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Showing posts with label Science News. Show all posts
Showing posts with label Science News. Show all posts

Friday, September 17, 2021

Study links severe COVID-19 to increase in self-attacking antibodies

 

Hospitalized COVID-19 patients are substantially more likely to harbor autoantibodies — antibodies directed at their own tissues or at substances their immune cells secrete into the blood — than people without COVID-19, according to a new study.

Autoantibodies can be early harbingers of full-blown autoimmune disease.

“If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover,” said PJ Utz, MD, professor of immunology and rheumatology at Stanford Medicine.

Utz shares senior authorship of the study, which was published Sept. 14 in Nature Communications, with Chrysanthi Skevaki, MD, PhD, instructor of virology and laboratory medicine at Philipps University Marburg in Germany, and Eline Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania. The study’s lead authors are Sarah Chang, a former technician in Utz’s lab; recent Stanford undergraduate Allen Feng, now a technician in the Utz lab; and senior research investigator Wenshao Meng, PhD, and postdoctoral scholar Sokratis Apostolidis, MD, both at the University of Pennsylvania.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found. This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them, Utz said.

If any of these antibodies block a cytokine’s ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.

Cancer Cells’ Unexpected Genetic Tricks for Evading the Immune System

 

Defective versions of genes known as tumor suppressors can help cancer cells (melanoma shown) evade the immune system. Until now, scientists believed these genes’ main role was encouraging tumor growth. Credit: Julio C. Valencia, NCI Center for Cancer Research/CC BY-NC 2.0

In a surprising new finding in mice, researchers have discovered that many genes linked to human cancer block the body’s natural defense against malignancies.

Hundreds of cancer-linked genes play a different role in causing disease than scientists had expected.

So-called tumor suppressor genes have long been known to block cell growth, preventing cancerous cells from spreading. Mutations in these genes, scientists believed, thus allow tumors to flourish unchecked.

Now, Howard Hughes Medical Institute Investigator Stephen Elledge’s team has uncovered a surprising new action for many of these defective genes. More than 100 mutated tumor suppressor genes can prevent the immune system from spotting and destroying malignant cells in mice, Elledge, a geneticist at Brigham and Women’s Hospital, reports September 16, 2021, in the journal Science. “The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’” he says.

Conventional wisdom had suggested that, for the vast major of tumor suppressor genes, mutations allow cells to run amok, growing and dividing uncontrollably. But that explanation had some gaps. For example, mutated versions of many of these genes don’t actually cause rampant growth when put into cells in a petri dish. And scientists couldn’t explain why the immune system, which is normally highly proficient at attacking abnormal cells, doesn’t do more to nip new tumors in the bud.

“The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’”
Steve Elledge, HHMI Investigator at Brigham and Women’s Hospital

Elledge’s new paper offers some answers. His team probed the effects of 7,500 genes, including genes known to be involved in human cancer. A third or more of those cancer-linked genes, when mutated, trigger mechanisms that prevent the immune system from rooting out tumors, often in a tissue-specific manner.

“These results reveal a fascinating and unexpected relationship between tumor suppressor genes and the immune system,” says HHMI Investigator Bert Vogelstein, a cancer geneticist at the Johns Hopkins University who was not involved in the research.

Wednesday, September 15, 2021

Have we detected dark energy?

 

A new study, led by researchers at the University of Cambridge and reported in the journal Physical Review D, suggests that some unexplained results from the XENON1T experiment in Italy may have been caused by dark energy, and not the dark matter the experiment was designed to detect.

They constructed a physical model to help explain the results, which may have originated from dark energy particles produced in a region of the Sun with strong magnetic fields, although future experiments will be required to confirm this explanation. The researchers say their study could be an important step toward the direct detection of dark energy.

Everything our eyes can see in the skies and in our everyday world – from tiny moons to massive galaxies, from ants to blue whales – makes up less than five percent of the universe. The rest is dark. About 27% is dark matter – the invisible force holding galaxies and the cosmic web together – while 68% is dark energy, which causes the universe to expand at an accelerated rate.

“Despite both components being invisible, we know a lot more about dark matter, since its existence was suggested as early as the 1920s, while dark energy wasn’t discovered until 1998,” said Dr Sunny Vagnozzi from Cambridge’s Kavli Institute for Cosmology, the paper’s first author. “Large-scale experiments like XENON1T have been designed to directly detect dark matter, by searching for signs of dark matter ‘hitting’ ordinary matter, but dark energy is even more elusive.”

To detect dark energy, scientists generally look for gravitational interactions: the way gravity pulls objects around. And on the largest scales, the gravitational effect of dark energy is repulsive, pulling things away from each other and making the Universe’s expansion accelerate.

About a year ago, the XENON1T experiment reported an unexpected signal, or excess, over the expected background. “These sorts of excesses are often flukes, but once in a while they can also lead to fundamental discoveries,” said Dr Luca Visinelli, a researcher at Frascati National Laboratories in Italy, a co-author of the study. “We explored a model in which this signal could be attributable to dark energy, rather than the dark matter the experiment was originally devised to detect.”

At the time, the most popular explanation for the excess were axions – hypothetical, extremely light particles – produced in the Sun. However, this explanation does not stand up to observations, since the amount of axions that would be required to explain the XENON1T signal would drastically alter the evolution of stars much heavier than the Sun, in conflict with what we observe.

We are far from fully understanding what dark energy is, but most physical models for dark energy would lead to the existence of a so-called fifth force. There are four fundamental forces in the universe, and anything that can’t be explained by one of these forces is sometimes referred to as the result of an unknown fifth force.

However, we know that Einstein’s theory of gravity works extremely well in the local universe. Therefore, any fifth force associated to dark energy is unwanted and must be ‘hidden’ or ‘screened’ when it comes to small scales, and can only operate on the largest scales where Einstein's theory of gravity fails to explain the acceleration of the Universe. To hide the fifth force, many models for dark energy are equipped with so-called screening mechanisms, which dynamically hide the fifth force.

Vagnozzi and his co-authors constructed a physical model, which used a type of screening mechanism known as chameleon screening, to show that dark energy particles produced in the Sun’s strong magnetic fields could explain the XENON1T excess.

“Our chameleon screening shuts down the production of dark energy particles in very dense objects, avoiding the problems faced by solar axions,” said Vagnozzi. “It also allows us to decouple what happens in the local very dense Universe from what happens on the largest scales, where the density is extremely low.”

The researchers used their model to show what would happen in the detector if the dark energy was produced in a particular region of the Sun, called the tachocline, where the magnetic fields are particularly strong.

“It was really surprising that this excess could in principle have been caused by dark energy rather than dark matter,” said Vagnozzi. “When things click together like that, it’s really special.”

Their calculations suggest that experiments like XENON1T, which are designed to detect dark matter, could also be used to detect dark energy. However, the original excess still needs to be convincingly confirmed. “We first need to know that this wasn’t simply a fluke,” said Visinelli. “If XENON1T actually saw something, you’d expect to see a similar excess again in future experiments, but this time with a much stronger signal.”

If the excess was the result of dark energy, upcoming upgrades to the XENON1T experiment, as well as experiments pursuing similar goals such as LUX-Zeplin and PandaX-xT, mean that it could be possible to directly detect dark energy within the next decade.

Source/Credit: University of Cambridge / Sarah Collins

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A rare Tibetan worm may hold key to long-acting COVID vaccines

 

Caterpillars with emerging Ophiocordyceps sinensis
Credit: William Rafti Institute
A molecule isolated from the world’s most valuable parasite, the caterpillar fungus (Ophiocordyceps sinensis), may provide clues to better and more stable mRNA vaccines, according to research being done in Australia.

The molecule was first isolated from cordyceps fungi in the 1950s. These fungi infect ghost moth larvae, to make 'summer grass' prized in Tibetan and Chinese medicines for its benefits as a tonic and as a treatment for sexual dysfunction.

Associate Professor Traude Beilharz, from the Biomedicine Discovery Institute at Monash University in Melbourne, and her team have been studying the cordycepin molecule because of its ability to trick cells into increasing nucleotides and making mRNA with longer 3'UTRs. According to Associate Professor Beilharz, understanding how 3' UTRs work is really important to improving the stability and function of vaccines. Their research was recently published in the eLife journal.

The lab is now using what they have learned about 3'UTRs from that study to create a screening

Associate Professor Traude Beilharz

platform to identify optimal 3'UTRs for new mRNA vaccines. These 3’UTRs are crucial in stimulating immunity and may reduce the need for booster shots to maintain this immunity. Rachael Turner, first author of the study, has nearly completed her PhD thesis. Next she will apply her expertise in 3’ UTR function toward improving future mRNA vaccines.

The caterpillar fungus, Ophiocordyceps sinensis, is the world’s most valuable parasite. It’s a relative of the tropical fungus that turns ants into zombies, but unlike its infamous cousin, it is found only on the Tibetan plateau, where it infects the larvae of ghost moths. It has long been part of traditional Chinese medicine, and demand for it has risen so sharply in recent decades that in Beijing it is now worth three times its weight in gold. In Bhutan, one of the countries where the fungus is harvested, it accounts for a significant slice of the gross domestic product.

The development of mRNA vaccines, largely due to COVID-19, has been rapid. In addition, the development of mRNA vaccines against cancer has also developed at pace. According to Associate Professor Beilharz, “mRNA vaccines are a promising technology as the production process is simple, safety profiles are better than those of DNA vaccines, and mRNA-encoded antigens are readily expressed in cells, which stimulate immunity against the virus.”

However, mRNA vaccines also possess some inherent limitations. While side effects such as allergy, renal failure, heart failure, and infarction remain a risk, the vaccine mRNA may also be degraded quickly after administration, leading to the need for boosters.

The best types of mRNA vaccines are those that only encode the target antigen (in the case of COVID vaccines, the spike protein) and contain 5' and 3' untranslated regions (UTRs), which provide comprehensive stimulation of the adaptive and innate immunity. “Studying the cordyceps fungi molecule and how it can be used to understand the function of 3’UTRs is a key step in making better vaccines against infectious diseases like COVID-19 and also cancers,” Associate Professor Beilharz said.

Monash is home to Australia's largest network of RNA and mRNA researchers. Keep up to date with our work on life-saving vaccines and therapeutic treatments on the Monash RNA webpage.

Source/Credit: Monash University

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Tuesday, September 14, 2021

Killing Covid, a spray away.

Credit: University of Queensland
 An antiviral surface coating technology sprayed on face masks could provide an extra layer of protection against COVID-19 and the flu.    

The coating developed at The University of Queensland has already proven effective in killing the virus that causes COVID-19, and shows promise as a barrier against transmission on surfaces and face masks.

UQ’s Australian Institute for Bioengineering and Nanotechnology researcher Professor Michael Monteiro said the water-based coating deployed worm-like structures that attack the virus.

“When surgical masks were sprayed with these ‘nanoworms’, it resulted in complete inactivation of the Alpha variant of Sars-CoV-2 and influenza A,” Professor Monteiro said.

The coating was developed with Boeing as a joint research project, and was tested at the Peter Doherty Institute for Infection and Immunity at The University of Melbourne.

 “These polymer ‘nanoworms’ rupture the membrane of virus droplets transmitted through coughing, sneezing or saliva and damage their RNA,” Professor Monteiro said.

“The chemistry involved is versatile, so the coating can be readily redesigned to target emerging viruses and aid in controlling future pandemics.”

Professor Monteiro said face masks would continue to be an important part of helping prevent or reduce community transmission of COVID-19.

“Antiviral coatings applied on mask surfaces could reduce infection and provide long-lasting control measures to eliminate both surface and aerosolized transmission,” he said.

“We know that COVID-19 remains infectious for many hours or days on some surfaces, and provides a direct route to infection.

“Therefore, there is greater emphasis on eliminating both surface and airborne transmission to complement vaccination of the population to stop the current pandemic.”

The coating is environmentally friendly, water-based and its synthesis aligns with manufacturing techniques used in the paint and coatings industry. 

The research is published in ACS Nano (doi.org/10.1021/acsnano.1c05075)

Source/Credit: University of Queensland

Pandemic proofing our future

Dr Kirsty Short Credit: University of Queensland
A project developing a test and treatments that would be effective against multiple viral threats could become a cornerstone of the world’s response to future pandemics.

University of Queensland virologist Dr Kirsty Short has been awarded $1.37 million from the National Health and Medical Research Council (NHRMC) to use her understanding of the immune response in COVID-19 and influenza to investigate a future pandemic response.

“The reality is the world was not prepared for COVID-19, so our aim is start developing broad spectrum diagnostics and drugs that work against multiple viruses,” Dr Short said.

“If we develop these things now, we can stockpile them so that any time there’s a viral outbreak, we have them on hand, ready to deploy.”

Dr Short said the project would look for a genetic marker or ‘signature’ in people with COVID-19 that could be used in a rapid test that can be picked up before the viral genetic material can be detected by standard diagnostic PCR.

“We’re working with health authorities to access samples from people going through hotel quarantine and we’re combining that with machine learning to try and identify a signature that will then allow for the development of early diagnostics.”

While existing anti-viral therapies are developed for a specific virus, Dr Short’s project will investigate a treatment that targets the immune response to multiple viruses.

“An out-of-control inflammatory response is the reason some people become seriously ill in a coronavirus infection, in a flu infection and in many other pandemic viruses,” she said.

“By targeting that response, we can develop an effective therapy that is useful against any pandemic virus that you could anticipate.”

Dr Short said identifying a ‘host signature of infection’ would also allow for earlier detection of any virus, benefiting both the public health response and individual patients.

“If we take SARS-COV-2 as an example, you can be infected with the virus but initially get a negative PCR test and maybe five days later you test positive.

“With an early diagnostic test, we could determine whether an individual carries the ‘host signature’, which would allow us to identify those likely to come down with an infection.

“If you didn’t have the signature, you might be released earlier from quarantine or maybe allowed to home quarantine, making the process less arduous for everyone.”

The test and therapies would initially be rolled out in Australia, but Dr Short hoped they would also make a difference elsewhere.

“Ideally, we could have this as part of a global pandemic preparedness plan, because ultimately there will be another,” Dr Short said.

 “What I really fundamentally hope is that this project will ensure that the next outbreak will be of much reduced severity and consequences compared to the COVID-19 pandemic.”

UQ received NHMRC grants for five Centers for Research Excellence (CRE), two Partnership Projects and 29 Investigator Grants in the latest round of funding.

Source/Credit: University of Queensland

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Molecular Achilles heel of cancer cells discovered

Tissue samples from 144 patients with colorectal cancer were analyzed
by mass spectrometry as part of the study. Image: W. Filser / TUM
 Changes in fat metabolism of colorectal cancer cells demonstrated for the first time Molecular Achilles heel of cancer cells discovered

Where does a malignant tumor obtain the energy to keep growing? That is a key question in cancer research. If the energy source were known, the tumor could be “starved”. Researchers have now laid the foundation for this approach: For the first time, they have demonstrated a fundamental difference in the fat metabolism of healthy cells in the inner lining of the intestinal tract and colorectal cancer cells. This could point the way to new treatment options targeting the changed metabolism of the tumor.

Some past measurements have also indicated significant differences in how fat is metabolized by healthy and cancerous cells. However, the results of this work have been highly inconsistent. Some investigations appeared to support such differences while others reported contrary results. “This question has been hotly debated”, says Prof. Klaus-Peter Janssen, a biologist at TUM’s university hospital Klinikum rechts der Isar.

To obtain clarity, surgeons at Klinikum rechts der Isar took tissue samples from the surgically removed tumors of 144 colorectal cancer (CRC) patients. The samples were immediately prepared onsite and then analyzed using mass spectrometry at the Institute for Food & Health (ZIEL) in Freising and at the University Hospital Regensburg. This is a biochemical procedure for the quantitative measurement of the type and mass of certain molecules in specially prepared tissue samples – in this case around 200 different fat molecules.

To prove that the results were reproducible, and not merely accidental, the patients were divided into two cohorts. The tissue samples were then analyzed separately and the results compared. In addition, the researchers incorporated the analysis of samples from another cohort of 20 CRC patients investigated independently at the University of Dresden.

In all three cohorts, the researchers were able to show that “CRC cells indeed have a specific lipid signature,” says Janssen. This means that they show a certain pattern of different lipid molecules – “A fingerprint, in a sense, with which we can distinguish between cancer cells and normal cells with a high degree of certainty. This signature also has prognostic relevance. In other words, it can be used to predict the course of the illness.”

The changes in the lipidome – i.e. the totality of lipids in a cell – related mainly to sphingo- and glycerolipids. These differences were also reflected at the genomic level: The team showed that the activity of certain genes that provide the blueprint for various enzymes was also significantly altered. Enzymes are functional proteins that play an important role in the production of metabolic products such as lipids, for example. This might be a starting point for cutting off the energy supply to cancer cells and thus slowing their growth – by finding drugs to activate or inhibit individual enzymes in order to starve the cancer.

“Lipids in tissue samples are highly sensitive molecules that are sometimes subject to rapid change or decay,” says Janssen. Unless tissue samples are shock-frozen immediately after dissection and properly handled and stored, some of the highly sensitive lipids will already be destroyed. This will invalidate the results of the analysis. That could be a reason for the inconsistent results of past studies: This kind of close cooperation is not guaranteed everywhere.

Janssen and his team were also able to clearly demonstrate that the lipid profile of the tissue samples undergoes changes when stored under sub-optimal conditions and over extended periods. They showed that some lipids remain stable in tissue samples and are therefore suitable as biomarkers, while others rapidly deteriorate and in some cases are entirely degraded within just an hour of the operation.

The metabolisms of healthy and diseased cells are different – and thus the types and quantity of the molecules produced in them such as sugars, proteins and lipids - i.e. fatty molecules. Lipids are important for obtaining and storing energy in cells, but also as important building blocks for cell membranes and as signaling molecules.

As the totality of all lipids in a cell is referred to as the lipidome, this term gives rise to “lipidomics” – an entirely new field of research. It compares the lipidome of different cells and seeks to draw conclusions based on the differences and changes: For example, how does the lipid profile of a CRC cell differ from that of a healthy cell in the lining of the intestinal tract? Are there changes typically seen in cancerous cells – and how can this knowledge be used to develop new drugs?

Lipidomics a subfield of the better-known area of metabolomics, which includes all metabolic products of a cell – the “metabolome”. Many research groups working in this area have generally focused on sugars, nucleic acids (DNA, RNA) and proteins, which are easier to analyze. Lipids are not only more sensitive. “For a long time, it was also difficult and time-consuming to measure them with conventional methods,” says Janssen. “They have become a focal point of research only since that changed.”

Publications:

Josef Ecker, Elisa Benedetti, Alida S.D. Kindt, Marcus Höring, Markus Perl, Andrea Christel Machmüller, Anna Sichler, Johannes Plagge, Yuting Wang, Sebastian Zeissig, Andrej Shevchenko, Ralph Burkhardt, Jan Krumsiek, Gerhard Liebisch, Klaus-Peter Janssen: The Colorectal Cancer Lipidome: Identification of a Robust Tumor-Specific Lipid Species Signature, Gastroenterology, Volume 161, Issue 3 (2021).

Source/Credit: Technical University of Munich

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Monday, September 13, 2021

New global dashboard sheds light on reasons behind COVID vaccine hesitancy, refusal

 

A woman works in a face mask manufacturing in factory in Harare, Zimbabwe. 
Credit: INTERNATIONAL LABOUR ORGANIZATION
In an ongoing global survey, more than half of those who are unvaccinated in more than 50 countries indicated in August that they definitely or probably won't get a COVID-19 vaccine. A new dashboard, launched today by the Johns Hopkins Center for Communication Programs, unpacks that survey data to help explain why—and how experts can work to increase acceptance rates.

The researchers found that the primary reasons around the world for resisting vaccination include fears about side effects, a desire to wait until more people have had the shots so they know they are safe, and a lack of confidence in whether the vaccine really works.

"Our analysis of this large trove of data finds that while vaccine hesitancy is real, there are many people around the globe who can be encouraged to get their doses—if public health officials can build and share their messages to address their concerns."

Dominick Shattuck
Johns Hopkins Center for Communication Programs

These latest survey results, based on responses gathered between Aug. 16 and 31, can be found in the new COVID Behaviors dashboard, an interactive tool created with data collected from more than 12 million people from 115 countries. The survey—believed to be the world's largest daily survey of global COVID knowledge, attitudes, and practices—has been fielded every day since May 20, 2021. It is expected to continue until the end of this year, and new data will become available every two weeks.

The dashboard is intended to be used by policymakers, government officials, and public health practitioners at national and sub-national levels to better understand the behavioral drivers behind vaccine uptake, masking, and physical distancing that can prevent the spread of COVID-19.

"Our analysis of this large trove of data finds that while vaccine hesitancy is real, there are many people around the globe who can be encouraged to get their doses—if public health officials can build and share their messages to address their concerns," says Dominick Shattuck, CCP's director of monitoring evaluation and learning and one of the leaders of the COVID behaviors project.

Adds Marla Shaivitz, CCP's director of digital strategy: "The dashboard can be used as a roadmap for policymakers to identify and engage with citizens to encourage them to be vaccinated to protect themselves and their families from COVID-19. In many countries, this dashboard fills an important data gap. It offers the most comprehensive data some governments have access to on how COVID behaviors are changing and what they can do to intervene."

The dashboard is the product of a collaboration among CCP, the World Health Organization's Global Outbreak Alert and Response Network, and Facebook. The data are generated from the COVID-19 Trends and Impact Survey, which is administered in the United States by the Delphi Group at Carnegie Mellon University and in other countries by the University of Maryland Social Data Science Center. The two universities collect the survey data from a random sample of Facebook users and CCP analyzes the responses.

A previous COVID behaviors dashboard, also led by CCP, was based on smaller, less frequent surveys from June 2020 through March 2021.

In this latest survey, reasons for vaccine hesitancy vary by country. In Senegal, the two most common reasons for hesitancy are concerns about side effects and whether the vaccine will work. Education around vaccine science and side effects could work to encourage vaccine uptake in Senegal. In the Netherlands, however, unvaccinated respondents were most likely to say that they don't believe they need a vaccine. When asked why not, their main reasons were because they are not a member of a high-risk group, or they don't believe COVID-19 is a serious illness. Each underlying perception requires a different messaging response.

The dashboard sheds light on how other behaviors have evolved over the last four months as well. In the United States, for example, 65% of those who responded to the survey between Aug. 16 and 31 said they had been shopping indoors in the previous 24 hours, and two-thirds those who had been shopping said they wore masks. Mask wearing steadily decreased in the U.S. until the middle of July but has been rising since the highly transmissible Delta variant became the dominant strain, and case counts and hospitalizations began rising again to record levels in many states.

In India, where an outbreak has fallen from its May peak, only 29% of respondents had been shopping indoors in the previous 24 hours and the vast majority of them (87%) were wearing masks, suggesting there is a long way to go before things get back to normal.

Since March 2020, a staggering 223 million COVID cases—and 4.6 million deaths—have been reported around the world, according to Johns Hopkins University's COVID-19 dashboard. More than 5.3 billion vaccine doses have been administered globally, though just over 2% of those doses have been administered in Africa.

USAID has sent more than 110 million doses to low- and middle-income countries and COVAX, a worldwide initiative aimed at equitable access to COVID-19 vaccines, has distributed more than 236 million doses. As vaccine access increases, governments will need to develop strategies to sensitize citizens to accurate information and the benefits of vaccines.

In addition to findings about vaccine hesitancy, the dashboard also features data on why many people who want vaccines can't seem to access them. In Brazil, for example, where 65% of the unvaccinated respondents in the Aug. 16-31 survey period said they probably or definitely want a vaccine, 23% of those who want one said they couldn't get a shot because they are not eligible for one, and 34% said there were no appointments available.

Armed with knowledge from the dashboard, officials in those countries can aim to work with local communities to make vaccine appointments more accessible—once vaccines are widely available—and to better spread the word about appointments that are available and when, where, and how to secure them.

"We are at a critical time for global COVID-19 vaccine rollouts, yet populations are oversaturated with information, disinformation, and rumors," says Jeni Stolow of WHO's Global Outbreak Alert and Response Network. "Continuously producing timely evidence-based and effective health communication is a major challenge in this second year of the pandemic. This dashboard can support public health practitioners around the globe in their endeavors to tailor, target, and reinvigorate their local COVID-19 vaccine outreach efforts."

While many unvaccinated people around the world say they are unlikely to get vaccinated, in many countries, large percentages of the population say they would choose to get their children vaccinated once a vaccine becomes available. In India and Guatemala, well over 90% of survey respondents said they would definitely or probably vaccinate their children. Data from Aug. 16 through 31 show the figure was 86% in Mozambique, 72% in the United States, and 47% in Serbia.

"The volume of data that has and will continue to be collected on COVID-19 will be of great value to policymakers and health practitioners, if the data are strategically used," says Douglas Storey, CCP's director for communication science and research. "This dashboard offers deep insights into behaviors around the world and will be a guide for those aiming to stop the spread of this devastating disease."

Source/Credit: Johns Hopkins University

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Fountain of youth for ageing stem cells in bone marrow

Stained calcium (dark brown) in stem cells from the bone marrow: 
Young stem cells (left) produce more material for bone than old stem cells (center). 
They can be rejuvenated by adding sodium acetate (right).
Credit/Source: Pouikli/Max Planck Institute for Biology of Ageing
As we age, our bones become thinner, we suffer fractures more often, and bone-diseases such as osteoporosis are more likely to occur. One responsible mechanism involves the impaired function of the bone-marrow stem cells, which are required for the maintenance of bone integrity. Researchers from the Max Planck Institute for Biology of Ageing and CECAD Cluster of Excellence for Ageing Research at the University of Cologne have now shown that the reduced stem cell function upon ageing is due to changes in their epigenome. They were able to reverse these changes in isolated stem cells by adding acetate. This fountain of youth for the epigenome could become important for the treatment of diseases such as osteoporosis.

Ageing Researchers have been looking at epigenetics as a cause of ageing processes for some time. Epigenetics looks at changes in genetic information and chromosomes that do not alter the sequence of the genes themselves, but do affect their activity. One possibility is changes in proteins called histones, which package the DNA in our cells and thus control access to DNA. The Cologne research group of Peter Tessarz has now studied the epigenome of mesenchymal stem cells. These stem cells are found in bone marrow and can give rise to different types of cells such as cartilage, bone and fat cells.

The epigenetic changes of ageing stem cells

"We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice," explains Andromachi Pouikli, first author of the study. "We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected."

Rejuvenation of the epigenome

The researchers then investigated whether the epigenome of stem cells could be rejuvenated. To do this, they treated isolated stem cells from mouse bone marrow with a nutrient solution which contained sodium acetate. The cell converts the acetate into a building block that enzymes can attach to histones to increase access to genes, thereby boosting their activity. "This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells," Pouikli said.

To clarify whether this change in the epigenome could also be the cause of the increased risk in old age for bone fractures or osteoporosis in humans, the researchers studied human mesenchymal stem cells from patients after hip surgery. The cells from elderly patients who also suffered from osteoporosis showed the same epigenetic changes as previously observed in the mice.

A new therapeutic approach against osteoporosis?

"Sodium acetate is also available as a food additive, however, it is not advisable to use it in this form against osteoporosis, as our observed effect is very specific to certain cells. However, there are already first experiences with stem cell therapies for osteoporosis. Such a treatment with acetate could also work in such a case. However, we still need to investigate in more detail the effects on the whole organism in order to exclude possible risks and side effects," explains Peter Tessarz, who led the study.

Source/Credit: Max-Planck-Gesellschaft

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Engineers grow pancreatic organoids

 

MIT and Cancer Research UK Manchester Institute researchers have
developed a synthetic gel that can be used to grow tiny
pancreatic organoids, seen here, from human pancreatic cells.
Credits: Courtesy of the researchers.
MIT engineers, in collaboration with scientists at Cancer Research UK Manchester Institute, have developed a new way to grow tiny replicas of the pancreas, using either healthy or cancerous pancreatic cells. Their new models could help researchers develop and test potential drugs for pancreatic cancer, which is currently one of the most difficult types of cancer to treat.

Using a specialized gel that mimics the extracellular environment surrounding the pancreas, the researchers were able to grow pancreatic “organoids,” allowing them to study the important interactions between pancreatic tumors and their environment. Unlike some of the gels now used to grow tissue, the new MIT gel is completely synthetic, easy to assemble and can be produced with a consistent composition every time.

“The issue of reproducibility is a major one,” says Linda Griffith, the School of Engineering Professor of Teaching Innovation and a professor of biological engineering and mechanical engineering. “The research community has been looking for ways to do more methodical cultures of these kinds of organoids, and especially to control the microenvironment.”

The researchers have also shown that their new gel can be used to grow other types of tissue, including intestinal and endometrial tissue.

Griffith and Claus Jorgensen, a group leader at the Cancer Research UK Manchester Institute, are the senior authors of the paper, which appears today in Nature Materials. The lead author is Christopher Below, a former graduate student at the Cancer Research UK Manchester Institute.

Mimicking the microenvironment

The researchers were also able to use their system to grow
supportive cells such as fibroblasts (green) and macrophages (orange)
surrounding the pancreatic organoids.
Credits: Joanna Kelly and Christopher Below
Traditionally, labs have used commercially available tissue-derived gel to grow organoids in a lab dish. However, as the most widely used commercial gel is a complex mixture of proteins, proteoglycans, and growth factors derived from a tumor grown in mice, it is variable from lot to lot and has undesirable components present, Griffith says. It also doesn’t always allow for growth of multiple types of cells. About 10 years ago, Griffith’s lab started to work on designing a synthetic gel that could be used to grow epithelial cells, which form the sheets that line most organs, along with other supportive cells.

The gel they developed is based on polyethylene glycol (PEG), a polymer that is often used for medical applications because it doesn’t interact with living cells. By studying the biochemical and biophysical properties of the extracellular matrix, which surrounds organs in the body, the researchers were able to identify features they could incorporate into the PEG gel to help cells grow in it.

One key feature is the presence of molecules called peptide ligands, which interact with cell surface proteins called integrins. The sticky binding between ligands and integrins allows cells to adhere to the gel and form organoids. The researchers found that incorporating small synthetic peptides derived from fibronectin and collagen in their gels allowed them to grow a variety of epithelial tissues, including intestinal tissue. They showed that supportive cells called stromal cells, along with immune cells, can also thrive in this environment.

In the new study, Griffith and Jorgensen wanted to see if the gel could also be used to support the growth of normal pancreatic organoids and pancreatic tumors. Traditionally, it has been difficult to grow pancreatic tissue in a manner that replicates both the cancerous cells and the supporting environment, because once pancreatic tumor cells are removed from the body, they lose their distinctive cancerous traits.

Griffith’s lab developed a protocol to produce the new gel, and then teamed up with Jorgensen’s lab, which studies the biology of pancreatic cancer, to test it. Jorgensen and his students were able to produce the gel and use it to grow pancreatic organoids, using healthy or cancerous pancreatic cells derived from mice.

“We got the protocol from Linda and we got the reagents in, and then it just worked,” Jorgensen says. “I think that speaks volumes of how robust the system is and how easy it is to implement in the lab.”

Other approaches they had tried were too complicated or did not recapitulate the microenvironment seen in living tissues, he says. Using this gel, Jorgensen’s lab was able to compare the pancreatic organoids to tissues they have studied in living mice, and they found that the tumor organoids express many of the same integrins seen in pancreatic tumors. Furthermore, other types of cells that normally surround tumors, including macrophages (a type of immune cells) and fibroblasts (a type of supportive cells), were also able to grow in the microenvironment.

Patient-derived cells

The researchers also showed that they can use their gel to grow organoids from pancreatic cancer cells from patients. They believe it could also be useful for studying lung, colorectal, and other cancers. Such systems could be used to analyze how potential cancer drugs affect tumors and their microenvironment.

“The discoveries described in this paper will facilitate further important questions concerning responses to novel drug treatment approaches,” says Hilary Critchley, a professor of reproductive medicine and co-deputy director of the MRC Centre for Reproductive Health at the University of Edinburgh, who was not involved in the study. “The cancer field has long relied upon other approaches (mouse models or isolated cell studies), and the contribution of the organoid approach, and notably the gel structure in which these mini groups of cells grow, will be pivotal to research advancement.”

Griffith also plans to use the gel to grow and study tissue from patients with endometriosis, a condition that causes the tissue that lines the uterus to grow outside the uterus. This can lead to pain and sometimes infertility.

One of the advantages of the new gel is that it is completely synthetic, and can be made easily in a lab by mixing together specific precursors, including PEG and some polypeptides. The researchers have filed a patent on the technology and are in the process of licensing it to a company that could produce the gel commercially.

The research was funded by Cancer Research UK, the Rosetrees Trust, a European Research Council Consolidator Award, the National Science Foundation, the National Institutes of Health, and the Defense Advanced Research Projects Agency.

Source/Credit: Massachusetts Institute of Technology

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Friday, September 10, 2021

Fat matters more than muscle for heart health, research finds

 

Photo by Polina Tankilevitch from Pexels
New research has found that changes in body fat impact early markers of heart health more than changes in body muscle, suggesting there are greater benefits to be expected from losing fat than from gaining muscle.

The observational study, led by researchers from the University of Bristol, was published in PLoS Medicine.

More than 3,200 young people in Bristol’s Children of the 90s birth cohort study were measured repeatedly for levels of body fat and lean mass using a body scanning device. These scans were performed four times across participants’ lives, when they were children, adolescents, and young adults (at ages 10, 13, 18 and 25 years). Handgrip strength was also tested when they were aged 12 and 25 years.

When the participants were 25 years old, blood samples were collected and a technique called “metabolomics” was used to measure over 200 detailed markers of metabolism including different types of harmful cholesterol, glucose, and inflammation, which together indicate one’s susceptibility to developing heart disease and other health conditions.

Dr Joshua Bell, senior research associate in epidemiology and lead author of the report, said: “We knew that fat gain is harmful for health, but we didn’t know whether gaining muscle could really improve health and help prevent heart disease. We wanted to put those benefits in context.”

The findings showed that gaining fat mass was strongly and consistently related to poorer metabolic health in young adulthood, as indicated, for example, by higher levels of harmful cholesterol. These effects were much larger (often about 5-times larger) than any beneficial effect of gaining muscle. Where there were benefits of gaining muscle, these were specific to gains that had occurred in adolescence – suggesting that this early stage of life is a key window for promoting muscle gain and reaping its benefits.

Dr Bell added: “Fat loss is difficult, but that does seem to be where the greatest health benefits lie. We need to double down on preventing fat gain and supporting people in losing fat and keeping it off.

“We absolutely still encourage exercise – there are many other health benefits and strength is a prize in itself. We may just need to temper expectations for what gaining muscle can really do for avoiding heart disease – fat gain is the real driver.”

The study also found that improving strength (based on handgrip) has slightly greater benefits for markers of heart health than gaining muscle itself, suggesting that the frequent use of muscle, rather than the bulking up of muscle, may matter more.

Professor Nic Timpson, the Principal Investigator of the Children of the 90s and one of the study’s authors, said: “This research provides greater clarity in the relative roles of fat and lean mass in the basis of cardio-metabolic disease. This is an important finding and clearly part of a complex picture of health that involves weight gain, but also the other indirect costs and benefits of different types of lifestyle. It is only through detailed, longitudinal, studies like Children of the 90s that these relationships can be uncovered. We extend our thanks to the participants of the Children of the 90s who make all of this work possible.”

Source/Credit: University of Bristol

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Thursday, September 9, 2021

How land birds cross the open ocean

 

Terrestrial birds are capable of flying for hundreds of kilometers over the open sea. Nourani et al. show that the autumn migration trajectories of some of these birds correspond with uplift over the sea surface. Suitable uplift means less drag, making sea-crossing less energetically demanding. Moreover, strong uplift can allow the birds to soar.
© Elham Nourani / Max Planck Institute of Animal Behavior

Migrating birds choose routes with the best wind and uplift conditions, helping them to fly nonstop for hundreds of kilometers over the sea

Researchers at the Max Planck Institute of Animal Behavior and University of Konstanz in Germany have identified how large land birds fly nonstop for hundreds of kilometers over the open ocean—without taking a break for food or rest. Using GPS tracking technology, the team monitored the global migration of five species of large land birds that complete long sea crossings. They found that all birds exploited wind and uplift to reduce energy costs during flight—even adjusting their migratory routes to benefit from the best atmospheric conditions. This is the most wide-ranging study of sea-crossing behavior yet and reveals the important role of the atmosphere in facilitating migration over the open sea for many terrestrial birds.

Flying over the open sea can be dangerous for land birds. Unlike seabirds, land birds are not able to rest or feed on water, and so sea crossings must be conducted as nonstop flights. For centuries, bird-watchers assumed that large land birds only managed short sea crossings of less than 100 kilometers and completely avoided flying over the open ocean.

However, recent advances in GPS tracking technology have overturned that assumption. Data obtained by attaching small tracking devices on wild birds has shown that many land birds fly for hundreds or even thousands of kilometers over the open seas and oceans as a regular part of their migration.

But scientists are still unraveling how land birds are able to accomplish this. Flapping is an energetically costly activity, and trying to sustain nonstop flapping flight for hundreds of kilometers would not be possible for large, heavy land birds. Some studies have suggested that birds sustain such journeys using tailwind, a horizontal wind blowing in the bird’s direction of flight, which helps them save energy. Most recently, a study revealed that a single species—the osprey—used rising air thermals known as “uplift” to soar over the open sea.

Now, the new study has examined sea-crossing behavior of 65 birds across five species to gain the most wide-ranging insight yet into how land birds survive long flights over the open sea. The researchers analyzed 112 sea-crossing tracks, collected over nine years, with global atmospheric information to pinpoint the criteria that the birds use for selecting their migration routes over the open sea. A large international collaboration of scientists shared their tracking data to make this study possible.

The findings not only confirm the role of tailwind in facilitating sea-crossing behavior, but also reveal the widespread use of uplift for saving energy during these nonstop flights. Suitable uplift means less drag, making sea crossing less energetically demanding.

“Until recently, uplift was assumed to be weak or absent over the sea surface. We show that is not the case,” says first author Elham Nourani, a DAAD PRIME postdoctoral fellow at the Department of Biology at the University of Konstanz, who did the work when she was at the Max Planck Institute of Animal Behavior.

Terrestrial birds are capable of flying for hundreds of kilometers over the open sea. Nourani et al. show that the autumn migration trajectories of

some of these birds correspond with uplift over the sea surface. Suitable uplift means less drag, making sea-crossing less energetically demanding. Moreover, strong uplift can allow the birds to soar.

“Instead, we find that migratory birds adjust their flight routes to benefit from the best wind and uplift conditions when they fly over the sea. This helps them sustain flight for hundreds of kilometers,” says Nourani.

The oriental honey buzzard, for example, flies 700 kilometers over the East China Sea during its annual migration from Japan to southeast Asia. The roughly 18-hour nonstop sea crossing is conducted in autumn when the air movement conditions are optimal. “By making use of uplift, these birds can soar up to one kilometer above the sea surface,” says Nourani.

The study also raises the question of how migration will be affected by a changing climate. “Our findings show that many land birds are dependent on atmospheric support to complete their migrations over the open sea, indicating their vulnerability to any changes to the Earth’s atmospheric circulation patterns,” says Nourani. “Collaborative studies like this are important to unravel general patterns about how migratory birds depend on the weather patterns. This enables future studies to make robust predictions about how these birds will be impacted by climate change.”

Source/Credit: Max-Planck-Gesellschaft

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The development of non-opioid painkillers to treat chronic pain

 
An image of the cryogenic electron microscopy structure of the human adenosine
A1 receptor (colored blue) bound to its signaling protein
(colored pink, green, and purple), adenosine (purple spheres)
and a proof-of-concept non-opioid analgesic (colored as orange spheres).
Monash University researchers have made a breakthrough discovery that could pave the way for the development of novel non-opioid painkillers (analgesics) to safely and effectively treat neuropathic pain.

The research was published today in the prestigious journal Nature.

Neuropathic pain is a type of chronic pain that can occur if your nervous system is damaged or not working correctly, and can be caused by injury, virus infection or cancer treatment, or be a symptom or complication of conditions such as multiple sclerosis and diabetes.

The new study, led by world-renowned drug researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) and the Monash Biomedicine Discovery Institute (BDI), has demonstrated a new mode of targeting the adenosine A1 receptor protein, which has long been recognized as a promising therapeutic target for non-opioid painkillers to treat neuropathic pain but for which the development of painkillers had failed due to a lack of sufficient on-target selectivity, as well as undesirable adverse effects.

In the study, Monash researchers used electrophysiology and preclinical pain models to demonstrate that a particular class of molecule, called a ‘positive allosteric modulator’ (PAM), can provide much more selective targeting of the A1 receptor by binding to a different region of the protein than traditional, previously investigated, activators.

Another breakthrough in the study was facilitated by the application of cryo electron microscopy (cryoEM) to solve the high-resolution structure of the A1 receptor bound to both its natural activator, adenosine, and an analgesic PAM, thus providing the first atomic level snapshot of where these drugs bind.

Chronic pain remains a widespread global health burden, with lack of current therapeutic options leading to an over-reliance on opioid painkillers, which provide limited relief in patients with chronic (particularly neuropathic) pain, while exhibiting severe adverse effects, such as respiratory depression and addiction.

The new Monash discovery provides the opportunity for researchers to develop non-opioid drugs that lack such side effects.

Co-corresponding author of the study and Dean of the Faculty of Pharmacy and Pharmaceutical Sciences (home to MIPS), Professor Arthur Christopoulos said: “The world is in the grip of a global opioid crisis and there is an urgent need for non-opioid drugs that are both safe and effective.”

Associate Professor Wendy Imlach, who is the head of the Pain Mechanisms lab at Monash BDI and a co-corresponding author of the work, stated: “This study has helped us to better understand mechanisms underpinning allosteric drug actions. One of the exciting things we found is that not only were the PAMs able to decrease neuropathic pain with minimal unwanted effects, but they actually increase their level of effectiveness as the pain signals in the spinal cord get stronger – thus highlighting the potential for allosteric medicines that are uniquely sensitive to disease context”.

Professor Christopoulos added: “This multidisciplinary study now provides a valuable launchpad for the next stage in our drug discovery pipeline, which will leverage structure-based insights for the design of novel non-opioid allosteric drugs to successfully treat chronic pain.”

This work was performed in collaboration with researchers from the Universities of Sydney, Kansas and Tokyo, Uppsala University, and the ARC Centre for cryo-Electron Microscopy of Membrane Proteins. It was supported by the National Health and Medical Research Council of Australia, the Australian Research Council, the Australian Heart Foundation, the American Heart Association and the National Institutes of Health, and the Swedish Research Council.

Source/Credit: Monash University

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Moth wingtips an ‘acoustic decoy’ to thwart bat attack

 

The Atlas moth (Attacus atlas) has a strong anti-bat acoustic decoy at the tip of its forewings. Composite image with photograph on right half and acoustic tomography on the left. Color indicates echo strength on a dB scale and red indicates highest echo amplitude. Note the red highly reflecting stripe created by the rippled part of the wingtip.
Image Credit: Dr Thomas Neil and Professor Marc Holderied

Wingtips of certain species of silkmoth are structured to reflect sound and throw off attackers, according to a new study.

Researchers at the University of Bristol have discovered that the tips of some saturniid moth forewings are curiously rippled and folded. They found that these unique structures strongly reflect sound, meaning that a bat hunting using echolocation is more likely to attack the wingtip region of the moth over the body, potentially saving the moth’s life.

Photograph of the Chinese tussar moth (Antheraea pernyi).
This silkmoth has a strong wingtip decoy based on ripples. 
Image Credit: Dr Thomas Neil
They also discovered that the ripples and folds of the forewing tips have evolved to act as hemispheric and corner retroreflectors respectively, meaning that they reflect sound strongly back to its point of origin. Coupled together, the folds and ripples of these wingtips cover a huge range of incident sounds angles, meaning that over the entire wingbeat cycle of a flying moth and most possible positions of an attacking bat, the wingtip would consistently produce the strongest echoes. The acoustic protection of wingtips is even stronger than that of common hindwing decoys.

Professor Marc Holderied of Bristol’s School of Biological Sciences explained: “We have demonstrated that the folded and rippled wingtips on the forewings of some silkmoths act as acoustic decoys.

“Structurally, the wingtips act as acoustic retroreflectors, reflecting sound back to its source from numerous angles, meaning a bat would be more likely to strike the wingtip over the more vulnerable body of the moth.”

The findings, published today in Current Biology, are the latest revelation in the bat-moth acoustic arms race - the battle between bats which hunt moths using echolocation, and the subsequent evolution of different defensive strategies amongst moths to increase their chances of survival.

Photograph of the Chinese tussar moth (Antheraea pernyi).
This silkmoth has a strong wingtip decoy
based on ripples. Image Credit: Dr Thomas Neil
Towed acoustic decoys are a well-established defense amongst some silkmoths. These species have evolved elongated hindwings which terminate in a coiled and twisted end. The morphology of these elongated hindwings means that they generate very strong echoes, so much so that they will often divert a bat’s acoustic gaze towards them, away from the exposed body of the moth, causing the bat to strike the expendable tail of the moth or miss the moth all together.

Lead author Dr Thomas Neil said: “There are many silkmoths that do not have these elongated hindwings, and we were interested in how they might protect themselves from bats. Through our research we discovered that there are many silkmoths that have rippled and folded structures not on the tips of their elongated hindwings but on the tips of their forewings. These resembled the twisted hindwing structures seen in other moths and so we wanted to know if they might also serve as an acoustic decoy to thwart a bat’s attack.

“To test this theory, we used innovative acoustic tomography analysis. We recorded echoes from moths from over 10,000 angles, to compare whether the echoes coming from the wingtips of these moths were stronger than the echoes from the body. If the echoes coming from the rippled and folded wingtips were stronger than that of the body, this would indicate that they were indeed acoustic decoys.

“Conclusive support for the idea that the forewing reflector is an acoustic decoy comes from our finding that acoustic forewing decoys always evolved as an alternative to acoustic hindwing decoys, with there being no species known to possess both.”

Now the researchers will try and collect behavioral data to corroborate their findings in the lab. They plan to monitor bats and moths with varying levels of folded wing morphologies to see how much of a survival advantage it really gives them.

Prof Holderied added:“The results of this study introduce another exciting aspect to the story of the bat-moths acoustic arms race. We have identified a novel form of acoustic defense amongst silkmoths which may give them an advantage over hunting bats. Wider implications might include improved man-made anti radar and sonar decoy architectures.”

Source/Credit: University of Bristol

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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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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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