New Strategy Blocks Chronic Lung Disease in Mice (Medicine)

Research involving cytokines and how they’re packaged sheds light on inflammation in asthma, COPD, COVID-19

Inflammatory lung diseases such as asthma, COPD and, most recently, COVID-19, have proven difficult to treat. Current therapies reduce symptoms and do little to stop such diseases from continuing to damage the lungs. Much research into treating chronic inflammatory diseases has focused on blocking chemicals called cytokines, which trigger cascades of molecular events that fuel damaging inflammation.

Now, scientists at Washington University School of Medicine in St. Louis have found that such cytokines can drive inflammation in more ways than previously understood, perhaps revealing new routes to potential treatments for chronic inflammatory conditions.

A new study demonstrates that in addition to raining down directly into tissues and triggering damaging events, cytokines can come packaged in tiny compartments called exosomes, making the packaged cytokines extremely difficult to detect and nearly impossible to study without specialized instruments. Not being able to study these exosomes means scientists could be missing important strategies to treat or prevent inflammatory disease.

The study, in JCI Insight, also demonstrates that understanding how these inflammatory cytokines are packaged can reveal new ways to block them, preventing lung disease from developing, at least in mice.

“In trying to understand and better treat inflammatory disease in patients, scientists have focused heavily on blocking cytokines, which we know are key players in setting off inflammatory processes and keeping them smoldering,” said senior author Jennifer Alexander-Brett, MD, PhD, an assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine. “How a particular family of cytokines gets out of cells to trigger inflammation has been a mystery that has stymied the field for a long time. At the same time, people started to recognize that these structures called exosomes are doing something, though it was unclear what. They’re small, difficult to isolate and easily overlooked. But with new technology, we’re starting to understand that key cytokines can be packaged in exosomes in ways that completely change the way we would target them to develop anti-inflammatory therapies.”

Based on prior work from Alexander-Brett, Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, and other investigators at Washington University, it has long been known that a specific cytokine called IL-33 is a central player in the development of chronic lung diseases, such as COPD and asthma. Indeed, this cytokine also is implicated in arthritis, inflammatory bowel disease, hepatitis, heart failure, inflammation of the central nervous system and cancer. But how it triggers inflammation was unknown. The new research shows that IL-33 is released into the airway, packaged with an exosome. Complicating matters further, IL-33 doesn’t travel inside the exosome; it piggybacks on the outside.

With a new understanding of the packaging, the researchers tried a different method to block the inflammatory signaling of IL-33. They studied mice that develop lung disease due to inhaling a type of fungus; the disease, mimics, for example, the development of asthma due to an inhaled allergen. The researchers showed that they could block airway disease from developing in mice exposed to the fungus by treating them with a compound that blocks exosome secretion, rather than IL-33 directly.

“This study opens up many new questions about how cytokine signaling might be different when the cytokine is bound to an exosome,” Alexander-Brett said. “It’s possible exosome packaging is a key feature of cytokines that are not secreted in the classical way. This new understanding of cytokine signaling could lead to completely different ways of targeting it to treat diseases such as COPD. At the moment, we have no treatments that reverse or even slow COPD. We can only treat symptoms.”

Alexander-Brett said that until recently, this type of exosome activity would have been extremely difficult to detect. Her lab has a relatively new instrument called a single-particle interferometric reflectance imaging system (SP-IRIS) that lets her team study exosomes using very small amounts of biological samples.

For asthma and COPD, Alexander-Brett said her lab is seeking more precise ways to block specific exosomes, since a strategy that blocks all of them across the board, as in this mouse study, likely would stop some beneficial processes as well.

“We need more research to find an inhibitor that might block IL-33 from even being incorporated into the exosome, which would theoretically stop the initial trigger of chronic lung disease,” Alexander-Brett said. “Ideally, we would like to find something that we could deliver as an inhaled drug that would target the effects to the airway, where it’s needed.”

This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), grant numbers K08 HL121168, R01 HL152245 and T32 HL007317; an Early Career Investigator Award from the American Thoracic Society; a career award for medical scientists from the Burroughs Wellcome Fund; and the fund to retain clinical scientists from the Doris Duke Foundation. Additional support and services were provided by the Washington University Digestive Diseases Research Core, grant number NIDDK P30 DK052574; the Siteman Center Flow Cytometry Core; the Washington University Center for Cellular Imaging, grant number ORIP OD021629; the Washington University Genome Engineering and iPSC Center; and the Pulmonary Morphology Core.

Featured image: Shown is a transmission electron microscope image of exosomes purified from fluid from the lungs of a patient with COPD. A new study from Washington University School of Medicine in St. Louis has uncovered a previously unknown role for exosomes in inflammatory respiratory diseases. The study has implications for finding new therapies. Exosomes are tiny compartments released from cells that carry different types of cargo, including inflammatory chemicals called cytokines that can drive lung disease. © DEB STEINBERG/WU CENTER FOR CELLULAR IMAGING


Reference: Katz-Kiriakos E, et al. Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease. JCI Insight. Feb. 22, 2021. https://insight.jci.org/articles/view/136166


Provided by Washington University School of Medicine in St Louis

Monoclonal Antibodies Against MERS Coronavirus Show Promise in Phase 1 NIH-sponsored Trial (Medicine)

A randomized, placebo-controlled Phase 1 clinical trial of two monoclonal antibodies (mAbs) directed against the coronavirus that causes Middle East respiratory syndrome (MERS) found that they were well tolerated and generally safe when administered simultaneously to healthy adults. The experimental mAbs, REGN3048 and REGN3051, target the MERS coronavirus (MERS CoV) spike protein used by the virus to attach to and infect target cells. The mAbs were discovered and developed by scientists at the biopharmaceutical company Regeneron, located in Tarrytown, New York. The trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The trial was the first to test the experimental antibodies Hyperlink Code in people. Conducted at WCCT Global, a clinical trial site in California, the study enrolled 48 healthy adults, 36 of whom received the mAbs. All volunteers were followed for 121 days after receiving mAbs (or placebo) by intravenous infusion. No serious adverse events occurred.

In preclinical studies, investigators at Regeneron and the University of Maryland, College Park, also administered REGN3048 and REGN3051 sequentially and in combination to genetically modified mice that, unlike wild-type mice, can be infected with MERS CoV. When administered one day prior to coronavirus exposure, both REGN3048 and REGN3051 reduced the levels of virus later detected in the lungs, with co-administration providing more potent protective effects than either mAb alone. Similarly, co-administering the mAbs one day after MERS CoV exposure provided a therapeutic benefit in mice by lowering viral levels and lessening tissue damage in the lungs as compared to mice that received placebo.

Together, the findings from the clinical trial and the preclinical mouse studies “demonstrate the potential efficacy and utility of monoclonal antibody therapy for the prevention or treatment of MERS-CoV and lays the groundwork for the development of spike-targeted mAb therapies for other infectious disease threats, including SARS-CoV-2,” which causes COVID-19, the authors conclude.

Featured image: MERS-CoV particles on camel epithelial cells. © NIAID and Colorado State University


Reference: S Sivapalasingam et al. Human monoclonal antibody cocktail for the treatment or prophylaxis of Middle East respiratory syndrome coronavirus (MERS-CoV). The Journal of Infectious Diseases DOI: 10.1093/infdis/jiab036 (2021).


Provided by NIAID/NIH

Scientists Proposes a New Heavy Particle With Properties Similar to Those of the Higgs Boson (Physics)

Unlike the Higgs boson, discovered at CERN’s Large Hadron Collider in 2012 after a 40-year quest, the new particle proposed by these researchers is so heavy that it could not be produced directly even in this collider

The University of Granada is among the participants in this major scientific advancement in Theoretical Physics, which could help unravel the mysteries of dark matter

Scientists from the University of Granada (UGR) and the Johannes Gutenberg University Mainz (Germany) have recently published a study in which they endeavour to extend the Standard Model of particle physics (the equivalent of ‘the periodic table’ for particle physics) and answer some of the questions that this model is unable to answer. Such puzzles include: What is dark matter made of? Why do the various constituents of fermionic dark matter have such different masses? Or, why is the force of gravity much weaker than electromagnetic interaction?

This work, published in the European Physical Journal C, is based on the existence of a dimension in spacetime that is “so small that we can only detect evidence of it through its indirect effects,” explains one of the authors of the article, Adrián Carmona, Athenea3i Fellow at the UGR and a member of the Department of Theoretical Physics and the Cosmos.  

As early as the 1920s, in an attempt to unify the forces of gravity and electromagnetism, Theodor Kaluza and Oskar Klein speculated on the existence of an extra dimension beyond the familiar three space dimensions and time (which, in physics, are combined into a 4-dimensional spacetime).

Such models became popular in the 1990s, when theoretical physicists realized that theories with curved extra dimensions could explain some of the major mysteries in this field. However, despite their many strengths, such models generally lacked a viable dark-matter candidate.

The UGR researcher Adrián Carmona Bermúdez, from the Department of Theoretical Physics and the Cosmos of the UGR

Now, more than 20 years later, Adrián Carmona and collaborators from the University of Mainz, Professor Matthias Neubert and doctoral student Javier Castellano, have predicted the existence of a new heavy particle in these models with properties similar to those of the famous Higgs boson.

A new dimension

“This particle could play a fundamental role in the generation of masses of all the particles sensitive to this extra dimension, and at the same time be the only relevant window to a possible dark sector responsible for the existence of dark matter, which would simultaneously solve two of the biggest problems of these theories that, a priori, appear disconnected,” explains the UGR researcher.

However, unlike the Higgs boson, which was discovered at CERN’s Large Hadron Collider in 2012 after a 40-year quest, the new particle proposed by these researchers is so heavy that it could not be produced directly even in this, the highest-energy particle collider in the world.

In the article, the researchers explore other possible ways of discovering this particle by looking for clues about the physics surrounding a very early stage in the history of our universe, when dark matter was produced.

Featured image: Simulation of a collision in the Large Hadron Collider, producing the Higgs boson. © 1997–2021 CERN (License: CC-BY-SA-4.0)


Bibliography:

Carmona, A., Castellano Ruiz, J. & Neubert, M. (2021) ‘A warped scalar portal to fermionic dark matter’, Eur. Phys. J. C 81,58. https://doi.org/10.1140/epjc/s10052-021-08851-0

https://link.springer.com/article/10.1140%2Fepjc%2Fs10052-021-08851-0


Provided by Canal/UGR

Supernova 1987A: Reclusive Neutron Star May Have Been Found in Famous Supernova (Astronomy)

  • Astronomers now have evidence from two X-ray telescopes (Chandra and NuSTAR) for a key component of a famous supernova remnant.
  • Supernova 1987A was discovered on Earth on February 24, 1987, making it the first such event witnessed during the telescopic age.
  • For decades, scientists have searched for a neutron star in SN 1987A, i.e. a dense collapsed core that should have been left behind by the explosion.
  • This latest study shows that a “pulsar wind nebula” created by such a neutron star may be present.

Astronomers have found evidence for the existence of a neutron star at the center of Supernova 1987A (SN 1987A), which scientists have been seeking for over three decades. As reported in our latest press release, SN 1987A was discovered on February 24, 1987. The panel on the left contains a 3D computer simulation, based on Chandra data, of the supernova debris from SN 1987A crashing into a surrounding ring of material. The artist’s illustration (right panel) depicts a so-called pulsar wind nebula, a web of particles and energy blown away from a pulsar, which is a rotating, highly magnetized neutron star. Data collected from NASA’s Chandra X-ray Observatory and NuSTAR in a new study support the presence of a pulsar wind nebula at the center of the ring.

If this result is upheld by future observations, it would confirm the existence of a neutron star in SN 1987A, the collapsed core that astronomers expect would be present after the star exploded. The pulsar would also be the youngest one ever found.

NuSTAR and Chandra images of Supernova 1987A

When a star explodes, it collapses onto itself before the outer layers are blasted into space. The compression of the core turns it into an extraordinarily dense object, with the mass of the Sun squeezed into an object only about 10 miles across. Neutron stars, as they were dubbed because they are made nearly exclusively of densely packed neutrons, are laboratories of extreme physics that cannot be duplicated here on Earth. Some neutron stars have strong magnetic fields and rotate rapidly, producing a beam of light akin to a lighthouse. Astronomers call these objects “pulsars,” and they sometimes blow winds of charged particles that can create pulsar wind nebulas.

With Chandra and NuSTAR, the team found relatively low-energy X-rays from the supernova debris crashing into surrounding material. The team also found evidence of high-energy particles, using NuSTAR’s ability to detect higher-energy X-rays.

There are two likely explanations for this energetic X-ray emission: either a pulsar wind nebula, or particles being accelerated to high energies by blast wave of the explosion. The latter effect doesn’t require the presence of a pulsar and occurs over much larger distances from the center of the explosion.

The latest X-ray study supports the case for the pulsar wind nebula on a couple of fronts. First, the brightness of the higher energy X-rays remained about the same between 2012 and 2014, while the radio emission increased. This goes against expectations in the scenario of energetic particles in the explosion debris. Next, authors estimate it would take almost 400 years to accelerate the electrons up to the highest energies seen in the NuSTAR data, which is over ten times older than the age of the remnant.

The Chandra and NuSTAR data also support a 2020 result from the Atacama Large Millimeter Array (ALMA) that provided possible evidence for the structure of a pulsar wind nebula in the radio band. While this “blob” had other potential explanations, its identification as a pulsar wind nebula could be substantiated with the new X-ray data.

The center of SN 1987A is surrounded by gas and dust. The authors used state-of-the-art simulations to understand how this material would absorb X-rays at different energies, enabling more accurate interpretation of the X-ray spectrum, that is, the spread of X-rays over wavelength. This enables them to estimate what the spectrum of the central regions of SN 1987A is without the obscuring material.

A paper describing these results is being published this week in The Astrophysical Journal and a preprint is available online. The authors of the paper are Emanuele Greco and Marco Miceli (University of Palermo in Italy), Salvatore Orlando, Barbara Olmi and Fabrizio Bocchino (Palermo Astronomical Observatory, a National Institute for Astrophysics, or INAF, research facility); Shigehiro Nagataki and Masaomi Ono (Astrophysical Big Bang Laboratory, RIKEN in Japan); Akira Dohi (Kyushu University in Japan), and Giovanni Peres (University of Palermo).

NASA’s Marshall Space Flight Center manages the Chandra program. The Smithsonian Astrophysical Observatory’s Chandra X-ray Center controls science from Cambridge Massachusetts and flight operations from Burlington, Massachusetts.

NuSTAR is a Small Explorer mission led by Caltech and managed by NASA’s Jet Propulsion Laboratory for the agency’s Science Mission Directorate in Washington. NuSTAR was developed in partnership with the Danish Technical University and the Italian Space Agency (ASI). The spacecraft was built by Orbital Sciences Corporation in Dulles, Virginia (now part of Northrop Grumman). NuSTAR’s mission operations center is at UC Berkeley, and the official data archive is at NASA’s High Energy Astrophysics Science Archive Research Center. ASI provides the mission’s ground station and a mirror archive. JPL is a division of Caltech.

Featured image: Supernova 1987A © Chandra X-ray Observatory


Provided by Chandra X-ray Observatory

UIC Researchers Invent New Gene-editing Tool (Biology)

Specially engineered guide RNA molecules called “proGuides” may allow scientists to program sequential gene edits over time.

Researchers from the University of Illinois Chicago have discovered a new gene-editing technique that allows for the programming of sequential cuts — or edits — over time.

CRISPR is a gene-editing tool that allows scientists to change the DNA sequences in cells and sometimes add a desired sequence or genes. CRISPR uses an enzyme called Cas9 that acts like scissors to make a cut precisely at a desired location in the DNA. Once a cut is made, the ways in which cells repair the DNA break can be influenced to result in different changes or edits to the DNA sequence.

The discovery of the gene-editing capabilities of the CRISPR system was described in the early 2010s. In only a few years, scientists became enamored with the ease of guiding CRISPR to target almost any DNA sequence in a cell or to target many different sites in a cell in a single experiment.

“A drawback of currently available CRISPR-based editing systems is that all the edits or cuts are made all at once. There is no way to guide them so that they take place in a sequential fashion, one after the other,” said UIC’s Bradley Merrill, associate professor of biochemistry and molecular genetics at the College of Medicine and lead author of the paper.

Merrill and colleagues’ new process involves the use of special molecules called guide RNA that ferry the Cas9 enzyme within the cell and determine the precise DNA sequence at which Cas9 will cut. They call their specially engineered guide RNA molecules “proGuides,” and the molecules allow for the programmed sequential editing of DNA using Cas9.

Their findings are published in the journal Molecular Cell.

While proGuide is still in the prototype phase, Merrill and colleagues plan to further develop their concept and hope that researchers will be able to use the technique soon.

“The ability to preprogram the sequential activation of Cas9 at multiple sites introduces a new tool for biological research and genetic engineering,” Merrill said. “The time factor is a critical component of human development and also disease progression, but current methods to genetically investigate these processes don’t work effectively with the time element. Our system allows for gene editing in a pre-programmed fashion, enabling researchers to better investigate time-sensitive processes like how cancer develops from a few gene mutations and how the order in which those mutations occur may affect the disease.”

UIC’s Ryan Clarke, Alexander Terry, Hannah Pennington, Cody Hasty, Matthew MacDougall and Maureen Regan are co-authors on the paper.

This research was supported by grants from the National Institutes of Health (R21OD027080, F30CA225058 and F30HD090938) and by the UIC Center for Clinical and Translational Sciences.

Featured image: Illustration of DNA double helix © UIC


Reference: Ryan Clarke, Alexander R. Terry et al., “Sequential Activation of Guide RNAs to Enable Successive CRISPR-Cas9 Activities”, Molecular Cell, 81(2), pp. 226-238, 2020. DOI: https://doi.org/10.1016/j.molcel.2020.12.003


Provided by UIC Today

Fat Cells May Influence How The Body Reacts to Heart Failure (Physiology)

Promising results in mice open door to new areas of research in treating patients with heart failure.

University of Alberta researchers have found that limiting the amount of fat the body releases into the bloodstream from fat cells during heart failure could help improve outcomes for patients.

In a recent study published in the American Journal of PhysiologyJason Dyck, professor of pediatrics in the Faculty of Medicine & Dentistry and director of the U of A’s Cardiovascular Research Centre, found that mice with heart failure that were treated with a drug blocking the release of fat into the bloodstream from fat cells saw less inflammation in the heart and throughout the body, and had better outcomes than a control group.

“Many people believe that, by definition, heart failure is only a condition of the heart. But it’s much broader and multiple organs are affected by it,” said Dyck, who holds the Canada Research Chair in Molecular Medicine and is a member of the Alberta Diabetes Institute and the Women and Children’s Health Research Institute. “What we’ve shown in mice is that if you can target fat cells with a drug and limit their ability to release stored fat during heart failure, you can protect the heart and improve cardiac function.

“I think it really opens the door for other avenues of investigation and therapies for treating heart failure,” Dyck noted.

“Cascade” of heart damage from stress

During times of stress, such as heart failure, the body releases stress hormones, such as epinephrine and norepinephrine, to help the heart compensate. But because the heart can’t function any better—and is in fact damaged further by being forced to pump faster—the body releases more stress hormones and the process cascades, with heart function continuing to decline. This is why a common treatment for heart failure is beta-blocker drugs, which are designed to block the effects of stress hormones on the heart.

The release of stress hormones also triggers the release of fat from its storage deposits in fat cells into the bloodstream to provide extra energy to the body, a process called lipolysis. Dyck’s team found that during heart failure, the fat cells in mice were also becoming inflamed throughout the body, mobilizing and releasing fat faster than normal and causing inflammation in the heart and rest of the body. This inflammation put additional stress on the heart, adding to the cascade effect, increasing damage and reducing heart function.

“Our research began by looking at how the function of one organ can affect other organs, so I thought it was very fascinating to find that a fat cell can influence cardiac function in heart failure,” Dyck said. “Fortunately, we had a drug that could inhibit fat mobilization from fat cells in mice, which actually protected the hearts from damage caused by inflammation.”

Next steps

Dyck points out that although his results are promising, more work is needed to better understand the exact mechanisms at play in the process and develop a drug that could work in humans.

“This work is a proof-of-concept showing that abnormal fat-cell function contributes to worsening heart failure, and now we’re working on understanding the mechanisms of how the drug works to limit lipolysis better,” he said. “Once we get that, that’s the launchpad for making sure it’s safe and efficacious, then advancing it to our chemists, and then maybe some early trials in humans.”

Dyck said the findings—and a better understanding of how organ functions affect other organs—could be used to develop new approaches to several other diseases.

“We know that people have high rates of lipolysis when they have heart failure, so I presume this approach would benefit all types of heart failure,” he said. “But if you consider that inflammation is associated with a wide variety of different diseases, like cancer, diabetes or other forms of heart disease, then this approach could have a much wider benefit.”

Dyck’s research was funded by the Heart and Stroke Foundation and the Canadian Institutes of Health Research.

Featured image: Pediatric cardiology researcher Jason Dyck and his team found that limiting the release of fat into the body from fat cells during heart failure led to better outcomes in mice—and could have the potential to eventually do the same in human patients. (Photo: Faculty of Medicine & Dentistry)


Reference: Shingo Takahara, Mourad Ferdaoussi, Nikola Srnic, Zaid H. Maayah, Shubham Soni, Anna K. Migglautsch, Rolf Breinbauer, Erin E. Kershaw, and Jason R. B. Dyck, “Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation”, American Journal of Physiology-Heart and Circulatory Physiology 2021 320:1, H432-H446. https://doi.org/10.1152/ajpheart.00737.2020


Provided by University of Alberta

“Good Bacteria” in Breast Milk Changes Over Time (Biology)

Scientists discover complex and dynamic bacterial ecosystem in human breast milk using genomic technology pioneered for the International Space Station

The cocktail of beneficial bacteria passed from mother to infant through breast milk changes significantly over time and could act like a daily booster shot for infant immunity and metabolism. The research, conducted by scientists from Montreal and Guatemala and published in Frontiers in Microbiology, has important implications for infant development and health.

Researchers discovered a range of microbiome species never before identified in human milk. Until now, relatively little was known about the role microbiome bacteria play in breast milk. These bacteria are thought to protect the infant gastrointestinal tract and improve aspects of long-term health, such as allergy prevention.

“Some bacterial species we observed in our sample breast milk had a common function in destroying foreign substances or xenobiotics and could play a role in protection against toxins and pollutants,” says co-author Emmanuel Gonzalez, a bioinformatics specialist at McGill University. The discovery sheds light on how mothers help lay the foundation for infant immunity.

Differences between early and late lactation

To learn more about the human milk microbiome, the scientists analyzed breast milk samples using high-resolution imaging technology, originally pioneered by McGill University and the University of Montreal to detect bacteria on the International Space Station.

They analyzed breast milk samples of Mam-Mayan mothers living in eight remote rural communities in the Western Highlands of Guatemala. This gave them a unique window to observe the human milk microbiome over time, specifically between early and late lactation (6-46 days versus 109-184 days).

Unlike most mothers in North America, nearly all Mam-Mayan mothers breastfeed for the World Health Organization’s recommended period of six months. In North America, only 26% of mothers do so. “This longer feeding time allowed us to observe important changes in the bacteria provided to infants over time, which could impact long-term health,” says Gonzalez.

The genomic technology used by the scientists revealed a range of microbiome species shared among Mam-Mayan mothers, providing a glimpse of a diverse community of bacteria being passed on to infants.

“Studying microbiomes of diverse communities is important in order to understand the variation present in humans,” says co-author Kristine Koski, an Associate Professor in the School of Human Nutrition at McGill. “Most human milk microbiome studies have been conducted with mothers from high income countries, generating an incomplete picture of the important bacteria passed to infants during early development.”

Working alongside underrepresented communities will be essential in getting an accurate picture of the human milk microbiome and the factors that shape it, according to the scientists. They hope that these discoveries will help encourage more inclusive and more robust research.


About this study

“Distinct Changes Occur in the Human Breast Milk Microbiome Between Early and Established Lactation in Breastfeeding Guatemalan Mothers” by Gonzalez Emmanuel, Brereton Nicholas J. B., Li Chen, Lopez Leyva Lilian, Solomons Noel W., Agellon Luis B., Scott Marilyn E., and Koski Kristine G. was published in Frontiers in Microbiology.

DOI: https://doi.org/10.3389/fmicb.2021.557180


Provided by McGill University


About McGill University

Founded in Montreal, Quebec, in 1821, McGill University is Canada’s top ranked medical doctoral university. McGill is consistently ranked as one of the top universities, both nationally and internationally. It is a world-renowned institution of higher learning with research activities spanning two campuses, 11 faculties, 13 professional schools, 300 programs of study and over 40,000 students, including more than 10,200 graduate students. McGill attracts students from over 150 countries around the world, its 12,800 international students making up 31% of the student body. Over half of McGill students claim a first language other than English, including approximately 19% of our students who say French is their mother tongue.

A Memory Without a Brain (Neuroscience)

How a single cell slime mold makes smart decisions without a central nervous system

Having a memory of past events enables us to take smarter decisions about the future. Researchers at the Max-Planck Institute for Dynamics and Self-Organization (MPI-DS) and the Technical University of Munich (TUM) have now identified how the slime mold Physarum polycephalum saves memories – although it has no nervous system.

The ability to store and recover information gives an organism a clear advantage when searching for food or avoiding harmful environments. Traditionally it has been attributed to organisms that have a nervous system.

A new study authored by Mirna Kramar (MPI-DS) and Prof. Karen Alim (TUM and MPI-DS) challenges this view by uncovering the surprising abilities of a highly dynamic, single-celled organism to store and retrieve information about its environment.

Window to the past

The slime mold Physarum polycephalum has been puzzling researchers for many decades. Existing at the crossroads between the kingdoms of animals, plants and fungi, this unique organism provides insight into the early evolutionary history of eukaryotes – to which also humans belong.

Its body is a giant single cell made up of interconnected tubes that form intricate networks. This single amoeba-like cell may stretch several centimeters or even meters, featuring as the largest cell on earth in the Guinness Book of World Records.

The network architecture as a memory

“It is very exciting when a project develops from a simple experimental observation”, says Karen Alim, head of the Biological Physics and Morphogenesis group at the MPI-DS in Göttingen and professor for the Theory of Biological Networks at the Technical University of Munich.

When the researchers followed the migration and feeding process of the organism and observed a distinct imprint of a food source on the pattern of thicker and thinner tubes of the network long after feeding.

“Given P. polycephalum’s highly dynamic network reorganization, the persistence of this imprint sparked the idea that the network architecture itself could serve as memory of the past“, says Karen Alim. However, they first needed to explain the mechanism behind the imprint formation.

Decisions are guided by memories

For this purpose the researchers combined microscopic observations of the adaption of the tubular network with theoretical modeling. An encounter with food triggers the release of a chemical that travels from the location where food was found throughout the organism and softens the tubes in the network, making the whole organism reorient its migration towards the food.

“The gradual softening is where the existing imprints of previous food sources come into play and where information is stored and retrieved”, says first author Mirna Kramar. “Past feeding events are embedded in the hierarchy of tube diameters, specifically in the arrangement of thick and thin tubes in the network.”

“For the softening chemical that is now transported, the thick tubes in the network act as highways in traffic networks, enabling quick transport across the whole organism”, adds Mirna Kramar. “Previous encounters imprinted in the network architecture thus weigh into the decision about the future direction of migration.”

Design based on universal principles

„Given the simplicity of this living network, the ability of Physarum to form memories is intriguing. It is remarkable that the organism relies on such a simple mechanism and yet controls it in such a fine-tuned manner,” says Karen Alim.

“These results present an important piece of the puzzle in understanding the behavior of this ancient organism and at the same time points to universal principles underlying behavior. We envision potential applications of our findings in designing smart materials and building soft robots that navigate through complex environments”, concludes Karen Alim.

Featured image: Prof. Dr. Karen Alim in her laboratory. Image: Bilderfest / TUM


Publications:

Encoding memory in tube diameter hierarchy of living flow network
Mirna Kramar and Karen Alim
PNAS, 22.02.2021 – DOI: 10.1073/pnas.2007815118


Provided by TUM

Kittens Could Hold Key to Understanding Deadly Diarrheal Disease in Children (Biology)

Kittens could be the model for understanding infectious, sometimes deadly, diarrheal disease in both animals and children, according to new research from North Carolina State University.

Diarrheagenic Escherichia coli (DEC) bacteria cause lethal diarrheal disease in children worldwide, killing up to 120,000 children under the age of five annually. Atypical enteropathic Escherichia coli (aEPEC) are a form of DEC increasingly associated with diarrheal disease in humans and in kittens.

“We were looking for causes of infectious diarrhea in kittens, which has a high mortality rate, and came across this pathogen,” says Jody Gookin, FluoroScience Distinguished Professor in Veterinary Scholars Research Education at NC State and corresponding author of the research.

“The interesting thing about aEPEC is that you can find it in both healthy and sick individuals. Having it in your intestinal tract doesn’t mean you’re sick, but those that are sick have a higher burden, or amount of the bacteria, in their bodies.”

Gookin and Victoria Watson, a former Ph.D. student at NC State and lead author of the study, performed a genomic analysis of aEPEC isolates from both healthy kittens who were colonized by the bacteria and kittens with lethal infections to try and determine why aEPEC causes illness in some kittens but remains dormant in others.

With collaborators at the University of Maryland, Gookin and Watson then compared the genomic data from both groups of kittens to human aEPEC isolates. However, there were no specific genetic markers that allowed the researchers to distinguish between the groups of isolates.

“The aEPEC isolated from humans is the same as that found in healthy and sick kittens,” Gookin says. “There weren’t any unique genetic markers that could explain why one group of bacteria causes disease while the other one doesn’t. The only thing we found were behavioral differences between the isolate groups.

“The pathogenic, or disease-causing, isolates had more motility – they were better swimmers. AEPEC bacteria cause disease by attaching to epithelial cells lining the intestine. Those cells then secrete fluids, causing diarrhea. So the better or further aEPEC bacteria could swim, the easier it would be to find cells and attach.”

The findings point to kittens as a potentially invaluable model for further exploration of aEPEC on the molecular level to inform treatment approaches for both humans and felines.

“This is the first report of the genetics being the same in groups of aEPEC isolates from humans and kittens, both healthy and sick,” Gookin says. “It is also further evidence that our companion animals can give us important insights into diseases that affect us both.”

The work appears in Infection and Immunity and was supported by the Winn Feline Foundation (grant W14-035) and the National Institutes of Health (grants U19AI110820 and T32OD011130). Watson is a veterinary pathologist currently at Michigan State University. Tracy Hazen and David Rasko from the University of Maryland School of Medicine also contributed to the work.

Featured image: Photo by The Lucky Neko on Unsplash


Reference:

“Comparative Genomics of Atypical Enteropathogenic Escherichia coli from Kittens and Children Identifies Bacterial Factors Associated with Virulence in Kittens”

DOI: 10.1128/IAI.00619-20

Authors: Victoria E. Watson, Megan E. Jacob, Johanna R. Elfenbein, Stephen H. Stauffer, Jody L. Gookin, North Carolina State University; Tracy H. Hazen, David A. Rasko, University of Maryland
Published: Feb. 16, 2021 in Infection and Immunity


Provided by NC State University