Culture

Steve Granick, Director of the IBS Center for Soft and Living Matter and Dr. Huan Wang, Senior Research Fellow, report together with 5 interdisciplinary colleagues in the July 31 issue of the journal Science that common chemical reactions accelerate Brownian diffusion by sending long-range ripples into the surrounding solvent.

The findings violate a central dogma of chemistry, that molecular diffusion and chemical reaction are unrelated. To observe that molecules are energized by chemical reaction is "new and unknown," said Granick. "When one substance transforms to another by breaking and forming bonds, this actually makes the molecules move more rapidly. It's as if the chemical reactions stir themselves naturally."

"Currently, Nature does an excellent job of producing molecular machines but in the natural world scientists have not understood well enough how to design this property," said Wang. "Beyond curiosity to understand the world, we hope that practically this can become useful in guiding thinking about transducing chemical energy for molecular motion in liquids, for nanorobotics, precision medicine and greener material synthesis."

The unexpected ripples generated by chemical reactions, especially when catalyzed (accelerated by substances not themselves consumed), propagate long-range. For chemists and physicists, this work challenges the textbook view that molecular motion and chemical reaction are decoupled, and that reactions affect only the nearby vicinity. For engineers, this work shows a powerful new approach to design nanomotors at the truly molecular level.

Screening 15 organic chemical reactions, the researchers study chemical reactions that are workhorses with wide application within the organic chemical, pharmaceutical and materials industries. For example, "click" reactions assist the assembly of libraries of biomedical compounds for screening and the "Grubbs" reaction used for plastic manufacture. Their economic impact is major. Estimates indicate that a majority of all products manufactured require catalysis somewhere in their production sequence.

Wang remarked with enthusiasm: "Now, we're like a baby taking her first steps and there's so much exciting opportunity to grow this baby."

In designing their study, the researchers were bio-inspired by noticing that motion can be powered by enzymes and other molecular motors that are prevalent in living systems. Pioneering earlier work by Dr. Ah-Young Jee in the same research center showed this. But there was no consensus among scientists if these reports could be correctly extended outside biology. Analyzing the problem, the researchers made a high-risk, high-payoff argument. They hypothesized that the phenomenon would form an approach to understand molecular machines in the real world.

Testing their hypothesis, the team developed new analytical techniques. Professor Tsvi Tlusty, a theorist, predicted that catalysts in reaction gradients should migrate "uphill" in the direction of lesser diffusivity. Professor Yoon-Kyoung Cho, a microfluidics expert, designed a tailor-made microfluidics chip to test this idea. Dr. Ruoyu Dong, a Research Fellow, performed numerical computer simulations. "Our interdisciplinary team responded incredibly quickly to the research opportunities thanks to the research freedom of the Korean Institute for Basic Science," said Granick.

The team presents guidelines showing that the magnitude of diffusion increase in different systems depends on the energy release rate. These guidelines can be useful practically to estimate the effect in as-yet untested reactions. Beyond this, the study is very useful for expanding understanding of active materials, a collective term that traditionally refers to things like cells and microorganisms.

Granick concluded: "The field of active materials, quite new and growing fast, is enriched by this discovery that chemical reactions behave as nanoswimmers made of individual molecules that stir up the reaction soup. The concept of active materials has shown its value in challenging a central dogma of chemistry."

These findings were published in the July 31, 2020 issue of Science magazine. The study was performed at the IBS Center for Soft and Living Matter by authors Huan Wang, Myeonggon Park, Ruoyu Dong, Junyoung Kim, Yoon-Kyoung Cho, Tsvi Tlusty, and Steve Granick.

Researchers who generated a strain of SARS-CoV-2 that can infect mice used it to produce a new mouse model of infection that may help facilitate testing of COVID-19 vaccines and therapeutics. Notably, they used their mouse model to test and confirm the protective efficacy of a COVID-19 vaccine candidate. The ongoing COVID-19 pandemic has prioritized the development of small animal models for SARS-CoV-2. As SARS-CoV-2 does not use mouse ACE2 - the entry point for this virus in humans - mice are thought to be less susceptible. To date, efforts to study virus infection and to evaluate vaccines in mice have required mice to be engineered to express human ACE2. Here, in a different approach, Hongjing Gu and colleagues adapted a strain of SARS-CoV-2 seen in the clinic in the mouse respiratory tract, developing a mutant version (MASCp6) that was able to replicate and cause disease in young and aged mice; both groups showed pneumonia and inflammatory responses after intranasal infection, clinical features seen in human patients. Deep sequencing of the genome of MASCp6 compared to SARS-CoV-2 revealed that a mutation in the spike protein in the virus's receptor binding domain may be responsible for MASCp6's ability to enter mouse ACE2 cells, the authors say. To show their new model's utility for testing vaccine candidates, the researchers immunized female mice with two doses of a recombinant subunit vaccine candidate and then infected them with the adapted virus. Viral loads were lower and no visible clinical symptoms were identified in the vaccinated mice, compared to non-vaccinated controls, they say. Their new mouse-adapted strain of SARS-CoV-2 and the corresponding mouse model of infection add to the repertoire of animal models for studying SARS-CoV-2 transmission. This is important as no single animal model of SARS-CoV-2 currently recapitulates all aspects of human disease.

Women who lack social ties have a greater likelihood of being obese, according to new UBC research published today in PLOS One. Men, on the other hand, were less likely to be obese if they lived alone and had a smaller social network.

Using data from the Canadian Longitudinal Study on Aging, researchers analyzed the social ties of 28,238 adults aged 45 to 85 and how these link to waist circumference, body mass index and general obesity.

They found that women who were single, widowed, divorced or separated had higher odds of abdominal and general obesity. There were higher odds if they had limited social participation--women who were not married, lived alone and had no monthly social activities had the highest average waist size.

In comparison, among men, the average waist size was greatest among those who were widowed, co-living and had a large social network. For example, men whose social network had more than 219 contacts were more likely to be obese than those with smaller networks.

"There is a lot of literature suggesting that marriage is health-promoting for men and potentially less so for women, so our results about marital status were kind of surprising," said principal investigator Annalijn Conklin, assistant professor in the faculty of pharmaceutical sciences at UBC and researcher with the Centre for Health Evaluation and Outcome Sciences. "The different types of social ties that we looked at had a more consistent relationship with obesity for women. Those patterns in men were less obvious and seemed to sometimes even be reversed to what we saw in women."

The study did not investigate why these gender differences exist. However, Conklin suggested the findings may be partly due to differing gender roles and different social expectations around those roles.

"You would think that having small social networks would be a kind of social stress and that would have consequences for obesity, but we found that it was potentially protective for men," Conklin said. "It could be that managing very large networks becomes a source of stress for men, as research has shown that men often assign to their wives the emotional labour of keeping track of birthdays, special events and organizing family or social gatherings." An earlier study of the Korean population by other researchers obtained similar results.

More research is needed to understand the factors at work, says lead author Zeinab Hosseini, who did the work as a former postdoctoral research fellow at UBC's Collaboration for Outcomes Research and Evaluation.

"Not only did we find that minimal social participation was associated with obesity in older women, but also that social participation altered the levels of obesity in widowed women," said Hosseini. "These findings call for studies that will follow the participants over time to understand the possible causal links between different social connections and the health of older women and men."

The study results do suggest that health care providers may want to begin including social activities alongside healthy diet and exercise when treating non-partnered older women, added the researchers.

"Clinicians could be encouraging older women patients who are non-partnered, especially widowed women, to participate in social community interventions as a way to address obesity. This would require clear implementation strategies, and a focus on social connection interventions by health care researchers and decision-makers," said Hosseini.

New Orleans, LA - A team of LSU Health New Orleans pathologists published what is believed to be the first case report on pathologic findings of vasculitis of the small vessels of the heart, which likely represents multisystem inflammatory syndrome (MIS). The report was published online in the Annals of Internal Medicine, available here.
The LSU Health New Orleans pathologists identified microscopic evidence of inflammation involving the small cardiac vessels during the autopsy of a patient who died weeks after initially recovering from COVID.
MIS is a severe illness featuring severe inflammation of multiple organs that occurs after the resolution of COVID symptoms. Similar to Kawasaki disease, MIS cases have been increasingly reported among children and young adults. Although vascular damage seems to be a component of both diseases, the pathologic features of MIS have not yet been described.

"We also found new pulmonary blood clots in a background of otherwise reparative changes in the lungs," notes Sharon Fox, MD, PhD, Associate Director of Research and Development in the Department of Pathology at LSU Health New Orleans School of Medicine. "These clots indicate a potential for increased clotting affecting the pulmonary blood vessels beyond the initial course of COVID-19, as well as the need for continued monitoring of laboratory markers and possible anticoagulation."

"Our report highlights the potential for serious complications due to damage to the lining of the vessels in the heart after COVID-19," adds Richard Vander Heide, MD, PhD, Professor and Director of Pathology Research at LSU Health New Orleans School of Medicine.

The team concludes, "Careful monitoring of laboratory markers of cardiac and systemic inflammation, as well as therapeutic intervention to target this inflammatory process, may improve patient outcomes."
Authors also include Drs. Elizabeth Rinker and Fernanda Lameira in the Department of Pathology at LSU Health New Orleans School of Medicine.

More than 30 million Americans are infected with a brain parasite spread by cats and contaminated meat, but most will never show symptoms. A new discovery from the University of Virginia School of Medicine explains why, and that finding could have important implications for brain infections, neurodegenerative diseases and autoimmune disorders.

The UVA researchers found that the parasite, Toxoplasma gondii, is kept in check by brain defenders called microglia. These microglia release a unique immune molecule, IL-1α, that recruits immune cells from the blood to control the parasite in the brain, the scientists discovered. This process works so well that very few people develop symptomatic toxoplasmosis, the disease the parasite causes.

Understanding the role of microglia is essential because they are normally the only immune cells inside the brain. The new finding reveals how they recruit help when needed, and that discovery could apply to any brain condition with an immunological component - including brain injury, neurodegenerative disease, stroke, multiple sclerosis and more.

"Microglia must die to save the brain from this infection," said researcher Tajie Harris, PhD, of UVA's Department of Neuroscience and the interim director of the Center for Brain Immunology and Glia (BIG). "Otherwise the IL-1α remains stuck inside the microglia and wouldn't alert the immune system that something is wrong."

The Brain and the Immune System

UVA's Department of Neuroscience and BIG center have in recent years completely rewritten our understanding of the brain's relationship with the body's immune system. For decades, textbooks taught that the brain was disconnected from the immune system. UVA research, however, showed that was not the case, to the shock of the scientific community. Many researchers are now exploring the implications of that major discovery.

One area of focus is microglia and their role in defending the brain. This has been a difficult question to answer because microglia are closely related to other immune cells elsewhere in the body. Until recently, laboratory tools made to target microglia have also targeted these other cells, making it hard to distinguish between the two.

UVA researcher Samantha J. Batista, a graduate student in Harris' lab, used an elegant approach that leveraged the long-lived nature of microglia to understand their role in brain infection. She and her colleagues found that infection caused microglia to die in an inflammatory fashion - a way that the closely related immune cells do not.

The microglia burst, the researchers determined, to recruit immune cells called macrophages to control the Toxoplasma gondii infection. This finding helps explain why most people have no trouble controlling the parasite, while some - especially people who are immunocompromised - can become very sick.

"Understanding pathways like this could be beneficial for other diseases involving neuroinflammation," Batista said. "We can ask whether promoting this pathway is helpful in situations where you need more of an immune presence in the brain, such as infections or cancers, and also whether inhibiting this molecule could be helpful in diseases driven by too much neuroinflammation, like multiple sclerosis. Targeting one specific pathway like this one could have less off-target effects than targeting inflammation more broadly."

In the future, Harris, Batista and their collaborators are interested in understanding how microglia detect the parasites in the brain. Microglia could recognize the parasite's presence directly, or they could recognize damage to brain tissue, a phenomenon that occurs in many diseases.

"The immune system must enter the brain to fight dangerous infections," said Harris, who is part of UVA's Carter Immunology Center. "We now understand how microglia sound the alarm to protect the brain. We suspect that similar signals are missed or misinterpreted in Alzheimer's disease, opening up an exciting new research avenue in the lab."

July 30, 2020--(BRONX, NY)--A new study shows how chronic psychological stress leads to painful vessel-clogging episodes--the most common complication of sickle-cell disease (SCD) and a frequent cause of hospitalizations. The findings, made in mice, show that the gut microbiome plays a key role in triggering those episodes and reveals possible ways to prevent them. The research was conducted by scientists at Albert Einstein College of Medicine and published online today in Immunity.

SCD occurs in about 1 in 365 African-American births. People with SCD have inherited a gene mutation that leads to abnormal hemoglobin, causing red cells (which contain hemoglobin) to take on a sickle shape and become less flexible. The sickled red cells tend to clog small vessels, impeding blood flow and preventing oxygen from reaching tissues. This can result in painful and debilitating vaso-occlusive episodes, or VOE, which can last for days. No therapies can reverse VOE and, over time, they cause significant damage to internal organs--the major reason that life expectancy for those with severe SCD is 20 to 30 years shorter than for those without the disease.

"Research for sickle-cell disease is chronically underfunded and those with the condition are in need--and deserve--new treatments that can help address this major health disparity," said study leader Paul S. Frenette, M.D., professor of medicine and of cell biology and chair and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein. "We hope our most recent findings can help point to novel solutions for treating this painful and deadly disease."

Using a mouse model, Dr. Frenette and colleagues found that the path to VOE begins in the brain. Stress triggers the secretion of glucocorticoid hormones in the brain, which make their way to the gut and increase its permeability. This greater permeability allows segmented filamentous bacteria (SFB)--a type of beneficial gut bacteria in mice--to interact with Th17 helper immune cells in the lining of the gut. The SFB stimulate those immune cells to produce pro-inflammatory molecules, which enter the circulation and promote the aging and accumulation of neutrophils, a type of white blood cell. In an earlier study, the Frenette laboratory had found that these aged neutrophils are inflammation-inducing cells that drive the VOE.

This chain of events was observed in both SCD mice and healthy mice that were subjected to psychological stress. However, lethal VOE occurred only in the sickle-cell disease mice. "Healthy mice don't have sickled blood cells and therefore don't suffer the ill effects caused by the buildup of aged neutrophils," Dr. Frenette noted.

"Importantly, we found we could markedly reduce stress-induced VOE in mice through several different interventions: inhibiting the synthesis of glucocorticoids, depleting SFB, or blocking the inflammatory molecules induced by these bacteria," Dr. Frenette said. "Each of those actions could potentially limit the impact of psychological stress on people with SCD."

While SFB are found only in rodents, some evidence indicates that similar beneficial bacteria in the human gut can also induce Th17 immune cells to produce inflammatory molecules. "We hope to learn whether there is any correlation between the abundance of these bacteria in patients with sickle-cell disease and the frequency or severity of VOEs that affect them," Dr. Frenette said.

When a natural disaster strikes, it often takes years for vulnerable communities to recover, long after the news coverage fades and the rest of the world seems to move on. A new Portland State University study that followed 400 households after the 2015 Nepal earthquakes provides insight into better understanding the factors that contribute to resilience and change in short-term rural natural disaster recovery.

"Recovery is a dynamic process with multiple dimensions which means that government and outside aid programs cannot be one size fits all," said Jeremy Spoon, the lead researcher and an associate professor of anthropology at PSU.

Spoon's team conducted surveys with 400 households in four communities both nine months and 1.5 years after the April and May 2015 earthquakes. The team also returned at 2.5 years for research workshops to connect the results to the participant experiences and perspectives. They used a novel methodology to document and analyze recovery as a multidimensional phenomenon with more than 30 recovery indicators, from rebuilding of homes and access to electricity to impacts on herding, farming, and wage labor.

Researchers found substantial geographic variation in recovery across the sites but were also able to identify several common patterns in recovery.

The households that appeared the most resilient nine months after the earthquakes were those that had less herding and farming-based livelihoods, more market connections to shops and tourism, and easier access to rebuilding funds from the government and through loans.

The results suggest that a settlement's proximity to the road and access to outside aid and government services may be negatively or marginally benefitting recovery in certain situations.

In Gatlang, a cluster of two settlements in northern Nepal, their growing dependence on outside aid and a more tourism-centric economy as a result of being close to the road actually impeded their recovery. For most households, their circumstances were getting worse a year and a half after the earthquakes. Only 8% of households had returned to their homes from temporary shelters and they were experiencing greater impacts to their herding, farming, and forest product collection.

The study suggests that access may be a trap, where individuals receiving assistance adapted to waiting for help rather than helping themselves. The aid received was also not enough to help the residents recover to a point that was comparable to where they were before the earthquakes and contained generic rebuilding solutions that did not take into account local knowledge or perspectives.

By contrast, in Kashigaun, a cluster of three settlements that is a two- to three-day walk from the road with very few aid organizations serving the area, households pooled their resources and collectively worked together to rebuild their community through work exchange. A year and a half after the earthquakes, 92% of households returned to their homes from temporary shelters; however, few, if any, were rebuilt to code. The earthquakes helped to revive and reinforce communal traditions of work exchange, which served as a safety net for the poorest and most marginal.

Spoon said the lessons learned can help evaluate relief and reconstruction interventions where outside expert knowledge ignores cultural diversity and place-specific dynamics, such as the roles of local knowledge and institutions.

"We feel that governments and aid organizations can use our approach to capture some of the most important facets of recovery in a variety of contexts over the short- and long-term, especially if they use participatory methods and outreach to develop appropriate recovery indicators," Spoon said. "Better understanding recovery dynamics then leads to improved natural disaster response."

Spoon, along with Drew Gerkey from Oregon State University, and their team received another grant from the National Science Foundation to continue their work in Nepal and collect data from the same 400 households in years six through nine. The study was published in the journal World Development. Its co-authors include Alisa Rai and Umesh Basnet from PSU; Gerkey from OSU; and Ram Bahadur Chhetri from Tribhuvan University in Nepal. Additional publications from this study are forthcoming.

The thymus is one of the organs of the immune system where T lymphocytes develop, a type of cells that is essential to fight infections and prevent cancer. Without them, it's impossible to live. The thymus is located just above the heart, being large in children and gradually reduces size as age progresses. In this organ, T lymphocytes develop from progenitor cells, which are born in the bone marrow and travel to the thymus through the blood stream. This is a continuous process, where cells enter the thymus, proliferate and develop into T lymphocytes. In the end, these cells leave the thymus to scout and defend the body.

The development of T lymphocytes is a tightly regulated process that aims at producing cells that protect the organism. However, these cells can also accumulate errors and cause cancer. Blood cell cancers, which include T lymphocytes, are called leukaemia. In the case of this study, the focus was on T cell acute lymphoblastic leukaemia and how it is normally prevented. This type of leukaemia is quite aggressive and, despite rare, it severely impacts mostly children, albeit affecting some adults.

The research team led by Vera Martins, principal investigator at Instituto Gulbenkian de Ciência, proposed to identify the cells that prevent this type of leukaemia and show that they are involved in a process of cell competition in the thymus. In this process, younger (and healthier) cells replace older (and less healthy) ones. Thus, younger cells always "win" and purge the older ones, which have the potential of causing leukaemia. But the researchers managed to go even further in their findings. Besides the leukaemia preventive role of these cells, they were also shown to receive signals that provide information on how fast (or slow) they are supposed to develop. The speed at which the development of T lymphocytes occurs is adjusted according to the intrinsic needs of the pool of precursor cells.

The team of researchers used mice as model organism, since the development of T lymphocytes is similar to what happens in humans, and made use of thymus transplants combined with different genetic models to explore the cellular interactions and the genes involved in this complex process. According to Vera Martins "the competitive cell interactions occur early in development and are regulated by a cytokine (interleukin 7) which is important throughout several developmental processes of the T lymphocytes". "We discovered that it is the availability of this cytokine that defines the size of the competing cell population" explains the researcher, reinforcing that "it is through the adjustment of the duration of the cell cycle during proliferation that interleukin 7 regulates the speed at which these cells differentiate and promote competition".

This study reveals that the development of T lymphocytes in a healthy thymus is not merely achieved because cells follow a pre-determined path of extrinsic signals. Rather, it is achieved through the integration of external signals and intrinsic properties of the cells that contribute to the normal functioning of the thymus.

In the future, it will be important to determine the importance of space constraints and resource availability for T lymphocyte precursor cells in shaping the observed competition. The team is also interested in understanding how deficiencies in cell competition in the thymus may promote the initiation of leukaemia. With this work, the researchers hope to contribute to a better prevention, or earlier diagnostics, of diseases about which very little is still known. "I am convinced that this approach, which integrates the healthy organism and the disease condition, is the best way to understand what causes leukaemia and I hope that the generated knowledge will pave the way to the development of more adequate responses for whomever has to face such a severe disease".

This study is a clear example of the contributions of fundamental science to the understanding of what maintains individuals healthy and what changes to cause disease.

HOUSTON -- According to researchers from The University of Texas MD Anderson Cancer Center, the implementation of social distancing policies corresponded with significant reductions in transmission of the SARS-CoV-2 virus and reduced community mobility, both in the U.S. and globally, providing evidence that social distancing is a useful tool in preventing further spread of COVID-19.

The study, published today in PLOS ONE, estimates that social distancing policies enacted nationally in 46 countries prevented an estimated 1.57 million cases of COVID-19 over a two-week period, representing a 65% reduction in new cases. The researchers suggest these data emphasize the significant benefits that can be achieved by individuals practicing social distancing measures.

"At MD Anderson, we are focused on caring for patients with cancer, and we know that our patients are highly vulnerable to COVID-19," said senior author Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology. "Therefore, we felt it important to conduct an unbiased analysis of safety measures that could benefit our patients as well as society at large. From our data-driven analysis, it became clear that practicing social distancing can have a huge impact on transmission rates."

Impact of social distancing policies in the U.S.

To determine the effectiveness of social distancing policies in the U.S., the researchers analyzed COVID-19 spread across each of the 50 states. Recognizing that many factors contribute to disease spread, they analyzed new cases before and after states enacted social distancing policies.

Three states did not implement such policies, providing an opportunity for comparisons. These were analyzed over similar time periods relative to other states.

"We found that states observed significant reductions in transmission rates following the implementation of social distancing policies, compared to states without such policies," said lead author Daniel McGrail, Ph.D., postdoctoral fellow in Systems Biology. "In fact, two of the smallest reductions in spread were seen in states without social distancing policies."

The 47 states with social distancing policies also saw greater reductions in average community mobility compared to states without policies, which measures the movement trends of residents across residential, workplace, retail and other locations. States without social distancing policies also saw decreased mobility, although the change was significantly smaller than states with distancing policies.

Impact of social distancing policies globally

Understanding that the U.S. analysis was limited by a small number of states without social distancing policies, the researchers analyzed the effects of social distancing policies globally. They were able to obtain sufficient data for 46 countries with national social distancing policies, 74 nations without such policies and 14 with regional policies.

Following a similar analysis, the data indicate that significantly greater reductions in transmission were seen in countries after implementing a national social distancing policy compared to those with regional policies or a matched time frame in countries without policies. No significant difference was observed between countries with regional policies and those without social distancing policies.

Countries with any social distancing policies had significantly reduced community mobility relative to nations without policies, and those with national policies saw greater decreases than countries with regional policies. There was a strong correlation between decreased mobility and decreased transmission of the virus, highlighting the importance of individuals practicing social distancing to effectively prevent transmission of the virus.

"This is clear evidence that social distancing measures can collectively have tremendous impacts on reducing transmission of SARS-CoV-2, and we encourage individuals to practice social distancing to help control spread of infections," said Kalluri. "We believe these data will provide useful evidence for public health officials and policy makers when considering future measures to reduce the spread of COVID-19 in their communities."

The authors acknowledge the study is limited by a reliance on direct COVID-19 testing, which may underestimate prevalence. Also, the researchers focused on spread rates following implementation of social distancing policies as an internal control for the numerous additional factors likely contributing to spread rates.

For the analysis, daily case numbers and population data were gathered from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University. Information on social distancing policies was obtained from the Aura Vision Global COVID-19 Lockdown Tracker and mobility data were acquired from Google mobility reports. All data for the study was collected on June 5, 2020.

Philadelphia, July 30, 2020--In the early days of the COVID-19 pandemic, the SARS-CoV-2 virus seemed only rarely to have serious complications in children. However, by April 2020, pediatricians had begun recognizing a syndrome in children who tested positive for COVID-19 involving hyperinflammation and some other attributes found in Kawasaki disease (KD). By May, the Centers for Disease Control and Prevention (CDC) had named the new condition Multisystem Inflammatory Syndrome in Children (MIS-C). Yet the biology of MIS-C and how it relates to or differs from severe COVID-19 in children has largely remained a mystery.

Now, researchers from Children's Hospital of Philadelphia (CHOP) report important data that differentiate MIS-C from severe COVID-19 in children and suggest that MIS-C is a post-infectious syndrome related to COVID-19 but distinct from KD. The findings were published today in The Journal of Clinical Investigation.

"This is the first report comparing, head-to-head, the distinct outcomes of SARS-CoV2 in children and provides novel information on disease biology, as well as clinical information that can help practitioners distinguish between the clinical syndromes," said Edward M. Behrens, MD, Chief of the Division of Rheumatology at CHOP, member of the Immune Dysregulation Frontier Program, and co-senior author of the paper. "The clinical and laboratory measures we describe accurately distinguish between patients with MIS-C and severe COVID-19, which will help physicians provide better, more accurate treatment for their patients."

Differing Cytokine Profiles

The researchers, led by Behrens and fellow Immune Dysregulation co-senior authors David T. Teachey, MD, and Hamid Bassiri MD, PhD, analyzed 20 patients with SARS-CoV-2: nine with severe COVID-19 disease, five with mild COVID-19, and six with MIS-C. To differentiate the biology of these conditions, the research team looked at patients' levels of cytokines, substances secreted by cells that send messages to the immune system and tell it what to do. When the body makes too many cytokines, the immune system to spins out of control, leading to severe inflammation and sometimes shock.

The researchers found that patients with MIS-C had elevated levels of two cytokines - IL-10 and TNF-? - whereas patients with severe or mild COVID-19 had no or minimally elevated levels of these cytokines. This profile for MIS-C is distinct from previously reported cytokine profiles in KD, which tend to be associated with mild elevations of other cytokines and not IL-10.

COVID-19 Connection

Additionally, the so-called viral cycle threshold - meaning how many times a test sample must be multiplied and amplified before SARS-CoV-2 is detected - also distinguished severe COVID-19 and MIS-C. Those with severe COVID-19 had low cycle thresholds, implying the virus was easily detectable and active, but those with MIS-C had high cycle thresholds, indicating the patient had been infected with the virus at some point in the distant past and had cleared most of the active virus. This bolsters the theory that MIS-C is a post-viral hyperinflammatory reaction to SARS-CoV-2.

Aside from patient cytokine profiles, which require sophisticated laboratory equipment, the researchers also found that simple peripheral blood smears could help distinguish the three conditions. Burr cells, which are red blood cells that appear scalloped or serrated when viewed under a microscope, were absent in patients with mild COVID-19 but present in 40% of patients with severe disease. However, all patients with MIS-C had at least some burr cells present, and more than half of them had the majority of their red blood cells appearing as burr cells on a peripheral blood smear.

MIS-C Distinct from Kawasaki

While the researchers did note some overlap in the clinical presentations of KD and MIS-C, they noted predominating symptoms did not overlap. Most patients in the MIS-C cohort had severe ventricular dysfunction at presentation, a finding that is unusual in KD. Patients with MIS-C also tended to have severe gastrointestinal inflammation, which combined with the cytokine data generated by the study, led the team to conclude that MIS-C is a distinct hyperinflammatory syndrome.

"Contrary to early reports that emphasized relatively mild disease outcomes in pediatric patients, we show that in some children SARS-CoV-2 appears to trigger a dysregulated hyperinflammatory pathophysiologic process," Behrens said. "Future work will need to examine why SARS-CoV-2 induces such a damaging inflammatory response in children."

Researchers at the University of Maryland School of Medicine (UMSOM) have for the first time identified stem cells in the region of the optic nerve, which transmits signals from the eye to the brain. The finding, published this week in the journal Proceedings of the National Academy of Sciences (PNAS), presents a new theory on why the most common form of glaucoma may develop and provides potential new ways to treat a leading cause of blindness in American adults.

"We believe these cells, called neural progenitor cells, are present in the optic nerve tissue at birth and remain for decades, helping to nourish the nerve fibers that form the optic nerve," said study leader Steven Bernstein, MD, PhD, Professor and Vice Chair of the Department of Ophthalmology and Visual Sciences at the University of Maryland School of Medicine. "Without these cells, the fibers may lose their resistance to stress, and begin to deteriorate, causing damage to the optic nerve, which may ultimately lead to glaucoma."

The study was funded by the National Institutes of Health's National Eye Institute (NEI), and a number of distinguished researchers served as co-authors on the study.

More than 3 million Americans have glaucoma, which results from damage to the optic nerve, causing blindness in 120,000 U.S. patients. This nerve damage is usually related to increased pressure in the eye due to a buildup of fluid that does not drain properly. Blind spots can develop in a patient's visual field that gradually widen over time.

"This is the first time that neural progenitor cells have been discovered in the optic nerve. Without these cells, the nerve is unable to repair itself from damage caused by glaucoma or other conditions. This may lead to permanent vision loss and disability," said Dr. Bernstein. "The presence of neural stem/progenitor cells opens the door to new treatments to repair damage to the optic nerve, which is very exciting news."

To make the research discovery, Dr. Bernstein and his team examined a narrow band of tissue called the optic nerve lamina. Less than 1 millimeter wide, the lamina lies between the light-sensitive retina tissue at the back of the eye and the optic nerve. The long nerve cell fibers extend from the retina through the lamina, into the optic nerve. What the researchers discovered is that the lamina progenitor cells may be responsible for insulating the fibers immediately after they leave the eye, supporting the connections between nerve cells on the pathway to the brain.

The stem cells in the lamina niche bathes these neuron extensions with growth factors, as well as aiding in the formation of the insulating sheath. The researchers were able to confirm the presence of these stem cells by using antibodies and genetically modified animals that identified the specific protein markers on neuronal stem cells.

"It took 52 trials to successfully grow the lamina progenitor cells in a culture," said Dr. Bernstein, "so this was a challenging process." Dr. Bernstein and his collaborators needed to identify the correct mix of growth factors and other cell culture conditions that would be most conducive for the stem cells to grow and replicate. Eventually the research team found the stem cells could be coaxed into differentiating into several different types of neural cells. These include neurons and glial cells, which are known to be important for cell repair and cell replacement in different brain regions.

This discovery may prove to be game-changing for the treatment of eye diseases that affect the optic nerve. Dr. Bernstein and his research team plan to use genetically modified mice to see how the depletion of lamina progenitor cells contributes to diseases such as glaucoma and prevents repair.

Future research is needed to explore the neural progenitors repair mechanisms. "If we can identify the critical growth factors that these cells secrete, they may be potentially useful as a cocktail to slow the progression of glaucoma and other age-related vision disorders." Dr. Bernstein added.

The work was supported by NEI grant RO1EY015304, and by a National Institutes of Health shared instrument grant 1S10RR26870-1.

"This exciting discovery could usher in a sea change in the field of age-related diseases that cause vision loss," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "New treatment options are desperately needed for the millions of patients whose vision is severely impacted by glaucoma, and I think this research will provide new hope for them."

WOODS HOLE, Mass. --A team at the Marine Biological Laboratory (MBL) has achieved the first gene knockout in a cephalopod using the squid Doryteuthis pealeii, an exceptionally important research organism in biology for nearly a century. The milestone study, led by MBL Senior Scientist Joshua Rosenthal and MBL Whitman Scientist Karen Crawford, is reported in the July 30 issue of Current Biology.

The team used CRISPR-Cas9 genome editing to knock out a pigmentation gene in squid embryos, which eliminated pigmentation in the eye and in skin cells (chromatophores) with high efficiency.

"This is a critical first step toward the ability to knock out -- and knock in -- genes in cephalopods to address a host of biological questions," Rosenthal says.

Cephalopods (squid, octopus and cuttlefish) have the largest brain of all invertebrates, a distributed nervous system capable of instantaneous camouflage and sophisticated behaviors, a unique body plan, and the ability to extensively recode their own genetic information within messenger RNA, along with other distinctive features. These open many avenues for study and have applications in a wide range of fields, from evolution and development, to medicine, robotics, materials science, and artificial intelligence.

The ability to knock out a gene to test its function is an important step in developing cephalopods as genetically tractable organisms for biological research, augmenting the handful of species that currently dominate genetic studies, such as fruit flies, zebrafish, and mice.

It is also a necessary step toward having the capacity to knock in genes that facilitate research, such as genes that encode fluorescent proteins that can be imaged to track neural activity or other dynamic processes.

"CRISPR-Cas9 worked really well in Doryteuthis; it was surprisingly efficient," Rosenthal says. Much more challenging was delivering the CRISPR-Cas system into the one-celled squid embryo, which is surrounded by an exceedingly tough outer layer, and then raising the embryo through hatching. The team developed micro-scissors to clip the egg's surface and a beveled quartz needle to deliver the CRISPR-Cas9 reagents through the clip.

Studies with Doryteuthis pealeii have led to foundational advances in neurobiology, beginning with description of the action potential (nerve impulse) in the 1950s, a discovery for which Alan Hodgkin and Andrew Huxley became Nobel Prize laureates in 1963. For decades D. pealeii has drawn neurobiologists from all over the world to the MBL, which collects the squid from local waters.

Recently, Rosenthal and colleagues discovered extensive recoding of mRNA in the nervous system of Doryteuthis and other cephalopods. This research is under development for potential biomedical applications, such as pain management therapy.

D. pealeii is not, however, an ideal species to develop as a genetic research organism. It's big and takes up a lot of tank space plus, more importantly, no one has been able to culture it through multiple generations in the lab.

For these reasons, the MBL Cephalopod Program's next goal is to transfer the new knockout technology to a smaller cephalopod species, Euprymna berryi (the hummingbird bobtail squid), which is relatively easy to culture to make genetic strains.

Coastal flooding events could threaten assets worth up to 20% of the global GDP by 2100, a study in Scientific Reports suggests. The areas predicted to be most impacted by flooding are north-west Europe, south-east and east Asia, north-east USA and northern Australia, according to the authors.

Ebru Kirezci and colleagues combined data on global sea levels during extreme storms with projections of sea level rises under different greenhouse gas emission scenarios. The authors used these data to model maximum sea levels that may occur by 2100. The researchers combined their model with topographic data to identify areas at risk of coastal flooding. Using data on global population distribution and GDP in affected areas, they estimated the population and assets at risk from flooding.

Under conditions of high greenhouse gas emissions and assuming no flood defences, the authors estimate that the land affected by coastal flooding could increase by 48% by 2100. Areas that could be at risk of extensive flooding include south-eastern China, Australia's Northern Territories, Bangladesh, West Bengal and Gujurat in India, the US states of North Carolina, Virginia and Maryland and north-west Europe including the UK, northern France and northern Germany. The authors suggest that the global population exposed to coastal flooding could be up to 287 million by 2100 (4.1% of the world's population) and that the assets threatened by flooding could be worth up to US $14.2 trillion (20% global GDP).

The findings indicate that without investment in flood defences or a reduction in greenhouse gas emissions, coastal flooding could have major implications for the global population and economy by the end of the century.

Experts add excessive alcohol intake and head injury in mid-life, and exposure to air pollution in later life to list of key modifiable risk factors for dementia - expanding number of preventable causes from 9 to 12 factors that span from childhood to later life

Report also highlights 9 recommendations for policymakers and individuals to help reduce risk, including providing primary and secondary education for all children, decreasing harmful alcohol drinking, preventing head injury, using hearing aids, protecting ears from high noise levels, and urgently improving air quality

The potential to prevent cases of dementia is high, and the biggest impact is likely to be seen in low- and middle-income countries where two-thirds of cases occur

Modifying 12 risk factors over the lifecourse could delay or prevent 40% of dementia cases, according to an update to The Lancet Commission on dementia prevention, intervention, and care, which is being presented at the Alzheimer's Association International Conference (AAIC 2020).

Combined, the three new risk factors are associated with 6% of all dementia cases - with an estimated 3% of cases attributable to head injuries in mid-life, 1% of cases to excessive alcohol consumption (of more than 21 units per week) in mid-life, and 2% to exposure to air pollution in later life.

The remaining risk factors are associated with 34% of all dementia cases [1]. The factors associated with the greatest proportion of dementia cases in the population are less education in early life, hearing loss in mid-life, and smoking in later life (7%, 8%, and 5%, respectively).

Led by 28 world-leading dementia experts, the report builds on the 9 risk factors identified in the 2017 Lancet Commission [2], and provides an up-to-date analysis of the best evidence on the prevention of dementia. The new report calls for nations and individuals to be ambitious about preventing dementia and lays out a set of policies and lifestyle changes to help prevent dementia.

Worldwide around 50 million people live with dementia, and this number is projected to increase to 152 million by 2050, rising particularly in low-income and middle-income countries (LMIC) where around two-thirds of people with dementia live. [3] Dementia affects individuals, their families, and the economy, with global costs estimated at about US$1 trillion annually. [3]

In certain countries, however, the proportion of older people with dementia has fallen, probably due to improvements in education, nutrition, health care, and lifestyle changes, demonstrating the possibility of reducing dementia through preventative measures.

"Our report shows that it is within the power of policy-makers and individuals to prevent and delay a significant proportion of dementia, with opportunities to make an impact at each stage of a person's life," says lead author Professor Gill Livingston, University College London, UK. "Interventions are likely to have the biggest impact on those who are disproportionately affected by dementia risk factors, like those in low- and middle-income countries and vulnerable populations, including Black, Asian and Minority Ethnic communities." [4]

Professor Livingston continues, "As societies, we need to think beyond promoting good health to prevent dementia, and begin tackling inequalities to improve the circumstances in which people live their lives. We can reduce risks by creating active and healthy environments for communities, where physical activity is the norm, better diet is accessible for all, and exposure to excessive alcohol is minimised." [4]

To address dementia risk, the authors call for 9 ambitious recommendations to be undertaken by policymakers and by individuals:

Aim to maintain systolic blood pressure of 130 mm Hg or less in midlife from around age 40 years.

Encourage use of hearing aids for hearing loss and reduce hearing loss by protecting ears from high noise levels.

Reduce exposure to air pollution and second-hand tobacco smoke.

Prevent head injury (particularly by targeting high risk occupations and transport)

Prevent alcohol misuse and limit drinking to less than 21 units per week.

Stop smoking uptake and support individuals to stop smoking (which the authors stress is beneficial at any age).

Provide all children with primary and secondary education.

Lead an active life into mid, and possibly later life.

Reduce obesity and diabetes.

These actions are especially important in LMICs where dementia rates are rising more rapidly than in high-income countries. This is a result of increasing life expectancy, and a higher frequency of certain dementia risk factors - such as lower rates of education; high rates of hypertension, obesity, and hearing loss, and rapidly growing rates of diabetes.

Based on their past model including 9 risk factors, the authors estimated that many more cases of dementia could be prevented in LMICs, compared to globally. While globally the 9 risk factors were estimated to contribute to 35% of all dementia cases, in China they might account for 40% of cases, 41% in India and 56% in Latin America.

The authors warn that estimates could be even higher, as they used conservative estimates for the prevalence of these risk factors in these populations, and because they do not account for the three new risk factors. The authors also note that nearly all the evidence for dementia is from studies in high-income countries, so risks might differ for LMICs and interventions might require modifying to best support different cultures and environments.

The authors note that the modelling for their prevention estimates globally and in LMICs assumes that there is a causal relationship between risk factors and dementia, but were careful to only include risk factors with strong evidence for a causal link.

Report co-author, Professor Adesola Ogunniyi, University of Ibadan, Nigeria, says: "In low- and middle-income countries, the higher prevalence of dementia risk factors means an even greater proportion of dementia is potentially preventable than in "higher-income countries". In this context, national policies addressing dementia risk factors, like primary and secondary education for all and stopping smoking policies, might have the potential for large reductions in dementia and should be prioritised. We also need more dementia research coming from low- and middle-income countries, so we can better understand the risks particular to these settings." [4]

In the final section of the report, the authors advocate for holistic and individualised evidence-based care that addresses physical and mental health, social care, and support that can accommodate complex needs. Keeping people with dementia physically healthy is important for their cognition but they often have other illnesses which they may struggle to manage on their own, resulting in potentially harmful preventable hospitalisations.

They note that people with dementia are particularly at risk from COVID-19 (due to age and having pre-existing illnesses, such as hypertension), and that physical-distancing measures can be challenging for dementia patients, who may find it difficult to adhere to the guidelines or distressing to be unable to have contact with carers and family. The authors call for people with unknown COVID-19 status to not be admitted to care homes to protect the existing residents, regular testing of staff and asymptomatic as well as symptomatic residents when there is exposure, not moving staff or residents between homes, and more research into how to protect dementia patients during the current pandemic and future public health emergencies.

Scientists at St. Jude Children's Research Hospital are studying how hearing loss can affect the neurocognitive abilities of childhood cancer survivors. Findings show that survivors with severe hearing loss are at a significant increased risk for neurocognitive deficits, independent of what type of therapy they receive. The work appears as an advance online publication today in JAMA Oncology.

"There has been a lot of research on how children who are born deaf can be affected academically and psychosocially, but far less for kids who acquire hearing loss at some point during their childhood," said corresponding author Johnnie Bass, Ph.D., of St. Jude Rehabilitation Services. "Our goal was to report on the prevalence, severity and risk of hearing loss in a large cohort of cancer survivors to assess the impact of hearing impairment on neurocognitive function."

The researchers evaluated 1,520 childhood cancer survivors and found that more than one-third had severe hearing loss. Those survivors with severe hearing loss were found to be at increased risk for neurocognitive deficits. This effect was independent of having been exposed to neurotoxic therapy, when compared to survivors with normal hearing or mild hearing loss.

This study is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures.

"Even patients not exposed to neurotoxic therapies who develop mild hearing deficits can have problems with their neurocognitive skills," said senior author Kevin Krull, Ph.D., of St. Jude Epidemiology and Cancer Control. "This makes it important to identify these patients early and suggest interventions to help improve their hearing and thus their neurocognitive outcomes."

Hearing aids are often recommended to assist with treatment-related hearing loss. The researchers found that of 330 survivors with severe hearing loss in the study for whom a hearing aid had been previously recommended, only 23% were consistently using the devices. Research in individuals who are born with hearing loss, as well as in the elderly with hearing loss, suggests that hearing aids can improve neurocognitive outcomes. More research is needed to determine if this is the case for childhood cancer survivors and to better understand barriers that prevent hearing aid use.

The work relied on hearing assessments gathered through the St. Jude Lifetime Cohort study (St. Jude LIFE). St. Jude LIFE brings long-term childhood cancer survivors back to the hospital for regular health screenings throughout their adult lives. Findings from the study help childhood cancer survivors learn more about their health needs, while providing novel insights into the late effects of childhood cancer treatment.