Showing posts with label Medical. Show all posts
Showing posts with label Medical. Show all posts

Monday, September 20, 2021

Major advance in race for SARS-CoV-2 inhibitor drugs

 
Mpro dimer from SARS-CoV-2 in complex with the inhibitory peptide (13)
 following 100 ns of molecular dynamics simulation.
Credit: University of Bristol
A new advance towards the development of drugs specifically designed to inhibit a key SARS-CoV-2 enzyme is reported in the Royal Society of Chemistry's leading journal, Chemical Science. The international team, led by scientists from the Universities of Oxford and Bristol, has designed new peptide molecules and shown that they block (inhibit) the virus’s main protease [Mpro] - a prominent SARS-CoV-2 drug target.

Once SARS-CoV-2 invades a healthy human cell, the virus's own genetic material commandeers the infected cell's machinery, forcing it to make new copies of the virus. A vital step in this viral life cycle involves cutting a very long 'polyprotein' into its constituent viral proteins. SARS-CoV-2 has two molecular machines called protease enzymes that act as 'molecular scissors'. One of these, called the main protease, or 'Mpro' for short, has the vital role of chopping up the polyprotein, cutting it at 11 different places.

In the early days of the pandemic lockdown, Professor Garrett Morris at the University of Oxford, brought together a group of scientists to try to understand Mpro, with the aim of helping develop drugs against COVID-19. Meeting weekly over many months by Zoom, this group combined their computational and experimental expertise, and grew to include scientists from several different countries. From Bristol, this included Professors Adrian Mulholland and Jim Spencer, Dr Deborah Shoemark, PhD student Becca Walters, and other colleagues. Using a wide array of computational molecular modelling techniques including interactive molecular dynamics in virtual reality, quantum mechanics, peptide design and protein-ligand interaction analysis, the scientists were able to build an atomic level picture of the structure, dynamics and interactions of Mpro.

From these models, the team were able to find how the viral Mpro 'molecular scissors' work. They then designed new peptides, which are short pieces of protein, as inhibitors, to bind tightly to Mpro and prevent it from working, stopping the virus dead in its tracks. But did they work?

All 11 protein cut sites and four of these designed peptides were synthesized and tested in the Chemistry Research Laboratory at the University of Oxford. Experiments, led by Professor Chris Schofield at Oxford, showed that the novel peptides - designed by Dr Deborah Shoemark, with software developed in Bristol - not only bound to the molecular scissors, but they outcompeted the natural protein cut sites and so inhibited Mpro.

Adrian Mulholland, Professor of Chemistry at the University of Bristol and one of the study's lead authors, said: "Despite the development of successful vaccines in record time, new antiviral drugs are desperately needed. To date there are no drugs designed specifically to target COVID-19. Computational molecular modelling can really help with this. As we’ve shown here, computational design can produce molecules that actually stop the Mpro enzyme from working."

Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, added: "It has been great to work together on this, combining our ideas and methods to get a really detailed picture of how this viral enzyme works – and to design molecules that actually stop it from working. Understanding Mpro specificity provides the potential to exploit vulnerabilities of the SARS-CoV-2 virus that may provide routes to new antivirals."

Professor Mulholland added: "This collaboration has really shown how sharing of models, data and expertise can help get understanding and make progress much more quickly. Garrett (Morris) built a fantastic team, and it has been exciting to work together on this. It’s how science should be done – particularly in the face of pressing problems like the COVID-19 pandemic."

The study was funded through several grants including support from the EPSRC, BBSRC and the Wellcome Trust.

Source/Credit: University of Bristol

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Autistic individuals are more likely to be LGBTQ+

The findings have important implications for the healthcare and support of autistic individuals. The results are published in the journal Autism Research.  

For many years it was wrongly assumed that autistic individuals are uninterested in sexual or romantic relationships, but this is not the case. In recent years, small studies have suggested that autistic individuals are more likely to experience a wider diversity of sexual orientations and are less likely to have sexually transmitted infections (STIs). However, the existing evidence has been limited in size and scope.

In the largest study to date on these topics, the team at the Autism Research Center used an anonymous, self-report survey to study the sexual activity, sexual orientation, and sexual health of autistic adults. Overall, 1,183 autistic and 1,203 non-autistic adolescents and adults (aged 16-90 years) provided information about their sexual activity, sexual orientation, and medical history of STIs.

The results showed that the majority of autistic adults (70% of autistic males and 76% of autistic females) engage in sexual activity—although they do so to a lesser degree than their non-autistic peers (89% of both non-autistic males and females report engaging in sexual activity). In contrast to previous findings, the results also found that there were no differences in likelihood of ever contracting an STI, or the age at which participants first engaged in sexual activity, between autistic and non-autistic individuals.

In addition, the study found that autistic adults and adolescents are approximately eight times more likely to identify as asexual and ‘other’ sexuality than their non-autistic peers. And there were sex differences in sexual orientation: autistic males are 3.5 times more likely to identify as bisexual than non-autistic males, whereas autistic females are three times more likely to identify as homosexual than autistic females.

When comparing autistic females and males directly, autistic females were more likely to be sexually active; more likely to identify as asexual, bisexual, and ‘other’ sexuality; and were less likely to identify as heterosexual.

Elizabeth Weir, a PhD candidate at the Autism Research Center in Cambridge, and the lead researcher of the study, said: “Understanding the intersectional identities of autistic individuals who are asexual, bisexual, homosexual, or ‘other’ sexuality is key. It is particularly important that healthcare providers and educators use language that is affirming and accepting of all sexual orientations and gender identities when providing sexual education and sexual health screening checks to autistic and non-autistic people alike.” 

Dr Carrie Allison, Director of Strategy at the Autism Research Center and a member of the team, said: “We must ensure that autistic individuals are receiving equal access to healthcare and support in their choices in their personal lives, to enjoy fulfilling lives and good mental health.”

Professor Simon Baron-Cohen, Director of the Autism Research Center and a member of the team, said: “This new study is an important example of applied health research with policy relevance for health and social care services.”

Source/Credit: University of Cambridge

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Pandemic Has Triggered a Cycle of Mental Health Struggles and Physical Inactivity

Photo by Liza Summer from Pexels

 A large, multi-state study highlights how the COVID-19 pandemic has created a cyclical public health problem by both exacerbating mental health challenges and making it more difficult for people to maintain physical activity. The study also reveals that lower-income households struggled more with both mental health challenges and maintaining physical activity levels.

“We know that physical activity is important for helping people maintain their mental health, but this study reveals the unforgiving cycle that the pandemic has imposed on many people,” says Lindsey Haynes-Maslow, co-author of the study and an associate professor of agricultural and human sciences at North Carolina State University.

“The pandemic has increased psychological distress, which makes it more difficult for people to maintain their physical activity levels. This, in turn, further hurts their mental health, which makes them less likely to be active, and so on. Once you get on this roller coaster ride, it’s hard to get off. And all of this is exacerbated by the pandemic making it harder for people to find safe spaces in which to exercise.”

For this study researchers were focused on two questions: How is the pandemic influencing physical activity and mental health status? And how, if at all, do physical activity and mental health status relate to each other?

To address those questions, the researchers conducted an in-depth, online survey of 4,026 adults in Louisiana, Montana, North Carolina, Oregon and West Virginia. The survey was conducted between April and September of 2020.

The researchers found that the more physically active people were, the better their mental health status. That held true even when accounting for an individual’s race/ethnicity, household income and other socioeconomic demographic variables.

Treatments that may protect eggs against ageing

 
The spindle is responsible for separating the chromosomes equally when the oocyte goes through specialist meiotic cell divisions. The spindle is made of fibers called microtubules (green) to which the chromosomes (red) are attached. The use of MitoQ or BGP-15 improves the organization of the microtubules and alignment of the chromosomes to the center of the spindle. The oocyte has an improved chance of properly separating chromosomes and thereby avoiding aneuploidy when the egg is activated by the fertilizing sperm.

A woman’s fertility decreases as she ages – largely because of fewer healthy oocytes or eggs, and those that are available for fertilization often have chromosomal abnormalities which result in a higher incidence of miscarriage and genetic disorders such as Down’s syndrome.

Now a team at the Monash Biomedicine Discovery Institute (BDI) and Robinson Research Institute, collaborating with Monash IVF, has found a potential treatment that targets mitochondria to help prevent these chromosomal errors in mouse and human eggs.

In a paper published in the journal Human Reproduction, researchers led by Professors John Carroll and Rebecca Robker used two mitochondria-targeted therapeutics – called MitoQ and BGP-15 – which appeared to protect eggs from the chromosomal disturbances seen in older or abnormal eggs.

In particular, the addition of these agents improved how immature human eggs organize their chromosomes when matured in laboratory conditions. If this effect holds true for eggs maturing in the body it may also prevent chromosomal abnormalities in human eggs, effectively protecting them against miscarriage or genetic consequences such as Down’s syndrome.

The first author, Dr Usama Al-Zubaidi from the Monash BDI says: “Given that increasing numbers of women delay childbearing there is an imperative to improve fertility and reduce miscarriage and chromosomal anomalies associated with maternal ageing.”

The study identified “two excellent candidates that may one day help to improve fertility in older women.”

The age-related decline in fertility is strongly attributed to ovarian ageing, diminished ovarian reserves, and a decline in oocyte quality. One cause of this is due to increased oxidative stress within the oocytes.

Mitochondria – whether in an oocyte or any other cell in the body - use oxygen to create energy and one of the by-products is the production of free radicals. Oocytes are made during fetal life so have a lot of time to accumulate oxidative damage. Also, as eggs age, their defenses against oxidative damage become compromised. MitoQ and BGP-15 appear to be protecting eggs at least in part by improving mitochondrial function and minimizing oxidative stress during critical periods when the eggs are dividing their chromosomes.

Next steps involve finding the best conditions for these therapies to work when eggs are maturing inside the ovary and if the effects seen on chromosome organization translate into healthier eggs that have a better chance to develop into healthy pregnancies.

“Increasingly, fertility science is turning to therapies that specifically target these mitochondria with a view to preventing the chromosomal abnormalities that occur due to ageing and oxidative stress,” Professor Carroll said.

“Our study looked at two of these candidates to see whether they in fact made a difference to older eggs from humans and mice and found they can make the older eggs ‘younger’ again.” They were very effective at one level, but we are now working on seeing if this approach can work in patients.”

Both MitoQ and BGP-15 are used in humans already, – with MitoQ used to treat age associated hypertension while BGP-15 has been used in clinical trials for diabetes where it was given orally.

Medical Director Monash IVF, Professor Luk Rombauts said that improving function of the mitochondria, which he calls “the little energy factories within the eggs”, is one of the potential strategies to enhance egg quality and reproductive success, even more so in older women. “Monash IVF is keen to continue its collaboration with Professor John Carroll’s lab to find meaningful ways to turn this research into new treatment strategies.”

Source/Credit: Monash University

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Sunday, September 19, 2021

Plasma doesn’t help severely ill COVID-19 patients

 

Giving severely ill COVID-19 patients a transfusion of blood from donors who have already recovered from the virus did not help them improve — and in some cases made them sicker, according to a major Canadian-led clinical trial reporting results in Nature Medicine.

“Convalescent plasma had been found to boost immunity in patients infected with some other viral entities, including SARS, in the past,” said local principal investigator Susan Nahirniak, professor of laboratory medicine and pathology in the University of Alberta’s Faculty of Medicine & Dentistry and medical/scientific lead for the Alberta Precision Laboratories transfusion and transplantation medicine program.

“But this trial did not demonstrate any benefit in terms of changing the course for patients who were admitted to hospital needing oxygen for SARS-CoV-2,” Nahirniak said. “It did not prevent intubation or death.”

The randomized controlled study followed 921 COVID-19 patients in Canada, the United States and Brazil who were admitted to hospital within 12 days of the onset of their respiratory symptoms. Two-thirds (614 patients) received convalescent plasma transfusions and one-third (307 patients) did not.

Of the convalescent plasma group, 199 of the patients required intubation or died, while 86 patients in the control group had these outcomes. Patients in the convalescent arm also experienced more serious adverse events such as needing more oxygen or worsening respiratory failure. The trial was terminated early when researchers realized the outcomes were not positive.

Varying immune responses

Another finding of the trial was that the level of neutralizing antibodies, or titres, in the blood of recovered COVID-19 patients was highly variable, which may have implications for how the population responds to vaccination.

“We were finding that several of the people who had signed up as donors were dropping their titres fairly quickly, so maintaining that donor pool was a challenge,” said Nahirniak. 

“It is proof that just because you’ve had COVID once doesn’t mean you can’t have it again,” she said. “It reinforces the need to be vigilant and possibly give boosters, similar to what we do with influenza.”

At the same time, the research team found that some donors had higher levels of non-functional antibodies against the virus’s spike protein. They reported that recipients of this plasma seemed to have poorer outcomes and recommended continued research on the prevalence and impact of these antibodies.

“If COVID is part of our lives going forward and there are certain antibodies that could be potentially harmful, is that something we need to be testing for and screening out for plasma donors?” Nahirniak posited.

Nahirniak noted that participating in the trial during the early days of the COVID-19 pandemic, when few treatments had been identified, helped to boost morale for both patients and clinical staff.

“We felt like we could do nothing, so at least this was an option, identifying the patients early on and getting them monitored.”

Nahirniak noted she was surprised by the disappointing results, but “that’s why we do a trial — we anticipated better success against the virus.”

The study was funded by the Canadian Institutes of Health Research and numerous local health agencies, including the University of Alberta Hospital Foundation and Alberta Health Services.

Source/Credit: University of Alberta

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Saturday, September 18, 2021

How a plant virus could protect and save your lungs from metastatic cancer

 
Nanoparticles engineered from the cowpea mosaic virus have shown efficacy
in treating and greatly reducing the spread of metastatic cancers in the lungs of mice.
Using a virus that grows in black-eyed pea plants, nanoengineers at the University of California San Diego developed a new treatment that could keep metastatic cancers at bay from the lungs. The treatment not only slowed tumor growth in the lungs of mice with either metastatic breast cancer or melanoma, it also prevented or drastically minimized the spread of these cancers to the lungs of healthy mice that were challenged with the disease.

The research was published in the journal Advanced Science.

Cancer spread to the lungs is one of the most common forms of metastasis in various cancers. Once there, it is extremely deadly and difficult to treat.

Researchers at the UC San Diego Jacobs School of Engineering developed an experimental treatment that combats this spread. It involves a bodily injection of a plant virus called the cowpea mosaic virus. The virus is harmless to animals and humans, but it still registers as a foreign invader, thus triggering an immune response that could make the body more effective at fighting cancer.

The idea is to use the plant virus to help the body’s immune system recognize and destroy cancer cells in the lungs. The virus itself is not infectious in our bodies, but it has all these danger signals that alarm immune cells to go into attack mode and search for a pathogen, said Nicole Steinmetz, professor of nanoengineering at UC San Diego and director of the university’s Center for Nano-ImmunoEngineering.

To draw this immune response to lung tumors, Steinmetz’s lab engineered nanoparticles made from the cowpea mosaic virus to target a protein in the lungs. The protein, called S100A9, is expressed and secreted by immune cells that help fight infection in the lungs. And there is another reason that motivated Steinmetz’s team to target this protein: overexpression of S100A9 has been observed to play a role in tumor growth and spread.

“For our immunotherapy to work in the setting of lung metastasis, we need to target our nanoparticles to the lung,” said Steinmetz. “Therefore, we created these plant virus nanoparticles to home in on the lungs by making use of S100A9 as the target protein. Within the lung, the nanoparticles recruit immune cells so that the tumors don’t take.”

“Because these nanoparticles tend to localize in the lungs, they can change the tumor microenvironment there to become more adept at fighting off cancer—not just established tumors, but future tumors as well,” said Eric Chung, a bioengineering Ph.D. student in Steinmetz’s lab who is one of the co-first authors on the paper.

To make the nanoparticles, the researchers grew black-eyed pea plants in the lab, infected them with cowpea mosaic virus, and harvested the virus in the form of ball-shaped nanoparticles. They then attached S100A9-targeting molecules to the surfaces of the particles.

The researchers performed both prevention and treatment studies. In the prevention studies, they first injected the plant virus nanoparticles into the bloodstreams of healthy mice, and then later injected either triple negative breast cancer or melanoma cells in these mice. Treated mice showed a dramatic reduction in the cancers spreading to their lungs compared to untreated mice.

In the treatment studies, the researchers administered the nanoparticles to mice with metastatic tumor in their lungs. These mice exhibited smaller lung tumors and survived longer than untreated mice.

What’s remarkable about these results, the researchers point out, is that they show efficacy against extremely aggressive cancer cell lines. “So, any change in survival or lung metastasis is pretty striking,” said Chung. “And the fact that we get the level of prevention that we do is really, really amazing.”

Steinmetz envisions that such a treatment could be especially helpful to patients after they have had a cancerous tumor removed. “It wouldn’t be meant as an injection that’s given to everyone to prevent lung tumors. Rather, it would be given to patients who are at high risk of their tumors growing back as a metastatic disease, which often manifests in the lung. This would offer their lungs protection against cancer metastasis,” she said.

Before the new treatment can reach that stage, the researchers need to do more detailed immunotoxicity and pharmacology studies. Future studies will also explore combining this with other treatments such as chemotherapy, checkpoint drugs or radiation.

Source/Credit: UC San Diego Jacobs School of Engineering

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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.

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

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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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

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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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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Tuesday, September 7, 2021

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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Monday, September 6, 2021

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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Sunday, September 5, 2021

Coronavirus Epidemics first hit more than 21,000 years ago

 

Sarbecoviruses have crossed into humans twice in the last decade, leading to the deadly SARS-CoV-1 outbreak in 2002-04 and the current COVID-19 pandemic, caused by the SARS-CoV-2 virus.  A new Oxford University Study, published today, shows that the most recent common ancestor of these viruses existed more than 21,000 years ago, nearly 30 times older than previous estimates.

‘Finding the evolutionary origins of pandemic viral infections such as COVID-19 help us understand how long humanity may have been exposed to these viruses, how frequently they might have caused disease outbreaks in the past, and how likely they might be to cause novel outbreaks in future.’ Said Prof Katzourakis, who led the work.

Despite having a very rapid rate of evolution over short timescales, to survive, viruses must remain highly adapted to their hosts - this imposes severe restrictions on their freedom to accumulate mutations without reducing their fitness. This causes the apparent rate of evolution of viruses to slow down over time. The new research, for the first time, successfully recreates the patterns of this observed rate decay in viruses. 

‘We developed a new method that can recover the age of viruses over longer timescales and correct for a kind of ‘evolutionary relativity’, where the apparent rate of evolution depends on the timescale of measurement. Our estimate based on viral sequence data, of more than 21,000 years ago, is in remarkable concordance with a recent analysis on human genomic dataset that suggests infection with an ancient coronavirus around the same time.’ Said Mahan Ghafari, from Oxford University.

The study also demonstrates that while existing evolutionary models have often failed to measure the divergence between virus species over periods - from a few hundred to a few thousands of years - the evolutionary framework developed in this study will enable the reliable estimation of virus divergence across vast timescales, potentially over the entire course of animal and plant evolution. 

The new model enables us to not only reconstruct the evolutionary history of viruses related to SARS-CoV-2, but also a much wider range of RNA and DNA viruses during more remote periods in the past. 

The model predictions for hepatitis C virus - a leading global cause of liver disease - are consistent with the idea that it has circulated for nearly a half a million years. HCV may thus have spread worldwide as an intrinsic part of the “Out-of-Africa” migration of modern humans around 150,000 years ago. 

The different genotypes of HCV indigenous to human populations in South and South-East Asia and Central Africa may have originated over this prolonged period and this revised timescale may resolve the longstanding riddle of their global distributions. 

‘With this new technique we can look much more widely at other viruses; re-evaluate the timescales of their deeper evolution and gain insights into host relationships that are key to understanding their ability to cause disease.’ Prof Simmonds, Oxford University

Source / Credit: University of Oxford

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Tuesday, August 31, 2021

New biomarkers identified to detect consumption of emerging illicit drug

Professor Eric Chan (middle) from the NUS Department of Pharmacy led the research which was conducted in collaboration with the Health Sciences Authority (HSA).
The research team included Ms Moy Hooi Yan (extreme left), HSA’s Laboratory Director of the Analytical Toxicology Lab - Drug Abuse Testing, and Dr Wang Ziteng (extreme right), Research Fellow at the NUS Department of Pharmacy.

 A team of researchers from the National University of Singapore (NUS) has come up with a new solution to boost the surveillance of designer drug abuse. Led by Professor Eric Chan from the NUS Department of Pharmacy, the team has identified three new urinary biomarkers that could be used to detect consumption of ADB-BUTINACA, an emerging synthetic cannabinoid which is a type of new psychoactive substance (NPS). The innovative approach used to identify the biomarkers can be applied to other existing and new synthetic cannabinoids.

NPS are drugs designed to mimic the effects of illegal substances such as cannabis, cocaine, heroin, ‘Ice’, Ecstacy and LSD. The intention of the clandestine laboratories to introduce synthetic cannabinoids with different chemical structures is to try to circumvent legislative bans.

Over the past two years, users of NPS made up the third largest proportion of drug abusers in Singapore, while synthetic cannabinoids have dominated Singapore’s NPS market for the past four years. As most synthetic cannabinoids are extensively metabolized in the body after consumption, they become virtually undetectable in urine samples.

Commenting on the significance of the team’s research, Prof Chan said, “Prior to our study, the metabolism and urinary biomarkers of ADB-BUTINACA were unclear. Our discovery and unique methodology offer assistance to the forensic fraternity who is constantly being challenged by the emergence of novel synthetic cannabinoids, and can also bring benefits to the international public communities to tackle the increasing abuse of this synthetic cannabinoid. This will bring us closer to the goal of having a drug-free world.”

The study, which was carried out in collaboration with the Analytical Toxicology Laboratory of Singapore’s Health Sciences Authority, was first published in the journal Clinical Chemistry on 13 August 2021.

New biomarkers for accurate detection of synthetic drug abuse

ADB-BUTINACA is a new synthetic cannabinoid that was first identified in Europe in 2019, and it entered Singapore’s drug scene last year. Although three existing metabolites of ADB-BUTINACA are available as reference standards for routine forensic monitoring, they have been found to be absent or detected at lower concentrations in some urine samples of abusers. This created an impetus to identify other potential metabolites for use as urinary biomarkers for the cannabinoid’s consumption.

Instead of using the conventional and more time-consuming method of chemically synthesizing metabolites of ADB-BUTINACA, Prof Chan and his team introduced an innovative method to identify the cannabinoid’s unique metabolites using the concepts of drug metabolism and pharmacokinetics.

The team synthesized key metabolites of ADB-BUTINACA using human liver enzymes in the laboratory for investigating their disposition and identifying novel biomarker metabolites in urine. From their studies, a total of 15 metabolites of ADB-BUTINACA and their respective pathways of biotransformation in the body were identified for the first time using this method.

Of the 15 new metabolites, the researchers proposed four as urinary metabolite biomarkers due to their metabolic stability, including one metabolite where its reference standard is currently available. A panel comprising either one or a combination of these four newly-established urinary biomarkers was developed for diagnosing the consumption of ADB-BUTINACA.

Moving forward, the team plans to extend their current strategy to better understand the disposition of novel metabolites of synthetic cannabinoids by kidneys and their eventual occurrence in urine.

Source/Credit: National University of Singapore

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