Culture

The release of massive amounts of proteins called cytokines can lead to some of the most severe symptoms of COVID-19. When large numbers of immune cells release cytokines, this increases inflammation and creates a feedback loop in which more immune cells are activated and this is sometimes called a cytokine storm. An August 19 study in the journal Cell now suggests that high levels of some cytokines may also prevent people who are infected from developing long-term immunity as affected patients were observed to make very few of the type of B cells needed to develop a durable immune response.

"We've seen a lot of studies suggesting that immunity to COVID-19 is not durable because the antibodies decline over time," says co-senior author Shiv Pillai, a professor at Harvard Medical School and member of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard. "This study provides a mechanism that explains this lower-quality immune response."

The investigators focused on germinal centers--the areas within the lymph nodes and spleens where B cells, the immune cells that produce antibodies, differentiate. Differentiation and changes in antibody genes are required to build immunity to an infectious agent.

"When we looked at the lymph nodes and spleens of patients who died from COVID-19, including some who died very soon after getting the disease, we saw that these germinal center structures had not formed," says co-senior author Robert Padera, a pathology professor at Harvard. "We decided to determine why that's the case."

Because the disease was so new, animal models for studying COVID-19 infection were not yet available at the time they began their study. The researchers instead gained insights from previous studies involving mouse models of other infections that induce cytokine storm syndrome--a malaria model and one of bacterial infection in which germinal centers were lost.

In people with severe COVID-19, one of most abundant cytokines released is called TNF. In the infected mice, TNF appeared to block the formation of germinal centers. In previous cytokine storm models, when the mice were given antibodies to block TNF or had their TNF gene deleted, the germinal centers were able to form. When the researchers studied the lymph nodes of patients who had died of the disease, they found high levels of TNF in these organs. This led them to conclude that TNF may be preventing the germinal centers from forming in people with COVID-19 as well.

"Studies have suggested this lack of germinal centers happens with SARS infections," Pillai says. "We even think this phenomenon occurs in some patients with Ebola, so it was not surprising to us."

The researchers also studied blood and lymphoid tissue from people with active infections who were in different stages of COVID-19. They found that although germinal centers were not formed, B cells were still activated and appeared in the blood, which would allow the patients to produce some neutralizing antibodies. "There is an immune response," Padera says. "It's just not coming from a germinal center."

"Without the germinal centers, there is no long-term memory to the antigens," Pillai adds. He notes that studies of other coronaviruses that cause colds have suggested that someone can get infected with the same coronavirus three or four times in the same year.

The authors say despite their findings, they still believe a successful COVID-19 vaccine can be developed as it should not cause high levels of cytokines to be released.

Covid-19 patients with hypoxia respond positively to icatibant treatment, Radboud university medical center researchers wrote in JAMA Network Open. These findings have led to a follow-up study at ten Dutch hospitals into a drug that may be even more effective. The current study has been funded by ZonMw.

Rapid fluid overload of the lungs - pulmonary edema - is a hallmark of severe infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In a previous article, Nijmegen researchers suggested that this involves the ACE2 receptor. The coronavirus enters the cells via this receptor, after which it can multiply. However, the ACE2 receptor not only provides a gateway for the coronavirus, but it also keeps vasodilatory kinins under control. The infection causes most of the ACE2 receptors of the lung cells to dysfunction. Without ACE2, these kinins have free rein and - by binding to bradykinin receptors - can make the blood vessels leaky. Internist Frank van de Veerdonk, hospital pharmacist Roger Brüggemann and colleagues hypothesized that this process plays an important role in severe Covid-19 infection.

Patient study

After consultation with the Central Committee on Research Involving Human Subjects (CMO) and the Health Care and Youth Inspectorate (IGJ), and with the informed consent of the participating patients, the researchers tested their hypothesis with the drug icatibant. Van de Veerdonk: "This drug is used in patients with the rare condition: hereditary angioedema. These patients sometimes develop acute subcutaneous fluid deposits due to local leakage of blood vessels. Icatibant blocks the bradykinin receptor B2R, which quickly stops the leakage. To determine whether the drug is also suitable for the specific group of Covid-19 patients with fluid in their lungs, earlier this year we administered this drug to nine patients in the Internal Medicine Department and one patient in the Intensive Care Unit."

Hypoxia

The results of this study have now been published in JAMA Network Open. All the patients, which were in need for oxygen treatment due to fluid in their lungs, were given three doses of icatibant by subcutaneous injection at six-hour intervals. The patient in the ICU recovered sufficiently within 24 hours to be moved to the ward and was discharged after 7 days. Eight of the remaining nine patients needed less oxygen supplementation within 24 hours and the ninth after 38 hours. In 18 comparable patients who served as controls, substantially higher levels of oxygen supplementation were needed over time.

Support for the hypothesis

Brüggemann: "Although this was not a randomized trial, the results support our hypothesis. In an early phase of the infection with severe oxygen deficit, we see that icatibant improves the situation. A disadvantage is the short-term effect of the drug. Half of the drug is broken down in two hours, so the effect diminishes quickly. After the treatment, three patients had to be given oxygen again because the drug had worn off."

Different drug

The research published in JAMA Network Open was actually a proof of concept, which the researchers have already built upon. Improved understanding of the role of the kinin-kallikrein system (KKS) in COVID-19 means that the researchers expect even better results from another drug. Brüggemann: "The drug lanadelumab remains active for much longer than icatibant, so you will probably only need to administer it only once or twice". Van de Veerdonk: "Lanadelumab also has a much broader effect. It inhibits the activation of the whole system that causes leakage of the blood vessels. It is therefore not only active for longer but might also be more effective."

Research in hospitals

Based on the initial results published in JAMA Network Open and these more recent insights, Van de Veerdonk and Brüggemann have been awarded a grant from ZonMw for a phase 2 clinical trial with lanadelumab for this specific group of COVID-19 patients. Several Dutch hospitals are participating in the study. If this approach works, Brüggemann and van de Veerdonk expect that the research can immediately be rolled out on a large scale internationally. This is not only important for rapid recovery of patients with hypoxia admitted to the hospital but can also reduce the pressure on IC capacity. Global organizations such as the World Health Organization (WHO) and REMAP-CAP are directly involved in this research, and the strategy is currently being considered by several others. With this strategy Van de Veerdonk and Brüggemann aim to help patients presenting with hypoxia to recover quickly and thus avoid ICU admission.

High blood pressure is often called a silent killer because it is the biggest risk factor for the most death and disability worldwide including heart disease and stroke, but presents no symptoms as a warning indicator. Many elderly people have high blood pressure that is difficult to treat, and good preventative methods and appropriate markers have not been elucidated.

It has been known that high salt intake causes hypertension, but its exact mechanism was not understood until this study which found for the first time that Klotho deficiency, an anti-aging factor produced in the kidneys causes aging-associated hypertension through high salt intake.

Klotho is an anti-aging protein that acts as a hormone and is secreted into the blood from the kidneys. Its presence decreases with age causing the vascular and arterial system to stiffen. A recent study had shown the inverse relationship between the Klotho concentration and BP salt sensitivity. Hypertension is caused by excessive intake of salt, but the sensitivity of blood pressure to salt varies from individual to individual, and highly sensitive people are more likely to have high blood pressure.

In general, young people are less sensitive and are unlikely to develop hypertension, whereas older people are more sensitive to salt and are likely to develop hypertension. However, the mechanism of increased salt sensitivity with aging was unknown. Therefore, the research group first confirmed that salt sensitivity increased in aged mice, and revealed that the cause is that the blood concentration of the anti-aging factor Klotho protein decreases with age. Furthermore, the group clarified the molecular mechanism Wnt5a-RhoA pathway for the first time. The results showed that Klotho supplementation could prevent the development of hypertension, and Klotho levels could be a predictive marker for the development of hypertension.

Corresponding author and Specially Appointed Professor Toshiro Fujita of Shinshu University School of Medicine and Research Center for Social Systems, and Division of Epigenetics, Research Center for Advanced Science and Technology, University of Tokyo states that it took time, "to elucidate the molecular mechanism of salt-sensitive hypertension with aging. Although Klotho deficiency was known to activate Wnt signaling, the detailed mechanism by which Wnt activation causes vasoconstriction was unknown. We found that the Wnt signal has two pathways, the canonical pathway which was understood as significant in oncological research, but it took time to demonstrate that the Wnt-RhoA pathway of the non-canonical pathway causes vasoconstriction in cell experiments and mouse experiments."

In experiments using aged mice and cells, abnormal activation of the above pathway could be reversed by supplementation with Klotho protein. As a result, it was possible to establish that the cause of salt-sensitive hypertension due to aging is Klotho protein decline.

The results of this experiment showed that Klotho supplementation could prevent the development of hypertension in the elderly and that Klotho levels could be a predictive marker for the development of hypertension. Trials for human verification is currently underway. Aging, a universal phenomenon causes not only hypertension but dementia and frailty, and impairs the healthy life expectancy of individuals. The aging-related phenomenon of Klotho protein deficiency may be related to the onset of dementia and sarcopenia, or the loss of muscle-mass and usage associated with aging. Its onset mechanism is currently under investigation.

All current breast cancer drugs were first tested in cell lines. Each cell line began as cancer in a patient. As such, each cell line is a surrogate for that patient's disease. A new database of 40 breast cancer cell lines, developed by Medical University of South Carolina investigators, will help researchers deepen their understanding of these cell lines and speed the development of new gene-targeted therapies.

"Cell lines are the front line for breast cancer research because they are derived from real patients and exhibit the characteristics of the disease that that patient experienced," remarked Stephen P. Ethier, Ph.D., a professor in the Department of Pathology and Laboratory Medicine at MUSC and an MUSC Hollings Cancer Center researcher.

Cell lines represent cancer for what it is, said Ethier -- a multifaceted disease of the genome. The broad picture of cancer as a complex disease, however, is often bypassed in research to laser-focus on only one or two gene changes. Ethier believes this -- the current way of doing research -- is too narrow and that developing better therapies will require evaluation of the entire genomic signature.

In an article recently published in npj Breast Cancer, Ethier and his team describe the implementation of a new resource for cancer researchers. The SUM Breast Cancer Cell Line Knowledge Base, or SLKBase, will push the field forward by providing easily navigable genomic, proteomic and other "omic" information on a total of 40 SUM and other patient-derived cell lines. The database could eventually contribute to the identification, development and implementation of truly personalized gene-targeted therapies for patients with breast cancer.

Dr. Stephen Ethier and his team hope their database will eventually expand to include cancer cell lines from all types of cancer.

Humans have approximately 24,000 genes, collectively called the genome. Written in the language of DNA, the genes act as instructions for how cells are to grow, live and replicate.

Errors in the DNA instructions within a cell can ultimately change how the cell grows, replicates and responds to natural signals that normally act as a brake to these functions. These changes cause the cell to become cancerous.

Personalized or targeted therapies, based on unique gene changes in each patient's cancer, have been a long-term goal in oncology research and medicine, and significant progress has been made. However, implementing truly personalized therapeutic strategies has been slow.

One obstacle has been difficulty identifying and targeting the gene changes that have a function in causing disease.

Several hundred genes might have developed errors in a cancer cell, according to Ethier. "Most of the genes that are changed, however, are playing no role whatsoever in the biology of the disease," he explained.

How can researchers identify which of those gene mutations matter and are worth targeting?

With funding from a South Carolina Clinical & Translational Research Institute pilot grant, Ethier and his team built specialized tools for SLKBase to aid in answering this very question.

"So the way to get from 500 gene changes to two or three that are playing an essential role in the biology of the disease is to do what are called genome-scale knock-out or knock-down experiments," Ethier explained.

In the knock-down experiments, Ethier and his team performed a series of tests in which every gene in the genome was turned off one by one and evaluated for its effects on the growth or survival of the cancer cell. If the cancer cell died or stopped duplicating itself, that gene was deemed to be essential for survival. If that gene also had an error, it meant the gene was not only essential but also performed a function that made the cell behave like cancer.

Each cancer cell line has a unique "functional gene signature," explained Ethier.

Therapies that target these functional genes that drive cancer growth are likely to be most effective. From a library of more than 800 targeted experimental medications, the "Druggable Signature Tool" identifies those that are likely to be effective against the cancer cells because they target the essential genes.

The SLKBase website is open to anyone who wants to know more about breast cancer cell lines or access the immense genomic and proteomic research knowledge base.

However, breast cancer is just the beginning. There are more than 500 cancer cell lines derived from patients with virtually every type of cancer, and Ethier hopes eventually to include them all in SLKBase.

For Ethier, the gene changes driving cancer matter more than the tissue in which they occur. Cancers are a disease of the genome, no matter in which part of the body they occur. Therefore, any cancer would be expected to respond to therapy targeted to its genomic signature.

"At some point, we have to stop worrying about whether it's breast cancer, lung cancer or colon cancer," said Ethier. "We should be putting more emphasis on the genomic features of that cancer because cancer is a disease of the genome."

Ethier recently signed an option agreement with the MUSC Foundation for Research Development that will enable his startup, Sextant Oncology LLC, to continue to promote the use of cancer cell lines and their functional derivatives. The mission of Sextant Oncology is to develop strategies for the reverse engineering of individual cell lines that will ultimately be useful for making targeted drug treatment predictions for patients.

When it comes to brain cells, one size does not fit all. Neurons come in a wide variety of shapes, sizes, and contain different types of brain chemicals. But how did they get that way? A new study in Nature suggests that the identities of all the neurons in a worm are linked to unique members of a single gene family that control the process of converting DNA instructions into proteins, known as gene expression. The results of this study could provide a foundation for understanding how nervous systems have evolved in many other animals, including humans. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"The central nervous systems of all animals, from worms to humans, are incredibly intricate and highly ordered. The generation and diversity of a plethora of neuronal cell types is driven by gene expression," said Robert Riddle, Ph.D., program director at NINDS. "So, it is surprising and exciting to consider that the cell diversity we see in the entire nervous system could come from a just a single group of genes."

Researchers led by Oliver Hobert, Ph.D., professor of biochemistry and molecular biophysics at Columbia University in New York City and graduate student Molly B. Reilly, wanted to know how brain cells in the C. elegans worm got their various shapes and functions. For these experiments, the researchers used a genetically engineered worm in which individual neurons were color coded. In addition, coding sequences for green fluorescence protein were inserted into homeobox genes, a highly conserved set of genes known to play fundamental roles in development. Homeobox gene expression patterns were determined by examining the patterns of the glowing fluorescent marker.

Dr. Hobert's team discovered that across the entire worm nervous system, each type of neuron contained a unique set of homeobox proteins. In other words, the identity of every neuron could be traced to a specific combination of homeobox genes that were switched on or off.

Homeobox genes were initially discovered for their role in ensuring that body parts end up in their proper places. These genes have since been found across all animal species, as well as in plants and fungi. Homeobox genes contain instructions for making transcription factors, which are proteins that can control the activity of other genes.

The nervous system of an adult C. elegans contains 302 neurons, which can be divided into 118 types. Dr. Hobert's team determined that 70 homeobox genes are involved in characterizing the neuronal types. In addition, further analysis suggested that the homeobox codes could be used to subdivide classes of neurons. For example, the additional analysis identified not only that a cell was a motor neuron, but its location in the ventral nerve cord, the worm's version of a spinal cord.

"The diversity in neurons may be driven by a gene family that distinguishes individual cell types in the brain," said Dr. Hobert, "There is a simplicity to this arrangement in the sense that just one gene family may explain all brain cell types. The complexity that arose from this simple 'barcode' gene family suggests a potential role for homeobox genes in the evolution of the nervous system."

Future studies will investigate whether brain cells in other organisms can also be identified by specific protein codes. In addition, researchers will examine the effects of changing the codes on identity and function of neurons.

BOSTON - Shiv Pillai, MD, PhD, investigator in the Ragon Institute of MGH, MIT and Harvard and professor at Harvard Medical School (HMS), recently published a paper in Cell showing that that high levels of some cytokines seen in COVID-19 patients, as part of a cytokine storm, may prevent the development of long-term immunity to SARS-CoV-2, the virus that causes COVID-19.

"We've seen a lot of studies suggesting that immunity in COVID-19 may not be durable because the antibodies decline over time," says Pillai. "More telling for us was that in patients with both mild as well as severe disease, asntibodies lacked a key structural feature that is a hallmark of the 'highest quality' antibodies in a normal immune response. By using our understanding of how two different types of immune cells normally collaborate to make the best antibodies, we were able to find a mechanism that could explain this lower-quality immune response in COVID-19 patients."

Pillai's group, working with Robert Padera, MD, PhD, associate professor at HMS, examined the spleens and lymph nodes of deceased COVID-19 patients and found that a lack of germinal centers, an essential part of a durable immune response.

Germinal centers are structures induced within the lymph nodes and spleens during infection or vaccination. In them, B cells, the immune cells that produce antibodies, mature to become long-lived "memory" cells. This process, along with controlled mutations in antibody genes, allows the immune system to select for and immortalize B cells that make the best antibodies against a particular pathogen. This creates a life-long "memory" of a pathogen which allows the body to quickly and effectively identify and attack the pathogen in the case of re-infection. Without germinal centers, there aren't enough B cells that can create a high-quality antibody response to produce long-term immunity. To form germinal centers, B cells depend on key support from another specialized type of cell called a helper T cell. Pillai's group showed that in COVID-19 patients the specialized type of helper T cell does not develop, and as a consequence B cells are not helped in the right way. The study found no germinal centers in acutely ill patients.

Previous studies with infectious disease in mice have shown that high levels of cytokines, small signalling molecules unique to the immune system, can prevent the formation of these helper T cells and therefore of germinal centers. Large amounts of a cytokine called TNF, in particular, prevented germinal center formation. Severe COVID-19 cases were found to have massive amounts of TNF in the location where germinal centers would normally form.

Lack of germinal centers has been observed in other diseases, including SARS, and does not mean there is no immune response. "There is an immune response in COVID-19," Padera says. "It's just not coming from a germinal center."
However, the lack of geminal centers could have major implications for development of herd immunity

"Without the formation of germinal centers, there is unlikely to be long-term memory to this virus developing from natural infections, meaning that while antibodies may protect people for a relatively short time, a single person who recovers from the disease could get infected again, perhaps six months later, or even multiple times with SARS-CoV-2. This suggests that developing herd immunity may be difficult," adds Pillai.

This finding would likely not affect vaccine-induced immunity, as vaccines do not induce cytokine storms. A vaccine-induced immune response would likely include the development of a germinal center, and the ensuing creation and immortalization of high-quality antibodies that would provide long-lasting protecting against COVID-19.

The question of whether life exists beyond the Earth is one of humanity's most fundamental questions. Future NASA missions, for example, aim to examine the ice moons of Jupiter and Saturn, which may potentially shelter life in the liquid oceans underneath the thick layer of ice, on the ground. Proving traces of life beyond the Earth is extremely challenging, however. Highly sensitive instruments which take measurements on the ground with the greatest possible degree of autonomy and with high precision - millions of kilometers from the Earth and thus without direct support from humankind - are required.

An international group of researchers under the leadership of Andreas Riedo and Niels Ligterink at the University of Bern have now developed ORIGIN, a mass spectrometer which can detect and identify the smallest amounts of such traces of life. They describe the instrument in a recently published article in the specialist journal Nature Scientific Reports. Niels Ligterink from the Center for Space and Habitability (CSH) is the lead author of the international study, and co-author Andreas Riedo from the Physics Institute at the University of Bern developed the instrument in the laboratories of the space research and planetary sciences divison of the Physics Institute. Various international space agencies, particularly NASA, have already expressed interest in testing ORIGIN for future missions.

New instrument required

Since the first Mars mission "Viking" in the 1970s, humanity has been searching for traces of life on Mars using highly specialized instruments which are installed on landing platforms and rovers. In its early years, Mars was Earth-like, had a dense atmosphere and even liquid water. However, as Niels Ligterink explains, Mars lost its protective atmosphere over the course of time: "As a result of this, the surface of Mars is subjected to high solar and cosmic radiation which makes life on the surface impossible." NASA's "Curiosity" rover is currently examining Mars in detail but with no concrete indications of traces of life to date.

Since the discovery by the Cassini and Galileo missions of the global oceans beneath kilometers of ice layers on Jupiter's moon Europa and Saturn's moon Enceladus, these two bodies have increasingly become the focus of the search for extraterrestrial life for researchers. According to current knowledge, the oceans have all of the properties which are not only needed for the occurrence of life, but also which provide environments in which life can exist in the long term. NASA therefore plans to land a mission on Jupiter's moon Europa around 2030 and take measurements on the ground. The goal: Identification of life. Co-author Prof. Dr. Peter Wurz from the Physics Institute at the University of Bern says: "Concepts which were specially developed for Mars cannot be simply applied to other bodies in our solar systembecause they are very different. New instruments with higher sensitivity and simpler and more robust analysis systems must be designed and used".

Unprecedented measurement sensitivity for proof of life in space

ORIGIN is one such new instrument which outperforms previous space instruments many terms over in terms of its measurement sensitivty. Various international space agencies have expressed great interest in the instrument for future missions. Andreas Riedo says: "NASA has invited us to particpaite and test our instrument in the Arctic. The Artic is the optimal test environment in the context of the EUROPA LANDER mission, which should start in 2025, which will allow us to demonstrate the performance of ORIGIN."

Amino acids are key components of life as we know it on Earth. Contemporaneous proof of certain amino acids on extraterrestrial surfaces, such as those of Europa, allow conclusions to be drawn about possible life. The measurement principle developed by the Bern-based researchers is simple. Niels Ligterink explains: "Laser pulses are directed at the surface to be examined. In the process, small amounts of material are detached, the chemical composition of which is analyzed by ORIGIN in a second step". Andreas Riedo adds: "The compelling aspect of our technology is that no complicated sample preparation techniques, which could potentially affect the result, are required. This was one of the biggest problems on Mars until now," says Riedo. The amino acids which have been analyzed with ORIGIN to date have a specific chemical fingerprint which allows them to be directly identified. Niels Ligterink: "To be honest, we didn't expect that our first measurements would already be able to identify amino acids."

The discovery of traces of past or present life on bodies in our solar system beyond the Earth is of great importance for a better understanding of the existence of life in the universe and its genesis. Andreas Riedo says: "Our new measurement technology is a real improvement on the instruments currently used on space missions. If we are taken along on a future mission, we may be able to answer one of humanity's most fundamental questions with ORIGIN: Is there life in space?".

PIM kinases are enzymes that promote metastatic growth and spread of cancer cells. Researchers from the University of Turku, Finland, have obtained new information on how the PIM kinases enhance cancer cell motility by regulating the formation of actin fibres in the cytoskeleton. The published results support the development of PIM-targeted therapies to prevent metastasis formation in cancer patients.

It is critical for the survival of cancer patients, whether the cancer cells remain in their primary location or start migrating around the body to form metastases into bones and other vital organs. In order to be able to prevent metastasis formation, more information is needed about the factors regulating cancer cell motility.

- We had previously observed that PIM kinases promote and PIM-inhibitory compounds reduce migration of prostate cancer cells, but now we found a new mechanism to explain these observations, says the leader of the research group, Dr. Päivi Koskinen from the Department of Biology at the University of Turku.

Cellular movements are motorised by cytoskeletal actin fibres which are constantly polymerised or depolymerised, unless they are capped by proteins that protect the ends of the fibres.

- We demonstrated that via phosphorylation, PIM kinases modify actin capping proteins so that they cannot bind to actin polymers. As a consequence, actin processing as well as cell motility are enhanced, describes PhD Niina Santio who had the main responsibility for the experimental research.

- By contrast, in the presence of PIM inhibitors, cells stuck to each other and did not move much.

Video Abstract Visualises the Results

The results published in the Cell Communication and Signaling journal help to better understand the pro-metastatic effects of both the PIM kinases and the anti-metastatic PIM inhibitors.

In addition to written and graphic abstracts, the research group also used a video abstract for the first time to present their data.

- A visual abstract is a nice way to summarise the main message of the research into a single figure. Now, we also had the opportunity to wrap up our results into a short informative video which was finalised by an expert team provided by the journal, explains Päivi Koskinen.

Few people who have undergone nasopharyngeal swabs for coronavirus testing would describe it as a pleasant experience. The procedure involves sticking a long swab up the nose to collect a sample from the back of the nose and throat, which is then analyzed for SARS-CoV-2 RNA by the reverse-transcription polymerase chain reaction (RT-PCR). Now, researchers reporting in ACS Nano have developed a prototype device that non-invasively detected COVID-19 in the exhaled breath of infected patients.

In addition to being uncomfortable, the current gold standard for COVID-19 testing requires RT-PCR, a time-consuming laboratory procedure. Because of backlogs, obtaining a result can take several days. To reduce transmission and mortality rates, healthcare systems need quick, inexpensive and easy-to-use tests. Hossam Haick, Hu Liu, Yueyin Pan and colleagues wanted to develop a nanomaterial-based sensor that could detect COVID-19 in exhaled breath, similar to a breathalyzer test for alcohol intoxication. Previous studies have shown that viruses and the cells they infect emit volatile organic compounds (VOCs) that can be exhaled in the breath.

The researchers made an array of gold nanoparticles linked to molecules that are sensitive to various VOCs. When VOCs interact with the molecules on a nanoparticle, the electrical resistance changes. The researchers trained the sensor to detect COVID-19 by using machine learning to compare the pattern of electrical resistance signals obtained from the breath of 49 confirmed COVID-19 patients with those from 58 healthy controls and 33 non-COVID lung infection patients in Wuhan, China. Each study participant blew into the device for 2-3 seconds from a distance of 1¬-2 cm. Once machine learning identified a potential COVID-19 signature, the team tested the accuracy of the device on a subset of participants. In the test set, the device showed 76% accuracy in distinguishing COVID-19 cases from controls and 95% accuracy in discriminating COVID-19 cases from lung infections. The sensor could also distinguish, with 88% accuracy, between sick and recovered COVID-19 patients. Although the test needs to be validated in more patients, it could be useful for screening large populations to determine which individuals need further testing, the researchers say.

The authors acknowledge funding from the Technion-Israel Institute of Technology.

The abstract that accompanies this paper can be viewed here.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS' mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people. The Society is a global leader in providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a specialist in scientific information solutions (including SciFinder® and STN®), its CAS division powers global research, discovery and innovation. ACS' main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive press releases from the American Chemical Society, contact newsroom@acs.org.

Follow us: Twitter | Facebook

New Orleans, LA -- An LSU Health New Orleans radiologist and evolutionary anatomist have teamed up to show the same techniques used for research on reptile and bird lungs can be used to help confirm the diagnosis of COVID-19 in patients. Their paper published in BMJ Case Reports demonstrates that 3D models are a strikingly clearer method for visually evaluating the distribution of COVID-19-related infection in the respiratory system.

Emma R. Schachner, PhD, Associate Professor of Cell Biology & Anatomy, and Bradley Spieler, MD, Vice Chairman of Radiology Research and Associate Professor of Radiology, Internal Medicine, Urology, & Cell Biology and Anatomy at LSU Health New Orleans School of Medicine, created 3D digital models from CT scans of patients hospitalized with symptoms associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2).

Three patients who were suspected of having COVID-19 underwent contrast enhanced thoracic CT when their symptoms worsened. Two had tested positive for SARS-CoV-2, but one was reverse transcription chain reaction (RT-PCR) negative. But because this patient had compelling clinical and imaging, the result was presumed to be a false negative.

"An array of RT-PCR sensitivities has been reported, ranging from 30-91%," notes Dr. Spieler. "This may be the result of relatively lower viral loads in individuals who are asymptomatic or experience only mild symptoms when tested. Tests performed when symptoms were resolving have also resulted in false negatives, which seemed to be the result in this case."

Given diagnostic challenges with respect to false negative results by RT-PCR, the gold standard for COVID-19 diagnostic screening, CT can be helpful in establishing this diagnosis. Importantly, these CT features can range in form and structure and appear to correlate with disease progression. This allows for 3D segmentation of the data in which lung tissue can be volumetrically quantified or airflow patterns could be modeled.

The CT scans were all segmented into 3D digital surface models using the scientific visualization program Avizo (Thermofisher Scientific) and techniques that the Schachner Lab uses for evolutionary anatomy research.

"The full effect of COVID-19 on the respiratory system remains unknown, but the 3D digital segmented models provide clinicians a new tool to evaluate the extent and distribution of the disease in one encapsulated view," adds Spieler. "This is especially useful in the case where RT-PCR for SARS-CoV-2 is negative but there is strong clinical suspicion for COVID-19."

To date, there haven't been good models of what COVID is doing to the lungs. So, this project focused on the visualization of the lung damage in the 3D models as compared to previous methods that have been published - volume-rendered models and straight 2D screen shots of CT scans and radiographs.

"Previously published 3D models of lungs with COVID-19 have been created using automated volume rendering techniques," says Dr. Schachner. "Our method is more challenging and time consuming, but results in a highly accurate and detailed anatomical model where the layers can be pulled apart, volumes quantified, and it can be 3D printed."

The three models all show varying degrees of COVID-19 related infection in the respiratory tissues - particularly along the back of the lungs, and bottom sections. They more clearly show COVID-19-related infection in the respiratory system compared to radiographs (x-rays), CT scans, or RT-PCR testing alone.

Demand for food is set to rise substantially in the coming decades, which raises a question: How well can the ocean fill the gap between current supply and future need?

To find an answer, the High Level Panel for a Sustainable Ocean Economy -- 14 world leaders working to facilitate a more resilient future for people and planet -- turned to an international consortium of experts whose breadth of knowledge encompasses economics, biology, ecology, nutrition, fisheries and mariculture.

"Basically the question we were trying to answer was: Does sustainably managing the ocean over the next 30 years mean we will produce more food, or less?" said Christopher Costello, a professor of environmental and resource economics at UC Santa Barbara's Bren School of Environmental Science & Management. Costello is the lead author of an Ocean Panel paper as well that is also new research published in the journal Nature.

Given the growing demand for food and the constraints of expanding land-based food production, ocean-based foods -- nutrient-rich and a good source of protein -- are poised to be the next great stand against food insecurity for the estimated 9.8 billion people on the planet by 2050. But can we produce more from the ocean without collapsing its ecosystems?

"I think many of us went into this thinking that to manage the ocean sustainably, we would have to extract less, which would mean less food from the sea," Costello said. What the researchers found, however, was the opposite.

"If done sustainably, you could actually increase food from the sea, and by an outsize proportion relative to expansion of land-based food," said Costello. "And it could be done in a way that's much more environmentally friendly for the climate, biodiversity and other ecosystem services than food production on land."

Start with Sustainability

In fact, sustainability is key to the successful increase in food production from the ocean. "By improving sustainability and equity through a range of actionable policy and business commitments, food from the sea has the potential to expand in the future, nourishing the growing human population," said Stefan Gelcich, an associate professor at the Pontificia Universidad Católica de Chile and a co-author on the study.

"We've had a history of overexploiting many fisheries, but we're seeing governments starting to implement better fisheries management policies," Costello said. "And when you rebuild fisheries, you restore the health of the ocean and that allows you to have more food." The researchers estimate a roughly 16% increase in wild-caught seafood by 2050 if fisheries are sustainably managed. Conversely, failure to improve management could lead to significant reductions in seafood production from wild fisheries.

Farmed seafood stands to see an even greater increase in food production if done in balance with nature; some places with unsustainable mariculture would have to be scaled back, possibly rehabilitated, and other areas encouraged to develop sustainable seafood farms. With innovations that reduce mariculture's dependency on fish-based feed and effective policies that can lower the barriers to initiating environmentally friendly mariculture operations, farmed fish and shellfish production can increase dramatically.

"More rapid alternative feed adoption and efficiency improvements in aquaculture will be key for scaling sustainable marine production," said Halley Froehlich, an assistant professor in UC Santa Barbara's Department of Ecology, Evolution, & Marine Biology and Environmental Studies and also a co-author on the study. While sustainable supply could increase by more than six-fold, when both supply and demand are considered, she added, the likely increase in mariculture is between 2 to 4 times, depending on future demand.

There's no better time than the present to start sustainably planning and growing the system that could be feeding us in a generation, according to Costello, who pointed out that increases in population and wealth, along with the awareness that seafood is particularly nutritious, will drive future demand.

"Demand for meat tends to increase with wealth," said Costello, adding that the group also looked at the potential demand for seafood -- a rare and sometimes overlooked assessment -- and found that potential growth in supply could more than meet projected demand.

Projections of population and income by 2050 suggest a future need for more than 500 million metric tons of edible meat per year for human consumption, a 38% increase from today's production. Supplying that demand with land-based meat production would be difficult due to less available space and environmental impacts; shifting to ocean production could ease that pressure while supplying meat that is sustainably sourced and overall healthier for people.

"As people's diets shift, as they get wealthier, as the population grows, as they start to realize that fish are more nutritious and healthier than land-based sources of meat, the demand grows," said Costello. "That raises prices and creates an economic incentive to generate food from the sea."

(Edmonton, AB) A University of Alberta researcher has found a treatment that increases the speed of nerve regeneration by three to five times, leading to much better outcomes for trauma surgery patients.

"We use the term 'time is muscle,'" said Christine Webber, an associate professor in the U of A's anatomy division and a member of the Neuroscience and Mental Health Institute. "If that regrowing nerve can't get to the muscle fast enough, you're not going to get a functional repair."

Peripheral nerve injury occurs in about three per cent of trauma victims. The slow nature of nerve regeneration means that often muscles atrophy before the nerve has a chance to grow and reconnect.

That's where conditioning electrical stimulation (CES) comes in.

Webber and her collaborators--plastic surgery resident and former PhD student Jenna-Lynn Senger, and physical rehabilitation clinician Ming Chan--have examined CES in many previous publications. The process involves electrically stimulating a nerve at the fairly low rate of 20 hertz for one hour. A week after the CES treatment, nerve surgery is done, and the nerves grow back three to five times faster than if the surgery was done without CES.

In their latest work on CES, Webber's group examined animal models with foot drop, a common injury that affects patients' quality of life by impeding their ability to walk normally. Previously, the only treatments for foot drop were orthotics that affect a patient's gait, or surgery.

Webber's lab performed a distal nerve transfer in which a nerve near the damaged one was electrically stimulated, then a week later a branch of the nerve was cut and placed near the target of the non-functioning nerve. The newly transferred nerve would then be primed and ready to regrow, at a much faster rate, into the muscles that lift the foot.

CES can be a tool for faster nerve regrowth in any portion of the peripheral nervous system. Ming Chan, also a Neuroscience and Mental Health Institute member, has started a clinical trial in which CES is used before a nerve repair of the carpal tunnel.

Webber hopes to bring the information gained from examining nerve transfers in the leg--a difficult body part for nerve regrowth due to the vast area the nerve must cover--to clinical trials within the next year or two.

KNOXVILLE, Tenn. -- The latest research from the University of Tennessee Institute of Agriculture indicates that during late April and early May 2020, approximately 525,000 Tennessee households were food insufficient, meaning they sometimes or often did not have enough to eat - that's one in 10 families. About 30% of these struggling households were food sufficient prior to the onset of the pandemic.

The data for the study of Tennessee households were drawn from a national survey, the Household Pulse Survey, from April 23 to May 26. This time period coincides with the end of Tennessee's statewide stay-at-home order. The survey's measurement of food insufficiency is similar to very low food security which the federal government measures annually. "Between 2016 and 2018, approximately 5.2% of Tennessee households experienced very low food security," said Jackie Yenerall, assistant professor in the Department of Agricultural and Resource Economics (ARE). "This makes the finding that 10% of Tennessee households were food insufficient in just the first few months of the pandemic all the more concerning."

Adding to concerns about the current food insufficiency status, nearly half of the food-insufficient households were not confident in their ability to afford food in in the next four weeks. "Household characteristics across food sufficiency tell a story that is even more concerning," said ARE professor and lead researcher Kim Jensen. "Food-insufficient families were more likely to have children under the age of 18 in the household and were less likely to be currently employed."

Among the weeks included in the study, the week of April 23 through May 5 was the peak of need, with approximately 83,000 Tennessee households seeking assistance with free food from schools or other programs aimed at children, followed by food banks, family and friends.

NASA's Mars rovers have been one of the great scientific and space successes of the past two decades.

Four generations of rovers have traversed the red planet gathering scientific data, sending back evocative photographs, and surviving incredibly harsh conditions -- all using on-board computers less powerful than an iPhone 1. The latest rover, Perseverance, was launched on July 30, 2020, and engineers are already dreaming of a future generation of rovers.

While a major achievement, these missions have only scratched the surface (literally and figuratively) of the planet and its geology, geography, and atmosphere.

"The surface area of Mars is approximately the same as the total area of the land on Earth," said Masahiro (Hiro) Ono, group lead of the Robotic Surface Mobility Group at the NASA Jet Propulsion Laboratory (JPL) -- which has led all the Mars rover missions -- and one of the researchers who developed the software that allows the current rover to operate.

"Imagine, you're an alien and you know almost nothing about Earth, and you land on seven or eight points on Earth and drive a few hundred kilometers. Does that alien species know enough about Earth?" Ono asked. "No. If we want to represent the huge diversity of Mars we'll need more measurements on the ground, and the key is substantially extended distance, hopefully covering thousands of miles."

Travelling across Mars' diverse, treacherous terrain with limited computing power and a restricted energy diet -- only as much sun as the rover can capture and convert to power in a single Martian day, or sol -- is a huge challenge.

The first rover, Sojourner, covered 330 feet over 91 sols; the second, Spirit, travelled 4.8 miles in about five years; Opportunity, travelled 28 miles over 15 years; and Curiosity has travelled more than 12 miles since it landed in 2012.

"Our team is working on Mars robot autonomy to make future rovers more intelligent, to enhance safety, to improve productivity, and in particular to drive faster and farther," Ono said.

NEW HARDWARE, NEW POSSIBILITIES

The Perseverance rover, which launched this summer, computes using RAD 750s -- radiation-hardened single board computers manufactured by BAE Systems Electronics.

Future missions, however, would potentially use new high-performance, multi-core radiation hardened processors designed through the High Performance Spaceflight Computing (HPSC) project. (Qualcomm's Snapdragon processor is also being tested for missions.) These chips will provide about one hundred times the computational capacity of current flight processors using the same amount of power.

"All of the autonomy that you see on our latest Mars rover is largely human-in-the-loop" -- meaning it requires human interaction to operate, according to Chris Mattmann, the deputy chief technology and innovation officer at JPL. "Part of the reason for that is the limits of the processors that are running on them. One of the core missions for these new chips is to do deep learning and machine learning, like we do terrestrially, on board. What are the killer apps given that new computing environment?"

The Machine Learning-based Analytics for Autonomous Rover Systems (MAARS) program -- which started three years ago and will conclude this year -- encompasses a range of areas where artificial intelligence could be useful. The team presented results of the MAARS project at hIEEE Aerospace Conference in March 2020. The project was a finalist for the NASA Software Award.

"Terrestrial high performance computing has enabled incredible breakthroughs in autonomous vehicle navigation, machine learning, and data analysis for Earth-based applications," the team wrote in their IEEE paper. "The main roadblock to a Mars exploration rollout of such advances is that the best computers are on Earth, while the most valuable data is located on Mars."

Training machine learning models on the Maverick2 supercomputer at the Texas Advanced Computing Center (TACC), as well as on Amazon Web Services and JPL clusters, Ono, Mattmann and their team have been developing two novel capabilities for future Mars rovers, which they call Drive-By Science and Energy-Optimal Autonomous Navigation.

ENERGY-OPTIMAL AUTONOMOUS NAVIGATION

Ono was part of the team that wrote the on-board pathfinding software for Perseverance. Perseverance's software includes some machine learning abilities, but the way it does pathfinding is still fairly naïve.

"We'd like future rovers to have a human-like ability to see and understand terrain," Ono said. "For rovers, energy is very important. There's no paved highway on Mars. The drivability varies substantially based on the terrain -- for instance beach versus. bedrock. That is not currently considered. Coming up with a path with all of these constraints is complicated, but that's the level of computation that we can handle with the HPSC or Snapdragon chips. But to do so we're going to need to change the paradigm a little bit."

Ono explains that new paradigm as commanding by policy, a middle ground between the human-dictated: "Go from A to B and do C," and the purely autonomous: "Go do science."

Commanding by policy involves pre-planning for a range of scenarios, and then allowing the rover to determine what conditions it is encountering and what it should do.

"We use a supercomputer on the ground, where we have infinite computational resources like those at TACC, to develop a plan where a policy is: if X, then do this; if y, then do that," Ono explained. "We'll basically make a huge to-do list and send gigabytes of data to the rover, compressing it in huge tables. Then we'll use the increased power of the rover to de-compress the policy and execute it."

The pre-planned list is generated using machine learning-derived optimizations. The on-board chip can then use those plans to perform inference: taking the inputs from its environment and plugging them into the pre-trained model. The inference tasks are computationally much easier and can be computed on a chip like those that may accompany future rovers to Mars.

"The rover has the flexibility of changing the plan on board instead of just sticking to a sequence of pre-planned options," Ono said. "This is important in case something bad happens or it finds something interesting."

DRIVE-BY SCIENCE

Current Mars missions typically use tens of images a Sol from the rover to decide what to do the next day, according to Mattmann. "But what if in the future we could use one million image captions instead? That's the core tenet of Drive-By Science," he said. "If the rover can return text labels and captions that were scientifically validated, our mission team would have a lot more to go on."

Mattmann and the team adapted Google's Show and Tell software -- a neural image caption generator first launched in 2014 -- for the rover missions, the first non-Google application of the technology.

The algorithm takes in images and spits out human-readable captions. These include basic, but critical information, like cardinality -- how many rocks, how far away? -- and properties like the vein structure in outcrops near bedrock. "The types of science knowledge that we currently use images for to decide what's interesting," Mattmann said.

Over the past few years, planetary geologists have labeled and curated Mars-specific image annotations to train the model.

"We use the one million captions to find 100 more important things," Mattmann said. "Using search and information retrieval capabilities, we can prioritize targets. Humans are still in the loop, but they're getting much more information and are able to search it a lot faster."

Results of the team's work appear in the September 2020 issue of Planetary and Space Science.

TACC's supercomputers proved instrumental in helping the JPL team test the system. On Maverick 2, the team trained, validated, and improved their model using 6,700 labels created by experts.

The ability to travel much farther would be a necessity for future Mars rovers. An example is the Sample Fetch Rover, proposed to be developed by the European Space Association and launched in late 2020s, whose main task will be to pick up samples dug up by the Mars 2020 rover and collect them.

"Those rovers in a period of years would have to drive 10 times further than previous rovers to collect all the samples and to get them to a rendezvous site," Mattmann said. "We'll need to be smarter about the way we drive and use energy."

Before the new models and algorithms are loaded onto a rover destined for space, they are tested on a dirt training ground next to JPL that serves as an Earth-based analogue for the surface of Mars.

The team developed a demonstration that shows an overhead map, streaming images collected by the rover, and the algorithms running live on the rover, and then exposes the rover doing terrain classification and captioning on board. They had hoped to finish testing the new system this spring, but COVID-19 shuttered the lab and delayed testing.

In the meantime, Ono and his team developed a citizen science app, AI4Mars, that allows the public to annotate more than 20,000 images taken by the Curiosity rover. These will be used to further train machine learning algorithms to identify and avoid hazardous terrains.

The public have generated 170,000 labels so far in less than three months. "People are excited. It's an opportunity for people to help," Ono said. "The labels that people create will help us make the rover safer."

The efforts to develop a new AI-based paradigm for future autonomous missions can be applied not just to rovers but to any autonomous space mission, from orbiters to fly-bys to interstellar probes, Ono says.

"The combination of more powerful on-board computing power, pre-planned commands computed on high performance computers like those at TACC, and new algorithms has the potential to allow future rovers to travel much further and do more science."

August 18, 2020 - Edison, NJ -- Researchers at Hackensack Meridian Health, New Jersey's largest and most comprehensive health network, have utilized its statewide observational database of more than 5,000 hospitalized COVID-19 patients to show that a drug normally used in rheumatoid arthritis and cancer treatments, tocilizumab, improves hospital survival in critically-ill patients admitted to the intensive care unit (ICU).

The findings were published in The Lancet Rheumatology on Aug. 14, and Hackensack Meridian Health researchers have updated the U.S. Food and Drug Administration and other national leaders of the findings to potentially accelerate improved outcomes.

"Our clinicians and researchers at Hackensack Meridian Health have moved quickly and intelligently since the start of this global health crisis," said Robert C. Garrett, FACHE, chief executive officer of Hackensack Meridian Health. "Their work in treating this terrible virus, and learning more about it each day, continues to benefit thousands of patients as the pandemic continues."

The study included 630 patients who were admitted to the ICUs of 13 Hackensack Meridian Health hospitals from March 1 to April 22 - the height of the pandemic in New Jersey. Among other treatments, tocilizumab was considered for off-label usage for the patients whose respiratory symptoms were declining; many of whom were requiring mechanical ventilator support. In the observational study 210 patients received tocilizumab, and the other 420 did not.

COVID-19 has three phases: the early or viral phase (with fast viral replication), the pulmonary phase (marked by inflammation and pneumonia as the body tries to fight the virus in the lungs) and the inflammatory phase (in which excessive inflammation reaches and affects many organs and patients are often in the ICU). As part of both the pulmonary and inflammatory phases the immune system is "supercharged" and secretes in the blood numerous cytokines, particularly interleukin (IL)-6, which induces further inflammation. Tocilizumab is a monoclonal antibody, which binds and blocks the interleukin (IL)-6 receptor and helps damper the inflammatory response. The activity of tocilizumab was first shown in chimeric antigen receptor (CAR) T-cell therapy, where a similar phenomenon of overactive and growing T cells induce a "cytokine storm." This provided a rationale to try tocilizumab in COVID-19 patients.

The findings showed a statistically-significant decrease in hospital-related deaths among the patients who received the tocilizumab: a roughly 36 percent decrease in hospital-related mortality among the ICU patients who received the drug, as compared with patients in the ICU who didn't receive it. The data from the outcomes was adjusted to account for multiple factors, including comorbidities, and was assessed using statistical survival models.

Importantly, it appeared that higher levels of a blood test marker of inflammation, C-reactive protein, could predict which ICU patients might benefit most from the tocilizumab therapy, potentially allowing doctors to tailor therapy to those most in need.

"These real-time findings have helped to point us the way forward," said Ihor Sawczuk, M.D., FACS, Hackensack Meridian Health regional president, Northern Market and chief research officer. "Our clinicians and scientists were at the forefront of COVID research from the beginning of the pandemic."

The results are based on evidence collected in the HMH Universal Observational Database for COVID-19, or RE-COV-RY, which compiles outcomes from 13 Hackensack Meridian Health hospitals throughout New Jersey, using electronic health records (EHRs).

The outcomes division of the John Theurer Cancer Center (JTCC) at Hackensack University Medical Center, under the leadership of Dr. Stuart Goldberg and Dr. Andrew Ip, created a database to guide the analysis of more than 3,000 patients admitted to Hackensack Meridian Health facilities for urgent care. The database has been used to constantly assess COVID-19 treatments over the last several months, including the most promising and high-profile drugs and interventions.

"We need to know more as soon as possible," said Stuart Goldberg, M.D., hematologist/oncologist and chief of the Division of Outcomes and Value Research at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey. "Our database has allowed us to rapidly expand our knowledge of COVID-19 throughout the Hackensack Meridian Health hospital network. We are moving fast to help guide interventions - and potentially save lives."

The lead co-authors on this study are John Theurer Cancer Center hematologist-oncologists Andrew Ip, M.D., from the Division of Outcomes and Value Research and Noa Biran, M.D., from the Division of Myeloma. Both had experience with tocilizumab as part of the JTCC active CAR-T cell transplant program and recognized the potential of this immune modulating therapy in COVID-19.

"This is a great example of our science having impact far beyond cancer," said Andre Goy, M.D., M.S., physician-in-chief of Oncology, Hackensack Meridian Health.