despite the fact that the T-cell receptor is one of the most extensively studied receptor protein complexes.

Increased risk of some neurological and psychiatric disorders remains two years after COVID-19 infection

New diagnoses of disorders including psychosis, dementia, seizures and ‘brain fog’ remain commoner two years after COVID-19 than after other respiratory infections, whereas the increased risks of depression and anxiety after COVID-19 are short-lived and there is no overall excess of cases.

Published in The Lancet Psychiatry, the new study from the University of Oxford and the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre investigated neurological and psychiatric diagnoses in over 1.25 million people following diagnosed COVID-19 infection, using data from the US-based TriNetX electronic health record network.

The study reports on 14 neurological and psychiatric diagnoses over a 2-year period and compares their frequency with a matched group of people recovering from other respiratory infections. It also reports data on children and older adults separately, and compares data across three waves of the pandemic. To our knowledge, these are the first robust data addressing these important questions.

Confirming previous studies, many of the disorders are more common after COVID-19. Notably, the increased risk of anxiety and depression subsides within two months of COVID-19 and, over the whole 2-year period, are no more likely to occur than after other respiratory infections. In contrast, diagnoses of many neurological disorders (such as dementia and seizures), as well as psychotic disorders and ‘brain fog’, continue to be made more often after COVID-19 throughout the 2 years.

Results in children (under 18) showed similarities and differences to adults. The likelihood of most diagnoses after COVID-19 was lower than in adults, and they were not at greater risk of anxiety or depression than children who had other respiratory infections. However, like adults, children recovering from COVID-19 were more likely to be diagnosed with some conditions, including seizures and psychotic disorders.

A new neuromorphic chip for AI on the edge, at a small fraction of the energy and size of today’s compute platforms

 The NeuRRAM chip is an innovative neuromorphic chip
Credit: David Baillot/University of California San Diego

An international team of researchers has designed and built a chip that runs computations directly in memory and can run a wide variety of AI applications–all at a fraction of the energy consumed by computing platforms for general-purpose AI computing.

The NeuRRAM neuromorphic chip brings AI a step closer to running on a broad range of edge devices, disconnected from the cloud, where they can perform sophisticated cognitive tasks anywhere and anytime without relying on a network connection to a centralized server. Applications abound in every corner of the world and every facet of our lives, and range from smart watches, to VR headsets, smart earbuds, smart sensors in factories and rovers for space exploration.

The NeuRRAM chip is not only twice as energy efficient as the state-of-the-art “compute-in-memory” chips, an innovative class of hybrid chips that runs computations in memory, it also delivers results that are just as accurate as conventional digital chips. Conventional AI platforms are a lot bulkier and typically are constrained to using large data servers operating in the cloud.

In addition, the NeuRRAM chip is highly versatile and supports many different neural network models and architectures. As a result, the chip can be used for many different applications, including image recognition and reconstruction as well as voice recognition.

Lungless Salamanders Develop Lungs as Embryos Despite Lung Loss in Adults for Millions of Years

 Hemidactylium scutatum larvae, lungless salamander native to eastern North America
Credit: Zachary R Lewis

Lungs are essential to many vertebrates including humans. However, four living amphibian clades have independently eliminated pulmonary respiration and lack lungs, breathing primarily through their wet skin. Little is known of the developmental basis of lung loss in these clades.

In a new study in Science Advances researchers in the Department of Organismic and Evolutionary Biology and the Museum of Comparative Zoology at Harvard University examined the Plethodontidae, a dominant family of salamanders, all of which are lungless as adults, and find they actually do develop lungs as embryos shedding light on the evolution of lung loss over millions of years.

The lungless salamander family Plethodontidae is the most species-rich family of salamanders accounting for more than two-thirds of existing salamander diversity. All adult plethondontids are lungless, breathing entirely through nonpulmonary tissues, mainly the skin and the mucus membranes in the mouth and throat. Lung loss has occurred independently at least four times among distantly related amphibians and there are other instances of lung reduction or loss in both amphibians and some vertebrates. The developmental reason for this loss, however, remains a mystery.

“Clearly lungless salamanders do fine without lungs given that they make up about two-thirds of all salamander species,” said lead author Zachary R. Lewis, former doctoral candidate (PhD ’16), “perhaps losing lungs enabled, rather than hindered, this remarkable evolutionary success.”

UBC researchers discover ‘weak spot’ across major COVID-19 variants

Cryo-electron microscopy reveals how the VH Ab6 antibody fragment (red) attaches to the vulnerable site on the SARS-CoV-2 spike protein (grey) to block the virus from binding with the human ACE2 cell receptor (blue).
Credit: Dr. Sriram Subramaniam, UBC

Researchers at the University of British Columbia have discovered a key vulnerability across all major variants of the SARS-CoV-2 virus, including the recently emerged BA.1 and BA.2 Omicron subvariants.

The weakness can be targeted by neutralizing antibodies, potentially paving the way for treatments that would be universally effective across variants.

The findings, published today in Nature Communications, use cryo-electron microscopy (cryo-EM) to reveal the atomic-level structure of the vulnerable spot on the virus’ spike protein, known as an epitope. The paper further describes an antibody fragment called VH Ab6 that is able to attach to this site and neutralize each major variant.

“This is a highly adaptable virus that has evolved to evade most existing antibody treatments, as well as much of the immunity conferred by vaccines and natural infection,” says Dr. Sriram Subramaniam (he/him), a professor at UBC’s faculty of medicine and the study’s senior author. “This study reveals a weak spot that is largely unchanged across variants and can be neutralized by an antibody fragment. It sets the stage for the design of pan-variant treatments that could potentially help a lot of vulnerable people.”

Scientists are relieved to discover ‘curious’ creature with no anus is not earliest human ancestor

Left to right: Saccorhytus, Saccorhytus dorsal, Saccorhytus side-on.
Credit: Philip Donoghue et al

An international team of researchers have discovered that a mysterious microscopic creature from which humans were thought to descend is part of a different family tree.

Resembling an angry Minion, the Saccorhytus is a spikey, wrinkly sack, with a large mouth surrounded by spines and holes that were interpreted as pores for gills – a primitive feature of the deuterostome group, from which our own deep ancestors emerged.

However, extensive analysis of 500-million-year-old fossils from China has shown that the holes around the mouth are bases of spines that broke away during the preservation of the fossils, finally revealing the evolutionary affinity of the microfossil Saccorhytus.

“Some of the fossils are so perfectly preserved that they look almost alive,” says Yunhuan Liu, professor in Paleobiology at Chang’an University, Xi’an, China. “Saccorhytus was a curious beast, with a mouth but no anus, and rings of complex spines around its mouth.”

The findings, published today in Nature, make important amendments to the early phylogenetic tree and the understanding of how life developed.

Climate-resilient breadfruit might be the food of the future

Breadfruit on a tree on the island of St. Vincent and the Grenadines.
Credit: Nyree Zerega/Northwestern University/Chicago Botanic Garden

In the face of climate change, breadfruit soon might come to a dinner plate near you.

While researchers predict that climate change will have an adverse effect on most staple crops, including rice, corn and soybeans, a new Northwestern University study finds that breadfruit — a starchy tree fruit native to the Pacific islands — will be relatively unaffected.

Because breadfruit is resilient to predicted climate change and particularly well-suited to growing in areas that experience high levels of food insecurity, the Northwestern team believes breadfruit could be part of the solution to the worsening global hunger crisis.

The study was published today (Aug. 17) in the journal PLOS Climate.

“Breadfruit is a neglected and underutilized species that happens to be relatively resilient in our climate change projections,” said Northwestern’s Daniel Horton, a senior author on the study. “This is good news because several other staples that we rely on are not so resilient. In really hot conditions, some of those staple crops struggle and yields decrease. As we implement strategies to adapt to climate change, breadfruit should be considered in food security adaptation strategies.”

Horton is an assistant professor of Earth and planetary sciences in Northwestern’s Weinberg College of Arts and Sciences, where he leads the Climate Change Research Group. Lucy Yang, a former student in Horton’s laboratory, is the paper’s first author. For this study, Horton and Yang collaborated with breadfruit expert Nyree Zerega, director of the Program in Plant Biology and Conservation, a partnership between Northwestern and the Chicago Botanic Garden.

Sleeping giant could end deep ocean life

Resting balloonfish near the Florida Keys.
Credit: (OAR/National Undersea Research Program (NURP); University of Maine)

A previously overlooked factor — the position of continents — helps fill Earth’s oceans with life-supporting oxygen. Continental movement could ultimately have the opposite effect, killing most deep ocean creatures.

“Continental drift seems so slow, like nothing drastic could come from it, but when the ocean is primed, even a seemingly tiny event could trigger the widespread death of marine life,” said Andy Ridgwell, UC Riverside geologist and co-author of a new study on forces affecting oceanic oxygen.

The water at the ocean’s surface becomes colder and denser as it approaches the north or south pole, then sinks. As the water sinks, it transports oxygen pulled from Earth’s atmosphere down to the ocean floor.

Eventually, a return flow brings nutrients released from sunken organic matter back to the ocean’s surface, where it fuels the growth of plankton. Both the uninterrupted supply of oxygen to lower depths and organic matter produced at the surface support an incredible diversity of fish and other animals in today’s ocean.

New findings led by researchers based at UC Riverside have found this circulation of oxygen and nutrients can end quite suddenly. Using complex computer models, the researchers investigated whether the locations of continental plates affect how the ocean moves oxygen around. To their surprise, it does.

First Structure of Key COVID Enzyme at Human Body Temperature

Scientists used x-rays to decipher the three-dimensional structure of the main protease of the virus that causes COVID-19 at different temperatures. The background image shows the full structure at 240 Kelvin (-28°F, cyan stick figure) and 100 K (-280°F, dark blue). The red and green blobs represent differences in the structure at these distinct temperatures. The study allowed the scientists to zero in on subtle shifts that occur in the structure as the temperature changes (inset), potentially pointing to areas of the enzyme that could be targeted with inhibitor drugs to impair its function.
 Source/Credit: Brookhaven National Laboratory

Daniel Keedy, City University of New York

Scientists studying a COVID-19 coronavirus enzyme at temperatures ranging from frosty to human-body warm discovered subtle structural shifts that offer clues about how the enzyme works. The findings, published in IUCrJ, the journal of the International Union of Crystallography, may inspire the design of new drugs to counteract COVID-19—and possibly help head off future coronavirus pandemics.

“No previous study has looked at this important coronavirus enzyme at physiological (or body) temperature,” said Daniel Keedy, a structural biologist at the City University of New York (CUNY), who conducted the study in collaboration with scientists at the U.S. Department of Energy’s Brookhaven National Laboratory.

Most structures to date come from frozen samples—far from the temperatures at which the molecules operate within living cells. “If you are working at physiological temperature, you should get a more realistic picture of what’s happening during an actual infection, because that’s where biology happens,” Keedy said.

In addition, he added, the team used temperature as a tool. “By turning that knob and seeing how the protein reacts, we can learn about its mechanics—how it physically works."

Machine learning meets medicine in the fight against superbugs

Scanning electron micrograph of a human neutrophil ingesting MRSA.
Image: National Institute of Allergy and Infectious Diseases, National Institutes of Health on Flickr, CC BY-NC 2.0

MRSA is an antibiotic-resistant staph infection that can be deadly for those in hospital care or with weakened immune systems. Staphylococcus aureus bacteria live in the nose without necessarily producing any symptoms but can also spread to other parts of the body, leading to persistent infections. Management of MRSA is long-term and laborious, so any steps to optimize treatments and reduce re-infections will benefit patients. This new research can predict how effective different treatments will be by combining patient data with estimates of how MRSA moves between different parts of the body. The study was published in the Journal of the Royal Society Interface.

The researchers compared data from 2000 patients with MRSA after hospital visits. In one group, patients were given standard information about how to treat MRSA and prevent its spread. The second group followed a more intensive ‘decolonization’ protocol to eliminate MRSA through wound disinfection, cleaning the armpits and groin, and using nasal spray. Both groups were tested for MRSA on different body parts at various time points over nine months.

The current state-of-the-art in medical research often involves comparing two groups in this way, to see if an intervention or treatment could be effective. The new study added another element: a mathematical model that looked at the interactions between treatments and body parts. 'The model shows how MRSA moves between body parts,' says senior author Pekka Marttinen, professor at Aalto University and the Finnish Center for Artificial Intelligence FCAI. 'It can help us optimize the combination of treatments and even predict how new treatments would work before they have been tested on patients.'