Biomarker predicts cognitive decline in Alzheimer’s disease

top-down view of a tau PET and MRI from a participant in the Northwestern study.
Warmer colors (red) indicate high Alzheimer's disease tau pathology.
(Image orientation: left is left, right is right).

 A biomarker in the brain predicts future cognitive decline in patients with the language form of Alzheimer’s disease 

Northwestern Medicine scientists discovered the buildup of tau protein in the brain predicts the amount of future cognitive decline over one year in individuals with AD. The study measured used a newer type of positron emission tomography (PET) imaging that shows the location of toxic tau protein in the brain. 

“Our new research shows tau PET imaging biomarkers can predict future decline in individuals with primary progressive aphasia due to AD,” said senior study author Emily Rogalski, associate director of Northwestern’s Mesulam Center for Cognitive Neurology and Alzheimer’s Disease. “These tau-based biomarkers may help predict the pace of progression of the disease and be important for early detection. They may eventually help us treat AD before we see symptoms.”

The higher the level of the bad form of tau in the brain, the worse a person’s cognitive performance, the study showed. The more tau protein a person had in a specific region of their brain, the more likely they were to have worse cognition a year later. The study also found the higher the level of tau, the more atrophy was occurring across the brain. 

The study was published Sept. 8 in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.

Early diagnosis of AD is important because the Food & Drug Administration recently approved Biogen’s Aduhelm (aducanumab) to treat patients in the disease’s mild stages, and other drugs are in the development pipeline. 

“The presence and level of these biomarkers might give us a picture of how aggressive the disease is going to be, providing important markers necessary for precision-medicine interventions,” said lead author Adam Martersteck. He conducted the research as a neuroscience graduate student at Northwestern University Feinberg School of Medicine and now is a postdoctoral fellow at the University of California Berkeley.

The study was among the first to show the amount of tau pathology in the brain predicts subsequent cognitive decline over time.

The individuals in the study had Progressive Primary Aphasia (PPA), which is often caused by an early-onset form of AD. In PPA, the parts of the brain that control language and speech degenerate.

“It’s important to show that AD in primary progressive aphasia is similar to the more common late-onset AD that causes memory problems, so that participants with PPA can be included in clinical trials and offered all the same opportunities,” Martersteck said.

The finding about predictive decline from tau pathology is also applicable to more common forms of AD in which memory loss is the primary symptom. One theory is that toxic forms of AD accumulate and then trigger events resulting in brain cell degeneration. This research supports this theory. 

Participants from around the country were seen locally or flown to Chicago for MRI, tau PET imaging and cognitive testing at Northwestern’s Mesulam Center for Cognitive Neurology and Alzheimer's Disease. The 19 participants all had been diagnosed with PPA. 

As a growing proportion of Americans age, the prevalence of AD is expected to rise. An estimated 50 million people worldwide and 6 million in the U.S. have AD, with those numbers expected to triple in the next 30 years.

In the study, scientists measured toxic tau at baseline and tested participants on their ability to name objects. Participants returned a year later and were tested again on their ability to name objects. The more tau they had in the left anterior temporal lobe on PET imaging, the more likely they were to have worse cognition and a decline in their naming. 

“The next steps for the research are to determine if these measurements are reliable at the individual level to guide prognosis and intervention targets,” Rogalski said. “We know some individuals with PPA progress more rapidly than others, but factors driving fast versus slow progression have been difficult to ascertain. Reliable biomarkers are one key to solving this conundrum.” 

Other Northwestern study authors are Jaiashre Sridhar, Christina Coventry, Sandra Weintraub and Dr. Marsel Mesulam.

Source/Credit: Northwestern University

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Coral cryopreservation for breeding key to survival

 

Fragment of endangered Caribbean elkhorn coral grown from cryopreserved sperm.
(Photo credit: Chris Page)

Flash-frozen sperm collected from corals in Florida and Puerto Rico was used to fertilize coral eggs from hundreds of miles away in Curaçao. The juvenile corals raised from this trans-Caribbean coupling demonstrate the reproductive compatibility of coral colonies that would otherwise be too far apart to produce offspring in the wild and they represent the largest wildlife population ever raised from cryopreserved material.

A paper describing this study, by an international team of researchers, including Mary Hagedorn at the University of Hawaiʻi at Mānoa School of Ocean and Earth Science and Technology (SOEST), was published in the Proceedings of the National Academy of Sciences.

The technique could be used as a conservation tool by introducing genetic variation into endangered corals and potentially accelerating their adaptation to climate change.

“Most corals only attempt sexual reproduction once a year and the eggs and sperm are only viable for a short time period,” said Hagedorn, a research biologist at the Smithsonian Conservation Biology Institute and UH Mānoa’s Hawaiʻi Institute of Marine Biology. She is the lead author of this study, and has developed the technique to cryopreserve coral sperm in her laboratory at UH. “Cryopreservation allows us to breed corals with parentage from hundreds of miles apart.”

Assisted gene flow

“Corals are a vital foundation species for reef ecosystems,” said Iliana Baums, professor of biology at Penn State and one of the leaders of the research team. “Reefs provide habitat for astonishing species diversity, protect shorelines and are economically important for fisheries, but they are suffering in many places due to warming ocean waters. Without intervention, we will continue to lose corals to climate change with potentially disastrous consequences.”

Genetic diversity is the fuel for species adaptation. One of the main sources of genetic diversity is sexual reproduction—new combinations of genes are created when a sperm fertilizes an egg. However, sexual reproduction by Caribbean corals in the wild is now vanishingly rare. Worse yet, because corals are sessile creatures (fixed in one place), they have a limited ability to gain new genetic diversity through gene flow, the evolutionary force that increases genetic diversity when distant populations come together, each bringing with them their own unique versions of genes.

“To increase genetic diversity in corals, we can use ‘assisted gene flow’ by bringing corals together that are physically distant in the wild, but this is logistically incredibly difficult,” said Baums.

Cryopreservation

Most corals reproduce by broadcasting bundles of eggs and sperm into the sea water in a spectacular spawning event timed with the full moon. The researchers collected these bundles from corals in Florida and Puerto Rico, separated the eggs and sperm, and then quickly froze the sperm cells using a liquid nitrogen cryopreservation technique.

“Because these corals only produce eggs and sperm once per year, frozen sperm collected in Florida and Puerto Rico needed to be cryopreserved in advance and stored for over a year until it could be used for a spawning event in Curaçao,” said Baums.

Some of the sperm were kept frozen at the USDA National Animal Germplasm Program’s gene bank for up to 10 years. The frozen sperm was transported to Curaçao where it was thawed and used to fertilize fresh eggs collected locally. The fertilized eggs developed into larvae that were then transported to Mote Marine Laboratory and The Florida Aquarium in Florida, where they were allowed to develop into adults.

Source/Credit: University of Hawaiʻi

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A source of hope for coral reefs

 

A healthy coral reef in the Phoenix Islands Protected Area in 2018.
Photo credit: Michael Fox

Some coral communities are becoming more heat tolerant as ocean temperatures rise, offering hope for corals in a changing climate.

After a series of marine heatwaves hit the Phoenix Islands Protected Area (PIPA) in the central Pacific Ocean, a new study finds the impact of heat stress on the coral communities lessened over time.

While a 2002-2003 heatwave devastated coral communities in PIPA, the reefs recovered and experienced minimal losses during a similar event in 2009-2010. Then, in 2015-2016, a massive heatwave put twice as much heat stress on the corals, yet the die-off was much less severe than expected, according to new research published in Geophysical Research Letters, AGU’s journal for high-impact reports with immediate implications spanning all Earth and space sciences.

The authors of the new study suspect heat-tolerant offspring from the surviving corals are repopulating the reefs, allowing the community to keep pace with warming seas, at least for the time being.

The new study could help coral reef managers identify coral communities most likely to survive in the warming ocean, improving conservation and restoration outcomes.

“It’s easy to lose faith in coral reefs,” said first author Michael Fox, a postdoctoral scientist and coral reef ecologist at the Woods Hole Oceanographic Institution (WHOI). “But in PIPA, which is protected from local stressors, and where reefs have enough time to recover between heatwaves, the coral populations are doing better than expected.”

Underwater heatwaves

Just like on land, heatwaves underwater are becoming more frequent and intense as the world warms, putting stress on ocean ecosystems. High temperatures hit coral reefs especially hard by causing widespread bleaching events, where corals eject the symbiotic algae in their tissues, further weakening the animals. With continued ocean warming, coral reefs face a dim future.

In the new study, researchers monitored coral communities at four islands within PIPA, an area encompassing over 400,000-square-kilometers of coral reef and deep-sea habitat. The Republic of Kiribati established the reserve in 2008, and the United Nations Educational, Scientific and Cultural Organization (UNESCO) designated PIPA as a World Heritage Site in 2010. “The protected area gives us a rare opportunity to study pristine and isolated coral reef ecosystems, a privilege for which we thank the people of Kiribati,” said co-author Anne Cohen, a marine scientist at WHOI.

The team used daily satellite data and temperature loggers to examine how each heatwave impacted the corals. They ruled out 11 environmental factors that might explain the higher-than-expected survival following the 2009-2010 and 2015-2016 heatwaves, such as greater cloud cover or more gradual warming.

After the 2002-2003 heatwave, the surveyed sites lost more than three-quarters of their coral cover. The reef was beginning to recover when the 2009-2010 heatwave hit, sparking fears of widespread bleaching, but two years later, coral cover had increased by more than 5%. Following the “Super El Niño” in 2015-2016, which raised ocean temperatures by 3 degrees Celsius (5.4 degrees Fahrenheit), the loss of coral cover was 40%— about half of the 2002 losses, despite causing twice the level of thermal stress.

A source of hope for coral reefs

Many of the reef-building species survived the heatwaves. “We’re seeing areas that were devoid of corals after 2002-2003 that are now flourishing with most of the original species,” Fox said.

At other reefs worldwide, sometimes only a handful of especially hardy or fast-growing species recover after a bleaching event. Coral larvae can float long distances on ocean currents, but due to PIPA’s isolation, the researchers hypothesize that local heat-tolerant individuals are repopulating the reefs.

Now that the researchers have shown that some coral communities have the potential to keep up with ocean warming, their next step is to figure out how they are doing it.

The findings are “important for giving us hope for the future of coral reefs, and also for helping to maintain support for protecting reefs, including efforts to reduce local threats, like pollution, sedimentation and overfishing that undermine the reefs’ ability to adapt,” said Lizzie McLeod, the Global Reef Systems Lead at the Nature Conservancy, who was not involved in the study.

She recommends reef conservationists prioritize the conservation of heat-tolerant reefs, because they can act as climate refuges that repopulate other sites decimated by heatwaves.

The study’s authors caution that even these remarkable corals have their limits and reversing climate change remains paramount. As heatwaves become more frequent or intense, even heat-tolerant communities could die out.

“We’re in a race against time, so anything that increases the chances that corals are going to make it is really good news,” said Nancy Knowlton, the Sant Chair in Marine Science Emerita at the Smithsonian National Museum of Natural History, who was not part of the study. “The corals are doing their part,” she said. “We have to do ours.”

Source/Credit: Woods Hole Oceanographic Institution

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Newly developed software unveils relationships between RNA modifications and cancers

Researchers from CSI Singapore have developed a software called ModTect that identifies relationships between RNA modifications and the development of diseases as well as survival outcomes

 In a research breakthrough, a team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore has developed a software that can help reveal the relationships between RNA modifications and the development of diseases and disorders.

Led by Professor Daniel Tenen and Dr Henry Yang, the scientists devised ModTect – a new computational software that can identify RNA modifications using pre-existing sequencing data from clinical cohort studies. With ModTect, the team carried out their own novel pan-cancer study covering 33 different cancer types. They found associations between these RNA modifications and the different survival outcomes of cancer patients.

“This work is one of few studies demonstrating the association of mRNA modification with cancer development. We show that the epitranscriptome was dysregulated in patients across multiple cancer types and was additionally associated with cancer progression and survival outcomes,” explained Dr Henry Yang, Research Associate Professor from CSI Singapore.

"In the past decade, the ability to sequence the Human Genome has transformed the study of normal processes and diseases such as cancer. We anticipate that studies like this one, eventually leading to complete sequencing of RNA and detecting modifications directly in RNA, will also have a major impact on the characterization of disease and lead to novel therapeutic approaches," commented Prof Tenen, Senior Principal Investigator from CSI Singapore.

What are RNA modifications?

While most people are familiar with DNA, RNA plays just as much of a vital role in the human body’s cellular functions. Unlike DNA, which has the double-helix structure that most people are familiar with, RNA is a family of single-stranded molecules that perform various essential biological roles.

For example, messenger RNA (mRNA) conveys genetic information that directs the production of different proteins. Imagine DNA as an expansive library filled with books that carry instructions on how to make different proteins. Each letter in the sequences of words that make up the books’ contents are called nucleotides, which are small molecules that are used to store genetic information. To make sure these instructions are followed, mRNA makes copies of the books and carries them from a cell’s nucleus, where DNA is stored, to the ribosomes. These ribosomes are the “factories” where proteins are synthesized. Without RNA, the valuable genetic instructions stored in our cells would never be used.

Additional types of RNA perform other important functions. Some help catalyze biochemical reactions, just like enzymes, while others regulate gene expression.

Small chemical modifications to RNA can sometimes occur and alter the function and stability of the molecules. The study of these modifications and their effects is called ‘epitranscriptomics’. Research in the past has suggested a link between the development of diseases like Alzheimer’s disease and cancer with certain RNA modifications. However, despite multiple attempts to study these associations in deeper detail, the study of epitranscriptomes has proven to be difficult until this breakthrough by scientists from CSI Singapore.

In large patient cohorts, collecting and processing patient samples is challenging. Detecting RNA modifications often involves technically complex processes, such as treating the samples with chemicals that are difficult to access. These techniques often also require the use of large quantities of sample that are hard to obtain for rarer conditions. Because of this, scientists have been limited in their capacity to establish relationships between specific RNA modifications and various human diseases.

Software makes epitranscriptomics easier

The software that the CSI Singapore team created uses RNA sequences available from other large clinical cohort studies. To detect modifications in these RNA sequences, ModTect looks for mismatch signals and deletion signals. Mismatch signals arise when the experimental enzymes scientists use to turn RNA back into DNA incorporates random nucleotides during sequencing. Deletion signals, on the other hand, are when the enzymes sometimes skip a portion of the sequence. Together, these signals are referred to as misincorporation signals.

Unlike other models, ModTect does not require a database of misincorporation signal profiles corresponding to different types of RNA modifications to identify or classify them. ModTect can even identify new signal profiles that drastically differ from what has been previously recorded.

By applying the software to around 11,000 cancer patient RNA-sequencing datasets, the CSI Singapore team was able to embark on a novel study that investigated the associations between RNA modifications and clinical outcomes in patients. ModTect was able to utilize these large datasets and process them with robust statistical filtering. It unveiled that some types of epitranscriptome were associated with cancer progression and survival outcomes in patients. This finding highlighted the potential use of RNA modifications as biomarkers – molecules that can be used to test for diseases.

Unravelling the mystery of sequence differences that escape detection

As explored before, the transmission of genetic information from DNA in a cell’s nucleus to RNA molecules that carry it to a cell’s ribosomes is a critical process. However, this transmission process is not perfect and leads to differences in RNA-DNA sequences. The sites of these mismatches have been widely documented. However, it is unclear whether these observations are caused by modifications in mRNA and why these sites have escaped detection by Sanger sequencing (one of the most popular methods of DNA sequencing).

The group at CSI Singapore uncovered a potential explanation as to why these RNA modification signals have eluded detection over the years. They explained how some epitranscriptomes impede the use of standard reverse transcriptase (RT), the enzyme that is used to convert RNA into DNA. This enzyme is used by scientists in genome sequencing and its use is one of the most critical steps for experimental success. Hence, RNAs that had these impeding modifications were under-represented in Sanger sequencing techniques.

To combat this, the team used newly developed RT enzymes that have been known for their ability to bypass the effects of these modification sites. This allowed them to observe epitranscriptomes that were originally undetectable with Sanger sequencing.

The discipline of epitranscriptomics is still an emerging and rapidly developing field with around 170 RNA modifications being detected so far. By harnessing ModTect, Prof Tenen and his team were able to provide novel insights into the relationships between human diseases – like cancer – and such RNA modifications. The software will be publicly available on Github for other scientists to use.

The team is hopeful that their contribution will help further research that establishes any potential causal or mechanistic relationships between RNA modifications and tumor formation.

Source/Credit: National University of Singapore

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Nature’s archive reveals Atlantic tempests through time

 

The North Atlantic network of sites that preserve records of hurricanes stretches along the coast from Canada to Central America, but with significant gaps. A new study led by scientists at Rice University shows filling those gaps with data from the mid-Atlantic states will help improve the historical record of storms over the past several thousand years and could aid in predictions of future storms in a time of climate change. Illustration by Elizabeth Wallace

Atlantic hurricanes don’t just come and go. They leave clues to their passage through the landscape that last centuries or more. Rice University scientists are using these natural archives to find signs of storms hundreds of years before satellites allowed us to watch them in real time.

Elizabeth Wallace.
(Credit: Abby Llona)

Postdoctoral fellow Elizabeth Wallace, a paleotempestologist who joined the lab of Rice climate scientist Sylvia Dee this year, is building upon techniques that reveal the frequency of hurricanes in the Atlantic basin over millennia.

The North Atlantic network of sites that preserve records of hurricanes stretches along the coast from Canada to Central America, but with significant gaps. A new study led by scientists at Rice University shows filling those gaps with data from the mid-Atlantic states will help improve the historical record of storms over the past several thousand years and could aid in predictions of future storms in a time of climate change. Illustration by Elizabeth Wallace

Paleoclimate hurricane data (or ‘proxy’ data) is found in archives like tree rings that retain signs of short-term flooding, sediments in blue holes (marine caverns) and coastal ponds that preserve evidence of sand washed inland by storm surges. These natural archives give researchers a rough idea of when and where hurricanes have come ashore.

In a new paper in Geophysical Research Letters, Wallace, Dee and co-author Kerry Emanuel, a climate scientist at the Massachusetts Institute of Technology, take hundreds of thousands of “synthetic” storms spun up from global climate model simulations of the past 1,000 years and examine whether or not they are captured by the vast network of Atlantic paleohurricane proxies.

Reconstructing the past will help scientists understand the ebb and flow of Atlantic hurricanes over time. Previous studies by Wallace and others have demonstrated that a single site capturing past storms cannot be used to reconstruct hurricane climate changes; however, a network of proxies might help refine models of how these storms are likely to be affected by climate change going forward.

Sylvia Dee.
(Credit: Rice University)

“These paleo hurricane proxies allow us to reconstruct storms into the past, and we’re using them to figure out how basin-wide storm activity has changed,” said Wallace, a Virginia native who earned her doctorate at MIT and the Woods Hole Oceanographic Institution last year and connected with Dee when the professor spoke there in 2017.

“If I have a sediment core from Florida, it’s only capturing storms that hit Florida,” she said. “I wanted to see if we can use the full collection of records collected from the Bahamas, the East Coast and the Gulf of Mexico over the past few decades to accurately reconstruct basin-wide storm activity over the last few centuries.”

The synthetic storms they built helped illustrate what Wallace already knew: There’s a bias toward the Caribbean and Gulf of Mexico, and a need for more proxies along the east coasts of North and Central America. The Rice team’s quest going forward will be to refine their climate simulations and add more sites to the networks to better reconstruct past hurricane activity.

“In particular, there aren’t really any sites from the Southeast U.S., places like the Carolinas,” she said. “One of the goals of this work is to highlight where scientists should go to core next.”

Wallace has first-hand experience drilling cores. “During a storm event, you get high winds and waves that take the sand from the beach and essentially just throw it back into a coastal pond,” she said. “Only during storm events do these sand layers get deposited in the pond, and in the sediment cores you can see them interspersed with the fine mud that’s typically there. We can date these sand layers and know when a hurricane struck the site.”

She noted there has not yet been an “intensive” effort to compare sediment and tree ring records. “The tree record is still an uncertain proxy,” Wallace said. “We’re looking for tree ring records with rainfall signatures that correspond to storms going over the past 200 or 300 years that match the sediment records for that same interval.”

Dee said the work is fundamentally different from the paleoclimate models she most often studies. “Here we’re taking climate models and generating hundreds of pseudo-tropical storms,” she said. “We’re ‘playing Gaia’ by making a plausible version of reality and combining it with our knowledge of available proxy sites.

“This tells us how many records from how many places we realistically need to capture a climate signal,” Dee said. “It’s really expensive to go out and drill cores, and this helps give us a way to prioritize where to drill.

“This research is crucial as we accelerate into a climate mean state with ever-warmer Atlantic Ocean temperatures,” she said. “Understanding how these storms have evolved over time provides a baseline against which to evaluate tropical cyclones with and without human impacts on the climate system.”

A Pan Postdoctoral Research Fellowship and Rice Academy Fellowship to Wallace and a Gulf Research Program grant to Dee supported the study. Dee is an assistant professor of Earth, environmental and planetary sciences. Emanuel is the Cecil & Ida Green Professor of Atmospheric Science and co-director of the Lorenz Center at MIT.

Abstract released at: AGU

Source/Credit: Rice University

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Scientists observe cross-immunity against the coronavirus

 

Researchers from Charité – Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH) and the Max Planck Institute for Molecular Genetics (MPIMG) have shown that certain immune cells, which are found in people previously exposed to common cold coronaviruses, enhance the body’s immune response to SARS-CoV-2, both during natural infection and following vaccination. The researchers, whose work has been published in Science, also report that this ‘cross-reactive immunity’ decreases with age. This phenomenon may help to explain why older people are more susceptible to severe disease and why their vaccine-induced immunity is often weaker than that of young people.

Last year, researchers from Charité and the MPIMG made a surprising discovery. They were the first to report that individuals with no prior exposure to SARS-CoV-2 nonetheless had immunological memory cells capable of recognizing this novel virus.

The researchers concluded that these ‘T helper cells’ must have been generated to deal with mostly harmless common cold coronaviruses and that, thanks to the structural similarities between coronaviruses (in particular the characteristic spike protein found on their outer surface), these T helper cells will also attack the novel coronavirus. This ‘cross reactivity’ hypothesis has since been confirmed by a range of studies.

Protective action by cross-reacting T helper cells

Still unclear, however – and the object of intense debate – is the question of whether these immune cells affect the course of subsequent SARS-CoV-2 infections. “Our assumption at the time was that cross-reactive T helper cells have a protective effect, and that prior exposure to endemic (i.e. long-established and widely circulating) coronaviruses therefore reduces the severity of COVID-19 symptoms,” says the study’s (and the previous study’s) first author, Dr. Lucie Loyal, a researcher based at both the Si-M (‘Der Simulierte Mensch – literally ‘The Simulated Human’, a joint research space of Charité and Technische Universität Berlin) and the BIH Center for Regenerative Therapies (BCRT).

She adds: “However, the opposite could have been true. With some viruses, a second infection involving a similar strain can lead to a misdirected immune response and a negative impact on clinical course.” In the current study, the Berlin-based research team presents evidence to support their previous assumptions regarding the existence of a protective effect. According to their data, cross-reactive immunity could be one of several reasons for the variability in disease severity seen with COVID-19 but might also explain differences in vaccine efficacy seen in different age groups.

A universal memory for coronaviruses

For the current study, the researchers recruited individuals with no prior exposure to SARS-CoV-2, testing them at regular intervals to establish whether they had contracted the infection. Out of a total of nearly 800 participants who were recruited from mid-2020 onwards, 17 persons tested positive. The researchers studied the affected individuals’ immune systems in detail. Their analyses showed that the immune response against SARS-CoV-2 also included the mobilization of T helper cells which had been generated in response to endemic common cold viruses.

The researchers also showed that the quality of the immune response against SARS-CoV-2 was linked to the quantity of cross-reactive cells which had been present in the body prior to infection. These cells were particularly effective at recognizing a certain area of the spike protein. In both the endemic viruses and the new coronavirus, this site was characterized by sequence similarities which were particularly well ‘preserved’.

“During infections with the more harmless coronaviruses, the immune system builds up a kind of protective ‘universal coronavirus’ memory,” explains the study’s corresponding author, Dr. Claudia Giesecke-Thiel, Head of the Flow Cytometry Service Group at the MPIMG. “Once exposed to SARS-CoV-2, these memory cells are reactivated and kick-start the response against the new pathogen. This could help accelerate the initial immune response to SARS-CoV-2 and limit viral propagation during the early stages of the infection and is therefore likely to have a positive effect on the course of the disease.”

Taking a more cautionary tone, the researcher adds: “This does not mean that prior exposure to common cold viruses will definitely protect an individual against SARS-CoV-2, nor does it change the course of the pandemic as of now because these underlying mechanisms have been operating all along. It in no way diminishes the importance of getting vaccinated. Our study provides one of several explanations for an observation made since the beginning of the pandemic, namely that the symptoms of SARS-CoV-2 infection can vary greatly between individuals.”

Immune-boosting effect also for vaccination

The researchers’ findings furthermore confirmed that the immunity-enhancing effects of cross-reactive T cells also occur following vaccination with the BioNTech COVID-19 vaccine. Just like natural infection, the vaccine prompts the body to produce the SARS-CoV-2 spike protein (including the well-preserved section of it) and present it to the immune system.

An analysis of the immune responses of 31 healthy individuals before and after vaccination revealed that, while the activation of normal T helper cells took place gradually over the course of two weeks, the activation of cross-reactive T helper cells was extremely rapid, taking place within one week of vaccination. Naturally, this also had a positive effect on the generation of antibodies. Even after the first dose of the vaccine, the body was able to produce antibodies against the preserved section of the spike protein at a rate normally only seen after booster vaccinations.

“Even following vaccination, the body is able to utilize at least some of its immunological memory – provided it has had previous exposure to endemic coronaviruses,” says co-corresponding author Prof. Dr. Andreas Thiel, a Charité researcher based at both the Si-M and the BCRT. He adds: “This might explain the surprisingly rapid and extremely strong protective effect we see after the initial dose of the COVID-19 vaccine, at least in younger individuals.”

Decline with age

In a second part of the study, the researchers analyzed T helper cells in approximately 570 healthy individuals. They were able to show that cross-reactive immunity declines in older adults. In fact, both the number of cross-reactive T cells and the strength of their binding interactions was shown to be lower in older participants than in younger participants. According to the authors, this decline in cross-reactive immunity is caused by normal, age-related changes. “Infection with an endemic coronavirus represents a benefit in younger people, helping them fight off SARS-CoV-2 or develop immunity following vaccination. Sadly, this benefit is less pronounced in older adults,” says Prof. Thiel. He adds: “It is likely that a third (or booster) dose would be able to compensate for this weaker immune response, ensuring that members of this high-risk group have adequate immunity.”

Source/Credit: Max-Planck-Gesellschaft

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Koala killer being passed to joeys from mum

 

A deadly koala virus that can cause immune depletion and cancer, known as koala retrovirus, is being transferred to joeys from their mothers, according to University of Queensland scientists.

Associate Professor Keith Chappell, from UQ’s School of Chemistry and Molecular Biosciences, said the virus predisposes koala to chlamydia and other disease, and was having a large impact on wild koala populations across Queensland and New South Wales.

“Koala retrovirus – also known as KoRV – and associated diseases are another threat facing koalas, along with climate change and habitat loss.

“The virus causes immune depletion, likely making it much harder for koalas to cope with these other, already-detrimental environmental stressors.

“All northern koalas share a single highly conserved version of KoRV that is integrated into the koala genome, however until now, we weren’t certain how other disease-causing variants are spread.

“By sequencing variations of the virus DNA in 109 captive koalas, we finally revealed how the virus spreads – from mother to joey.

“It seems that transmission between mother and joey likely occurs due to close proximity, via a joey’s exposure to a mother’s potentially infectious fluids, like their milk.

“Mothers were sharing their virus variants three times more than fathers, suggesting this is the dominant pathway of spread for the virus.

“And, unlike other diseases affecting koalas like chlamydia, there’s no evidence of sexual transmission.”

The 109 koalas were housed in two sites in south-east Queensland, helping identify a total of 421 unique koala retrovirus sequences.

Collaborator and lead author, PhD candidate Briony Joyce said the research may lead to a re-think in how conservation plans are executed.

“This work will be highly informative for koala conservation, as it suggests that captive breeding programs focused on mothers that have a low amount of retrovirus variants, could result in healthier animals for release,” Ms Joyce said.

“Also, we propose that antiretroviral treatment – if shown to be safe in koala and effective against KoRV – could be used specifically in mothers during breeding seasons to prevent transmission.

“This work helps pave the way for evidence-based conservation, increasing koala resilience to help them cope with a changing and challenging environment.

“We must do everything we can to ensure the survival of this culturally important species.”

Source/Credit: University of Queensland

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Scientists awarded $6 million to plan brain-inspired computer that runs on probability

 

Conventional computers can look at the optical illusion on the left and normally only see a vase or two faces. Sandia National Laboratories is laying the groundwork for a computer that, like our brains, can glance many times and see both.
(Image by Laura Hatfield)

If you’ve ever asked a car mechanic how long a part will last until it breaks, odds are they shrugged their shoulders. They know how long parts last on average, and they can see when one is close to breaking. But knowing how many miles are left is extremely difficult, even using a supercomputer, because the exact moment a belt snaps or a battery dies is to some extent random.

Scientists at Sandia National Laboratories are creating a concept for a new kind of computer for solving complex probability problems like this. They propose that a “probabilistic computer” could not only create smarter maintenance schedules but also help scientists analyze subatomic shrapnel inside particle colliders, simulate nuclear physics experiments and process images faster and more accurately than is possible with conventional computers.

As part of a new microelectronics codesign research program, the Department of Energy’s Office of Science recently awarded the project $6 million over the next three years to develop the idea. Sandia will be working with Oak Ridge National Laboratory, New York University, the University of Texas at Austin and Temple University in Philadelphia.

A codesign microelectronics project involves multidisciplinary collaboration that takes into account the interdependencies among materials, physics, architectures and software. Researchers also will look at ways to incorporate machine learning methods.

The concept for a probabilistic computer runs opposite to how computers are normally built and programmed, Sandia scientist Brad Aimone said. Instead of making one that is perfectly predictable, Sandia wants one with built-in randomness that computes information differently every time.

“To a large degree, and at a great energy cost, we engineer computers to eliminate randomness. What we want to do in this project is to leverage randomness. Instead of fighting it, we want to use it.” said Aimone, who leads the project he and his team call COINFLIPS (short for CO-designed Improved Neural Foundations Leveraging Inherent Physics Stochasticity).

“What if, when I’m communicating with you, I flip a coin?” Aimone said. “If heads, you act on my message; if tails, you ignore it. We want to discover how you can use randomness like this to solve problems where probability is important.”

Concept modeled after unpredictable connections between brain cells

Aimone is an expert in technology that mimics the brain, including machine learning. He got his idea for a probabilistic computer from how brain cells talk to each other.

Inside your brain there are billions of cells called neurons that pass information across trillions of cell-to-cell connections called synapses, Aimone said. Whenever one neuron has a message, it sends a signal to lots of other neurons at the same time. But, only a random fraction on the receiving side carry on the message to more cells. Neuroscientists don’t agree why, but Aimone thinks it could be a reason why brains do some tasks better than computers, such as learning and adapting, or why they use less energy.

To imitate this brain behavior, scientists need to figure out how to generate trillions of random numbers at a time. That much randomness is too complex and takes too much power for computers, said Sandia’s Shashank Misra, who leads the COINFLIPS hardware team.

“We will need to get creative with new approaches, including new materials, atomic-scale control and machine learning-driven designs to generate the sheer volume of randomness needed and to make it useful for computation,” Misra said.

COINFLIPS will also identify tasks that benefit from randomness.

Probabilistic computers are part of a larger effort at Sandia to explore what computers in the future might look like. Researchers around the world have recognized that the rate at which computers are improving is slowing down, Aimone said. To break past the apparent limits of computers, scientists are looking at new, original ways of designing them.

Conrad James, the Sandia manager of the COINFLIPS team said, “Several of us at Sandia have been exploring brain-inspired computing and new design approaches for years. Encouraging more communication between mathematicians, algorithm developers and device physicists led to the formation of this team and research proposal.”

Sandia adds to other efforts to rethink computers

COINFLIPS was one of only 10 proposals selected nationwide to receive funding to design new, energy-efficient microelectronics. Separately, Sandia is lending its expertise in nanotechnology and computer modeling to another selected project led by Lawrence Berkeley National Laboratory.

These researchers will be redesigning nanosized sensors used in communications, imaging, remote sensing and surveillance technologies to be more compact, efficient and integrated into a computer processor.

“The photon absorption, the transduction to an electrical event and the measurement will all be part of one quantum system,” said Sandia physicist François Léonard, who is a member of the collaboration.

They will also attempt to enhance these sensors with advanced materials, such as carbon nanotubes, hollow carbon straws that are 100,000 times thinner than a strand of hair.

A third Sandia team consisting of researchers Alec Talin and Matt Marinella will be supporting another selected project that Oak Ridge National Laboratory is leading. Their research could help improve the energy efficiency of processing of information from sensors in autonomous vehicles, handheld devices and satellites.

Most of the time and energy that a computer chip needs are spent shuttling information between where it is stored and where it is processed, Talin said. But it might be possible to slash the power computers use by combining these two elements using brain-inspired devices developed at Sandia.

“The key idea is that in the brain, the memory and the logic (processing) are co-located in the same basic element, the neuron,” Talin said.

Fast, energy-efficient systems could potentially process complex tasks, such as recognizing images and translating languages in real time, on portable devices like smartphones without needing the computing power of the cloud, Talin said.

Source/Credit: Sandia National Laboratories

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Messengers from gut to brain

 

Thomas Korn is a professor for Experimental Neuroimmunology at TUM.
Image: Magdalena Jooss / TUM

Scientists have long been aware of a link between the gut microbiome and the central nervous system (CNS). Until now, however, the immune cells that move from the gut into the CNS and thus the brain had not been identified. A team of researchers in Munich has now succeeded in using violet light to make these migrating T cells visible for the first time. This opens up avenues for developing new treatment options for diseases such as multiple sclerosis (MS) and cancer.

The link between the gut microbiome and the CNS, known as the gut/brain axis (GBA), is believed to be responsible for many things: a person’s body weight, autoimmune diseases, depression, mental illnesses and Alzheimer’s disease. Researchers at the Technical University of Munich (TUM) and LMU University Hospital Munich have now succeeded in making this connection visible for the first time. This is cause for hope – for those suffering from MS, for example. It may offer ways to adapt treatments, and T cells could perhaps be modified before reaching the brain.

The immune system is affected by environmental factors – also in the central nervous system in case of MS patients. This autoimmune disease is subject to repeated flare-ups, experienced by patients as the improvement or worsening of their condition. T cells collect information and, in MS patients, carry it to the central nervous system (in the brain or spinal cord) where an immune response is triggered. Until now, however, it was long uncertain how and from where the T cells were traveling to the CNS.

The team working with Thomas Korn, a professor of experimental neuroimmunology at TUM, has developed a method for marking immune cells in mice using photoconvertible proteins. The T cells can then be made visible with violet light. The researchers successfully tested this method with the mouse model in lymph nodes, both in the gut and the skin. They were able to track the movement of the T cells from those locations into the central nervous systems.

T cells from the skin migrated into the gray and white matter of the CNS, while almost all T cells from the gut ended up in the white matter. For T cells in the brain, it was still possible to determine their origin. “What makes these insights so important is that they demonstrate for the first time that environmental influences impact the T cells in lymph nodes in the gut and the skin, which then carry this information into the distant organs,” says Prof. Thomas Korn. “The characteristics of the T cells are sufficiently stable for us to determine whether immune responses are influenced by skin or gut T cells,” adds LMU researcher Dr. Eduardo Beltrán, who performed the bioinformatic analyses in this study.

An important insight for MS patients: “If gut or skin cells were known to be the cause, the T cells could be treated at the source of the disease and predictions could be made on the progress of the chronic inflammation and autoimmune condition,” says first author Michael Hiltensperger. The results of the study could also mean a breakthrough for research on other autoimmune diseases or cancer.

Paper released in publication Nature Immunology

Source/Credit: Technical University of Munich

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Spread of Delta SARS-CoV-2 variant driven by combination of immune escape and increased infectivity

 

Visualization of the Covid-19 virus 
Credit: Fusion Medical Animation via Unsplash

The Delta variant of SARS-CoV-2, which has become the dominant variant in countries including India and the UK, has most likely spread through its ability to evade neutralizing antibodies and its increased infectivity, say an international team of researchers.

The findings are reported today in Nature.

As SARS-CoV-2 replicates, errors in its genetic makeup cause it to mutate. Some mutations make the virus more transmissible or more infectious, some help it evade the immune response, potentially making vaccines less effective, while others have little effect. One such variant, labelled the B.1.617.2 Delta variant, was first observed in India in late 2020. It has since spread around the globe – in the UK, it is responsible nearly all new cases of coronavirus infection.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge, one of the study’s senior authors, said: “By combining lab-based experiments and epidemiology of vaccine breakthrough infections, we’ve shown that the Delta variant is better at replicating and spreading than other commonly-observed variants. There’s also evidence that neutralizing antibodies produced as a result of previous infection or vaccination are less effective at stopping this variant.

“These factors are likely to have contributed to the devastating epidemic wave in India during the first quarter of 2021, where as many as half of the cases were individuals who had previously been infected with an earlier variant.”

To examine how well the Delta variant was able to evade the immune response, the team extracted serum from blood samples collected as part of the COVID-19 cohort of the NIHR BioResource. The samples came from individuals who had previously been infected with the coronavirus or who had been vaccinated with either the Oxford/AstraZeneca or Pfizer vaccines. Serum contains antibodies raised in response to infection or vaccination. The team found that the Delta variant virus was 5.7-fold less sensitive to the sera from previously-infected individuals, and as much as eight-fold less sensitive to vaccine sera, compared with the Alpha variant - in other words, it takes eight times as many antibodies from a vaccinated individual to block the virus.

Consistent with this, an analysis of over 100 infected healthcare workers at three Delhi hospitals, nearly all of whom had been vaccinated against SARS-CoV-2, found the Delta variant to be transmitted between vaccinated staff to a greater extent than the alpha variant.

SARS-CoV-2 is a coronavirus, so named because spike proteins on its surface give it the appearance of a crown (‘corona’). The spike proteins bind to ACE2, a protein receptor found on the surface of cells in our body. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. The virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

Using 3D airway organoids – ‘mini-organs’ grown from cells from the airway, which mimic its behaviour – the team studied what happens when the virus reaches the respiratory tract. Working under secure conditions, the team used both a live virus and a ‘pseudo typed virus’ – a synthetic form of the virus that mimicked key mutations on the Delta variant – and used this to infect the organoids. They found that the Delta variant was more efficient at breaking into the cells compared with other variants as it carried a larger number of cleaved spikes on its surface. Once inside the cells, the variant was also better able to replicate. Both of these factors give the virus a selection advantage compared to other variants, helping explain why it has become so dominant.

Dr Partha Rakshit from the National Centre for Disease Control, Delhi, India, joint senior author, said: “The Delta variant has spread widely to become the dominant variants worldwide because it is faster to spread and better at infecting individuals than most other variants we’ve seen. It is also better at getting around existing immunity – either through previous exposure to the virus or to vaccination – though the risk of moderate to severe disease is reduced in such cases.”

Professor Anurag Agrawal from the CSIR Institute of Genomics and Integrative Biology, Delhi, India , joint senior author, added: “Infection of vaccinated healthcare workers with the Delta variant is a significant problem. Although they themselves may only experience mild COVID, they risk infecting individuals who have suboptimal immune responses to vaccination due to underlying health conditions – and these patients could then be at risk of severe disease. We urgently need to consider ways of boosting vaccine responses against variants among healthcare workers. It also suggests infection control measures will need to continue in the post-vaccine era.”

The research was largely supported in India by the Ministry of Health and Family Welfare, the Council of Scientific and Industrial Research, and the Department of Biotechnology; and in the UK by Wellcome, the Medical Research Council and the National Institute of Health Research.

Credit/Source: University of Cambridge

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