Study Provides Novel Platform to Study How SaRS-CoV-2 Affects the Gut (Medicine)

May help design better diagnostic and therapeutic tools to fight the virus

How could studying gastrointestinal cells help the fight against COVD-19, which is a respiratory disease? According to a team led by Gustavo Mostoslavsky, MD, PhD, at the BU/BMC Center for Regenerative Medicine (CReM) and Elke Mühlberger, PhD, from the National Emerging Infectious Diseases Laboratories (NEIDL) at Boston University, testing how SARS-CoV-2 affects the gut can potentially serve to test novel therapeutics for COVID-19.

In order to study SARS-CoV-2, models are needed that can duplicate disease development in humans, identify potential targets and enable drug testing. BU researchers have created human induced pluripotent stem cells (iPSC)-derived intestinal organoids or 3-D models that can be infected and replicated with SARS-CoV-2.

iPSC are stem cells derived from the donated skin or blood cells that are reprogrammed back to an embryonic stem cell-like state and then can be developed into any cell type in the body.

“Human induced pluripotent stem cell derived intestinal organoids represent an inexhaustible cellular resource that could serve as a valuable tool to study SARS-CoV-2, as well as other intestinal viruses that infect the intestinal epithelium,” explained corresponding author Mostoslavsky, associate professor of microbiology at Boston University School of Medicine (BUSM) and co-director of the CReM.

Using human induced pluripotent stem cells (iPSC) the researchers differentiated the iPSC cells into colonic and small intestine 3D organoids. The organoids were then passed along to the Mühlberger lab at the NEIDL where they were infected with SARS-CoV-2 to analyze the effect of infection on the cells by staining against markers, by electron microscopy and by RNA-sequencing.

“Our findings suggests that different epithelial tissues (such as the lung and the gut) react in similar manner to SARS-CoV-2 infection and therefore can help identify common mechanisms of disease that can be targeted by drugs,” added Mühlberger, director of Integrated Science Services at the NEIDL and professor of microbiology at BUSM.

These findings appear online in the journal Stem Cell Reports.

Funding for this research was provided by Evergrande MassCPR, Fast Grants, and NIH NCATS grant UL1TR001430 awards to EM. AM is supported by the Kilachand Multicellular Design Program at Boston University. GM is supported by NIH Grants N0175N92020C00005 and 1R01DA05188901

Reference: Aditya Mithal, Adam J. Hume, “Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response”, 16(4), pp. 940-953, 2021. DOI:

Provided by Boston University School of Medicine

Human Screams Communicate at Least Six Emotions (Biology)

Human screams signal more than fear and are more acoustically diverse than previously thought, according to a study published April 13th 2021 in the open-access journal PLOS Biology by Sascha Fruhholz of the University of Zurich, and colleagues. Remarkably, non-alarming screams are perceived and processed by the brain more efficiently than alarming screams.

In nonhuman primates and other mammalian species, scream-like calls are frequently used as an alarm signal exclusively in negative contexts, such social conflicts or the presence of predators or other environmental threats. Humans are also assumed to use screams to signal danger and to scare predators. But humans scream not only when they are fearful and aggressive, but also when they experience other emotions such as despair and elation. Past studies on this topic largely focused on alarming fear screams, so the broader significance of various scream types has not been clear. In the new study, the researchers addressed this knowledge gap using four different psychoacoustic, perceptual decision-making, and neuroimaging experiments in humans.

Twelve participants were asked to vocalize positive and negative screams that might be elicited by various situations. A different group of individuals rated the emotional nature of the screams, classified the screams into different categories, and underwent functional magnetic resonance imaging (fMRI) while listening to the screams.

The results revealed six psycho-acoustically distinct types of scream calls, which indicated pain, anger, fear, pleasure, sadness, and joy. Perhaps surprisingly, listeners responded more quickly and accurately, and with higher neural sensitivity, to non-alarm and positive scream calls than to alarming screams. Specifically, less alarming screams elicited more activity across many auditory and frontal brain regions. According to the authors, these findings show that scream calls are more diverse in their signaling and communicative nature in humans than frequently assumed.

Dr. Fruhholz notes “The results of our study are surprising in a sense that researchers usually assume the primate and human cognitive system to be specifically tuned to detect signals of danger and threat in the environment as a mechanism of survival. This has long been supposed to be the primary purpose of communicative signaling in screams. While this seems true for scream communication in primates and other animal species, scream communication seemed to have largely diversified in humans, and this represents is a major evolutionary step. Humans share with other species the potential to signal danger when screaming, but it seems like only humans scream to signal also positive emotions like extreme joy and pleasure. Signaling and perceiving these positive emotions in screams seemed to have gained priority in humans over alarm signaling. This change in priority might be likely due to the requirements of evolved and complex social contexts in humans.”

Funding: This study was supported by the Swiss National Science Foundation (SNSF PP00P1_157409/1 and PP00P1_183711/1 to SF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Reference: Frühholz S, Dietziker J, Staib M, Trost W (2021) Neurocognitive processing efficiency for discriminating human non-alarm rather than alarm scream calls. PLoS Biol 19(4): e3000751.

Provided by Plos

JNCCN Study: Important Potential Role for Routine Brain Imaging in Advanced Kidney Cancer (Medicine)

International study finds 4% of patients with metastatic renal cell carcinoma developed asymptomatic brain metastases, which correlated to poorer outcomes.

The April 2021 issue of JNCCN—Journal of the National Comprehensive Cancer Network publishes new research from Memorial Sloan Kettering Cancer Center (MSK) and Gustave Roussy Institute, which suggests that baseline brain imaging should be considered in most patients with metastatic kidney cancer. The researchers studied 1,689 patients with metastatic renal cell carcinoma (mRCC) who had been considered for clinical trial participation at either of the two institutions between 2001 and 2019 and had undergone brain imaging in this context, without clinical suspicion for brain involvement. The researchers discovered 4% had asymptomatic brain metastases in this setting. This group was found to have a low median 1-year overall survival rate (48%), and median overall survival (10.3 months).

“With 4% overall incidence in this cohort, one might conclude that baseline brain imaging should be considered in all patients with metastatic kidney cancer, particularly those with multiorgan involvement and/or pulmonary metastases” said lead MSK researcher Ritesh R. Kotecha, MD, who also worked with investigators from Gustave Roussy, a leading academic cancer center located just outside Paris, France.

“Brain imaging is routinely obtained for kidney cancer patients with symptoms that suggest central nervous system (CNS) metastases, but none of the patients with brain metastases included here were symptomatic,” added senior researcher Martin H. Voss, MD, also with MSK. “In current practice chest, abdomen, and pelvis are routinely imaged from the time that metastatic disease is first detected yet many oncologists do not image the brain.”

The researchers found 86% of the patients with asymptomatic brain metastases harbored metastatic disease in 2 or more additional organ systems, most-commonly the lung, followed by liver and bone.

“The retrospective study by Kotecha, et. al. demonstrates that incidental brain metastases occur in a clinically significant percentage of patients with newly diagnosed metastatic renal cell carcinoma,” commented Eric Jonasch, MD, Professor, Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, who was not involved in this research.

Dr. Jonasch, who is Vice-Chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Panel for Kidney Cancer, continued: “The findings in this study are important for two reasons. First, they show that the overall prognosis of patients with brain metastases is consistently worse than the broader population of patients with metastatic renal cell carcinoma. We need to develop a deeper scientific understanding of why this patient population has a worse outcome, and we need to include them in future clinical trials. Second, they underscore the utility for MRI imaging of all patients with metastatic renal cell carcinoma both at initial diagnosis, and at regular intervals, to detect occult brain metastases, since specific treatment strategies are required for this patient population.”

The researchers acknowledged that their data cannot provide input as to how frequently brain surveillance should be repeated, and called for additional study.

To read the entire article, visit Complimentary access to “Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma” is available until July 10, 2021.

Featured image: JNCCN April 2021 Cover © JNCCN

Provided by NCCN

About JNCCN—Journal of the National Comprehensive Cancer Network

More than 25,000 oncologists and other cancer care professionals across the United States read JNCCN—Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about innovation in translational medicine, and scientific studies related to oncology health services research, including quality care and value, bioethics, comparative and cost effectiveness, public policy, and interventional research on supportive care and survivorship. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside. Visit To inquire if you are eligible for a FREE subscription to JNCCN, visit Follow JNCCN on Twitter @JNCCN.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing educationglobal initiativespolicy, and research collaboration and publication in oncology. Visit for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

Researchers Discover New Way to Monitor and Prevent Nerve Cell Deterioration after Brain Injury (Neuroscience)

Potential mechanistic link shown between Traumatic Brain Injury and Alzheimer’s disease

Violent blows or jolts to the head can cause traumatic brain injury (TBI), and there are currently about five million people in the U.S. living with some form of chronic impairment after suffering a TBI. Even in a mild form, TBI can lead to lifelong nerve cell deterioration associated with a wide array of neuropsychiatric conditions. Tragically, there are no medicines to protect nerve cells after injury. Behind aging and genetics, TBI is the third leading cause of Alzheimer’s disease (AD), yet the link between these two conditions is not understood.  

In a new study, published online today in Cellresearchers have discovered a new way to prevent brain nerve cells from deteriorating after injury, which also revealed a potential mechanistic link between TBI and AD. Their discovery also yielded a new blood biomarker of nerve cell degeneration after injury, which is significant because there is an urgent need for mechanism-based blood biomarkers that can diagnose TBI and stage its severity.

Prior to this study, it had been previously reported that a small protein in nerve cells, called tau, was modified by a chemical process called acetylation in the post-mortem brains of AD patients. But how this modification came about, as well as its role in the disease process, was not understood. 

“Normally, tau functions in nerve cells to maintain the appropriate structure of the axon, which is the nerve cell extension required for nerve cells to communicate with one another,” said Andrew A. Pieper, MD, PhD, senior author on the study, Harrington Discovery Institute (HDI) Investigator and Director of the HDI Neurotherapeutics Center at University Hospitals (UH), Morley-Mather Chair in Neuropsychiatry at UH, Director of the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center, and VA Geriatric Research, Educational and Clinical Care (GRECC) Investigator. “Given the relationship between AD and TBI, we wondered whether elevated acetylated-tau (ac-tau) might also occur in TBI, and if so, then whether this could provide an experimental platform to study its potential role in nerve cell deterioration.”

Dr. Pieper’s lab discovered that ac-tau increased rapidly in multiple forms of TBI in mice and rats, and persisted chronically when nerve cell degeneration was untreated. They also showed that the increased ac-tau in human AD brain was further exacerbated when the AD patient also had a prior history of TBI.

“Our research showed that after ac-tau rises, a specific structure at the junction of the nerve cell body and its axon, called the axon initial segment, breaks down,” explained Min-Kyoo Shin, PhD, co-first author of the study. “As a result, tau is no longer appropriately sequestered in axons. This leads to axonal degeneration, followed by neurologic impairment.”

The team tested therapeutic interventions after TBI at each of the three nodal points in the new signaling pathway that they identified as leading to increased nerve cell ac-tau after injury. Using known medicines or experimental drugs, they saw that all three points provided effective therapeutic opportunity.

Strikingly, they found that two FDA-approved medicines of the NSAID class (anti-inflammatory medicines commonly used as pain relievers), salsalate and diflunisal, were potently neuroprotective after TBI in mice. Relative to all other NSAIDs and distinct from their anti-inflammatory property, these two medicines inhibit the acetyltransferase enzyme in nerve cells that adds the acetyl group onto tau protein after brain injury.

Next, they examined more than seven million patient records and learned that usage of either salsalate or diflunisal was associated with decreased incidence of both AD and clinically diagnosed TBI, compared to usage of aspirin in other patients for the same time period. The protective effect was stronger in diflunisal and salsalate, which correlates with diflunisal’s superior potency in inhibiting the acetyltransferase enzyme, relative to salsalate. The NSAID aspirin was used as a comparison group because it does not inhibit the acetyltransferase.

Lastly, because the tau protein freely diffuses from the brain into the blood, the researchers examined whether ac-tau might also be elevated in the blood after TBI. In mice, they found that blood levels of ac-tau correspond tightly with brain levels, and that blood levels return to normal when mice are treated with therapeutics that lower brain ac-tau and thereby protect nerve cells. Importantly, they also found that ac-tau was significantly increased in the blood of human TBI patients.

“This work has a number of potential clinical implications,” explained Edwin Vázquez-Rosa, PhD, co-first author on the study. “First, it shows that the medicines salsalate and diflunisal provide previously unidentified neuroprotective activity by this new mechanism, and that in the course of being prescribed these medicine for traditional indications patients appear to also be relatively protected from developing neurodegenerative conditions. Accordingly, these medicines may also help protect TBI patients from developing AD. Finally, our work provides a new blood biomarker of neurodegeneration in the brain after TBI that could be harnessed to stage severity and progression of nerve cell deterioration after injury.”

Robert A. Bonomo, MD, Associate Chief of Staff at VA Northeast Ohio Healthcare System and professor at Case Western Reserve School of Medicine added, “Many of our patients suffer from TBI or AD. These important findings will have a tremendous, long-term impact on our Veteran population.”

Next steps in the research involve further investigation of the applicability of ac-tau as a biomarker in neurodegenerative disease and the potential utility of diflunisal or salsalate as neuroprotective medicines for people, as well as deeper study of the mechanisms by which ac-tau causes nerve cell deterioration.

The findings from the Pieper lab represent an outgrowth of collaborative efforts from investigators across the Cleveland community at UH, HDI, Case Western Reserve, VA Northeast Ohio Healthcare System, Cleveland Clinic and The MetroHealth System.

This study was also supported by the Brockman Foundation; the AHA/Allen Initiative in Brain Health and Cognitive Impairment; The Neuropathology Core of Northwestern University; Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center; and the Departments of Neurology and Neurosurgery of McGovern Medical School of The University of Texas Health Science Center at Houston.

Featured image: In a new study, published online today in Cell, researchers have discovered a new way to prevent brain nerve cells from deteriorating after injury, which also revealed a potential mechanistic link between TBI and AD. © University Hospitals/The Pieper Lab

Reference: Shin, M, Vázquez-Rosa, E., et al. “Reducing acetylated-tau is neuroprotective in brain injury.” CellDOI: 10.1016/j.cell.2021.03.032.

Provided by UH Cleveland Medical Center

Gene Therapy Shows Promise in Treating Rare Eye Disease in Mice (Medicine)

Findings suggest combination gene therapies that target multiple causes of eye cell death in mice could be an effective approach for treating people with retinitis pigmentosa and similar conditions.

A gene therapy protects eye cells in mice with a rare disorder that causes vision loss, especially when used in combination with other gene therapies, shows a study published today in eLife.

The findings suggest that this therapy, whether used alone or in combination with other gene therapies that boost eye health, may offer a new approach to preserving vision in people with retinitis pigmentosa or other conditions that cause vision loss.

Retinitis pigmentosa is a slowly progressive disease, which begins with the loss of night vision due to genetic lesions that affect rod photoreceptors – cells in the eyes that sense light when it is low. These photoreceptors die because of their intrinsic genetic defects. This then impacts cone photoreceptors, the eye cells that detect light during the day, which leads to the eventual loss of daylight vision. One theory about why cones die concerns the loss of nutrient supply, especially glucose.

Scientists have developed a few targeted gene therapies to help individuals with certain mutations that affect the photoreceptors, but no treatments are currently available that would be effective for a broad set of families with the disease. “A gene therapy that would preserve photoreceptors in people with retinitis pigmentosa regardless of their specific genetic mutation would help many more patients,” says lead author Yunlu Xue, Postdoctoral Fellow at senior author Constance Cepko’s lab, Harvard Medical School, Boston, US.

To find a widely effective gene therapy for the disease, Xue and colleagues screened 20 potential therapies in mouse models with the same genetic deficits as humans with retinitis pigmentosa. The team chose the therapies based on the effects they have on sugar metabolism.

Their experiments showed that using a virus carrier to deliver a gene called Txnip was the most effective approach in treating the condition across three different mouse models. A version of Txnip called C247S worked especially well, as it helped the cone photoreceptors switch to using alternative energy sources and improved mitochondria health in the cells.

The team then showed that giving the mice gene therapies that reduced oxidative stress and inflammation, along with Txnip gene therapy, provided additional protection for the cells. Further studies are now needed to confirm whether this approach would help preserve vision in people with retinitis pigmentosa.

“The immediate next step is to test Txnip for safety in animals beyond mice, before moving on to a clinical trial in humans,” explains senior author and Howard Hughes Institute Investigator Constance Cepko, the Bullard Professor of Genetics and Neuroscience at Harvard Medical School. “If it ultimately proves safe in people, then we would hope to see it become an effective approach for treating those with retinitis pigmentosa and other forms of progressive vision loss, such as age-related macular degeneration.”

Featured image: High magnification images taken with an electron microscope, focusing on mitochondria (shown in magenta) in a degenerating retinal cone photoreceptor. The image on the right shows a single mitochondrion following treatment with Txnip, which has a healthier appearance compared to mitochondria before treatment, on the left. Image credit: Yunlu Xue (CC BY 4.0)

Reference: Yunlu Xue et al., “AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa”, elife, 2021. DOI: 10.7554/eLife.66240

Provided by Elife

Study Warns Of ‘Oxygen False Positives’ in Search For Signs of Life on Other Planets (Planetary Science)

Oxygen in the atmosphere may not be an entirely reliable ‘biosignature,’ but there are ways to distinguish false positives from signs of life, scientists say

In the search for life on other planets, the presence of oxygen in a planet’s atmosphere is one potential sign of biological activity that might be detected by future telescopes. A new study, however, describes several scenarios in which a lifeless rocky planet around a sun-like star could evolve to have oxygen in its atmosphere.

The new findings, published April 13 in AGU Advances, highlight the need for next-generation telescopes that are capable of characterizing planetary environments and searching for multiple lines of evidence for life in addition to detecting oxygen.

“This is useful because it shows there are ways to get oxygen in the atmosphere without life, but there are other observations you can make to help distinguish these false positives from the real deal,” said first author Joshua Krissansen-Totton, a Sagan Fellow in the Department of Astronomy and Astrophysics at UC Santa Cruz. “For each scenario, we try to say what your telescope would need to be able to do to distinguish this from biological oxygen.”

In the coming decades, perhaps by the late 2030s, astronomers hope to have a telescope capable of taking images and spectra of potentially Earth-like planets around sun-like stars. Coauthor Jonathan Fortney, professor of astronomy and astrophysics and director of UCSC’s Other Worlds Laboratory, said the idea would be to target planets similar enough to Earth that life might have emerged on them and characterize their atmospheres.

“There has a been a lot of discussion about whether detection of oxygen is ‘enough’ of a sign of life,” he said. “This work really argues for needing to know the context of your detection. What other molecules are found in addition to oxygen, or not found, and what does that tell you about the planet’s evolution?”

This means astronomers will want a telescope that is sensitive to a broad range of wavelengths in order to detect different types of molecules in a planet’s atmosphere.

Rocky planet evolution

The researchers based their findings on a detailed, end-to-end computational model of the evolution of rocky planets, starting from their molten origins and extending through billions of years of cooling and geochemical cycling. By varying the initial inventory of volatile elements in their model planets, the researchers obtained a surprisingly wide range of outcomes.

Oxygen can start to build up in a planet’s atmosphere when high-energy ultraviolet light splits water molecules in the upper atmosphere into hydrogen and oxygen. The lightweight hydrogen preferentially escapes into space, leaving the oxygen behind. Other processes can remove oxygen from the atmosphere. Carbon monoxide and hydrogen released by outgassing from molten rock, for example, will react with oxygen, and weathering of rock also mops up oxygen. These are just a few of the processes the researchers incorporated into their model of the geochemical evolution of a rocky planet.

“If you run the model for Earth, with what we think was the initial inventory of volatiles, you reliably get the same outcome every time–without life you don’t get oxygen in the atmosphere,” Krissansen-Totton said. “But we also found multiple scenarios where you can get oxygen without life.”

For example, a planet that is otherwise like Earth but starts off with more water will end up with very deep oceans, putting immense pressure on the crust. This effectively shuts down geological activity, including all of the processes such as melting or weathering of rocks that would remove oxygen from the atmosphere.

In the opposite case, where the planet starts off with a relatively small amount of water, the magma surface of the initially molten planet can freeze quickly while the water remains in the atmosphere. This “steam atmosphere” puts enough water in the upper atmosphere to allow accumulation of oxygen as the water breaks up and hydrogen escapes.

“The typical sequence is that the magma surface solidifies simultaneously with water condensing out into oceans on the surface,” Krissansen-Totton said. “On Earth, once water condensed on the surface, escape rates were low. But if you retain a steam atmosphere after the molten surface has solidified, there’s a window of about a million years when oxygen can build up because there are high water concentrations in the upper atmosphere and no molten surface to consume the oxygen produced by hydrogen escape.”

A third scenario that can lead to oxygen in the atmosphere involves a planet that is otherwise like Earth but starts off with a higher ratio of carbon dioxide to water. This leads to a runaway greenhouse effect, making it too hot for water to ever condense out of the atmosphere onto the surface of the planet.

“In this Venus-like scenario, all the volatiles start off in the atmosphere and few are left behind in the mantle to be outgassed and mop up oxygen,” Krissansen-Totton said.

He noted that previous studies have focused on atmospheric processes, whereas the model used in this study explores the geochemical and thermal evolution of the planet’s mantle and crust, as well as the interactions between the crust and atmosphere.

“It’s not computationally intensive, but there are a lot of moving parts and interconnected processes,” he said.

In addition to Krissansen-Totton and Fortney, the coauthors include Francis Nimmo, professor of Earth and planetary sciences at UC Santa Cruz, and Nicholas Wogan at the University of Washington, Seattle. This research was supported by NASA.

Featured image: By varying the initial inventory of volatile elements in a model of the geochemical evolution of rocky planets, researchers obtained a wide range of outcomes, including several scenarios in which a lifeless rocky planet around a sun-like star could evolve to have oxygen in its atmosphere. (Illustration by J. Krissansen-Totton)

Reference: Krissansen‐Totton, J., Fortney, J. J., Nimmo, F., & Wogan, N. (2021). Oxygen false positives on habitable zone planets around sun‐like stars. AGU Advances, 2, e2020AV000294.

Provided by University of California Santa Cruz

Researchers Develop New Method For Putting Quantum Correlations To The Test (Quantum)

Physicists from Swansea University are part of an international research collaboration which has identified a new technique for testing the quality of quantum correlations.

Quantum computers run their algorithms on large quantum systems of many parts, called qubits, by creating quantum correlations across all of them. It is important to verify that the actual computation procedures lead to quantum correlations of desired quality.

However, carrying out these checks is resource-intensive as the number of tests required grows exponentially with the number of qubits involved.

Researchers from the College of Science, working with colleagues from Spain and Germany, have now proposed a new technique that helps to overcome this problem by significantly reducing the number of measurements while increasing the resilience against noise.

Their method offers a solution to the problem of certifying correlations in large systems and is explained in a new paper which has just been published in PRX Quantum, a prestigious journal from American Physical Society.

Research fellow Dr Farid Shahandehthe lead scientist of this research, said: “To achieve this we combine two processes. Firstly, consider a juicer – it extracts the essence of the fruit by squeezing it into a small space. Similarly, in many cases quantum correlations in large systems can also be concentrated in smaller parts of the system. The ‘squeezing’ is done by measurements on the rest of the system called the localization process.

“Suppose the juicer directly converts the fruit into juice boxes without any labels. We don’t know what is inside — it could be apple juice, orange juice, or just water. One way to tell would be to open the box and taste it. The quantum comparison of this is to measure a suitable quantity that tells us whether quantum correlations exist within a system or not.

“This process is called witnessing and we call the combination of the two approaches conditional witnessing.”

In their research the physicists prove their method is efficient and generically tolerates higher levels of noise in experiments. They have also compared their approach with previous techniques in a class of quantum processors that use ions to demonstrate its efficiency.

Dr Shahandeh, the recipient of a Royal Commission for the Exhibition of 1851 research fellowship, added: “This is of crucial importance in current technology where the addition of each qubit unavoidably amplifies the complexity of quantum states and experimental imperfections.”

Reference: Efficient and robust certification of genuine multipartite entanglement in noisy quantum error correction circuits
Andrea Rodriguez-Blanco, Alejandro Bermudez, Markus Müller, and Farid Shahandeh

Provided by Swansea University

Amoeba Biology Reveals Potential Treatment Target for Lung Disease (Medicine)

In a series of experiments that began with amoebas — single-celled organisms that extend podlike appendages to move around — Johns Hopkins Medicine scientists say they have identified a genetic pathway that could be activated to help sweep out mucus from the lungs of people with chronic obstructive pulmonary disease a widespread lung ailment.

“Physician-scientists and fundamental biologists worked together to understand a problem at the root of a major human illness, and the problem, as often happens, relates to the core biology of cells,” says Doug Robinson, Ph.D., professor of cell biology, pharmacology and molecular sciences, medicine (pulmonary division), oncology, and chemical and biomedical engineering at the Johns Hopkins University School of Medicine.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the U.S., affecting more the 15 million adults, according to the U.S. Centers for Disease Control and Prevention. The disease causes the lungs to fill up with mucus and phlegm, and people with COPD experience chronic cough, wheezing and difficulty breathing. Cigarette smoking is the main cause in as many as three-quarters of COPD cases, and there is no cure or effective treatment available despite decades of research.

In a report on their new work, published Feb. 25 in the Journal of Cell Science, the researchers say they took a new approach to understanding the biology of the disorder by focusing on an organism with a much simpler biological structure than human cells to identify genes that might protect against the damaging chemicals in cigarette smoke.

Robinson and his collaborator, Ramana Sidhaye, M.D., also a professor of medicine in the Division of Pulmonology at Johns Hopkins, with their former lab member Corrine Kliment, M.D., Ph.D., counted on the knowledge that as species evolved, genetic pathways were frequently retained across the animal kingdom.

Enter the soil-dwelling amoeba Dictyostelium discoideum, which has long been studied to understand cell movement and communication. The scientists pumped lab-grade cigarette smoke through a tube and bubbled it into the liquid nutrients bathing the amoeba. Then, the scientists used engineered amoeba to identify genes that could provide protection against the smoke.

Looking at the genes that provided protection, creating “survivor” cells, one family of genes stood out among the rest: adenine nucleotide translocase (ANT). Proteins made by this group of genes are found in the membrane, or surface, of a cell’s energy powerhouse structure, known as mitochondria. Typically, mitochondria help make the fuel that cells use to survive. When an ANT gene is highly active, cells get better at making fuel, protecting them from the smoke.

Kliment, Robinson and the team suspected they also help amoeba overcome the damaging effects of cigarette smoke.

To better understand how ANT genes behave in humans, the scientists studied tissue samples of cells lining the lungs taken from 28 people with COPD who were treated at the University of Pittsburgh and compared the lung cells’ genetic activity with cells from 20 people with normal lung function.

The scientists found that COPD patients had about 20% less genetic expression of the ANT2 gene than those with normal lung function. They also found that mice exposed to smoke lose ANT2 gene expression.

Next, Robinson, Kliment and their research team sought to discover how ANT2 might provide protection from cigarette smoke chemicals and, in the process, discovered something completely unexpected.

Cells lining the lungs use fingerlike projections called cilia to sweep mucus and other particles out of the lungs. In mammals, including people, the scientists found that the ANT2 gene produces proteins that localize in and around the cilia that work to release tiny amounts of the cell’s fuel into a watery substance next to the cell. The fuel enhances the ability of the cilia to “beat” rhythmically and regularly to sweep away the mucus.

“In COPD patients, mucus becomes too thick to sweep out of the lungs,” says Robinson.

The Johns Hopkins Medicine team found that, compared with human lung cells with normal ANT2 function, cilia in human lung cells lacking ANT2 beat 35% less effectively when exposed to smoke. In addition, the watery liquid next to the cell was about half the height of normal cells, suggesting the liquid was denser, which can also contribute to lower beat rates.

When the scientists genetically engineered the lung cells to have an overactive ANT2 gene and exposed them to smoke, the cells’ cilia beat with the same intensity as normal cells not exposed to smoke. The watery layer next to these cells was about 2.5 times taller than that of cells lacking ANT2.

“Cells are good at repurposing cellular processes across species, and in our experiments, we found that mammals have repurposed the ANT gene to help deliver cellular cues to build the appropriate hydration layer in airways,” says Robinson. “Who would have thought that a mitochondrial protein could also live at the cell surface and be responsible for helping airway cilia beat and move?”

Robinson says that further research may yield discoveries to develop gene therapy or drugs to add ANT2 function back into lung-lining cells as a potential treatment for COPD.

Robinson is now working to start a biotechnology company to further develop the technology. Kliment is continuing the work in her new laboratory at the University of Pittsburgh, where she is now an assistant professor of medicine in the Division of Pulmonary, Allergy and Critical Care Medicine.

Other scientists who contributed to the research include Jennifer Nguyen, YaWen Lu, Steven Claypool, and Pablo Iglesias from Johns Hopkins, and Mary Jane Kaltreider, Josiah Radder, Frank Sciurba, Yingze Zhang, and Alyssa Gregory from the University of Pittsburgh.

Funding for the research was provided by the National Institutes of Health’s National Heart, Lung, and Blood Institute (F32HL129660, K08HL141595, R01HL124099, R01HL108882); National Institute of General Medical Sciences (R01GM66817); a Biochemistry, Cellular, and Molecular Biology Program Training Grant (T32GM007445); the Burroughs Wellcome Fund; Parker B Francis Pulmonary Fellowship; the Johns Hopkins Bauernschmidt Fellowship Foundation; the Thomas Wilson Foundation; the American Heart Association; the Airway Cell and Tissue Core; the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation.

Featured image: Illustration of cilia and surface hydration among normal airway cells and those affected by cigarette smoke. Credit: Corinne Sandone, Johns Hopkins Medicine

Reference: Corrine R. Kliment, Jennifer M. K. Nguyen, Mary Jane Kaltreider, YaWen Lu, Steven M. Claypool, Josiah E. Radder, Frank C. Sciurba, Yingze Zhang, Alyssa D. Gregory, Pablo A. Iglesias, Venkataramana K. Sidhaye, Douglas N. Robinson, “Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function”, Journal of Cell Science 2021 134: jcs257162 doi: 10.1242/jcs.257162 Published 25 February 2021

Provided by Johns Hopkins Medicine

New Research Shows How Immune Response to TB Differs in Babies (Medicine)

The immune response to tuberculosis (TB) differs in adults and newborn babies due to the way immune cells use energy to kick into gear in a bid to kill the bacteria. This fresh discovery – just published in leading journal, Frontiers in Immunology – offers hope for improving treatments for what remains a deadly disease.

TB is still one of the biggest infectious killers in the world and babies are more likely than adults to get this infection and for it to spread outside of the lungs. Thanks to the work of scientists in Professor Joseph Keane’s TB Immunology lab, based in the Trinity Translational Medicine Institute at St James’s Hospital, we now have a better idea why.

Dr Cilian Ó Maoldomhnaigh, a paediatrician who undertook this research as part of a PhD project explains:

“We found fundamental differences in how a baby’s immune cells respond to TB compared to those of an adult and hope that this will eventually lead to new ways to target this infection.

“Babies’ immune cells don’t have the capacity to change their energy profile in the same way adults do after being exposed to bacteria. This shift in cellular energetics is crucial to mounting pro-inflammatory responses that defend the host against infection. We also found that babies produce less TNF, which is a key inflammatory mediator needed to fight TB.”

“We would like to thank all of the parents who consented for us to take placental blood post-birth, from which we collected the baby immune cells, and to our funders, the National Children’s Research Centre and the Royal City of Dublin Hospital Trust, for making this research possible.”

The work also highlights that a special shift in the way cells use energy, called the Warburg effect, occurs in human immune cells.

Though this has been documented in animal models previously, it is the first time that it has been shown in human cells and the timing and type of energy shifts are different than that described in animal cells.

By understanding how the immune system uses energy, scientists and doctors are aiming to develop better treatments to help support the immune response to infection.

Senior author on the paper, Dr Sharee Basdeo, is excited about the impact this work may have. She said:

“Our work indicates that the function and energy profile of human immune cells in response to infection may change during childhood development, and with ageing.

“Understanding the differences in the profiles of key immune cells over a human lifetime will enable us to design immuno-supportive therapies to help protect vulnerable populations, such as the very old and the very young, against infections.”

Reference: Cilian Ó Maoldomhnaigh et al., “The Warburg Effect Occurs Rapidly in Stimulated Human Adult but Not Umbilical Cord Blood Derived Macrophages”, Front. Immunol., 13 April 2021 |

Provided by Trinity College Dublin