Publisher Health

Researchers at the University of Arizona Health Sciences are closer to developing a safe and effective non-opioid pain reliever after a study showed that a new compound they created reduces the sensation of pain by regulating a biological channel linked to pain.
Most people experience pain at some point in their lives, and the National Institutes of Health estimates 100 million people in the U.S. suffer from chronic pain. Approximately 21-29% of patients prescribed opioids for chronic pain misuse them and 8-12% of people using an opioid for chronic pain develop an opioid use disorder, according to the National Institute on Drug Abuse. In 2019, nearly 50,000 people in the U.S. died from opioid-involved overdoses.
“Drug discovery for chronic pain is at the forefront of this research, and it’s being amplified by the intersection of the COVID-19 pandemic and the opioid epidemic,” said Rajesh Khanna, PhD, associate director of the UArizona Health Sciences Comprehensive Pain and Addiction Center, professor of pharmacology in the UArizona College of Medicine — Tucson and member of the BIO5 Institute. “Drug discovery is a very arduous process. Our lab looked at a fundamental mechanism of pain, came up with a way to differentiate it from those before us and found a compound that has the potential as a new non-opioid treatment for pain.”
The paper, “Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents,” was published today in Science Translational Medicine.
The biological mechanism at the heart of the research is NaV1.7, a sodium ion channel that previously was linked to the sensation of pain through genetic studies of people with rare pain disorders.
Nerve cells, or neurons, use electrical currents to send signals to the brain and throughout the body, and sodium ion channels are vital to a cell’s ability to generate those electrical currents. When a neuron is stimulated, the NaV1.7 channel opens and allows positively charged sodium ions to cross the cell membrane and enter the previously negatively charged cell. The change in charge across the cell membrane generates an electrical current, which increases the excitability of the neuron and sets in motion a cascade of events that leads to pain.

People rarely walk at a constant speed and a single incline. We change speed when rushing to the next appointment, catching a crosswalk signal, or going for a casual stroll in the park. Slopes change all the time too, whether we’re going for a hike or up a ramp into a building. In addition to environmental variably, how we walk is influenced by sex, height, age, and muscle strength, and sometimes by neural or muscular disorders such as stroke or Parkinson’s Disease.
This human and task variability is a major challenge in designing wearable robotics to assist or augment walking in real-world conditions. To date, customizing wearable robotic assistance to an individual’s walking requires hours of manual or automatic tuning — a tedious task for healthy individuals and often impossible for older adults or clinical patients.
Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new approach in which robotic exosuit assistance can be calibrated to an individual and adapt to a variety of real-world walking tasks in a matter of seconds. The bioinspired system uses ultrasound measurements of muscle dynamics to develop a personalized and activity-specific assistance profile for users of the exosuit.
“Our muscle-based approach enables relatively rapid generation of individualized assistance profiles that provide real benefit to the person walking,” said Robert D. Howe, the Abbott and James Lawrence Professor of Engineering, and co-author of the paper.
The research is published in Science Robotics.
Previous bioinspired attempts at developing individualized assistance profiles for robotic exosuits focused on the dynamic movements of the limbs of the wearer. The SEAS researchers took a different approach. The research was a collaboration between Howe’s Harvard Biorobotics Laboratory, which has extensive experience in ultrasound imaging and real-time image processing, and the Harvard Biodesign Lab, run by Conor J. Walsh, the Paul A. Maeder Professor of Engineering and Applied Sciences at SEAS, which develops soft wearable robots for augmenting and restoring human performance.

Researchers at East Carolina University’s Brody School of Medicine have found a new way to detect the virus that causes COVID-19 by testing the air passing through building ventilation systems. The discovery could lead to earlier detection of the virus, improved quarantine protocols, reduced transmission and fewer outbreaks.
Dr. Sinan Sousan, an assistant professor in Brody’s Department of Public Health and Research Faculty at North Carolina Agromedicine Institute, and expert of environmental and occupational airborne exposure, and Dr. Rachel Roper, a professor in the Department of Microbiology and Immunology with an extensive background studying coronaviruses, spearheaded the effort to learn whether SARS-CoV-2 could be detected through the heating, ventilation and air conditioning (HVAC) systems in student dorms.
Their research was recently published in The American Journal of Infection Control, and represents a breakthrough in the way the virus can be detected before an individual tests positive.
“I think it’s important because you want to know if someone in the building is infected, potentially contagious and infecting other people, so it’s a really important public health measure,” Roper said of the study, adding that this method could also be used to test for other airborne viruses and pathogens such as influenza.
Researchers collected samples from two large student dorms and an isolation suite housing students that had tested positive for COVID-19 several times per week for more than three months beginning in January 2021.
Sousan’s team collected a total of 248 air samples, testing four collection methods that deposited samples into small filters, saline solutions and cartridges that were then preserved and transported to Roper’s lab for RT-PCR analysis. The testing revealed the presence of SARS-COV-2 in the isolation suite air samples 100% of the time. In the dorms where students were not already in COVID-19 isolation, researchers were able to detect the virus in the air samples 75% of the time when students on the same floor later tested positive via nasal swab.
The trick to success was capturing air samples with virus that was concentrated enough to be detected, and maintaining the virus’s stability within the samples to get it back to lab with intact RNA for the PCR analysis, Roper said.
Similarly to testing a building’s wastewater, implementing building air sampling on a broader scale could allow for earlier detection of the virus, particularly in shared spaces.
“Detection in air provides advance notice of potential exposures in specific locations within a building,” said Mike Van Scott, interim vice chancellor for ECU’s Division of Research, Economic Development and Engagement. “It was fortuitous that SARS-CoV-2 could be detected in wastewater, but the next respiratory virus that we encounter may not be as stable, and detection in air would allow us to respond quickly.”
The research was funded by university COVID-19 relief funds, and completed with assistance research specialist Ming Fan and former undergraduate students Kathryn Outlaw and Sydney Williams. ECU Facilities Services staff also assisted, drilling holes into the HVAC units and ductwork of three student dormitories and provided building access, allowing the researchers to collect samples.
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Materials provided by East Carolina University. Original written by Natalie Sayewich. Note: Content may be edited for style and length.

Usually diagnosed in children, teens and young adults, type 1 diabetes is an autoimmune disease in which the immune system attacks and destroys insulin-secreting β-cells in the pancreas. As a result, people with type 1 diabetes can’t regulate their blood sugar levels and require insulin treatment for survival. Now, researchers reporting in ACS Applied Materials & Interfaces have reversed new-onset type 1 diabetes in mice with pyramid-like DNA molecules called tetrahedral framework nucleic acids (tFNAs).
About 64,000 people in the U.S. are diagnosed with type 1 diabetes each year, according to the Juvenile Diabetes Research Foundation. There is no cure for the disease, and to manage symptoms, people must measure their blood sugar levels throughout the day and administer insulin through an injection or pump. Although scientists still don’t know exactly what causes the body to turn against itself and attack insulin-secreting cells, people with type 1 diabetes have fewer regulatory T cells (Tregs) — immune cells that suppress the differentiation and activation of other, self-attacking T cells. In a recent study published in ACS’ Nano Letters, Yunfeng Lin and colleagues showed that treating mice with tFNAs could prevent type 1 diabetes, in part by increasing Treg numbers. Originally designed to carry other therapeutic molecules into cells, tFNAs have recently been shown to modulate the immune system on their own. Now, the researchers wanted to find out if these molecules could reverse new-onset type 1 diabetes, before pancreatic β-cells were completely destroyed.
The researchers made tFNAs from four single-stranded DNA segments that self-assembled into pyramid-like shapes, called tetrahedrons. But whereas a pyramid is square at its base, tetrahedrons are triangular. Then, every other day for 4 weeks, they injected the tFNAs into 10 mice with new-onset type 1 diabetes, while 10 other diabetic mice were injected with saline. In the control mice, blood glucose levels continued to rise, and 60% of the mice died during the 12-week follow-up period. In contrast, blood glucose levels in mice treated with tFNAs went down to normal levels, and none of the rodents died. In a further analysis of the tFNA-treated mice, the team found that pancreatic β-cells were protected, and Tregs were restored to normal levels, while auto-reactive T cells decreased in the pancreas. Although the findings still need to be verified in people, tFNAs are one of the most promising candidates for type 1 diabetes immunotherapy, the researchers say.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

A gene-silencing therapy protected against Zika virus transmission from pregnant mice to the mouse fetuses, finds a study published November 10th in the journal Molecular Therapy. The treatment, which harnesses nanoparticles called small extracellular vesicles (sEVs) for drug delivery, crossed the placenta and blood-brain barrier to greatly reduce fetal neurological damage, including virus-induced brain shrinkage.
“Our experiments indicated that targeted delivery via modified sEVs is a promising alternative to the traditional methods of delivery, especially for the treatment of brain viral infection,” says senior study author Zhiwei Wu of Nanjing University. “Increasing the yield and efficiency of producing sEVs and developing sEVs that target other tissues will broaden their application and will expand the effectiveness of this gene delivery technique.”
The Zika virus epidemic swept across the Asia-Pacific region in 2015-2017 and remains a global health threat to this day. The virus causes neurological and congenital conditions such as microcephaly, in which the baby’s head is smaller than expected. It can cross the placenta and the blood-brain barrier — a network of blood vessels and tissue that is made up of closely spaced cells.
The blood-brain barrier controls the exchange of substances between the central nervous system (CNS) and the blood, helping to keep harmful substances from reaching the brain. Few drugs specifically target brain tissue, and most are highly toxic and do not efficiently cross the blood-brain barrier. Treatment for viral infections of the brain is generally ineffective due to blood-brain barrier blocking of drugs. “Currently, there is no Zika virus-specific therapy or vaccine available,” Wu says. “Safe and effective antiviral drugs that can effectively cross the blood-brain barrier and placental barrier are urgently needed, especially to prevent microcephaly.”
In particular, gene silencing therapies using oligonucleotides have demonstrated unique advantages in clinical settings, but the delivery of nucleic acids into cells remains a major challenge. One potential solution is offered by sEVs — natural, biodegradable nanoparticles that are released from cells and are important mediators of cell-to-cell communication. Emerging evidence suggests that they could be a powerful tool to deliver drugs for the treatment of cancer, cardiovascular conditions, and infectious diseases. Recently, Wu and his collaborators leveraged sEVs to deliver an antiviral molecule across the placental barrier to inhibit Zika virus infection in the mouse fetus.
In the new study, Wu and his team demonstrated for the first time that sEVs could deliver antiviral drugs to achieve targeted suppression of Zika virus infection in the fetal CNS and to control neurological damage. To home in on neurons, the researchers engineered sEVs that expressed rabies virus glycoprotein (RVG) on their surface. They then loaded them with Zika virus-specific small interfering RNA (siRNA) and injected them into pregnant mice.
The RVG-modified sEVs crossed the placental barrier and blood-brain barrier, protecting against Zika virus transmission to the fetus. They concentrated in the fetal brain, where they suppressed infection and reduced inflammation and neurological damage, including microcephaly and defects in a brain region called the cerebellum. The findings echo another recent study showing that RVG-modified sEVs could cross the blood-brain barrier in mice to treat manifestations of Parkinson’s disease. “Our therapeutic approach expanded the application of sEVs to treat viral infection of brains by intravenous injection,” Wu says.
Despite the promising results, many questions remain. For example, the researchers delivered the virus and the first dose of the therapy simultaneously, so it is not clear whether treatment after a time lag would also be effective. “A delayed injection after viral infection may provide more confidence in the ability to translate this research to human trials,” Wu says. “Nevertheless, our study provides a proof of concept for such a possibility.”
Moving forward, the researchers plan to investigate the molecular mechanisms by which the sEVs penetrate the placenta and blood-brain barrier. They will also pin down the precise rate of sEV penetration and determine the factors that control delivery efficiency. “Since small extracellular vesicles are of biological origin, they can be a safe drug delivery vehicle,” Wu says. “However, the current study remains preliminary and many more issues need to be resolved. For human use, there is a long way to go.”
This work was supported by National Natural Science Foundation of China, the Major Research and Development Project, Nanjing University-Ningxia University Collaborative Project.
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Materials provided by Cell Press. Note: Content may be edited for style and length.

A new Cleveland Clinic study found that people with certain sleep disorders have more severe outcomes from COVID-19, including a 31 percent higher rate of hospitalization and mortality.
The research team, led by Reena Mehra, M.D., analyzed retrospective data from 5,400 Cleveland Clinic patients. The findings, published in JAMA Network Open, showed that while patients with sleep-disordered breathing and sleep-related hypoxia do not have increased risk of developing COVID-19, they have a worse clinical prognosis from the disease.
“As the COVID-19 pandemic continues and the disease remains highly variable from patient to patient, it is critical to improve our ability to predict who will have more severe illness so that we can appropriately allocate resources,” said Dr. Mehra, director of Sleep Disorder Research at Cleveland Clinic. “This study improved our understanding of the association between sleep disorders and the risk for adverse COVID-19 outcomes. It suggests biomarkers of inflammation may mediate this relationship.”
Researchers used Cleveland Clinic’s COVID-19 research registry, which includes data from nearly 360,000 patients tested for COVID-19 at Cleveland Clinic, of which 5,400 had an available sleep study record. Sleep study findings and COVID-19 positivity were assessed along with disease severity. The team also accounted for co-morbidities such as obesity, heart and lung disease, cancer and smoking.
The findings set the stage for additional studies to identify whether early effective treatments such as PAP (positive airway pressure) or oxygen administration can improve COVID-19 outcomes.
“Our findings have significant implications as decreased hospitalizations and mortality could reduce the strain on healthcare systems,” said first author of the study Cinthya Pena Orbea, M.D, of Cleveland Clinic’s Sleep Disorders Center. “If indeed sleep-related hypoxia translates to worse COVID-19 outcomes, risk stratification strategies should be implemented to prioritize early allocation of COVID-19 therapy to this subgroup of patients.”
The study was funded by a Neuroscience Transformative Research Resource Development Award that was given to Dr. Mehra.
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Materials provided by Cleveland Clinic. Note: Content may be edited for style and length.

Neurons communicate with each other via electrical impulses, which are produced by ion channels that control the flow of ions such as potassium and sodium. In a surprising new finding, MIT neuroscientists have shown that human neurons have a much smaller number of these channels than expected, compared to the neurons of other mammals.
The researchers hypothesize that this reduction in channel density may have helped the human brain evolve to operate more efficiently, allowing it to divert resources to other energy-intensive processes that are required to perform complex cognitive tasks.
“If the brain can save energy by reducing the density of ion channels, it can spend that energy on other neuronal or circuit processes,” says Mark Harnett, an associate professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.
Harnett and his colleagues analyzed neurons from 10 different mammals, the most extensive electrophysiological study of its kind, and identified a “building plan” that holds true for every species they looked at — except for humans. They found that as the size of neurons increases, the density of channels found in the neurons also increases.
However, human neurons proved to be a striking exception to this rule.
“Previous comparative studies established that the human brain is built like other mammalian brains, so we were surprised to find strong evidence that human neurons are special,” says former MIT graduate student Lou Beaulieu-Laroche.

Next generation vaccines for Covid-19 should aim to induce an immune response against ‘replication proteins’, essential for the very earliest stages of the viral cycle, concludes new research carried out by UCL scientists.
By designing vaccines that activate immune memory cells, known as T cells, to attack infected cells expressing this part of the virus’s internal machinery, it may be possible to eliminate SARS-CoV-2 at the very outset, thereby helping stop its spread.
This approach could complement currently licensed Covid-19 vaccines in the UK, which only trigger immune responses to the spike protein that protrudes from the outside of the virus.
Researchers say the discovery, published in Nature, could lead to the creation of a pan-coronaviruses vaccine, that not only protects against SARS-CoV-2 and its variants, but also against coronaviruses that cause common colds, and to new emerging animal coronaviruses.
Senior author Professor Mala Maini (UCL Infection & Immunity) said: “Our research shows that individuals who naturally resisted detectable SARS-CoV-2 infection generated memory T cells that target infected cells expressing the replication proteins, part of the virus’s internal machinery.
“These proteins — required for the earliest stage of the virus’s life cycle, as soon as it enters a cell — are common to all coronaviruses and remain ‘highly conserved’, so are unlikely to change or mutate.

A needle-free technology that would allow people with diabetes to measure blood sugar levels without having to stick a needle into their fingertips, has been bought closer to reality by researchers at the Auckland Bioengineering Institute (ABI), University of Auckland, New Zealand.
The researchers turned their attentions to needle-free jet injection, an emerging but well-developed technique in which a drug is delivered directly with a high-speed narrow jet of fluid. In a study published in the Journal of Diabetes Science and Technology, led by ABI researchers Jiali Xu and James McKeage, researchers demonstrated for the first time that a jet injector could also be used to collect blood samples from humans — that is, release enough blood for glucose sampling, sans needles.
People with diabetes typically need to measure their blood glucose concentration several times each day. They do so by pricking their fingers with a needle to release a drop of blood. A glluclose meter then indicated how much insulin is required for the person to maintain their blood sugar.
Fingertips are the preferred site for blood sampling because they have a high density of blood vessels. But the fingertips are also sensitive, and pain, skin damage, bruising and risk of infection from regular ‘pricking’ has spurred increasing efforts to develop needle-free methods of blood testing for people with diabetes.
Jet injection has been the subject of years of research by the ABI Bioinstrumentation Lab at the ABI, University of Auckland, which includes developing jet injectors for delivering drugs such as insulin, nicotine, and as local anaesthetic for dental treatment.Ms Xu and her team demonstrated that the technology could also be used to pierce the skin with a small volume of harmless saline solution, and this would release enough blood for glucose concentration measurement — that is, for extraction rather than injection.
The study involved 20 healthy participants, who each volunteered four fingertips, each of whom received a lancet prick (the standard needle) and jet injection through three differently shaped and sized nozzles. “These were were designed to mimic the wound left from a lancet prick, in the anticipation that it might release blood in a way similar to a lancet prick,” says Ms Xu.
The study showed that indeed it did, with some nozzle shapes performing better than others — a ‘slot’ shaped nozzle released more blood than a circle-shaped nozzle, for instance. Most of the different jet injection nozzles were generally perceived as no more painful than a standard lancet, and in some cases, less so: participants were blinded by an opaque barrier that prevented them from seeing the procedure but allowed them to communicate with the practitioner. They were also asked to complete a questionnaire 24 hours later, to reassess the level of pain, swelling or bruising.
“When you know there’s not a device that is pricking your skin, you could speculate that people will find jet injection more acceptable,” says Professor Andrew Taberner, head of the Bioinstrumentation Lab at the ABI, and Ms Xu’s supervisor. “But we don’t have evidence to back that up. That wasn’t part of this study. We were first trying to find out if it worked, and it did.”
He was pleased, but not surprised. “Diesel mechanics have known for years that you should never put your finger in front of a fuel injector, because it will inject fuel into your finger. They found this out the hard way. But we’re taking advantage of what diesel mechanics discovered accidentally years ago, with a very small amount of harmless liquid, to deliberately release blood.”
The team is now investigating if they can use jet injection not only to release blood, but to suck back, to extract fluid. This would allow for the design of an even smaller nozzle. They have the technology, having developed the world’s first jet injection device that uses electric motors to pressurise the drug — this allows for more precise control than the more common spring-actuated jet injector.
“Our technology has the capability to both deliver and withdraw fluid. No other jet projection technology has that capacity,” says Dr Taberner.
Research into needle-free injections is a long game, as is the potential commercialisation of the technology he says, but he believes Ms Xu’s research will contribute to the ultimate aim, of the development of a single lancet-free reversible technology that will allow for both blood sampling and insulin delivery based on the glucose measurement in one device. “I hope that this research will contribute to that, and the improvement in human healthcare, especially in the management of diabetes,” says Ms Xu.

A simple RNA molecule jumpstarts the immune system’s “first responders” to viral infection and can even eradicate the SARS-CoV-2 virus in mice with chronic cases of COVID-19, a new Yale School of Medicine study finds.
The molecule, known as SLR14, is a simple, easy to manufacture, loop of RNA that can trigger the production of interferons, a group of proteins produced by immune cells that are key to the body’s innate, or initial, response to infection. Multiple studies have shown that COVID-19 patients who produce high levels of interferons have far better outcomes than those for whom interferon levels are low during early days of infection.
Treated mice also responded well to numerous variants of SARS-CoV-2, the virus that causes COVID-19, including the Delta variant, currently the predominant strain of the virus in the United States, according to the new report published Nov. 10 in the journal Experimental Medicine.
If clinical trials in humans confirm the efficacy of SLR14, the relatively inexpensive compound could help reduce COVID-19 cases in low-income countries where vaccine availability is limited, the researchers say. It can also provide important benefits for immunocompromised individuals who are not able to create sufficient levels of antibody-producing B cells and virus-killing T cells.
“SLR14 therefore holds great promise as a new class of RNA therapeutics that can be applied as antivirals against SARS-CoV-2,” said Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular, and Developmental Biology at Yale and corresponding author of the paper. “Moreover, because this RNA-based therapeutic approach is simple and versatile, our study will facilitate pandemic preparedness and response against future respiratory pathogens sensitive to Type I interferons.”
Typically, vaccines such as those that combat COVID-19 introduce harmless elements of the virus to elicit T and B cell production by the body’s adaptive immune system, which can recognize previous pathogens and mount a targeted response. Treatments such as monoclonal antibodies also aim to mimic this later-stage immune response.
For the new study, however, a team led by first author Tianyang Mao, a graduate student in Iwasaki’s lab, explored whether compounds such as SLR14 might activate the innate immune system and protect against viral infections, including COVID-19.
In experiments, the researchers found that a single dose of the compound was sufficient to protect mice against severe disease and death, worked against a variety of variants, and could even eradicate the virus from mice with chronic infections.
“The results of innate immune activation clearing chronic infection were surprising and spectacular,” Iwasaki said.
Patent rights to SLR14 and similar compounds are owned by RIGimmune — a company cofounded by Iwasaki and Anna Pyle, Sterling Professor of Molecular, Cellular, and Developmental Biology at Yale and a co-author of this study — which is searching for novel agents that can combat a variety of pathogens.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.