Publisher Health

Combining two agents to block a parasitic worm’s life cycle boosted survival from a potentially deadly tropical disease to 85% in animal models, far better than either treatment alone, according to a proof-of-concept study led by UT Southwestern Medical Center pharmacologists.
The Strongyloides infestation — brought by tiny worms known as nematodes that can enter through your feet — can cause strongyloidiasis, a chronic infection found in some 600 million worldwide. While mostly found in tropical and subtropical regions, the parasite has recently been identified in Texas, Alabama, and the Appalachian Mountains region in the eastern and northeastern U.S. and caused reported deaths in 36 of 50 states over the years. Mortality from complications with hyperinfection is up to 87% of reported cases, according to a 2020 modeling study.
“Parasitic nematodes that infect humans, animals, and plants are an enormous health and economic burden on society. We think the pathway we discovered could serve as a universal target for all parasitic nematode species,” said Howard Hughes Medical Center Investigator David Mangelsdorf, Ph.D., Chair of Pharmacology at UT Southwestern. “This strategy could potentially offer a cure for the millions of people around the world who have strongyloidiasis — the disease caused by Strongyloides stercoralis – and points to a new way to fight many other parasitic nematode diseases.”
Researchers studying gerbils initially found that administering dafachronic acid in drinking water for two weeks reduced fecal S. stercoralis larval output by 90%. In animals that became hyperinfected, which dramatically increases mortality, treatment with ivermectin or dafachronic acid alone increased survival to about 25% and 70%, respectively. But when combined, survival climbed to about 85% and S. stercoralis infection ended, representing a potential cure, said co-author Steven A. Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology at UT Southwestern.
The two run the joint Mangelsdorf/Kliewer lab at UT Southwestern studying signal transduction pathways that offer new therapeutic potential for treating diseases such as diabetes, obesity, cancer, and parasitism. The Mangelsdorf/Kliewer lab discovered the existence of a nuclear receptor pathway in parasitic nematodes and has shown that pharmacophores that target this pathway may represent a new class of anthelmintic agents.
In this study published online in eLife, researchers targeted Strongyloides stercoralis, which can lead to a severe and potentially deadly hyperinfection syndrome for people who are immunocompromised, such as those taking glucocorticoids, a common steroid used to treat other medical conditions.
“Glucocorticoids were one of the first treatments used for severe COVID-19. WHO raised the concern that using steroids in countries where S. stercoralis is prevalent could set off a fatal hyperinfection in patients with chronic, subclinical strongyloidiasis. That possibility has elevated the urgency for finding new ways to treat the disease,” said Dr. Mangelsdorf, one of 25 members of the National Academy of Sciences at UT Southwestern.
Drs. Mangelsdorf, Kliewer and colleagues looked for vulnerabilities in the larval stage of S. stercoralis’ life cycle. By purifying extracts of S. stercoralis, the team discovered that the parasite synthesizes the hormone dafachronic acid, which acts by binding to a receptor called DAF-12. Further research identified the enzymatic pathway that S. stercoralis uses to generate the hormone and showed that the DAF-12 receptor acts as an on-off switch controlling larval development based on the availability of dafachronic acid. Importantly, when the hormone is present at the wrong time, the parasite is unable to develop into the infectious form and dies.
Pure dafachronic acid in its present form may be unsuitable for treating humans because of its short half-life in the body, said Dr. Kliewer, also a member of the National Academy of Sciences. However, if chemistry techniques can be used to alter its structure, it could lead to a useful drug. Because all parasitic nematodes have a similar stage in their life cycles, he added, targeting this hormone and other points along the dafachronic acid pathway could eventually be used to treat diseases caused by other parasitic worms.
Work was funded by grants from the National Institutes of Health (AI105856, GM141088, and AI050886), The Welch Foundation (I-1275, I-1558, and I-2010-20190330), UT Southwestern Eugene McDermott Scholarship, and the Howard Hughes Medical Institute. Researchers Zhu Wang, Mi Cheong Cheong, Jet Tsien, Heping Deng, and Tian Qin at UT Southwestern also contributed to the study, along with researchers from the Millersville University of Pennsylvania and the University of Pennsylvania, Philadelphia.

Researchers at Vanderbilt University Medical Center have discovered a nanoparticle released from cells, called a “supermere,” which contains enzymes, proteins and RNA associated with multiple cancers, cardiovascular disease, Alzheimer’s disease and even COVID-19.
The discovery, reported in Nature Cell Biology, is a significant advance in understanding the role extracellular vesicles and nanoparticles play in shuttling important chemical “messages” between cells, both in health and disease.
“We’ve identified a number of biomarkers and therapeutic targets in cancer and potentially in a number of other disease states that are cargo in these supermeres,” said the paper’s senior author, Robert Coffey, MD. “What is left to do now is to figure out how these things get released.”
Coffey, the Ingram Professor of Cancer Research and professor of Medicine and Cell & Developmental Biology, is internationally known for his studies of colorectal cancer. His team is currently exploring whether the detection and targeting of cancer-specific nanoparticles in the bloodstream could lead to earlier diagnoses and more effective treatment.
In 2019 Dennis Jeppesen, PhD, a former research fellow in Coffey’s lab who is now a research instructor in Medicine, used advanced techniques to isolate and analyze small membrane-enclosed extracellular vesicles called “exosomes.”
That year, using high-speed ultracentrifugation, another of Coffey’s colleagues, Qin Zhang, PhD, research assistant professor of Medicine, devised a simple method to isolate a nanoparticle called an “exomere” that lacks a surface coat.

Scientists at the University of Tsukuba demonstrated how conventional magnetic resonance imaging (MRI) machines can be retrofitted to detect sodium ions using a cross band radio-frequency repeater. This work may allow for new medical diagnostics to be performed without expensive new equipment.
Magnetic resonance imaging has become a crucial part of the medical toolkit for non-invasive visualization of internal organs. MRI machines operate by placing the patient in a very strong magnetic field, which will cause the nuclear spins of atoms in the body to align in the same direction, essentially acting like tiny magnets. Then, a radio-frequency (RF) signal of a very specific frequency is applied, which has the ability to flip the direction of the spins. When the nuclei relax back to their original aligned state, the precession of these spins about the magnet field direction can be measured by RF detector coils to determine the concentration of that particular atom. The majority of MRI machines in use today are optimized to look for the presence of hydrogen (1H) nuclei, which are naturally abundant in the body as a component of water molecules. Retrofitting such a machine for detecting other isotopes, like sodium-23 23Na, would require a great deal of expensive hardware upgrades.
Now, a team of researchers at the University of Tsukuba have demonstrated a proof-of-concept method for equipping a conventional MRI machine with the capability to image 23Na by installing a cross band RF repeater system. This is a device that receives signals at a certain frequency and rebroadcast at a different one. “The RF repeater, which is a commonly used device in amateur radio, can be placed directly inside the magnet bore of an existing MRI machine as a cost-effective upgrade,” explains author Professor Yasuhiko Terada. This allows the frequency produced by 23Na, which is around 17 MHz, to be detected by the coils tuned at the 64 MHz of MRI.
The research team tested the system with a saline “phantom” and an anesthetized mouse. Even though the resulting signal was much lower compared with custom-built 23Na machines, it could be amplified to produce comparable images. “Watching the motion of sodium ions inside the body provides detailed metabolic information not available from conventional MRI images,” Professor Terada says. 23Na imaging has already been shown to be useful for applications involving the kidney, owing to its large sodium concentration, as well as the brain and heart. This approach may substantially reduce health care costs by providing completely new abilities to existing machines without requiring a complete refurbishment.
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A new copper surface that kills bacteria more than 100 times faster and more effectively than standard copper could help combat the growing threat of antibiotic-resistant superbugs.
The new copper product is the result of a collaborative research project with RMIT University and Australia’s national science agency, CSIRO, with findings just published in Biomaterials.
Copper has long been used to fight different strains of bacteria, including the commonly found golden staph, because the ions released from the metal’s surface are toxic to bacterial cells.
But this process is slow when standard copper is used, as RMIT University’s Distinguished Professor Ma Qian explained, and significant efforts are underway by researchers worldwide to speed it up.
“A standard copper surface will kill about 97% of golden staph within four hours,” Qian said.
“Incredibly, when we placed golden staph bacteria on our specially-designed copper surface, it destroyed more than 99.99% of the cells in just two minutes.”
“So not only is it more effective, it’s 120 times faster.”

People who suffer from both insomnia and obstructive sleep apnoea are more likely to suffer from heart problems and are almost 50% more likely to die than those without either condition, say Flinders University researchers, who advise people being tested for one of the disorders be tested for the other.
“Insomnia and obstructive sleep apnoea are the two most common sleep disorders, affecting 10 to 30% of the population, but people can often suffer from both at the same time,” says Dr Bastien Lechat from Flinders Health and Medical Research Institute: Sleep Health.
“Previously, little was known about the impact of co-morbid insomnia and obstructive sleep apnoea (COMISA) but what we did know is that for people with both conditions, health outcomes are consistently worse than those with neither condition or those with either condition alone.”
Now, in a new study published in the European Respiratory Journal, Flinders researchers have studied a large US-based dataset of over 5000 people to understand the risks of COMISA.
The participants, aged around 60 years of age at the beginning of the study and 52% female, were followed for approximately 15 years, with 1210 people dying during that time.
The results suggested that participants with COMISA were two times more likely to have high blood pressure and 70% more likely to have cardiovascular disease than participants with neither insomnia nor sleep apnoea.
The study also showed participants with COMISA had a 47% increased risk of dying (for any reason) compared to participants with no insomnia or sleep apnoea, even when other factors known to increase mortality were taken into account.
“This is the first study to assess mortality risk in participants with co-morbid insomnia and sleep apnoea,” says Dr Lechat, who led the research.
“Given that these people are at higher risk of experiencing adverse health outcomes, it is important that people undergoing screening for one disorder should also be screened for the other.”
While further research is needed to investigate what might be causing the higher mortality risk for those with COMISA, researchers say further investigation is also warranted to ensure treatments are working effectively.
“Specific treatments may be needed for people with co-occurring disorders so it’s important we examine the efficacy of insomnia and sleep apnoea treatments in this specific population,” says Dr Lechat.
The Adelaide Institute for Sleep Health at Flinders University is continuing to conduct research to understand the reasons that insomnia and sleep apnoea co-occur so frequently, and to develop more effective treatment approaches.
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Fragile X syndrome, or FXS, a leading genetic cause of autism, affects around one in 4,000 males and one in 6,000 females. Its symptoms include increased anxiety, intellectual disability, repetitive behaviors, social communication deficits, and abnormal sensory processing. People living with FXS generally lack the fragile X mental retardation 1 gene, or Fmr1, in their brain cells. If their cells have this gene, it is silent and not producing a protein called FMRP.
Researchers at the University of California, Riverside, report in the journal Neurobiology of Disease they were able to ameliorate FXS symptoms after inserting Fmr1 into the brains of very young transgenic mice that had been genetically engineered to lack this gene. When the researchers measured brain activity for signs of anxiety and hyperactivity in response to stimuli such as stresses and sounds, they found that the reactivation of the Fmr1 gene in these mice had led them to no longer show FXS symptoms.
“Our work shows beneficial effects of reactivating the Fmr1 gene, which would be very welcome news for young children living with FXS,” said Iryna M. Ethell, a professor of biomedical sciences in the UCR School of Medicine, who led the research.
In their study, Ethell’s laboratory, in collaboration with Khaleel A. Razak, a professor of psychology, selected very young mice — less than 3 weeks old — because brains are most plastic early in life; the equivalent in humans is around the first 3-5 years.
“For humans, the first 3-5 years are critical in brain development,” Ethell said. “It’s important, therefore, that this early period be targeted in FXS.”
The mouse brain, like the human brain, has excitatory and inhibitory neurons. Unlike excitatory neurons that lead to a forward propagation of information, inhibitory neurons work like a brake by suppressing unnecessary activity and tuning brain activity to specific signals.

Biophysicists in Japan have found ways to make and manipulate capsule-like DNA structures that could be used in the development of artificial molecular systems. Such systems could function, for example, inside the human body. The study was a collaboration between Yusuke Sato of Tohoku University and Masahiro Takinoue of the Tokyo Institute of Technology (Tokyo Tech), and the findings were published in the JACS Au.
To make the capsules, the researchers first created two different types of DNA nanostructures. Each type was made using three single-stranded DNA molecules with sticky bits at their ends. Due to differences in their DNA sequences, only similar nanostructures stuck together when the two types were mixed.
Sato and Takinoue then combined the nanostructures in solution with an oily mixture of charged and non-charged molecules. The mixture was first heated and then cooled, and finally examined under a microscope.
The researchers found that water-in-oil droplets had formed, with the DNA nanostructures accumulating at the water-oil interface. The nanostructures came together in different kinds of patch-like patterns, depending on the concentration of each type relative to the other.
The scientists also found that the DNA nanostructures agglomerated in a more homogeneous way when an extra X-shaped DNA nanostructure was added to the mix to connect the two types together.
This worked just as well inside lipid vesicles as in water-in-oil droplets. Sato and Takinoue were also able to separate the DNA capsules from the droplets and vesicles without losing their capsule-like shapes. Finally, they were able to open the capsules and degrade them using specific enzymes.
The findings demonstrate an approach for constructing and modifying DNA capsules that could have a variety of different functions and purposes. For example, they could be used to carry substances to specific target organs, releasing their cargo when exposed to certain enzymes. They could also be made mobile by using DNA nanostructures that can be manipulated to alter the shapes of the capsules. Or they could be modified with proteins or DNA-based molecular devices to make functional compartmental structures, like cellular membranes.
“We believe that functional capsules made from DNA, like the ones we have designed, could provide a new approach for developing capsular structures for artificial cell studies and molecular robotics,” say Sato and Takinoue.
The team will next work on inserting different types of cargo into the capsules, including DNA information processors, and releasing them in response to specific stimuli.
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Mount Sinai researchers have solved a major mystery in cancer research: How cancer cells remain dormant for years after they leave a tumor and travel to other parts of the body, before awakening to create metastatic cancer.
According to findings reported in Nature Cancer in December, the cells remain quiet by secreting a type of collagen, called type III collagen, in the environment around themselves, and only turn malignant once the level of collagen tapers off. The researchers found that by enriching the environment around the cells with this collagen, they could force the cells to remain in a dormant state and prevent tumor recurrence.
“Our findings have potential clinical implications and may lead to a novel biomarker to predict tumor recurrences, as well as a therapeutic intervention to reduce local and distant relapses,” said senior author Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai. “This intervention aimed at preventing the awakening of dormant cells has been suggested as a therapeutic strategy to prevent metastatic outgrowth.As the biology of tumor dormancy gets uncovered and new specific drugs are developed, a combination of dormancy-inducing treatments with therapies that specifically target dormant cells will ultimately prevent local recurrence and metastasis and pave the way to cancer remission.”
Most cancer deaths are due to metastases, which can occur several years after a tumor is removed. Previous research has studied how dispersed tumor cells come out of dormancy; this new work showed how the cells remain dormant.
The study used high-resolution imaging techniques, including intravital two-photon microscopy, a technology that allows the visualization of dormant cells in their environment in real time in a living animal. This technology allowed the researchers to track dormant tumor cells in mouse models using breast and head and neck cancer cell lines. By using this technology, the researchers were able to visualize the changes in the architecture of the extracellular matrix as tumor cells became dormant and how it changed when these cells awoke.
In patient samples, the researchers showed that an abundance of the collagen could be used as a potential measurement to predict tumor recurrence and metastasis. In the mouse models, when scientists increased the amount of type III collagen around cancer cells that had left a tumor, cancer progression was interrupted and the disseminated cells were forced into a dormant state. Similar to wound treatment, in which collagen scaffolds have been proposed as a therapeutic alternative for complex skin wounds, this study suggest that by using strategies that aim to enrich the tumor microenvironment in type III collagen, metastasis may be prevented by activating tumor cell dormancy.
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Scientists have discovered a new potential treatment that has the ability to reverse antibiotic resistance in bacteria that cause conditions such as sepsis, pneumonia, and urinary tract infections.
Carbapenems, such as meropenem, are a group of vital often ‘last-resort’ antibiotics used to treat serious, multi-drug resistant infections when other antibiotics, such as penicillin, have failed. But some bacteria have found a way to survive treatment with carbapenems, by producing enzymes called metallo-beta-lactamases (MBLs) that break down the carbapenem antibiotics, stopping them from working.
Highly collaborative research, conducted by scientists from the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford and several institutions across Europe, found that the new class of enzyme blockers, called indole carboxylates, can stop MBL resistance enzymes working leaving the antibiotic free to attack and kill bacteria such as E. coli in the lab and in infections in mice.
The new research, published today (Monday) in Nature Chemistry, was funded by the Innovative Medicines Initiative (IMI) through the European Lead Factory (ELF) and the European Gram-Negative Antibacterial Engine (ENABLE) programmes.
The researchers first screened hundreds of thousands of chemicals to see which would attach tightly to MBLs to stop them working, and which didn’t react with any human proteins, leading to the discovery of the indole carboxylates as promising new candidates. Using a process called crystallography to zoom in to take a closer look at how they work, the researchers found these potential drugs attach to MBLs in a completely different way to any other drugs – they imitate the interaction of the antibiotic with the MBLs. This clever Trojan Horse trick allows these potential drugs to be highly effective against a very wide range of MBL-producing superbugs.
After their initial discovery, the researchers chemically changed aspects of the drugs to make them as effective as possible, and tested them in combination with carbapenems against multi-drug resistant bacteria in both dishes in the lab and in mice. The potential new drugs in combination with carbapenems were found to be 5 times more potent at treating severe bacterial infections than carbapenems alone, and at a less concentrated dose. Importantly, these potential drugs show only mild side effects in mice.

COVID-19 convalescent plasma showed a likely benefit for patients early in the pandemic before remdesivir and corticosteroids were in use, according to results of a landmark study published today in JAMA Internal Medicine that included physician-scientists at The University of Texas Health Science Center at Houston (UTHealth Houston).
UTHealth Houston and The University of Texas Health Science Center at Tyler participated in the National Institutes of Health-funded randomized clinical trial as part of the Center for Clinical and Translational Sciences (CCTS). Called CONTAIN COVID-19, the clinical trial was established by New York University (NYU) and Montefiore Medical Center/Albert Einstein College of Medicine to evaluate the safety and efficacy of convalescent plasma in hospitalized coronavirus patients. UTHealth Houston carried out this study locally in partnership with Memorial Hermann and Harris Health’s Lyndon B. Johnson Hospital, enrolling underserved populations throughout Harris County.
The trial showed that convalescent plasma was safe and well tolerated. It worked best in the early days of the pandemic, when plasma had higher antibody levels, when it was given early in the disease, and particularly for immunosuppressed people.
“This landmark study shows once and for all that convalescent plasma is an important countermeasure early in a pandemic when no other therapies are available. It was an important finding that lays the foundation for the rapid response to future pandemics,” said Luis Ostrosky, MD, professor and director of the Division of Infectious Diseases at McGovern Medical School at UTHealth Houston. “This trial, the largest of its kind, also showed that with proper funding and structure, researchers across the country were able to come together quickly in the middle of a global crisis to explore this therapeutic intervention.”
Results of the trial also showed that after the introduction of remdesivir and corticosteroids, efficacy dropped and by the end of the 11-month trial, there was no difference in outcome between plasma and placebo in patients at 14 and 28 days. However, patients on corticosteroids, but not remdesivir, appeared to benefit from convalescent plasma at day 14.
Because the patient characteristics, available treatments, and the virus, changed over time, subgroup analyses were done, which revealed the possible benefit for patients in the first quarter of the trial, a period from April to June 2020.
Participants in that first quarter were older, less severely ill, had a longer duration of symptoms, and received high-titer plasma. A shorter duration of symptoms is an indication of a more severe case of the viral infection.
“Convalescent plasma could be an important early treatment tool in places that don’t have access to monoclonal antibodies, corticosteroids, remdesivir, or other therapies,” said Bela Patel, MD, co-investigator, professor and director of the Division of Critical Care, and Graham Distinguished University Chair at McGovern Medical School. “It should also be considered for patients who are immunosuppressed and those whose B cell function is compromised.”
Researchers also reported that, in addition to the introduction of corticosteroids and remdesivir, the decrease in efficacy over time may have been due to using convalescent plasma that originated from New York City before other viral variants emerged.
“It is vitally important to do research such as this during a pivotal public health crisis to determine what works and what doesn’t and use that information for future pandemics. We are proud to be part of such a milestone clinical trial,” said David McPherson, MD, co-investigator for the trial, principal investigator of CCTS, chair of the Department of Internal Medicine at McGovern Medical School at UTHealth Houston, and James T. and Nancy B. Willerson Chair.
The trial was in funded in past with an $8 million grant (3UL1TR003167-02S1) from the National Center for Advancing Translational Sciences, part of the National Institutes of Health.