Discovery of how blood clots harm brain and body in COVID-19 points to new therapy

In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also suppressing the body's ability to clear the virus.

Importantly, the team also identified a new antibody therapy to combat all of these deleterious effects.

Published in Nature, the study by Gladstone Institutes and collaborators overturns the prevailing theory that blood clotting is merely a consequence of inflammation in COVID-19. Through experiments in the lab and with mice, the researchers show that blood clotting is instead a primary effect, driving other problems -- including toxic inflammation, impaired viral clearance, and neurological symptoms prevalent in those with COVID-19 and long COVID.

The trigger is fibrin, a protein in the blood that normally enables healthy blood coagulation, but has previously been shown to have toxic inflammatory effects. In the new study, scientists found that fibrin becomes even more toxic in COVID-19 as it binds to both the virus and immune cells, creating unusual clots that lead to inflammation, fibrosis, and loss of neurons.

"Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can build a new path forward for treating the disease at the root," says Katerina Akassoglou, PhD, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. "In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection."

From the earliest months of the pandemic, irregular blood clotting and stroke emerged as puzzling effects of COVID-19, even among patients who were otherwise asymptomatic. Later, as long COVID became a major public health issue, the stakes grew even higher to understand the cause of this disease's other symptoms, including its neurological effects. More than 400 million people worldwide have had long COVID since the start of the pandemic, with an estimated economic cost of about $1 trillion each year.

Flipping the Conversation

Many scientists and medical professionals have hypothesized that inflammation from the immune system's rapid reaction to the COVID-causing virus is what leads to blood clotting and stroke. But even at the dawn of the pandemic in 2020, that explanation didn't sound right to Akassoglou and her scientific collaborators.

"We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity like we see with COVID," says Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, who co-led the study with Akassoglou.

"We began to wonder if blood clots played a principal role in COVID -- if this virus evolved in a way to hijack clotting for its own benefit," Akassoglou adds.

Indeed, through multiple experiments in mice, the researchers found that the virus spike protein directly binds to fibrin, causing structurally abnormal blood clots with enhanced inflammatory activity. The team leveraged genetic tools to create a specific mutation that blocks only the inflammatory properties of fibrin without affecting the protein's beneficial blood-clotting abilities.

When mice were genetically altered to carry the mutant fibrin or had no fibrin in their bloodstream, the scientists found that inflammation, oxidative stress, fibrosis, and clotting in the lungs didn't occur or were much reduced after COVID-19 infection.

In addition to discovering that fibrin sets off inflammation, the team made another important discovery: fibrin also suppresses the body's "natural killer," or NK, cells, which normally work to clear the virus from the body. Remarkably, when the scientists depleted fibrin in the mice, NK cells were able to clear the virus.

These findings support that fibrin is necessary for the virus to harm the body.

Mechanism Not Triggered by Vaccines

The fibrin mechanism described in the paper is not related to the extremely rare thrombotic complication with low platelets that has been linked to adenoviral DNA COVID-19 vaccines, which are no longer available in the U.S.

By contrast, in a study of 99 million COVID-vaccinated individuals led by The Global COVID Vaccine Safety Project, vaccines that leverage mRNA technology to produce spike proteins in the body exhibited no excessive clotting or blood-based disorders that met the threshold for safety concerns. Instead, mRNA vaccines protect from clotting complications otherwise induced by infection.

Protecting the Brain

Akassoglou's lab has long investigated how fibrin that leaks into the brain triggers neurologic diseases, such as Alzheimer's disease and multiple sclerosis, essentially by hijacking the brain's immune system and setting off a cascade of harmful, often irreversible, effects.

The team now showed that in COVID-infected mice, fibrin is responsible for the harmful activation of microglia, the brain's immune cells involved in neurodegeneration. After infection, the scientists found fibrin together with toxic microglia and when they inhibited fibrin, the activation of these toxic cells in the brains of mice was significantly reduced.

"Fibrin that leaks into the brain may be the culprit for COVID-19 and long COVID patients with neurologic symptoms, including brain fog and difficulty concentrating," Akassoglou says. "Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection."

The team tested its approach on different strains of the virus that causes COVID-19, including those that can infect the brain and those that do not. Neutralizing fibrin was beneficial in both types of infection, pointing to the harmful role of fibrin in brain and body in COVID-19 and highlighting the broad implications of this study.

A New Potential Therapy

This study demonstrates that fibrin is damaging in at least two ways: by activating a chronic form of inflammation and by suppressing a beneficial NK cell response capable of clearing virally infected cells.

"We realized if we could neutralize both of these negative effects, we could potentially resolve the severe symptoms we're seeing in patients with COVID-19 and possibly long COVID," Greene says.

Akassoglou's lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on fibrin's inflammatory properties without adverse effects on blood coagulation and protects mice from multiple sclerosis and Alzheimer's disease.

In the new study, the team showed that the antibody blocked the interaction of fibrin with immune cells and the virus. By administering the immunotherapy to infected mice, the team was able to prevent and treat severe inflammation, reduce fibrosis and viral proteins in the lungs, and improve survival rates. In the brain, the fibrin antibody therapy reduced harmful inflammation and increased survival of neurons in mice after infection.

A humanized version of Akassoglou's first-in-class fibrin-targeting immunotherapy is already in Phase 1 safety and tolerability clinical trials in healthy people by Therini Bio. The drug cannot be used on patients until it completes this Phase 1 safety evaluation, and then would need to be tested in more advanced trials for COVID-19 and long COVID.

Looking ahead to such trials, Akassoglou says patients could be selected based on levels of fibrin products in their blood -- a measure believed to be a predictive biomarker of cognitive impairment in long COVID.

"The fibrin immunotherapy can be tested as part of a multipronged approach, along with prevention and vaccination, to reduce adverse health outcomes from long COVID," Greene adds.

The Power of Team Science

The study's findings intersect the scientific areas of immunology, hematology, virology, neuroscience, and drug discovery -- and required many labs across institutions to work together to execute experiments required to solve the blood-clotting mystery. Akassoglou founded the Center for Neurovascular Brain Immunology at Gladstone and UCSF in 2021 specifically for the purpose of conducting multidisciplinary, collaborative studies that address complex problems.

"I don't think any single lab could have accomplished this on their own," says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-author of the study, noting important contributions from teams at Stanford, UC San Francisco, UC San Diego, and UCLA. "This tour-de-force study highlights the importance of collaboration in tackling these big questions."

Not only did this study address a big question, but it did so in a way that paves a clear clinical path for helping patients who have few options today, says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.

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A backpack full of multiple sclerosis therapy

Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients' ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.

A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the "innate" immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These "acute inflammatory lesions" then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system's second arm, known as the "adaptive immune system" and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.

Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to existing small molecule and protein therapies that leverages myeloid cells, the very type of immune cells that cause the MS-triggering nerve inflammation in patients.

To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed "backpacks," to the cells' surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells' differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNAS).

"Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state," said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. "In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients' peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly." Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.

New spin for cellular backpacks

Mitragotri's group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells' surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells' behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.

"Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense," said first author Neha Kapate, a graduate student working with Mitragotri. "We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect."

The team fabricated their micrometer-size backpacks via a process known as serial "spin coating," in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.

Cellular backpacks get legs

To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model. "When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome," said Kapate. "The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response."

The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals' hind limbs. The treatment also extended the animals' survival -- all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent "relapsing-remitting" form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.

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Key protein identified for brain stem cell longevity

A receptor that was first identified as necessary for insulin action, that also is located on the neural stem cells found deep in the brains of mice, is pivotal for brain stem cell longevity, according to a Rutgers study, a finding that has important implications for brain health and future therapies for brain disorders.

The study, appearing in the journal Stem Cell Reports, pinpoints a specific protein known as the insulin receptor (INSR), which is abundant on the neural stem cells that reside in the brain's subventricular zone. During development, neural stem cells give rise to the entire nervous system, and they persist into adulthood. Over the lifespan these neural stem cells produce new neurons and non-neuronal cells that maintain the infrastructure and functioning of the brain.

Separately, the scientists made another finding when examining brain tumors: INSR plays a crucial role in sustaining and maintaining a population of specialized brain cancer cells known as glioblastoma (GBM) stem cells. When they inactivated the INSR in the GBM stem cells they inhibited the growth of those primitive tumor forming cells.

"It's important to understand the molecular mechanisms that are critical for the growth and sustenance of the brain's stem cells under normal and abnormal growth states," said study author Steven Levison, a professor of neuroscience in the Department of Pharmacology, Physiology and Neuroscience and director of the Laboratory for Regenerative Neurobiology at Rutgers New Jersey Medical School. "Comprehending the signals that regulate these primitive cells could one day lead to new therapeutics for brain disorders."

Many neurodegenerative disorders, such as multiple sclerosis, Parkinson disease and Alzheimer's disease, are connected with the destruction of brain cells, said co-author Teresa Wood, a Distinguished Professor and Rena Warshow Endowed Chair in Multiple Sclerosis in the Department of Pharmacology, Physiology and Neuroscience at Rutgers New Jersey Medical School.

"If we could influence how brain stem cells function then we can use this knowledge to replace diseased or dead brain cells with living ones, which would advance the treatment of neurological diseases and brain injuries," said Wood, who also teaches and conducts research at the Cancer Institute of New Jersey.

Cell receptors such as INSR are protein molecules that reside on the surfaces of cells. Substances, either natural or human-made, that open the "lock" of a receptor can spur a cell to divide, differentiate or die. By identifying which receptors perform these functions on specific cell types, and by understanding their structures and functions, scientists can design substances that act as keys to receptors, to turn them "on" or "off."

Previous studies by this research team had shown that a certain "key," the signaling protein known as the insulin-like growth factor-II (IGF-II), was necessary to maintain the neural stem cells in the two places of the adult brain that harbor these primitive cells. In the current experiment, scientists were looking to identify the receptor. To do so, they used genetic tools that allowed them to both delete the INSR and introduce a fluorescent protein so they could track the neural stem cells and the cells they generate. They found that the numbers of neural stem cells in the subventricular zone in the brains of mice lacking the INSR collapsed.

Adult neurogenesis -- the idea that new cells are produced in the adult brain -- has been a burgeoning field of scientific inquiry since the late 1990s, when researchers confirmed what had only been a theory in lab studies of human, primate and bird brains. Neural stem cells in the adult are stem cells that can self-renew and produce new neurons and the supporting cells of the brain, oligodendrocytes and astrocytes.

"Given the widespread interest in stem cells as well as interest in whether alterations to adult stem cells might contribute to cancer, our research findings should be of interest," Levison said.

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New study reveals why HIV remains in human tissue even after antiretroviral therapy

Thanks to antiretroviral therapy, HIV infection is no longer the life sentence it once was. But despite the effectiveness of drugs to manage and treat the virus, it can never be fully eliminated from the human body, lingering in some cells deep in different human tissues where it goes unnoticed by the immune system.

Now, new research by University of Alberta immunologist Shokrollah Elahi reveals a possible answer to the mystery of why infected people can't get rid of HIV altogether.

Elahi and his team found that in HIV patients, killer T cells -- a type of white blood cells responsible for identifying and destroying cells infected with viruses -- have very little to none of a protein called CD73.

Because CD73 is responsible for migration and cell movement into the tissue, the lack of the protein compromises the ability of killer T cells to find and eliminate HIV-infected cells, explained Elahi.

"This mechanism explains one potential reason for why HIV stays in human tissues forever," he said, adding that the research also shows the complexity of HIV infection.

"This provides us the opportunity to come up with potential new treatments that would help killer T cells migrate better to gain access to the infected cells in different tissues."

After identifying the role of CD73 -- a three-year project -- Elahi turned his focus to understanding potential causes for the drastic reduction. He found it is partly due to the chronic inflammation that is common among people living with HIV.

"Following extensive studies, we discovered that chronic inflammation results in increased levels of a type of RNA found in cells and in blood, called microRNAs," he explained. "These are very small types of RNA that can bind to messenger RNAs to block them from making CD73 protein. We found this was causing the CD73 gene to be suppressed."

The team's discovery also helps explain why people with HIV have a lower risk of developing multiple sclerosis, Elahi noted.

"Our findings suggest that reduced or eliminated CD73 can be beneficial in HIV-infected individuals to protect them against MS. Therefore, targeting CD73 could be a novel potential therapeutic marker for MS patients."

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Toward 'off-the-shelf’ immune cell therapy for cancer

Immunotherapies, which harness the body's natural defenses to combat disease, have revolutionized the treatment of aggressive and deadly cancers. But often, these therapies -- especially those based on immune cells -- must be tailored to the individual patient, costing valuable time and pushing their price into the hundreds of thousands of dollars.

Now, in a study published in the journal Cell Reports Medicine, UCLA researchers report a critical step forward in the development of an "off-the-shelf" cancer immunotherapy using rare but powerful immune cells that could potentially be produced in large quantities, stored for extended periods and safely used to treat a wide range of patients with various cancers.

"In order to reach the most patients, we want cell therapies that can be mass-produced, frozen and shipped to hospitals around the world," said Lili Yang, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the study's senior author. "That way, doses of these therapies can be ready and waiting for patients as soon as they are needed."

For the study, Yang and her colleagues focused on invariant natural killer T cells, or iNKT cells, which are unique not only for their power and efficacy but also because they don't carry the risk of graft-versus-host disease, which occurs when transplanted cells attack a recipient's body and which is the reason most cell-based immunotherapies must be created on a patient-specific basis, Yang said.

The researchers developed a new method for producing large numbers of these iNKT cells using blood-forming stem cells, which can self-replicate and produce all kinds of blood and immune cells. The team used stem cells obtained from four donor cord-blood samples and eight donor peripheral blood samples.

"Our findings suggest that one cord blood donation could produce up to 5,000 doses of the therapy and one peripheral blood donation could produce up to 300,000 doses," said Yang, who is also an associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. "At this yield, the cost of producing immune cell products could be dramatically reduced."

The researchers first used genetic engineering to program the blood-forming stem cells to make them more likely to develop into iNKT cells. Next, these genetically engineered stem cells were placed into artificial thymic organoids, which mimic the environment of the thymus, a specialized organ in which T cells naturally mature in the body. After eight weeks in the organoids, each stem cell produced, on average, 100,000 iNKT cells.

Yang and her collaborators then tested the resulting cells, called hematopoietic stem cell-engineered iNKT cells, or HSC-iNKT cells, by comparing their cancer-fighting abilities with those of immune cells called natural killer cells, or NK cells. In a lab dish, the HSC-iNKT cells were significantly better at killing multiple types of human tumor cells -- including leukemia, melanoma, lung cancer, prostate cancer and multiple myeloma cells -- than the NK cells, the researchers found.

Even more importantly, the HSC-iNKT cells sustained their tumor-killing efficacy after being frozen and thawed, an essential requirement for widespread distribution of an off-the-shelf cell therapy.

The researchers next equipped the HSC-iNKT cells with a chimeric antigen receptor, or CAR, a specialized molecule used in some immunotherapies to enable immune cells to recognize and kill a specific type of cancer. In this case, they added to the HSC-iNKT cells a CAR that targets a protein found on multiple myeloma cells and then tested the cells' ability to fight human multiple myeloma tumors that had been transplanted into mice.

These CAR-equipped HSC-iNKT cells eliminated the multiple myeloma tumors, and the mice that underwent this treatment remained tumor-free and showed no signs of complications such as graft-versus-host disease throughout their lives.

The researchers are now working to improve their manufacturing methods by moving to a feeder-free system that eliminates the need for supportive cells -- such as those used in the thymic organoids -- to assist blood stem cells in producing iNKT cells. Yang says she hopes this advance will better enable mass-production of the therapy and, ultimately, its clinical and commercial development.

The paper's co-first authors are UCLA doctoral students Yan-Ruide (Charlie) Li and Yang (Alice) Zhao. Additional authors include UCLA professors Dr. Sarah Larson, Dr. Joshua Sasine, Dr. Xiaoyan Wang, Matteo Pellegrini, Dr. Owen Witte and Dr. Antoni Ribas.

The researchers' genetic engineering of blood-forming stem cells utilized methods developed by Dr. Donald Kohn, and the artificial thymic organoids were developed by Dr. Gay Crooks, Dr. Chris Seet and Amélie Montel-Hagen, all of the UCLA Broad Stem Cell Research Center.

The methods and products described in this study are covered by patent applications filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Li, Yu Jeong Kim, Jiaji Yu, Pin Wang, Yanni Zhu, Crooks, Montel-Hagen and Seet listed as co-inventors. The treatment strategy was used in preclinical tests only; it has not been tested in humans or approved by the U.S. Food and Drug Administration as safe and effective for use in humans.

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Potential strategy for fighting obesity

UT Southwestern scientists may have identified a method of safely mimicking the weight-loss benefits of a plant compound that -- despite its harmful side effects -- hold critical answers to developing therapies for obesity.

Celastrol, derived from the root extracts of a white-flowered plant in China, has drawn increased attention in recent years after studies showed it can both prevent and reverse obesity in mice. However, because celastrol can cause reactions such as high blood pressure and lethargy in mice, researchers have sought to understand how the compound works and use that knowledge to develop safe weight-loss treatments for people.

UT Southwestern may have solved part of the puzzle in a new study that shows celastrol requires a specific protein in a type of neuron that influences metabolism. Scientists found they can mimic a "fed" signal to mouse brains by deleting this protein from the neurons, resulting in mice losing 7% of their body weight in two weeks despite being a fed high-fat diet.

Key to the findings: The mice did not appear to endure the same physical ailments documented in previous research in which celastrol was administered.

"This new understanding of how celastrol works on the cellular level opens more possibilities for targeting pathways that can improve our metabolism without the negative health impact," said study author Kevin W. Williams, Ph.D., an investigator at UT Southwestern's Center for Hypothalamic Research. "We haven't uncovered all the cell populations that influence weight loss, but each of these findings brings us closer to developing effective, safe therapies for obesity."

The study, published in JCI Insight, is the latest research from Dr. Williams that may someday help improve glucose metabolism in patients with obesity-driven conditions such as diabetes. More than 30 million Americans have diabetes, accounting for nearly 10% of the population, according to the Centers for Disease Control and Prevention.

The new research focused on a class of cells in the brain called POMC neurons, which are associated with reduced appetite, lower blood glucose levels, and higher energy burning when activated. A 2019 study from Dr. Williams showed a single bout of exercise can boost the activity of POMC for up to two days.

In the latest research, the Williams lab found this neuron also plays a critical part in how celastrol impacts weight loss. Mice given the compound saw decreased activity of a protein called PERK within the region of the brain where POMC neurons reside. The lab further found that deleting PERK from these neurons can replicate much of the weight-loss effects of celastrol, and appears to do so without causing harmful side effects often associated with anti-obesity drugs.

"The mice were leaner and had the same activity levels; they didn't appear lethargic, sickly or ill," Dr. Williams said. "But this is through observation only. Further study is needed to verify how targeting this pathway may be influencing their cardiovascular systems and other functions."

The Food and Drug Administration cautions people against the use of celastrol, a substance also known as thunder god vine used in traditional Chinese medicine. Although extracts from the plant are sold as supplements, the National Institutes of Health (NIH) has posted cautionary statements saying scientists do not yet have enough data about celastrol's safety and effectiveness.

But the compound has already given scientists important insight into how safer strategies for weight loss may be developed in the lab. In the new study, for instance, deleting PERK from the POMC neurons blocked about half the food intake-reducing effect of celastrol.

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Researchers find warning signs for dementia in the blood

Researchers at the DZNE and the University Medical Center Göttingen (UMG) have identified molecules in the blood that can indicate impending dementia. Their findings, which are presented in the scientific journal EMBO Molecular Medicine, are based on human studies and laboratory experiments. Various university hospitals across Germany were also involved in the investigations. The biomarker described by the team led by Prof. André Fischer is based on measuring levels of so-called microRNAs. The technique is not yet suitable for practical use; the scientists therefore aim to develop a simple blood test that can be applied in routine medical care to assess dementia risk. According to the study data, microRNAs could potentially also be targets for dementia therapy.

"When symptoms of dementia manifest, the brain has already been massively damaged. Presently, diagnosis happens far too late to even have a chance for effective treatment. If dementia is detected early, the odds of positively influencing the course of the disease increase," says André Fischer, research group leader and spokesperson at the DZNE site in Göttingen and professor at the Department of Psychiatry and Psychotherapy at UMG. "We need tests that ideally respond before the onset of dementia and reliably estimate the risk of later disease. In other words, tests that give an early warning. We are confident that our current study results pave the way for such tests."

Molecular Signature

The biomarker that Fischer and his colleagues have found is based on measuring so-called microRNAs in the blood. MicroRNAs are molecules with regulatory properties: they influence the production of proteins and thus a key process in the metabolism of every living being. "There are many different microRNAs and each of them can regulate entire networks of interdependent proteins and thus influence complex processes in the organism. So, microRNAs have a broad impact. We wanted to find out whether there are specific microRNAs whose presence in the blood correlates with mental fitness," Fischer says.

Through extensive studies in humans, mice and cell cultures, the researchers ultimately identified three microRNAs whose levels were associated with mental performance. For this, they analyzed data from both young, cognitively normal individuals and from elderly people with mild cognitive impairment (MCI). For the data from healthy individuals, the Göttingen scientists cooperated with Munich University Hospital. The data from MCI patients came from a DZNE study that has been running for years and involves university clinics throughout Germany.

Omens of Dementia

In the end, the various findings came together like pieces of a puzzle: In healthy individuals, levels of microRNAs correlated with mental fitness. The lower the blood level, the better the subjects performed in cognition tests. In mice, in turn, this score increased even before the rodents started to show mental decline -- regardless of whether this was due to age or because they developed symptoms similar to those of Alzheimer's dementia. Further evidence came from patients with MCI: Of those in whom the blood marker was highly elevated, about 90 percent developed Alzheimer's disease within two years. "We therefore see an increased blood level of these three microRNAs as a harbinger of dementia," Fischer says. "We estimate that in humans this biomarker indicates a development that is about two to five years in the future."

Potential Targets for Therapy

In their studies on mice and cell cultures, the researchers also found that the three identified microRNAs influence inflammatory processes in the brain and "neuroplasticity" which includes the ability of neurons to establish connections with each other. This suggests that the three microRNAs are more than warning signals. "In our view, they are not only markers, but also have an active impact on pathological processes. This makes them potential targets for therapy," Fischer says. "Indeed, we see in mice that learning ability improves when these microRNAs are blocked with drugs. We've observed this in mice with age-related mental deficits, as well as in mice with brain damage similar to that occurring in Alzheimer's disease."

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Natural immunity to malaria provides clues to potential therapies

WEHI researchers have identified how natural human antibodies can block malaria parasites from entering red blood cells, potentially indicating how new protective therapies could be developed against this globally significant disease.

The research provides greater insight into how antibodies block the entry of Plasmodium vivax malaria parasites into young red blood cells called reticulocytes. It builds on an earlier discovery that the P. vivax latches onto the transferrin receptor 1 (TfR1) to enter cells.

The research, led by Associate Professor Wai-Hong Tham and PhD student Li-Jin Chan from WEHI, alongside Professor Christopher King from Case Western University, US, was published in Nature Communications.

At a glance
 

• By examining antibodies from people with a history of malaria infection, researchers observed that naturally occurring antibodies can block Plasmodium vivax from latching onto transferrin receptor 1 on reticulocytes.
• One way the antibodies work is by preventing parasite proteins from getting close enough to the cell to allow parasite entry.
• The discovery opens up new avenues for developing antibody-based therapies for malaria.
   
• Shedding light on pathogen-blocking antibodies
   
• Plasmodium vivax is the most widespread malaria parasite in the world, and the predominant cause of malaria in the vast majority of countries outside Africa. It is also the main parasite responsible for recurrent malaria infections.

The malaria parasite is a complex single-celled organism, with diverse proteins that help it to invade red blood cells, reproduce and spread. Adhesins on the surface of the parasite are key-like proteins that 'unlock' cells, allowing the parasite to enter.

Previous research studies in Papua New Guinea, Thailand and Brazil showed antibodies against P. vivax adhesins were correlated with protection against infection and disease, Associate Professor Tham said.

"We wanted to understand how these human antibodies in natural infection block the parasite from getting in. By extracting and examining antibodies from people who have had P. vivax infections, we identified the different ways human antibodies against P. vivax work. One of these ways, is by stopping the parasite adhesins from getting too close to the reticulocyte membrane, denying the parasite entry," she said.

This discovery opens the door to potentially preventing not only P. vivax malaria, but also P. falciparum malaria, another significant cause of deaths globally.

"Although this was a vivax study, we believe the implications are that a broadly neutralising antibody could be created to target both P. vivax and P. falciparum malaria infections," Associate Professor Tham said.

Improving detection of relapsing malaria

WEHI Professor Ivo Mueller said beyond understanding how antibodies can block infection, there was also a crucial need to understand the development of immunity and how this could be used to detect P. vivax infections in endemic populations.

"We are currently using this information to develop diagnostic tests that will be used in the field to identify and treat people with hidden vivax infection in their livers and spleens. This is a key step towards eliminating malaria, by preventing silently infected people reinfecting their communities," he said.

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Study reveals how some antibodies can broadly neutralize ebolaviruses

Some survivors of ebolavirus outbreaks make antibodies that can broadly neutralize these viruses -- and now, scientists at Scripps Research have illuminated how these antibodies can disable the viruses so effectively. The insights may be helpful for developing effective therapies.

Ebolavirus is a family of often-deadly viruses that includes Ebola virus and many lesser-known viruses such as Bundibugyo virus, Sudan virus and Reston virus.

Structural biologists at Scripps Research used electron microscopy techniques to visualize a set of antibodies that target a key site on these viruses called the "glycan cap." Their research showed that the antibodies work against ebolaviruses using the same three mechanisms to prevent the virus from infecting host cells.

The research, published in Cell Reports, is a step toward the creation of an antibody-based treatment that will be useful against a broad range of ebolaviruses.

"We now understand the molecular basis for these antibodies' abilities to neutralize ebolviruses with broad reactivity against different viral species," says the study's first author Daniel Murin, PhD, a staff scientist in the laboratory of Andrew Ward, PhD.

Ward, a professor in the Department of Integrative Structural and Computational Biology at Scripps Research, says he hopes the work will contribute the development of a "cocktail" of therapeutic antibodies that can save lives by treating many forms of the Ebola virus.

"The goal is to provide doctors in Ebola-prone regions their best weapon yet against these deadly outbreaks," Ward says. "The insights we have gained through our structural studies of the virus show how this may be possible."

Ever-emergent Ebola

The first known ebolavirus, now called Zaire ebolavirus or simply Ebola virus, was identified in 1976, named for the site of an outbreak that year near the Ebola river in what was then Zaire and is now the Democratic Republic of Congo.

Other species have since been added to this family of viruses, including Sudan ebolavirus and Bundibugyo ebolavirus. Ebola viruses colonize African fruit bats, often cause disease in chimpanzees and other non-human primates, and trigger outbreaks in humans every few years, on average. Infected people develop a hemorrhagic syndrome that is fatal in roughly half of untreated cases.

Vaccines against Ebola have been developed recently but have not yet been widely used. And although antibody-based treatments also have been developed, none has been shown effective against a broad range of ebolavirus species.

Nevertheless, studies in recent years have shown that some survivors of Ebola infections carry antibodies that, in lab-dish tests, can neutralize multiple ebolavirus species. A surprisingly high proportion of these broadly neutralizing antibodies target the glycan cap, a sugar-slathered site on a stalk-like protein -- called the glycoprotein -- that enables Ebola viruses to enter host cells.

In the new study, Murin and Ward, along with their colleagues in the James Crowe Lab at Vanderbilt University where the antibodies were isolated, used electron microscopy to analyze a set of glycan cap-targeting antibodies from survivors of various ebolaviruses. Their aim was to understand better how these antibodies target the virus so effectively.

Three ways to defeat the virus

Their analysis suggested that the most broadly effective of these glycan cap-targeting antibodies hit the same vulnerable site on the glycan cap, allowing them to thwart viral infectivity in three ways.

First, the antibody displaces a long viral structure near the glycan cap in a way that destabilizes the entire viral glycoprotein structure, sometimes causing it to fall apart.

Second, the glycan cap antibody -- when it binds to its target site -- can block a key event in the infection process, in which an enzyme called a cathepsin cleaves off the glycan cap. Blocking this cleavage event blocks the glycoprotein's ability to enter host cells.

Finally, the glycan cap antibody, by displacing the loose structure near the glycan cap, enables another type of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can "synergize" with another antibody to hit the virus significantly harder than either antibody does alone.

The scientists also determined the key genetic elements that allow glycan-cap antibodies to thwart ebolaviruses in these three ways.

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Friends fur life help build skills for life

 A new UBC Okanagan study finds children not only reap the benefits of working with therapy dogs-they enjoy it too.

"Dog lovers often have an assumption that canine-assisted interventions are going to be effective because other people are going to love dogs," says Nicole Harris, who conducted this research while a master's student in the School of Education. "While we do frequently see children improve in therapy dog programs, we didn't have data to support that they enjoyed the time as well."

Harris was the lead researcher in the study that explored how children reacted while participating in a social skill-training program with therapy dogs.

The research saw 22 children from the Okanagan Boys and Girls Club take part in a series of sessions to help them build their social skills. Over six weeks, the children were accompanied by therapy dogs from UBC Okanagan's Building Academic Retention through K9s (BARK) program as they completed lessons.

Each week the children were taught a new skill, such as introducing themselves or giving directions to others. The children would first practice with their assigned therapy dog before running through the exercise with the rest of the group. In the final phase, the children -- accompanied by their new furry friend and volunteer handler -- would practice their new skills with university students located in the building.

"Therapy dogs are often able to reach children and facilitate their growth in surprising ways. We saw evidence of this in the social skills of children when they were paired with a therapy dog," says Dr. John-Tyler Binfet, associate professor in the School of Education and director of BARK. "The dogs helped create a non-threatening climate while the children were learning these new skills. We saw the children practice and hone their social skills with and alongside the dogs."

While the children were learning and practising their new skills, the research team collected data.

"Findings from our observations suggested that canine-assisted social and emotional learning initiatives can provide unique advantages," says Harris. "Our team saw that by interacting with the therapy dogs, the children's moods improved and their engagement in their lessons increased."

In fact, 87 per cent of the team rated the children's engagement level as very or extremely engaged during the sessions.

At the end of the six weeks, Harris interviewed eight children, aged 5 to 11 years old, who regularly attended the sessions. Each child indicated the social skill-training program was an enjoyable and positive experience and the dogs were a meaningful and essential part of the program.

One participant noticed that the children behaved better at the sessions than at their regular after-school care program, and they thought it was because the children liked being around the dogs.

Half of the children mentioned ways that they felt the dogs helped with their emotional well-being, with one participant crediting a dog with helping him "become more responsible and control his silliness."

As a full-time elementary school teacher, Harris notes that schools have become increasingly important in helping students develop social and emotional skills, and this research could contribute to the development of future school-based or after-school programs.

"Dogs have the ability to provide many stress-reducing and confidence-boosting benefits to children," says Harris. "It was really heartwarming to see the impact the program had on the kids."

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Virtual reality helping to treat fear of heights

 Researchers from the University of Basel have developed a virtual reality app for smartphones to reduce fear of heights. Now, they have conducted a clinical trial to study its efficacy. Trial participants who spent a total of four hours training with the app at home showed an improvement in their ability to handle real height situations.

Fear of heights is a widespread phenomenon. Approximately 5% of the general population experiences a debilitating level of discomfort in height situations. However, the people affected rarely take advantage of the available treatment options, such as exposure therapy, which involves putting the person in the anxiety-causing situation under the guidance of a professional. On the one hand, people are reluctant to confront their fear of heights. On the other hand, it can be difficult to reproduce the right kinds of height situations in a therapy setting.

This motivated the interdisciplinary research team led by Professor Dominique de Quervain to develop a smartphone-based virtual reality exposure therapy app called Easyheights. The app uses 360° images of real locations, which the researchers captured using a drone. People can use the app on their own smartphones together with a special virtual reality headset.

Gradually increasing the height

During the virtual experience, the user stands on a platform that is initially one meter above the ground. After allowing acclimatization to the situation for a certain interval, the platform automatically rises. In this way, the perceived distance above the ground increases slowly but steadily without an increase in the person's level of fear.

The research team studied the efficacy of this approach in a randomized, controlled trial and published the results in the journal NPJ Digital Medicine. Fifty trial participants with a fear of heights either completed a four-hour height training program (one 60-minute session and six 30-minute sessions over the course of two weeks) using virtual reality, or were assigned to the control group, which did not complete these training sessions.

Before and after the training phase -- or the same period of time without training -- the trial participants ascended the Uetliberg lookout tower near Zurich as far as their fear of heights allowed them. The researchers recorded the height level reached by the participants along with their subjective fear level at each level of the tower. At the end of the trial, the researchers evaluated the results from 22 subjects who completed the Easyheights training and 25 from the control group.

The group that completed the training with the app exhibited less fear on the tower and was able to ascend further towards the top than they could before completing the training. The control group exhibited no positive changes. The efficacy of the Easyheights training proved comparable to that of conventional exposure therapy.

Therapy in your own living room

Researchers have already been studying the use of virtual reality for treating fear of heights for more than two decades. "What is new, however, is that smartphones can be used to produce the virtual scenarios that previously required a technically complicated type of treatment, and this makes it much more accessible," explains Dr. Dorothée Bentz, lead author of the study.

The results from the study suggest that the repeated use of a smartphone-based virtual reality exposure therapy can greatly improve the behavior and subjective state of well-being in height situations. People who suffer from a mild fear of heights will soon be able to download the free app from major app stores and complete training sessions on their own. However, the researchers recommend that people who suffer from a serious fear of heights only use the app with the supervision of a professional.

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Forgotten tale of phage therapy history revealed

In the current situation when the fear of virus infections in the public is common, it is good to remember that some viruses can be extremely beneficial for humankind, even save lives. Such viruses, phages, infect bacteria. The research conducted at the University of Jyväskylä shed some light on the phage therapy history. It revealed that Brazil was a strong user and developer of phage therapy in 1920-40's. The research was published in Lancet Infectious Diseases -publication on March 2020.

After decades of antibiotic use and misuse, natural selection is giving bacteria the upper hand. The World Health Organization (WHO) warned that we are reaching the post-antibiotic era. As more pathogens become resistant, our chances to find new antibiotics diminish. Therefore, alternatives are urgently needed.

Use of phages, viruses that kill bacteria, as therapeutics was developed in Paris around 1920. Since these viruses could be safely used to treat patients, phage therapy quickly spread, but then slowly disappeared from the western world decades later, as antibiotics became common. Now, the revival of phage therapy is considered one viable solution to the antimicrobial resistance crisis.

Researchers of the University of Jyvaskyla investigated a forgotten hotspot of phage therapy of the past. Historical medical records in Portuguese (1915-1952) revealed that Brazil was a strong user and developer of phage therapy. From pioneer mass testing of phage products to routine, details have been uncovered about the safe use of phages against dysentery and staphylococcal infections. This information was made available to the modern research community by a historical review publication.

The practical and clinical data revealed can be important to shape modern phage therapy, against acute dysenteric infections and against dangerous resistant pathogens such as MRSA.

"The literature researched was an interesting trip to the past. This work is in principle a historical review, but it also provides relevant information to modern researchers. It might be an incentive to similar investigations on other countries, besides being a spark of hope to the recent Brazilian research community," says Postdoctoral Researcher Gabriel Almeida from the University of Jyväskylä.

From Science Daily