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Researchers from Cleveland Clinic’s Florida Research and Innovation Center (FRIC) found that disruption of a cellular structure, known as the actin cytoskeleton, is a “priming signal” for the body to respond to a virus. These findings, published in Cell this week, potentially lay the groundwork for development of new anti-viral vaccines and treatments.
Previously, viral genetic material such as RNA was considered the sole requirement for certain sensor molecules that live in cells to trigger an immune response — an “alarm system” for many types of cells. RNA also serves as a basis for vaccines through training a patient’s immune system to recognize a virus. This new study showed that the signaling process also requires disrupting the actin cytoskeleton inside cells, which occurs when a virus infects cells.
“It’s a fundamental new way of considering how the immune system can be activated, and the implications are that this could lead to broad antiviral therapeutics,” says Michaela Gack, Ph.D.,the Arthur and Marylin Levitt Endowed Chair and Scientific Director of the FRIC. “Our data shows this process is common across different types of RNA viruses.”
Cytoskeletons, made up of the protein actin, serve as structural support for cells but are also key in processes like the cell’s ability to grow, divide and internalize key substances. A virus disturbs the cytoskeleton, but so can vaccine components and certain therapeutics, Dr. Gack says.
“Whether this process is sensed by our cellular immune surveillance system and can trigger an antiviral response has been unknown,” says Dr. Gack. “Our work showed that specific immune receptors sense actin cytoskeleton rearrangements induced by viruses and then trigger alarm.”
Despite being around for decades, interest in using RNA as the basis for vaccines and therapeutics grew exponentially during the COVID-19 pandemic. The research showed that the triggering system is similar across multiple viruses, including Zika, the flu or SARS-CoV-2, the virus that causes COVID-19.
Dr. Gack’s team, including lead author Dhiraj Acharya, Ph.D., research associate at FRIC, also discovered that lipid components or virus-like particles such as those used in vaccines or RNA-based therapeutics can cause the cytoskeletal disturbance necessary for prompting an immune response. These results could help developers “fine-tune” the immunostimulatory potencies of therapeutics or vaccines.
Dr. Gack’s lab, operating under Cleveland Clinic’s multi-site Global Center for Pathogen and Human Health Research, investigates virus-host interactions on a molecular level, identifying host responses that can play a key role in developing new treatments and vaccines. The center is a cornerstone of the Cleveland Innovation District.
The study was a collaboration with Konstantin Sparrer, Ph.D., Ulm University in Germany, and other collaborators from multiple institutions. Funding was provided by the National Institutes of Health, the Federal Ministry of Education and Research Germany, and the German Research Foundation.
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Materials provided by Cleveland Clinic. Note: Content may be edited for style and length.

A research team funded by the National Institutes of Health has shown that commercially available rapid antigen tests can detect past and present variants of concern and has identified potential mutations that may impact test performance in the future. As new variants of the SARS-CoV-2 virus continue to emerge, concerns have been raised about the performance of rapid antigen tests.
The team, which was funded by NIH’s Rapid Acceleration of Diagnostics (RADx®) Tech program, developed a method to evaluate how mutations to SARS-CoV-2 can affect recognition by antibodies used in rapid antigen tests. Since most rapid antigen tests detect the SARS-CoV-2 nucleocapsid protein, or N protein, the team directly measured how mutations to the N protein impacted diagnostic antibodies’ ability to recognize their target.
“Rapid antigen tests remain an important COVID-19 mitigation tool, and it is essential to ensure that these tests can detect the SARS-CoV-2 virus as it continues to evolve,” said Bruce J. Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and lead for the RADx Tech program at the NIH. “Considering the endless cycle of new variants, the data from this study will be useful for years to come.”
The study, published in Cell, used a method called deep mutational scanning to simultaneously evaluate how any single amino acid substitution in the N protein could affect diagnostic antibody binding. The researchers generated an exhaustive library of N protein variations, which includes nearly 8,000 single amino acid substitutions — representing more than 99.5% of all possible mutations — and evaluated their interaction with 17 different diagnostic antibodies used in 11 commercially available rapid antigen tests. Rapid antigen tests often employ two different diagnostic antibodies for the detection of the SARS-CoV-2 virus.
For each diagnostic antibody evaluated, the researchers documented which mutations to the N protein affected antibody recognition. From this information, they created an ‘escape mutation profile’ for each antibody, which lists the specific mutations to the N protein that have an effect on the antibody’s ability to bind to its target. While several diagnostic antibodies recognized the same region of the N protein, the researchers found that each antibody had a unique escape mutation profile. As the SARS-CoV-2 virus continues to develop mutations, this data can be used to flag specific antibodies whose diagnostic performance may need to be re-assessed.
“Based on our findings, none of the major past and present SARS-CoV-2 variants of concern contain N protein mutations that would affect recognition by antibodies used in current rapid antigen tests,” said first study author Filipp Frank, Ph.D., an assistant professor in the department of biochemistry at Emory University, Atlanta. “Further, this data could inform test design by identifying which diagnostic antibodies should be paired to identify the maximum amount of potential N protein variations.”
“Accurate and efficient identification of infected individuals remains a critically important strategy for COVID-19 mitigation, and our study provides information about future SARS-CoV-2 mutations that may interfere with detection,” said senior study author Eric Ortlund, Ph.D., a professor in the department of biochemistry at Emory University. “The results outlined here can allow us to quickly adapt to the virus as new variants continue to emerge, representing an immediate clinical and public health impact.”
While many variants of concern contain multiple mutations to the N protein, the study authors note that their method does not evaluate how multiple mutations could affect diagnostic antibody recognition, representing a limitation of the study.
The project was supported in part by funds from the American Rescue Plan Act of 2021 administered by NIBIB under award numbers U54EB015408 and U54EB027690. The work was also supported under award number 75N92019P00328. This support was part of the RADx initiative, launched to speed innovation in the development, commercialization, and implementation of technologies for COVID-19 testing.
Researchers were also supported by the National Institute of Diabetes and Digestive and Kidney Diseases under award number R01DK115213; the National Institute of Allergy and Infectious Diseases under award number K99AI153736; and the American Heart Association under career development award 848388.

The rare genetic disease cystinosis is caused by mutations in the gene for a protein called cystinosin. A team of scientists has now solved the structure of cystinosin and determined how mutations interfere with its normal function, providing insights into the underlying mechanisms and suggesting a way to develop new treatments for the disease.
The new study, published September 15 in Cell, involved a collaborative effort by researchers at UC Santa Cruz, Stanford University, and the University of Texas Southwestern Medical Center, who combined their expertise in three specialized methods for studying protein structure and function: x-ray crystallography, cryogenic electron microscopy (cryo-EM), and double electron-electron resonance (DEER).
“This paper could set a model for how to combine those three areas, along with biochemical assays, to quickly narrow in on how a protein functions and identify a therapeutic strategy,” said Glenn Millhauser, distinguished professor and chair of chemistry and biochemistry at UC Santa Cruz and a corresponding author of the paper.
Cystinosin is a specialized transporter protein that plays a crucial role in how cells manage the essential amino acid cysteine. Cells are constantly recycling proteins, breaking them down into their constituent amino acids for use in building new proteins. Transporters like cystinosin move the amino acids out of lysosomes — the cellular compartments where proteins are broken down — into the cell to be reused. When cystinosin isn’t functioning properly due to mutations, a form of cysteine (a dimer called cystine) builds up inside the lysosomes.
The abnormal accumulation of cystine causes widespread damage to tissues and organs and can lead to kidney failure, muscle wasting, and other problems.
“It’s a rare disease, but it can be deadly,” Millhauser said. “If it’s untreated, people with cystinosis usually die by age ten.”
Cystinosin adopts different conformations when it is open to the inside of the lysosome to load cystine and when it is open to the outside to release cystine. The research teams at Stanford (led by Professor Liang Feng) and at UT Southwestern (led by Professor Xiaochun Li) solved the structures of cystinosin in these different structural conformations using x-ray crystallography and cryo-EM.
Understanding cystinosin’s structural changes through the transport process, however, required the DEER studies performed by Millhauser’s lab. DEER is a specialized magnetic resonance technique that can be used to determine how a protein changes its shape.
“With that we were able to figure out the mechanism that allows cystinosin to switch between those different states, and we could narrow in on which of the protein’s amino acids were driving the transition,” Millhauser said. “Now we can see how the mutations are changing the protein’s ability to change shape and pump cystine out of the lysosome.”
These new insights into the molecular mechanics of cystinosin’s transport activity not only provide a more detailed understanding of the pathogenesis of cystinosis, but also suggest a possible therapeutic strategy to treat the disease. “It may be possible to enhance the transport activity of cystinosin by developing conformation-selective small molecules or biologics that favor a cytosol-open conformation,” the authors wrote.
A similar approach could be used to target other transporter proteins, which are involved in a wide range of diseases.
The authors of the paper include co-first authors Tufa Assafa at UC Santa Cruz, Xue Guo at Stanford, and Philip Schmiege at UT Southwestern, and coauthors Yan Xu at Stanford, Rong Wang, Linda Donnelly, and Michael Fine at UT Southwestern, and Xiaodan Ni and Jiansen Jiang at the National Heart, Lung, and Blood Institute. This work was funded in part by the National Institutes of Health.
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Materials provided by University of California – Santa Cruz. Original written by Tim Stephens. Note: Content may be edited for style and length.

There are more than two million people living with an amputation in the United States, with about 400 being added daily. For many of them, prostheses or artificial limbs are a part of their lives, and they need to relearn how their bodies move with their new limbs all over again.
The trick to learning how to use a new limb — and regaining confidence in movement — has less to do with the prosthesis itself and more to do with the mind, according to newly published research by UNLV physical therapy researcher Szu-Ping Lee. By adopting the right attentional focus during rehab, patients can learn new skills better and faster.
“Vascular diseases and diabetes are becoming more common and one of the long-term consequences is amputation,” said Lee. “It is important that clinicians like prosthetists and physical therapists apply the newest science so that their patients can learn faster and retain the skills that they learned better.”
The current standard of practice in rehabilitating the millions of amputees in the country prioritizes internally focused instructions where the patients are told to move their joints or contract their muscles in certain ways, which is a suboptimal mindset that Lee says we should think about changing. And the science is grounded in sports kinesiology research built by fellow UNLV professor Gabriele Wulf.
Let’s go golfing for a better understanding:
After approaching the ball and reading the green, you square your shoulders — lining up the putt. At this point, most of us are concentrating on our form and measuring every muscle movement like a pseudo-pro. This is the standard process for rehab, internal focus.
But there’s another path forward. Instead of prioritizing our body movement, focusing on the path of the ball or simply the hole is more intuitive and works better. This is what Wulf and Lee are talking about — the focus is on the outcome, not the movement itself.
Professor Wulf’s research over the last 20 years has shown that external-focus for motor tasks leads to faster learning and improved movement effectiveness and neuromuscular efficiency. Lee is hoping that this technique can help amputees more quickly master the use of artificial limbs.
“With the wrong kind of focus or instruction being used during physical therapy, the consequences can be catastrophic-the artificial leg becomes a paperweight in a closet,” said Lee. “We want to advance clinical practice and that’s the ultimate goal. We want physical therapy to get better and better for the patients.”
The lower-limb prosthesis rehabilitation of 21 adults was monitored for this research, along with the verbal instructions provided. Results showed that most of the verbal interactions were internally-focused (standard) on patients’ body movements and not externally on the movement effects. More research is being done to evaluate how motor learning outcomes such as balance and fall prevention may be improved with better instructions.
The study, “Direction of attentional focus in prosthetic training: Current practice and potential for improving motor learning in individuals with lower limb loss,” was published in July in the journal PLOS One. UNLV graduate students Alexander Bonczyk, Maria Katrina Dimapilis, Sarah Partridge, and Samantha Ruis contributed to the study, as well as University of Illinois at Chicago professor Andrew Sawers.
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Materials provided by University of Nevada, Las Vegas. Original written by John Domol. Note: Content may be edited for style and length.

The COVID-19 pandemic has had many deleterious consequences for health care workers, including the challenges of caring for severely ill patients. Resident physicians, in particular, may have been affected by physical as well as psychological consequences of the pandemic. At present, data are sparse on the perceptions, coping strategies and mental health of residents during COVID-19.
Researchers from Florida Atlantic University’s Schmidt College of Medicine explored these issues through data from its community-based academic residency programs in the southeast United States. They administered multiple-choice online anonymous surveys to assess resident perceptions, coping strategies and self-reported levels of depression, anxiety and stress experienced during the early phase of the pandemic.
Results of the original research, published in the Southern Medical Journal, showed that 88.1 percent of residents felt they were likely or very likely to become infected with COVID-19. If infected, 28.8 percent felt that their illness would be serious or very serious. With respect to depression, anxiety and stress, all the mean scores were in the normal range. For depression, residents in emergency medicine and surgery reported higher levels. The trainees’ top three strategies to cope with COVID-19 included acceptance, self-distraction, and use of emotional support. The three least used strategies included behavioral disengagement, substance use and denial.
“The residents we surveyed in our programs reported effective coping strategies during the early phase of the COVID-19 pandemic,” said Allison H. Ferris, M.D., director, internal medicine residency program, and chair, Department of Medicine, FAU Schmidt College of Medicine. “It seems important and timely to continue to explore perceptions, coping strategies and mental health of residents as they play essential roles serving our patients and communities. Such information may be helpful to future residents and residency program directors as our trainees are the pipeline of future physicians and inevitably will face many challenging circumstances as they serve on the frontlines of health care.”
The survey included FAU residents in four specialties: internal medicine, surgery, emergency medicine and psychiatry. Researchers used the Brief COPE questionnaire, which included 28 items to assess coping strategies. They also measured dimensions of depression, anxiety and stress using the validated 21-item Depression, Anxiety, Stress Scale (formally recognized as the DASS-21).
“Further research is needed to better understand the challenges that residents face and the resources they need as new members on the frontline of the health care workforce, so that program leaders can proactively support them in an evidence-based and thoughtful manner,” said Sarah K. Wood, M.D., senior author, professor of pediatrics, vice dean for medical education, and chair of the Department of Women’s and Children’s Health, FAU Schmidt College of Medicine.
The authors note that this survey was conducted in May 2020 at the time when U.S. deaths from COVID-19 surpassed 100,000. In Florida, however, the first peak was in July 2020, a second peak was January 2021, and a third and highest peak was August 2021. The authors note that it is plausible that the responses may have been different had the residents been surveyed at a later time when cases and deaths were peaking in Florida.
“We believe the most plausible interpretation of the data to be that, during the U.S. epidemic of the COVID-19 pandemic, these residents reported effective coping strategies, namely, acceptance, self-distraction, and use of emotional support,” said Michael DeDonno, Ph.D., first author, a research psychologist and an associate professor in FAU’s College of Education and Schmidt College of Medicine.
Study co-authors are Andreea Molnar, M.D., a first year FAU resident in internal medicine; Henry M. Haire, M.D., an associate professor in the Department of Medicine; Sachin S. Sule, M.D., an associate professor in the Department of Medicine; and Charles H. Hennekens, M.D., Dr.PH, first Sir Richard Doll Professor of Medicine and senior academic adviser, all within the FAU Schmidt College of Medicine.

What happens when people unknowingly eat, drink or inhale nearly invisible pieces of plastic? Although it’s unclear what impact this really has on humans, researchers have now taken a step toward answering that question. In ACS’ Environmental Science & Technology, a team reports laboratory results indicating that tiny plastic particles could enter liver and lung cells and disrupt their regular processes, potentially causing adverse health outcomes.
Plastic can’t be avoided in daily life. Many products that we bring into our homes are made of plastic or wrapped in plastic packaging — all of which could release micro- and nanometer-sized pieces that could be accidentally consumed or inhaled. Although the health risks to humans from taking in nanoplastics isn’t entirely clear, researchers recently have shown that particles less than 100 nm-wide can enter animals’ blood and organs, causing inflammation, toxicity and neurological changes. So, Zongwei Cai, Chunmiao Zheng and colleagues wanted to examine the molecular-level and metabolic impacts when human lung and liver cells are exposed to similarly sized nanoplastics.
The researchers cultured human liver and lung cells separately in laboratory plates and treated them with different amounts of 80 nm-wide plastic particles. After two days, electron microscopy images showed that nanoplastics had entered both types of cells without killing them.
To learn more about what happened to the cells, the researchers looked at the compounds released by mitochondria — crucial energy-producing organelles that are thought to be sensitive to nanoplastics — during metabolism. As liver and lung cells were exposed to more nanoplastics, they produced more reactive oxygen species and different amounts of nucleotides, nucleosides, amino acids, peptides and carboxylic acids, indicating that multiple metabolic processes were disturbed. In some cases, mitochondrial pathways appeared to be dysfunctional. These observations demonstrate that while nanoplastics exposure doesn’t kill human lung and liver cells, it could disrupt critical processes, potentially causing negative impacts to organs, the researchers say.
The authors acknowledge funding from the Hong Kong General Research Fund and the National Science Foundation of China.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

A significant number of people who have survived cancer are living in poverty, which can have negative effects on their physical and mental health, according to researchers at the Medical College of Georgia and the Georgia Cancer Center at Augusta University.
Using the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System, which contains data from people across the US regarding health-related risk behaviors, chronic health conditions and their use of preventive services, they found that 12% of some 28,000 cancer survivors were living in poverty.
“The high cost of oncology care in the United States and its adverse effects on cancer survivors is of increasing concern,” they write in the journal JCO Oncology Practice. “The financial burden of cancer often persists years after diagnosis, due to ongoing costs of cancer care and late effects of cancer treatment, as well as incurred debt, lost income and inability to work.”
Many cancer treatments now total $100,000 or more annually, and without health insurance, those costs can be entirely out-of-pocket.
“We are always focused on curing cancer. That is our goal. That is our first objective when we are finding therapies and discussing treatment options and executing the treatment plan,” says Dr. Jorge Cortes, director of the Georgia Cancer Center and the paper’s senior author. “The problem we also need to address is what comes next.”
Looking to replicate findings from pilot studies in breast cancer, the research team looked at patients with leukemia and lymphoma from the national dataset and identified the same issues. As in the national dataset, many leukemia and lymphoma survivors at the Georgia Cancer Center are low-income and struggle to make ends meet.

Children are more likely to develop asthma if their father was exposed to second-hand smoke when he was a child, according to a study published today in the European Respiratory Journal.
Led by University of Melbourne researchers, Mr Jiacheng Liu and Dr Dinh Bui, the study also shows that children’s risk of asthma is even higher if their father was exposed to second-hand smoke and went on to become a smoker.
The researchers say their findings highlight how smoking can damage health not only for smokers and their children, but also their grandchildren.
The study was based on data from the Tasmanian Longitudinal Health Study (TAHS), led by University of Melbourne Professor Shyamali Dharmage.
TAHS began in 1968 and is one of the world’s largest and longest ongoing respiratory studies.
For this study, researchers looked at 1689 children who grew up in Tasmania, their fathers and their paternal grandparents.

Drugs like enzalutamide that inhibit male hormones from activating the androgen receptor have been used to treat advanced prostate cancer for more than a decade. While successful in most cases, these drugs can eventually stop working, but there is a limited understanding about how this change occurs.
A new study from the University of Michigan Rogel Cancer Center suggests androgen receptor inhibitors can fundamentally rewire and reshape how prostate tumors function, and in certain cases even make them more aggressive. These findings will be published in Nature Communications on Sept. 15.
Male hormones function as fuel, turning on the androgen receptor that acts as the engine of prostate cancer cells. For the past 80 years, treatment for patients with advanced prostate cancer has focused on interfering with these hormone levels — now typically done through hormone lowering shots and drugs like enzalutamide. Eventually, nearly all tumors develop workarounds and escape treatment, and in most cases, tumors remain dependent on male hormones to power their growth. Other examples of treatment resistance remain poorly understood.
“The greatest unmet need in the clinic right now is understanding the workarounds in a tumor that becomes resistant to androgen receptor targeting drugs so we can determine how best to treat the patient whose tumor has begun to grow,” said Joshi Alumkal, M.D., Wicha Family Professor of Oncology and Professor of Internal Medicine, whose team led this research in collaboration with the Zheng Xia laboratory at the Oregon Health & Sciences University Knight Cancer Institute. Thomas Westbrook, M.D., hematology-oncology fellow, was the study’s co-first author along with post-doctoral fellow Xiangnan Guan, Ph.D. “Once enzalutamide stops working, there are limited options. We don’t know how or why most tumors become resistant.”
Alumkal wanted to understand what was present in these tumors to begin with and what happened after tumors started to grow on enzalutamide treatment.
He and colleagues recruited patients to a longitudinal study to obtain metastatic biopsies before enzalutamide treatment and at the time the tumor became resistant to treatment. His team collected serial biopsies from 21 patients, enabling them to understand the workarounds in the tumor from each patient.

Cow mucus provides the basis for a synthetic prophylactic gel developed at KTH Royal Institute of Technology to protect against HIV and herpes transmission. The lubricating gel proved 70 percent effective in lab tests against HIV, and 80 percent effective against herpes.
The viral prophylactic tests were conducted in a lab on several types of cells. The results were reported today in the scientific journal, Advanced Science.
Hongji Yan, a biomaterials researcher at KTH, says the promising results raise hope that when it becomes available as a product, the gel could help reverse troubling trends in the spread of sexually transmitted infections. More than 1 million STIs are acquired every day worldwide and most of these are asymptomatic, according to the World Health Organization (WHO). AIDS, the disease caused by HIV, remains a significant global epidemic, and adolescent girls and young women are twice as likely as men to contract HIV as their male counterparts according to UNAIDS.
The lubricant is derived from mucin, a main component of mucus that is produced in the human body, though suppliers provide the bovine type in purified form for fabrication of hydrogels.
Hongji says the natural complexity of the mucin molecules is the reason the synthetic gel is so effective at stopping the HIV and herpes, without the risk of side effects or development of resistance as with other antiviral compounds. Such functions would be difficult to achieve with a polymer made from scratch, he says.
In our body, mucin molecules can bind to and trap virus particles, which are then cleared through active mucus turnover. Hongji says the synthetic gel replicates this self-healing function, which is a key material property that enables mucus’ lubricity and prophylaxis against infection.
Hongji says the gel could help more people take greater control of their sexual health. It could offer protection when condom protection is not an available option, or even as back-up protection in case of condom failure or incorrect use. It could be used in both female-to-male sex and male-to-male sex.
The mucins in the synthetic gel also help to dampen the activation of immune cells, he says. This is important because activated immune cells stimulate HIV replication.
The project is a collective effort of laboratories at KTH Royal Institute of Technology, the Technical University of Munich (TUM) and Karolinska Institutet. Analysis of the lubricating properties of the gel was performed by first author Martin Kretschmer at TUM. Viral tests were performed by first author Rafael Ceña-Diez at Karolinska Institutet.
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Materials provided by KTH, Royal Institute of Technology. Original written by David Callahan. Note: Content may be edited for style and length.