Culture

People who are dogmatic about their views seek less information and make less accurate judgements as a result, even on simple matters unrelated to politics, according to a study led by UCL and Max Planck Institute for Biological Cybernetics researchers.

The researchers say their findings, published in PNAS, point to differences in thinking patterns that lead people to hold rigid opinions.

First author Lion Schulz, a PhD candidate at the Max Planck Institute in Germany who began the research while at UCL, said: "Anecdotally, it seems that dogmatic people are less interested in information that might change their mind. However, it was unclear if this is because a specific opinion is of high importance to them or if more fundamental processes are at play that transcend specific opinions."

Dogmatic people are characterised by a belief that their worldview reflects an absolute truth and are often resistant to change their mind, for example when it comes to partisan issues. This tendency can have societal impacts by polarising political, scientific and religious debates. However, the cognitive drivers of dogmatism are still poorly understood.

To investigate this, the researchers asked over 700 people to perform a simple decision-making task. Participants saw two boxes with flickering dots and had to decide which box contained more of the dots. Critically, after the participants had made an initial choice, the researchers gave them the chance to view another, clearer version of the boxes. They then made a final decision.

Schulz explained: "This mirrors many real-life situations - for example, when we hear a rumour but aren't sure if it's true. Do we share it, or do we check a credible source beforehand?"

Joint first author, Dr Max Rollwage (Wellcome Centre for Human Neuroimaging at UCL and Max Planck UCL Centre for Computational Psychiatry & Ageing Research) said: "By using simple tasks, we were able to minimise motivational or social influences and pin down drivers of altered evidence processing that contribute to dogmatic beliefs."

The task was followed by a comprehensive set of questionnaires that allowed the researchers to measure participants' political orientation and levels of dogmatism.

Dogmatic individuals and moderates did not differ in their accuracy or confidence of their decisions. However, the researchers found that more dogmatic participants were more likely to decline the helpful additional information.

The differences between more and less dogmatic participants were especially large when participants had little confidence in a decision. Senior author Dr Steve Fleming (Wellcome Centre for Human Neuroimaging at UCL, Max Planck UCL Centre for Computational Psychiatry & Ageing Research and UCL Experimental Psychology) said: "Previous work has found that there is a close link between how confident we feel and whether or not we seek out new information. In the current study we found that this link was weaker in more dogmatic individuals."

In general, the reduced search was detrimental, with more dogmatic people being less accurate in their final judgements.

Dr Fleming added: "It is striking that we could detect links between dogmatism about issues such as politics, and information-seeking in a simple online game. This tells us that real-world dogmatism isn't just a feature of specific groups or opinions but may be associated with more fundamental cognitive processes."

The study highlights that simply having corrective information available does not necessarily mean people will consume it.

Schulz said: "This is particularly relevant today. We have never been so free to decide if we have enough evidence about something or whether we should seek out further information from a reliable source before believing it.

"It is also important to stress that the differences between more and less dogmatic people were subtle, and we don't know yet how they would manifest when considering real-world information such as news about political parties. In the end, it's a cautionary tale, whether we think of ourselves as dogmatic or not: when uncertain, it might be wise to check the information again."

The researchers are now trying to further unravel the underlying cognitive algorithms which trigger people to search for further information in situations of uncertainty.

An international team comprising researchers from the University of Bristol, and Hunan and Central South Universities in China, have prepared biocompatible protocells that generate nitric oxide gas - a known reagent for blood vessel dilation - that when placed inside blood vessels expand the biological tissue.

In a new study published today in Nature Chemistry, Professor Stephen Mann and Dr Mei Li from Bristol's School of Chemistry, together with Associate Professor Jianbo Liu and colleagues at Hunan University and Central South University in China, prepared synthetic protocells coated in red blood cell fragments for use as nitric oxide generating bio-bots within blood vessels.

Coating the protocells led to increased levels of biocompatibility and longer blood circulation times. Critically, the team trapped an enzyme inside the protocells which, in the presence of glucose, produced hydrogen peroxide. This was then used by haemoglobin in the protocell membrane to degrade the drug molecule hydroxyurea into nitric oxide gas.

When placed inside small pieces of blood vessels, or injected into a carotid artery, the protocells produced sufficient amounts of nitric oxide to initiate the biochemical pathways responsible for blood vessel vasodilation.

Although at a very early stage of development, the new approach could have significant benefits in biomedicine, cellular diagnostics and bioengineering.

Professor Stephen Mann, Co-Director of the Max Planck Bristol Centre for Minimal Biology at Bristol, said: "This work could open up a new horizon in protocell research because it highlights the opportunities for creating therapeutic, cell-like objects that can directly interface with living biological tissues."

Associate Professor Jianbo Liu at Hunan University added: "We are all really excited about our proof-of-concept studies but there is a lot of work still to be done before protocells can be used effectively as bio-bots in therapeutic applications. But the potential looks enormous."

HERSHEY, Pa. -- A genetic modification in the 'coat' of a brain infection-causing virus may allow it to escape antibodies, according to Penn State College of Medicine researchers. They say testing people for this and other viral mutations may help identify patients at risk for developing a fatal brain disease.

Dr. Aron Lukacher, professor and chair of the Department of Microbiology and Immunology at the College of Medicine, and Susan Hafenstein, professor of medicine and microbiology and immunology at the College of Medicine and professor of biochemistry and molecular biology at Penn State Eberly College of Science, co-led a research team that used high-resolution microscopy to study the capsid, or outer shell of mouse polyomavirus (MuPyV). This virus is a genetic model of JC polyomavirus (JCPyV), which is present and harmless in most people and can cause progressive multifocal leukoencephalopathy (PML), a brain disease, in people taking immunosuppressive therapies.

Genetic mutations in the capsid of JCPyV are common in PML patients and scientists have struggled to understand whether they allow the virus to infect brain cells or whether the resulting changes allow the virus to evade elimination by antiviral antibodies and then cause brain infection. Lukacher and Hafenstein studied the mouse equivalent of a common genetic mutation in JC polyomavirus to try and better understand how it may cause PML.

"Not much is known about how this particular genetic mutation in the JC polyomavirus capsid leads to PML," Lukacher said. "It has been detected in the blood, cerebrospinal fluid and brain tissues of PML patients but not in their urine. This unmutated virus typically sits dormant in the kidneys of healthy people, which got us wondering how this particular mutation contributes to disease progression."

The researchers introduced a genetic mutation in the MuPyV capsid similar to one found in JCPyV and conducted a series of experiments to compare outcomes between MuPyV and the altered virus. The virus mutates by swapping out one amino acid, the chemical ingredients used to build the capsid, for another. They found the virus was still able to cause central nervous system infection and hydrocephalus, or brain swelling.

To study how the mutation allows the virus to evade antibodies, the research team, including doctoral student Matthew Lauver and medical scientist training program student Daniel Goetschius, used cryogenic electron microscopy to determine the 3D, atomic resolution structure of the virus particles bound to monoclonal antibodies. The results of their analyses were published in the journal eLife.

The team examined the structural features to see how the monoclonal antibodies recognize the virus capsid and neutralize it. They found that the capsid mutation prevents the monoclonal antibody from being able to interact with the virus, increasing the chances that the virus can infect the brain when patients become immune-suppressed.

"We studied how other mutations affected MuPyV and found many of them result in impaired kidney and retained brain viral infection," said Lukacher, a Penn State Cancer Institute researcher. "However, only a few of these result in the ability of the virus to evade the immune response."

According to Lukacher, more research is needed to determine which JCPyV mutations cause the virus to evade antibodies. He said the goal would be to develop screenings for patients with multiple sclerosis receiving immune-modulating therapies, as well as those immune-compromised by cancers and AIDS, to see who might be at increased risk for developing PML.

Study of patients attending a hospital-based obesity service shows no difference in weight loss between those under 60 years old and those from 60 to 78 years old

The University of Warwick-led study conducted at University Hospitals Coventry and Warwickshire (UHCW) concludes that lifestyle changes to manage weight loss are effective in reducing obesity regardless of age

Aims to dispel myths about effectiveness of weight loss in older people

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study from the University of Warwick and University Hospitals Coventry and Warwickshire (UHCW) NHS Trust that demonstrates that age is no barrier to losing weight.

The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

The findings are based on analysis of patient records from a hospital-based obesity service and are reported in the journal Clinical Endocrinology.

This retrospective study was conducted at the Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) at UHCW. The researchers randomly selected 242 patients who attended the WISDEM-based obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service.

All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the WISDEM-based obesity service, and the percentage reduction in body weight calculated across both groups. When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years.

The hospital-based programme used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with BMIs typically over 40Kgm-2.

There are more than fifty co-morbidities of obesity that can be lessened as we lose weight, including diabetes, psychiatric conditions such as depression and anxiety, osteoarthritis and other mechanical problems. Obesity is also linked to increased mortality and poor wellbeing.

Lead author Dr Thomas Barber of Warwick Medical School at the University of Warwick said: "Weight loss is important at any age, but as we get older we're more likely to develop the weight-related co-morbidities of obesity. Many of these are similar to the effects of aging, so you could argue that the relevance of weight loss becomes heightened as we get older, and this is something that we should embrace.

"There are a number of reasons why people may discount weight loss in older people. These include an 'ageist' perspective that weight-loss is not relevant to older people and misconceptions of reduced ability of older people to lose weight through dietary modification and increased exercise. Older people may feel that hospital-based obesity services are not for them. Service providers and policymakers should appreciate the importance of weight loss in older people with obesity, for the maintenance of health and wellbeing, and the facilitation of healthy ageing. Furthermore, age per se should not contribute towards clinical decisions regarding the implementation of lifestyle management of older people.

"Age should be no barrier to lifestyle management of obesity. Rather than putting up barriers to older people accessing weight loss programmes, we should be proactively facilitating that process. To do otherwise would risk further and unnecessary neglect of older people through societal ageist misconceptions."

Conclusion:

The cytokine family including interleukin-2 and -15 (IL-2 and IL-15) started out in a primitive vertebrate species with three related cytokines IL-2, IL-15, and IL-15-like (IL-15L), all sharing binding capacity for receptor chain IL-15Rα. IL-15L was conserved in fishes, reptiles, and some mammals but lost in human and mouse. Researchers in Japan, Germany, and the UK, have now determined the function of IL-15L using rainbow trout. Data suggest that in the jawed vertebrate ancestor IL-15 and IL-15L, forming "heterodimer cytokine" complexes with IL-15Rα, selectively induced type 1 (aka Th1) and type 2 (aka Th2) immunity, respectively, whereas free IL-2 efficiently stimulated activated and regulatory T cells by binding their surface IL-15Rα. Insights into their evolution should inspire further studies of human IL-2 and IL-15, both of which are used or tested in cancer immunotherapy.

Background:

In human and mouse, the closely related cytokines IL-2 and IL-15 both signal through IL-2Rβ heterodimer receptors, and also bind to a third receptor chain of a different molecular family, cytokine-specific IL-2Rα or IL-15Rα, which has no homologues in receptors for other human or murine cytokines. IL-2 is secreted by activated T cells, and predominantly functions as a free cytokine that binds IL-2Rαβ heterotrimer complexes on target cells. IL-2Rαβ complexes are abundant on activated T cells and, constitutively, on regulatory T cells (Tregs). Therefore, IL-2 both participates in an immuno-stimulatory positive feedback loop through activated T cells and an immuno-inhibitory negative feedback loop through Tregs. IL-15, on the other hand, predominantly uses IL-15Rα as a "heterodimer cytokine" partner at the membrane of the expressing cells or as released free IL-15+IL-15Rα complexes. IL-15 predominantly stimulates "type 1 immunity" by specifically stimulating natural killer (NK) cells and CD8+ cytotoxic T cells, and is important for the maintenance of several lymphocyte populations in intestine, lung, and skin. Recombinant IL-2 is an established anti-cancer drug (e.g. "proleukin"), but in several clinical trials IL-15 (complexed or not with IL-15Rα) is preferred as IL-15 does not have the complicating factor of specifically stimulating Tregs.

The findings:

Associate Professor Johannes M. Dijkstra and co-workers at Fujita Health University, Japan, together with the groups of Professor Uwe Fischer at the Friedrich-Loeffler-Institute, Germany, and Professor Christopher J. Secombes, University of Aberdeen, UK, have been instrumental in elucidating the evolution of IL-2 and IL-15. In their recent study [1], for which most experiments were done by the first author Dr. Takuya Yamaguchi at the Friedrich-Loeffler-Institute, they determined that in rainbow trout all the three cytokines IL-2, IL-15, and IL-15L can bind to IL-15Rα. The tandem gene duplication that resulted in IL-15Rα plus IL-2Rα probably occurred in a primitive tetrapod species, and in fish only a single molecule of this receptor chain family is found that is very similar to mammalian IL-15Rα while quite different from mammalian IL-2Rα that acquired substantial modifications during its evolution [2]. Dijkstra and co-workers previously determined that cytokine IL-15L already existed at the evolutionary level of sharks [3] and is conserved in some mammals like cattle but inactivated in human and mouse [2]. In cattle, they found that IL-15 and IL-15L selectively bind to IL-15Rα, whereas IL-2 selectively binds to IL-2Rα [1,3], which for IL-2 and IL-15 agrees with human and mouse. However, for mammalian IL-15L a function could not be determined so far. The Yamaguchi et al. study [1], using rainbow trout, now is the first to identify the function of IL-15L. This function is the stimulation of the expression of cytokines IL-4 and IL-13 homologs, as shown both in vitro and in vivo, and thereby of type 2 immunity. Under similar conditions, trout IL-15 was found to selectively stimulate cytokine interferon-g expression, a marker for type 1 immunity, concluding that IL-15 and IL-15L have opposing immune functions; meanwhile, trout IL-2 was found to induce a broader cytokine palette than either IL-15 or IL-15L [1]. All three trout cytokines IL-2, IL-15, and IL-15L, were found to induce activation of transcription factor STAT5 [1]. IL-15 and IL-15L transcripts are abundant and also found in epithelial cells and fibroblasts, and Yamaguchi et al. speculate that the multiple AUG codons in their 5' untranslated regions prohibit translation unless the cell experiences proper signals for inducing type 1 or type 2 immunity [1]. In mammals, such "alarmin" function of IL-15L for inducing type 2 immunity may have been taken over by newer cytokines that seem to be absent in fish, such as IL-25, IL-33, and TSLP. The trout cells most sensitive to IL-15L appear to be innate lymphocytes and they may be equivalent to mammalian ILC2 cells [1].

Reminiscent of IL-15 and IL-2 in mammals, trout IL-15 is more dependent on co-presentation with IL-15Rα than IL-2 [1], and also in fish IL-2 appears to participate in an immune-stimulatory positive feedback loop involving activated T cells [4] and an immuno-inhibitory negative feedback loop through the stimulation of IL-15Rα-expressing Tregs [5]. The dependency of IL-15L on co-presentation with IL-15Rα was found to be even larger than that of IL-15, since for unbound IL-15 but not for unbound IL-15L functional activity could be observed [1]. Retainment of IL-15+IL-15Rα complexes at the surface of expressing cells can contain cytokine activity within confined niches, which may explain why in both mammals and fish IL-15 was selected over IL-2 for stimulation of lymphocytes in mucosal tissues [1]. However, to some extent, as known in mammals for IL-2+IL-2Rα, trout IL-2 can be presented at the cell surface together with IL-15Rα [1], and this type of IL-2 presentation probably deserves more attention including in mammals. Similarly, the ease with which a function of free IL-15 can be found in both mammals and trout, whereas not found for free IL-15L [1], underlines that the possibility of free IL-15 representing a distinct function from IL-15+IL-15Rα should be given more consideration. For trout IL-2 and IL-15L probable homodimer complexes were found [1], suggesting that previous observations of IL-2 and IL-15 homodimers in mammals should be studied more seriously as a potentially important trait of the IL-2/15/15L family.

Professor Dijkstra, who wrote and largely conceptualized the Yamaguchi et al. study [1] and is one of the two corresponding authors together with Professor Fischer, explains why understanding the evolution of this cytokine family is important: "Although IL-2 and IL-15 are very powerful and important cytokines, we only partially understand them. IL-2 and IL-2Rα are relatively simple to understand at the molecular level but complicated at the functional level because IL-2 simultaneously induces opposing functions. On the other hand, IL-15 and IL-15Rα seem relatively simple to understand at the functional level but are far from understood at the molecular level. Peculiarities such as the extremely long "leader" sequence of IL-15, multiple AUG codons in the IL-15 transcript 5'UTR, and multiple splicing forms of IL-15Rα, are poorly understood, yet seem to be important since conserved in both mammals and fish. Basically, finding similar features despite evolutionary separation for hundreds of millions of years indicates the importance of those features, and urges us to study them better not only in the non-model species but also in human and mouse."

In short, the recent Yamaguchi et al. study, Ancient cytokine interleukin 15-like (IL-15L) induces a type 2 immune response, published in Frontiers in Immunology https://doi.org/10.3389/fimmu.2020.549319 [1], concludes that the IL-2/15/15L cytokine family already played a major role in immune polarizations in an ancestor of jawed vertebrates, with opposing functions for IL-15 and IL-15-like.

Can schools safely remain open or reopen during periods of significant community spread of COVID-19? According to predictions from a model of SARS-CoV-2 transmission in the school setting, yes - if appropriate precautions are followed both in school and in the community.

The study results are published in BMC Public Health.

School closures during the COVID-19 pandemic have been based predominantly on models of pandemic influenza transmission. However, say the study's authors, recent evidence suggests that "children under the age of 10, are less susceptible to SARS-CoV-2 infection and rarely transmit the infection to adults or schoolmates."

For their study, University of Vermont researchers adapted a previously-published model using contact data from Shanghai, China to investigate the impact of open schools on community spread of SARS-CoV-2 infection.

A critical feature of the model is the measurement of contact structure across all age groups, with a focus on the rate of daily contacts in the community and social contacts in school - and how a reduction in contact frequency affects transmission risk.

The team combined contact patterns observed between different age groups during pre- and post-pandemic "lockdown" periods to simulate various levels of school reopening and also tested these effects across a range of estimates of lower susceptibility rates to infection in younger children.

According to first author Benjamin Lee, M.D., associate professor of pediatrics and a pediatric infectious diseases specialist, the model helped identify conditions that would support keeping schools open. Ideally, he said, the average number of daily social contacts in the community needs to be reduced to about 40 percent of pre-pandemic baseline, and total contacts for children aged 10 to 19 needs to be reduced to 33 percent of pre-pandemic baseline. If this can be achieved, having open schools would be feasible even starting from a point of significant community transmission.

"In other words, necessary restrictions in the community with careful mitigation for older kids is the trade-off that will enable schools to remain open," said Lee. "Schools should be the last to close and first to re-open."

The study demonstrates how considering a combination of different measures is beneficial in creating a path to having schools be open to the extent possible, within a broader set of restrictions.

"It's not just about the scale of restrictions, but also about how targeted these restrictions are, because the structure of contacts matters," said senior author Laurent Hébert-Dufresne, Ph.D., assistant professor of computer science.

"This study provides a basic proof-of-principle that we believe can be applicable to many settings that have similar contact structures," said Lee.

WASHINGTON -- U.S. Naval Research Laboratory researchers led a team of scientists who discovered some of the youngest known radio jets launched by growing supermassive black holes in the centers of distant galaxies.

Watching and recording the jets, which are believed to be only decades old, in their infancy allows researchers to observe their formation and growth and study how they influence their environments.

"Timing and navigation are a fundamental portion of the Navy mission and constitute part of the key infrastructure the DOD relies on," said Henrique Schmitt, Ph.D., an astronomer at NRL. "Understanding the evolution of jets in active galaxies is important for day-to-day tools like GPS. Such active galaxies define the celestial reference frame from which precision timing and positioning are derived."

The team discovered the jets after reviewing images from the Very Large Array Sky Survey (VLASS) that contained unusually bright radio sources in comparison to previous studies with the Karl G. Jansky Very Large Array (VLA) in Socorro, New Mexico. The paper was accepted into publication by the Astrophysical Journal.

"This is a new topic that has yet to be fully explored," said Kristina Nyland, Ph.D., a National Research Council postdoctoral fellow in residence at NRL. "Studying the launching of powerful jets is important for us to understand how galaxies and supermassive black holes grow in tandem over billions of years."

According to Nyland, older jets shine for millions of years and may extend far beyond the confines of their host galaxies, while newborn jets stay within the boundaries of their hosts. Known as the interstellar medium, this area contains the raw materials that give rise to new stars and planetary systems. It is hypothesized newborn jets may interact with these dense clouds of gas and play an important role in galaxy formation and evolution.

"When you have compact, powerful jets of radio plasma colliding with a reservoir of star-forming gas, the jets may alter the efficiency of new stellar births and the future appearance and properties of the galaxy," Nyland said. "Studying young jets in particular is essential for understanding our cosmic origins. It is important for us to measure the rate at which new jets are launched by supermassive black holes to ultimately understand how they influence the lives of the galaxies in which they reside."

The U.S. Naval Observatory (USNO) maintains a celestial reference frame used to provide a reference of the skies and space. That celestial reference frame appears in grid form and encompasses more than 4,000 known radio sources. New radio sources, like newborn jets, can add reference points to the grid.

Living on the grid

Reference points on the grids can change in appearance over time. Researchers are trying to fill in sparse areas of the grid by coupling an optical reference frame to the celestial reference frame. However, the physics of the optical and radio energy emissions from the supermassive black holes are not fully understood. These emissions look different over time and researchers find that when optical and celestial grids are overlaid they do not always match up perfectly.

"Without understanding the physics of those radio sources, what you see is those two reference frames don't always line up," said Tracy Clarke, Ph.D., a radio astronomer in NRL's Remote Sensing Division. "That's because we are looking at a different part of the radio source compared to the optical host galaxy--they are shifted a bit."

"Understanding the source of radio emission from AGN is a key area of interest to the USNO and the Navy, and helps us better understand the nature of the quasar sources that comprise the International Celestial Reference Frame," said Megan Johnson, Ph.D. at USNO.

Numerous studies are underway to gain a better understanding of the physics. That information could be used to build a more comprehensive and predictive reference frame. Navy assets can utilize the reference frame in a GPS constrained environment. To do that, researchers want to give operators the sources of bias in a fixed grid (such as a shift in brightness in one of the jet sources) to offset the reference frame.

"The physics of what Kristina Nyland is doing helps us understand how to tie those two reference frames tightly together, and that's going to give the Navy a fantastic multiwavelength reference frame," Clarke said.

Clarke currently serves as co-chair of the Survey Science Group for the VLA Sky Survey (VLASS). This group played a key role in developing the VLASS survey and it currently serves as the interface to the scientific community.

Astronomical collaboration

VLASS is building a richer understanding of space by combining imagery and data of the entire sky visible from a telescope taken multiple times over several years. NRL is supporting the VLASS through commensal observations with the VLA Low Band Ionosphere and Transient Experiment (VLITE), operated out of NRL. VLITE is a powerful addition to the survey, providing complementary information on radio source properties over a different range of frequencies and spatial scales.

"While VLASS data have allowed the discovery of these newly formed jets, understanding the history of galaxy evolution may require additional radio data," Clarke said. "This is where VLITE comes in. VLITE operates at longer observing wavelengths and observes in parallel to VLASS."

Clarke believes VLITE is a powerful addition to the survey since it provides complementary information on radio source properties that allows NRL researchers to better understand the evolution of the supermassive black hole that is powering each newborn radio jet.

Nyland is leading the research project in the remote sensing division of NRL through the NRC postdoctoral fellowship program. She continues to study the newborn jets and observe how they change over time.

"This research contributes overall to human exploration," said Nyland. "It contributes to a richer understanding of fundamental physics and the fascinating link between supermassive black holes and galaxy evolution."

A basic science discovery by researchers at the Johns Hopkins Bloomberg School of Public Health reveals a fundamental way cells interpret signals from their environment and may eventually pave the way for potential new therapies.

The finding involves a signaling pathway in cells, called the Hippo pathway, which normally constrains cell division and regulates the size of organs, and also plays a role in tissue growth and development as well as tumor suppression. The Hippo pathway is so fundamental that it is found in species ranging from humans to flies.

The Bloomberg School researchers clarified the working of this signaling pathway by solving a long-standing mystery of how one of its core components, an enzyme called MST2, can be activated by multiple signaling inputs.

The discovery is reported in a paper on November 20 in the Journal of Biological Chemistry.

"We knew that this pathway could be activated by different upstream signals, and here we've revealed the mechanism by which that happens," says study senior author Jennifer Kavran, PhD, assistant professor in the Bloomberg School's Department of Biochemistry and Molecular Biology.

The Hippo pathway normally works as a brake on cell division that stops organs from growing larger once they have reached the appropriate size. Mutations or other abnormalities in the pathway that take the brakes off cell division have been found in many cancers, making elements of the Hippo pathway potential targets for future cancer treatments.

Due to its fundamental role of tissue and organ growth, the pathway also is of great interest to researchers who are developing techniques to improve wound healing and stimulate the regeneration of damaged tissue.

The heart of the Hippo pathway begins with the activation of two highly related enzymes, MST1 and MST2, which are almost identical and perform overlapping functions. A variety of biological events, including cell-to-cell contacts, certain nutrients, stress, and signaling through cell receptors, can cause MST1/2 to become activated--a process in which the enzyme becomes tagged with sets of phosphorus and oxygen atoms called phosphoryl groups.

Once activated by this "autophosphorylation," MST1/2 can send signals downstream to complete the signaling chain and inhibit cell division. Normally, proteins that undergo autophosphorylation are activated by a single molecular "event"--such as binding a particular molecule or interacting with another copy of the same enzyme. How such a variety of inputs can each trigger MST1/2's activation has been a mystery.

"In cell biology, we're used to the idea that when an enzyme is transmitting a signal, a single molecular event turned that enzyme on," Kavran says.

In the study, she and her colleagues used test tube and cell culture experiments with human MST2 to show that the myriad upstream activators of this enzyme trigger MST2 autophosphorylation the same way--simply by increasing the local concentration of these enzymes--thus reducing the distance between the enzymatic sites on individual enzymes and making it easier for them to phosphorylate one another.

The researchers believe their discovery is likely to apply not only to MST2 but also its twin MST1 as well as the very similar versions of the enzyme produced in other species.

Although this was principally a basic science study, the results should enhance the ability of researchers to manipulate Hippo pathway signaling, both for basic research as well as for potential therapeutic applications for tissue regeneration and anti-cancer therapies.

"The techniques we used to activate MST2 in cell cultures should be useful to other labs that are studying the Hippo pathway and need a way to turn it on in a controlled manner," Kavran says.

She and her lab plan to investigate how other enzymes in the pathway are regulated.

For more than a decade, Hiranmoy Das, Ph.D., has been investigating how Kruppel-like Factor 2 (KLF2), a gene that codes protein into a specific human chromosome, influences the development of bone and musculoskeletal diseases such as rheumatoid arthritis and osteoporosis.

In 2006, Das, a professor in the Department of Pharmaceutical Sciences at the Texas Tech University Health Sciences Center (TTUHSC) Jerry H. Hodge School of Pharmacy, was the first to publish research in the peer-reviewed scientific journal, Proceedings of the National Academy of Sciences, U.S.A., showing KLF2 regulates monocyte activation and function. Monocytes, the largest type of white blood cells in our immune system, help defend the human body from bacteria, viruses and fungi. His past research also has demonstrated that low levels of KLF2 promote osteoclast, a specialized cell that helps in the bone degradation process, a key factor in developing bone and musculoskeletal diseases as the body ages.

Homeostasis, a process by which new bone is built and old bone is removed, is maintained by two important cells: osteoclasts, which decrease bone levels by removing damaged bone; and osteoblasts, which form new bone. Through a process known as osteoblast differentiation, mesenchymal stem cells, which are found in bone marrow and fat, acquire the bone building characteristics of osteoblasts.

Most recently, the Das lab attempted to determine if inducing KLF2 levels in dental pulp derived stem cells (DPSCs) will promote osteoblast and the building of new bone. Their study, "KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism," was published in the September issue of Redox Biology. His team included TTUHSC research associates Jyotirindra Maity and Moonmoon Deb and research assistant Carl Greene.

Das said his team used DPSCs in their latest study because DPSCs have the same characteristics as mesenchymal stem cells, which means they also can differentiate into bone building osteoblasts.

"We wanted to see what happens in the DPSCs at the KLF2 level," Das explained. "To our surprise, we found that during the differentiation, the KLF2 level was very highly increased."

Das said KLF2 is known to play a protective role in certain aspects of human health. For instance, various statins used to treat high cholesterol also increase the KLF2 level in endothelial cells. Because endothelial cells are primarily found in arteries, veins and capillaries, increasing their KLF2 level helps protect against cardiovascular disease.

If osteoblastic differentiation can be promoted more efficiently by inducing KLF2 in the DPSCs, Das believes those stem cells can be used to help reduce the occurrence and severity of rheumatoid arthritis, osteoporosis and other bone and musculoskeletal diseases not yet tested.

"Think about it: if we can induce KLF2, that will help in osteoblastic differentiation and it will inhibit osteoclastic differentiation," Das said. "It also will help the stem cells to make more osteoblasts so they can form more bone. So basically, it is two different angles we are treating that will reduce bone related diseases such as osteoporosis, arthritis, spondyloarthritis and all kinds of diseases."

A new assessment tool developed by Kaiser Permanente researchers and physicians helps guide clinical decisions in emergency departments and urgent care centers

PASADENA, Calif. -- A study published in the American Journal of Emergency Medicine this month reports on an assessment tool developed by Kaiser Permanente researchers and physicians that helps ensure patients get the right care, when they need it, by accurately predicting the probability that patients with COVID-19 symptoms will experience severe disease or even death.

"As the pandemic surges again across the country and hospitalizations are increasing, front-line physicians often must make quick decisions to hospitalize or discharge patients with COVID-19 symptoms," said Adam Sharp, MD, an emergency medicine physician who also is a researcher for the Kaiser Permanente Southern California Department of Research & Evaluation. "We created a risk assessment that looks at many different patient variables that might predict a critical poor outcome -- without any lab or diagnostic testing."

The risk score is particularly helpful to physicians in making these decisions at the time of the emergency department visit, Dr. Sharp said.

The assessment tool, called the COVAS score because it looks at comorbidities, obesity, vital signs, age, and sex, has already been incorporated into the electronic health record system throughout Kaiser Permanente in Southern California, where it guides clinical decisions in emergency departments and urgent care centers. In this study, the COVAS score accurately predicted the probability of death or the need for critical respiratory care within 7 days for patients seen at Kaiser Permanente emergency departments in Southern California.

"I have used this tool successfully with my own patients in the emergency department and it helps provide necessary information to make informed decisions with patients," Dr. Sharp said. "It can help to reassure low-risk patients, and alternatively can encourage those at high risk to receive hospital-based care that may speed their recovery."

Researchers conducted a retrospective study of 26,600 emergency department visits by adults for symptoms suspicious for COVID-19 at 15 Kaiser Permanente hospitals in Southern California between March 1, 2020, to April 30, 2020, a period of time when substantial community spread of COVID-19 was prevalent in the region but immediate COVID-19 test results were not.

The results inform front-line health professionals and health systems about which patients with COVID-19 symptoms, which include fever, cough, difficulty breathing, and fatigue, are at greatest risk of death or respiratory decompensation that would require ventilation or high-flow oxygen.

Previous studies have focused on hospitalized patients, with little information about those treated outside of the inpatient setting. This work examines emergency department patients with suspected COVID-19 and provides helpful information to front-line physicians to inform care decisions, particularly during surges when hospital capacity can be limited.

Ludwig-Maximilians-Universitaet (LMU) in Munich physicists have introduced a new method that allows biological pattern-forming systems to be systematically characterized with the aid of mathematical analysis. The trick lies in the use of geometry to characterize the dynamics.

Many vital processes that take place in biological cells depend on the formation of self-organizing molecular patterns. For example, defined spatial distributions of specific proteins regulate cell division, cell migration and cell growth. These patterns result from the concerted interactions of many individual macromolecules. Like the collective motions of bird flocks, these processes do not need a central coordinator. Hitherto, mathematical modelling of protein pattern formation in cells has been carried out largely by means of elaborate computer-based simulations. Now, LMU physicists led by Professor Erwin Frey report the development of a new method which provides for the systematic mathematical analysis of pattern formation processes, and uncovers the their underlying physical principles. The new approach is described and validated in a paper that appears in the journal Physical Review X.

The study focuses on what are called 'mass-conserving' systems, in which the interactions affect the states of the particles involved, but do not alter the total number of particles present in the system. This condition is fulfilled in systems in which proteins can switch between different conformational states that allow them to bind to a cell membrane or to form different multicomponent complexes, for example. Owing to the complexity of the nonlinear dynamics in these systems, pattern formation has so far been studied with the aid of time-consuming numerical simulations. "Now we can understand the salient features of pattern formation independently of simulations using simple calculations and geometrical constructions," explains Fridtjof Brauns, lead author of the new paper. "The theory that we present in this report essentially provides a bridge between the mathematical models and the collective behavior of the system's components."

The key insight that led to the theory was the recognition that alterations in the local number density of particles will also shift the positions of local chemical equilibria. These shifts in turn generate concentration gradients that drive the diffusive motions of the particles. The authors capture this dynamic interplay with the aid of geometrical structures that characterize the global dynamics in a multidimensional 'phase space'. The collective properties of systems can be directly derived from the topological relationships between these geometric constructs, because these objects have concrete physical meanings - as representations of the trajectories of shifting chemical equilibria, for instance. "This is the reason why our geometrical description allows us to understand why the patterns we observe in cells arise. In other words, they reveal the physical mechanisms that determine the interplay between the molecular species involved," says Frey. "Furthermore, the fundamental elements of our theory can be generalized to deal with a wide range of systems, which in turn paves the way to a comprehensive theoretical framework for self-organizing systems."

Simon Fraser University professors Paul Tupper and Caroline Colijn have found that physical distancing is universally effective at reducing the spread of COVID-19, while social bubbles and masks are more situation-dependent.

The researchers developed a model to test the effectiveness of measures such as physical distancing, masks or social bubbles when used in various settings.

Their paper was published Nov. 19 in the journal Proceedings of the National Academy of Sciences
of the United States of America (PNAS).

They introduce the concept of "event R," which is the expected number of people who become infected with COVID-19 from one individual at an event.

Tupper and Colijn look at factors such as transmission intensity, duration of exposure, the proximity of individuals and degree of mixing - then examine what methods are most effective at preventing transmission in each circumstance.

The researchers incorporated data from reports of outbreaks at a range of events, such as parties, meals, nightclubs, public transit and restaurants. The researchers say that an individual's chances of becoming infected with COVID-19 depend heavily on the transmission rate and the duration - the amount of time spent in a particular setting.

Events were categorized as saturating (high transmission probability) or linear (low transmission probability). Examples of high transmission settings include bars, nightclubs and overcrowded workplaces while low transmission settings include public transit with masks, distancing in restaurants and outdoor activities.

The model suggests that physical distancing was effective at reducing COVID-19 transmission in all settings but the effectiveness of social bubbles depends on whether chances of transmission are high or low.

In settings where there is mixing and the probability of transmission is high, such as crowded indoor workplaces, bars and nightclubs and high schools, having strict social bubbles can help reduce the spread of COVID-19.

The researchers found that social bubbles are less effective in low transmission settings or activities where there is mixing, such as engaging in outdoor activities, working in spaced offices or travelling on public transportation wearing masks.

They note that masks and other physical barriers may be less effective in saturating, high transmission settings (parties, choirs, restaurant kitchens, crowded offices, nightclubs and bars) because even if masks halve the transmission rates that may not have much impact on the transmission probability (and so on the number of infections).

The novel coronavirus is relatively new but the science continues to evolve and increase our knowledge of how to effectively treat and prevent this highly contagious virus. There is still much that we do not know and many areas requiring further study.

"It would be great to start collecting information from exposures and outbreaks: the number of attendees, the amount of mixing, the levels of crowding, the noise level and the duration of the event," says Colijn, who holds a Canada Research Chair in Mathematics for Evolution, Infection and Public Health.

For COVID-19 Surveillance, Test Frequency and Turnaround Time Are Paramount, Modeling Suggests
Speed of test results and frequency of testing are paramount for effective COVID-19 surveillance, suggests a new study that modeled trade-offs in test sensitivity, test frequency, and sample-to-answer reporting time, in select scenarios. Test sensitivity is secondary to these factors in the scenarios studied, the authors say. "If the availability of point-of-care or self-administered screening tests leads to faster turnaround time or more frequent testing, our results suggest that they would have high epidemiological value," Daniel Larremore and colleagues write. Because SARS-CoV-2 can spread from individuals with pre-symptomatic, symptomatic, and asymptomatic infections, diagnosis and isolation based on symptoms alone won't prevent spread. Rather, robust population screening, for which virus testing is often central, will be critical. However, related surveillance testing programs must make concrete choices, including: What are the tradeoffs between cost, frequency, test sensitivity, and the speed with which diagnoses can be returned? To evaluate this, Larremore and colleagues modeled how changing viral load (different levels of infectiousness) impacted the ability of an assay, or test, to diagnose infection. They calculated what percentage of these people's total infectiousness would be removed by screening and isolation, using different testing approaches. They also evaluated the impact of surveillance at the population level using two epidemiological models that incorporated viral load dynamics, one of which mimicked aspects of the contact structure of New York City. Across their analyses of individuals and populations, the inclusion of viral load in surveillance modeling revealed that the limits in detection abilities of tests mattered less than previously thought, the authors say. But delays in returning diagnoses were highly impactful, with even one-day delays between sample and answer undercutting otherwise impactful surveillance plans. As well, the frequency of surveillance testing plays a crucial role, the authors say. They note that communities vary in their transmission dynamics, so specific strategies for successful population screening will depend on the current community infection prevalence and transmission rate in a given location. They also identify other limitations in their study. Still, they say their findings could aid some groups planning societal reopening, refocusing their efforts on rapid turnaround times instead of highly sensitive tests. They may also inform regulatory agencies and test manufacturers about the importance of developing and approving such tests, optimized for surveillance (as opposed to clinical diagnosis).

There is growing evidence that adipose tissue plays a key role in the aggravation of COVID-19. One of the theories under investigation is that fat cells (adipocytes) act as a reservoir for SARS-CoV-2 and increase viral load in obese or overweight individuals. Scientists also suspect that during infection fat cells release into the bloodstream substances that boost the inflammatory reaction triggered by the virus in the organism.

These hypotheses are being investigated by researchers at the University of São Paulo’s Medical School (FM-USP) in Brazil under the coordination of Marilia Cerqueira Leite Seelaender, a professor in the Department of Clinical Surgery. Peter Ratcliffe, a professor at the University of Oxford in the UK and one of the winners of the 2019 Nobel Prize for Medicine, is collaborating.

“A cytokine storm resulting in systemic inflammation similar to sepsis occurs in some severe COVID-19 patients. We believe these inflammatory factors come from adipose tissue. It’s been shown that when adipocytes expand too much, they can cause inflammation throughout the body, even in the brain,” Seelaender told Agência FAPESP.

The FM-USP group analyzed samples of adipose tissue obtained from autopsies of people who died from COVID-19, and also from patients infected with SARS-CoV-2 who had to be submitted to emergency surgery at the university’s hospital for appendicitis or other reasons not related to the viral infection. Preliminary results confirmed that the virus can be found in fat cells, whose membranes are rich in ACE-2, the main receptor used by the virus to invade human cells. The researchers have yet to confirm that once it has invaded adipocytes, it can remain there long enough to replicate inside them.

“It’s worth noting that visceral adipocytes [located deep in the abdomen and around internal organs] have much more ACE2 than subcutaneous adipose tissue,” Seelaender said. “In addition, they’re much more inflammatory. As a result, visceral obesity tends to be even more harmful as far as COVID-19 is concerned.”

The preliminary findings also brought to light a change in the pattern of exosome secretion in the adipose tissue of infected people. Exosomes are extracellular vesicles, comparable to tiny bubbles, released by cells into the bloodstream with proteins and other types of signaling molecules. This is one of the mechanisms whereby information is exchanged between different tissues as the body adapts to changes in its environment.

The aims of the research conducted by the FM-USP group include investigating whether infection by SARS-CoV-2 makes adipocytes release more exosomes containing inflammatory factors. So far it has shown that the number of vesicles released into the bloodstream does indeed increase. The researchers will now analyze the contents of these circulating vesicles, as well as those remaining inside cells. They also plan to investigate the inflammatory pathways presumably activated by these molecules.

“We first assumed that as a person gets fat, their adipose tissue becomes hypoxic, meaning the person has less oxygen available. Hypoxia is itself a cause of inflammation, so one of the things we want to investigate is whether COVID-19 causes hypoxia in adipocytes,” Seelaender said.

Research on how human cells adapt to hypoxia won Ratcliffe the Nobel with William G. Kaelin (Harvard University) and Gregg Semenza (Johns Hopkins School of Medicine).

Sir Radcliffe's group is now interested in exploring the possibility that the SARS-CoV-2 virus interacts with hypoxia signalling pathways, and the Brazilian and British groups are collaborating as to address this hypothesis.

The FM-USP group, meanwhile, is concentrating on an effort to understand the effect of infection on adipose tissue. “We’re analyzing everything secreted by fat cells: proteins, saturated fatty acids, prostaglandins [lipids with diverse hormone-like effects], microRNAs [small non-coding RNA molecules that regulate gene expression] and exosomes,” Seelaender said.

Inflammatory factors released by adipose tissue in COVID-19 patients may be the cause of damage to the heart, lungs, and nervous system described in such patients, she added. “Our hypothesis is that obese COVID-19 patients undergo a similar process to that observed in the adipose tissue of patients with cachexia [significant rapid weight loss and muscle wasting associated with AIDS, heart failure and cancer, among other diseases],” she said. “Adipocytes in cachexic individuals release more exosomes, and their contents are altered so that they have a pro-inflammatory profile. We know there’s inflammation in both cachexia and obesity. The difference lies in the type of inflammatory mediator released and the signaling pathways activated.”

Seelaender and her group have been researching the links between cachexia and inflammation since 2013 with FAPESP’s support.

Opposite but similar

In an article published in the journal Advances in Nutrition, Seelaender and her group discuss how nutritional status can influence a patient’s response to COVID-19. According to the authors, both obesity and malnutrition – including cachexia and sarcopenia (loss of skeletal muscle mass associated with aging) – can impair the immune response and prevent the organism from combating viral infection.

“Immune cells require more energy during an infectious process, especially if the body takes a long time to overcome it. Their metabolism needs to change so that they can multiply rapidly, but in an undernourished organism, this isn’t possible. During an infection the number of T-lymphocytes in a malnourished individual is much smaller than in a eutrophic [well-nourished] individual,” Seelaender said.

Moreover, she continued, undernourished organisms suffer from atrophy of the lymphoid organs (especially bone marrow, thymus and lymph nodes), in which the lymphocytes are produced and reach maturity. As a result, the number of circulating defense cells declines. Experiments with animals have also shown that an organism suffering from malnutrition takes longer to eliminate viruses.

“Fat can be a problem when it’s excessive or insufficient. However paradoxical it may seem, both extremes are dangerous,” she explained. “Adipose tissue secretes leptin, a hormone that regulates T-lymphocyte metabolism. Leptin signaling falls in a body with very low fat. Excessively high fat makes cells less sensitive to leptin, so the amount of leptin released rises sharply.”

Aging affects several of the factors mentioned by Seelaender. The immune system becomes less responsive. Skeletal muscle mass dwindles, visceral fat increases, and the proportion between lean and fat mass worsens.

“Loss of lean mass can worsen the outcome of chronic and acute diseases in older people. Muscle is a reservoir of energy substrate [amino acids] that can be mobilized at times of need, such as during an infection,” she said. “That’s why it’s important to stress that not just adiposity but also the lean-to-fat mass ratio is a problem in COVID-19 patients. If a person has a lot of fat and little muscle, it’s worse than if they have a lot of fat but a good muscular condition.”

If songbirds could appear on "The Masked Singer" reality TV competition, zebra finches would likely steal the show. That's because they can rapidly memorize the signature sounds of at least 50 different members of their flock, according to new research from the University of California, Berkeley.

In findings recently published in the journal Science Advances, these boisterous, red-beaked songbirds, known as zebra finches, have been shown to pick one another out of a crowd (or flock) based on a particular peer's distinct song or contact call.

Like humans who can instantly tell which friend or relative is calling by the timbre of the person's voice, zebra finches have a near-human capacity for language mapping. Moreover, they can remember each other's unique vocalizations for months and perhaps longer, the findings suggest.

"The amazing auditory memory of zebra finches shows that birds' brains are highly adapted for sophisticated social communication," said study lead author Frederic Theunissen, a UC Berkeley professor of psychology, integrative biology and neuroscience.

Theunissen and fellow researchers sought to gauge the scope and magnitude of zebra finches' ability to identify their feathered peers based purely on their unique sounds. As a result, they found that the birds, which mate for life, performed even better than anticipated.

"For animals, the ability to recognize the source and meaning of a cohort member's call requires complex mapping skills, and this is something zebra finches have clearly mastered," Theunissen said.

A pioneer in the study of bird and human auditory communication for at least two decades, Theunissen acquired a fascination and admiration for the communication skills of zebra finches through his collaboration with UC Berkeley postdoctoral fellow Julie Elie, a neuroethologist who has studied zebra finches in the forests of their native Australia. Their teamwork yielded groundbreaking findings about the communication skills of zebra finches.

Zebra finches usually travel around in colonies of 50 to 100 birds, flying apart and then coming back together. Their songs are typically mating calls, while their distance or contact calls are used to identify where they are, or to locate one another.

"They have what we call a 'fusion fission' society, where they split up and then come back together," Theunissen said. "They don't want to separate from the flock, and so, if one of them gets lost, they might call out 'Hey, Ted, we're right here.' Or, if one of them is sitting in a nest while the other is foraging, one might call out to ask if it's safe to return to the nest."

These days, Theunissen keeps a few dozen zebra finches in aviaries on and around campus, 20 of which were used in this latest experiment.

In a two-part experiment, 20 captive zebra finches were trained to distinguish between different birds and their vocalizations. At first, half the birds were tested on memorizing songs, while the other half were assessed on distance or contact calls. They then switched those tasks.

Next, the zebra finches were placed, one at a time, inside a chamber and listened to sounds as part of a reward system. The goal was to train them to respond to particular zebra finches by hearing several different renditions of those birds' distinct vocalizations and memorizing them.

By pecking a key inside the chamber, the bird subjects triggered an audio recording of a zebra finch vocalization. If they waited until the six-second recording ended, and it was part of the reward group, they received birdseed. If they pecked before the recording was finished, they moved to the next recording. Over several trials, they learned which vocalizations would yield birdseed, and which ones to skip.

Next, the zebra finches were introduced to more audio recordings from new zebra finches, to teach them to distinguish which vocalizations belonged to which bird. They soon learned to differentiate between 16 different zebra finches.

In fact, the zebra finches, both male and female, performed so well in the tests that four of them were given the more challenging task of distinguishing between 56 different zebra finches. On average, they succeeded in recognizing 42 different zebra finches, based on their signature sounds. Plus, they were still able to identify the birds based on their unique sounds a month later.

"I am really impressed by the spectacular memory abilities that zebra finches possess in order to interpret communication calls," Theunissen said. "Previous research shows that songbirds are capable of using simple syntax to generate complex meanings and that, in many bird species, a song is learned by imitation. It is now clear that the songbird brain is wired for vocal communication."