This Protein Is Highly Potent In Blocking SARS-CoV-2 (Biology)

Recep Ahan and colleagues evaluated the activity of griffithsin lectin protein (GRFT) from Griffithsia sp. against the novel human coronavirus, SARS-CoV-2. They demonstrated that this protein can not only block the entry of the Sars-CoV-2 but also inhibit its infection by attaching to spike protein of the Sars-CoV-2, both in vitro VeroE6 cell line and in vivo mouse model. Their study recently appeared in BioRxiv.

Lectin proteins isolated from seaweeds are shown to be potent antiviral agents against enveloped viruses e.g., HIV-1, herpes virus as well as two deadly human coronaviruses, SARS-CoV and MERS-CoV. Antiviral activity of seaweed lectins arises from their affinity to surface glycoproteins on viruses such as gp-120 protein of HIV-1 and spike proteins of SARS-CoV and MERS-CoV. Upon binding to surface proteins, lectins generally block the viral internalization step and thereby prevent the viral infection.

Now, Recep Ahan and colleagues evaluated the activity of griffithsin lectin protein (GRFT) from Griffithsia sp. against the novel human coronavirus, SARS-CoV-2.

Schematic representation of rGRFT inhibiting SARS-CoV-2 infection in Vero E6 cells. Created with BioRender.com © authors

For this purpose, they recombinantly expressed GRFT in E. coli with histidine tag and purified. Later, they validated and characterized binding of recombinant GRFT to whole inactivated SARS-CoV-2 as well as purified spike protein from HEK293 with the help of ELISA, ITC and QCM. Finally, they assessed the activity of GRFT in vitro with Vero6 cells, and in vivo with Syrian hamsters.

They demonstrated that griffithsin protein from Griffithsia sp. recombinantly produced in E. coli can bind spike (S) protein of SARS-CoV-2 in vitro and inhibit its infection both in vitro VeroE6 cell line and in vivo mouse model when applied prophylactically. In addition, toxicity assays of rGRFT with mouse models indicated that, it is a tolerable agent even at concentrations higher than its therapeutic concentration window.

“Our results indicate that GRFT is a potent non-mutagenic antiviral agent against SARS-CoV-2, reducing virus transmission through blocking its entry into the cells.”

— they said.

Finally, upon very promising results from in vitro and in vivo assays and experiments, they formulated GRFT as a nasal spray for upcoming human phase trials.

“We believe that GRFT protein-based drugs will have a high impact in preventing the transmission both on Wuhan strain as well as any other emerging variants including delta variant causing high speed spread of COVID-19.”

— they concluded.

Reference: Recep Erdem Ahan, Alireza Hanifehnezhad, Ebru Şahin Kehribar, Tuba Cigdem Oguzoglu, Katalin Földes, Cemile Elif Özçelik, Nazlican Filazi, Sıdıka Öztop, Sevgen Önder, Eray Ulaş Bozkurt, Koray Ergünay, Aykut Özkul, Urartu Özgür Şafak Şeker, “A Highly Potent SARS-CoV-2 Blocking Lectin Protein”, bioRxiv 2021.07.22.453309; doi: https://doi.org/10.1101/2021.07.22.453309


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Exploring Quantum Systems That Don’t Find Equilibrium (Quantum)

Some physical systems, especially in the quantum world, do not reach a stable equilibrium even after a long time. An ETH researcher has now found an elegant explanation for this phenomenon.

If you put a bottle of beer in a big bathtub full of ice-cold water, it won’t be long before you can enjoy a cold beer. Physicists discovered how this works more than a hundred years ago. Heat exchange takes place through the glass bottle until equilibrium is reached.

However, there are other systems, especially quantum systems, that don’t find equilibrium. They resemble a hypothetical beer bottle in a bath of ice-​cold water that doesn’t always and inevitably cool to the temperature of the bath water, but rather reaches different states depending on its own initial temperature. Until now, such systems have puzzled physicists. But Nicolò Defenu, a postdoc at the ETH Zurich Institute for Theoretical Physics, has now found a way to elegantly explain this behaviour.

A more distant influence

Specifically, we are talking about systems in which the individual building blocks influence not only their immediate neighbours, but also objects further away. One example would be a galaxy: the gravitational force of their individual stars and planetary systems acts not only on the neighbouring celestial bodies, but far beyond that – albeit ever more weakly – on the other components of the galaxy.

Defenu’s approach begins by simplifying the problem to a world with a single dimension. In it, there is a single quantum particle that can reside only in very specific locations along a line. This world resembles a board game like Ludo, where a little token hops from square to square. Suppose there is a game die whose sides are all marked “one” or “minus one”, and suppose the player whose token it is now rolls the die over and over again in succession. The token will hop to a neighbouring square, and from there it will either hop back or else on to the next square. And so on.

The question is, What happens if the player rolls the die an infinite number of times? If there are only a few squares in the game, the token will return to its starting point every now and then. However, it is impossible to predict exactly where it will be at any given time because the throws of the die are unknown.

Back to square one

It’s a similar situation with particles that are subject to the laws of quantum mechanics: there’s no way to know exactly where they are at any given time. However, it is possible to establish their whereabouts using probability distributions. Each distribution results from a different superposition of the probabilities for the individual locations and corresponds to a particular energy state of the particle. It turns out that the number of stable energy states coincides with the number of degrees of freedom of the system and thus corresponds exactly to the number of allowed locations. The important point is that all the stable probability distributions are non-​zero at the starting point. So at some point, the token returns to its starting square.

The more squares there are, the less often the token will return to its starting point; eventually, with an infinite number of possible squares, it will never return. For the quantum particle, this means there are an infinite number of ways in which the probabilities of the individual locations can be combined to form distributions. Thus, it can no longer occupy only certain discrete energy states, but all possible ones in a continuous spectrum.

None of this is new knowledge. There are, however, variants of the game or physical systems where the die can also contain numbers larger than one and smaller than minus one, i.e. the steps allowed per move can be larger – to be precise, even infinitely large. This fundamentally changes the situation, as Defenu has now been able to show: in these systems, the energy spectrum always remains discrete, even when there are infinite squares. This means that from time to time, the particle will return to its starting point.

Peculiar phenomena

This new theory explains what scientists have already observed many times in experiments: systems in which long-​range interactions occur do not reach a stable equilibrium, but rather a meta-​stable state in which they always return to their initial position. In the case of galaxies, this is one reason they develop spiral arms rather than being uniform clouds. The density of stars is higher inside these arms than outside.

An example of quantum systems that can be described with Defenu’s theory are ions, which are charged atoms trapped in electric fields. Using such ion traps to build quantum computers is currently one of the largest research projects worldwide. However, for these computers to really deliver a step change in terms of computational power, they will need a very large number of simultaneously trapped ions – and that is exactly the point at which the new theory becomes interesting. “In systems with a hundred or more ions, you would see peculiar effects that we can now explain,” says Defenu, who is a member of ETH Professor Gian Michele Graf’s group. His colleagues in experimental physics are getting closer every day to the goal of being able to realise such formations. And once they’ve got there, it might be worth their while to have a cold beer with Defenu.

Featured image: Not only quantum systems, but also large objects such as the spiral galaxy NGC 1300 can adopt a meta-stable state that leads to surprising effects. (Picture: Hubble Heritage Team, ESA, NASA)


Reference

Defenu N: Metastability and discrete spectrum of long-range systems. Proceedings of the National Academy of Sciences, July 26 2021: doi: 10.1073/pnas.2101785118


Provided by ETH Zurich

How Cells Remember Inflammation? (Biology)

When a tissue experiences inflammation, its cells remember. Pinning proteins to its genetic material at the height of inflammation, the cells bookmark where they left off in their last tussle. Next exposure, inflammatory memory kicks in. The cells draw from prior experience to respond more efficiently, even to threats that they have not encountered before. Skin heals a wound faster if it was previously exposed to an irritant, such as a toxin or pathogen; immune cells can attack new viruses after a vaccine has taught them to recognize just one virus. 

Now, a new study in Cell Stem Cell describes the mechanism behind inflammatory memory, also commonly referred to as trained immunity, and suggests that the phenomenon may be universal across diverse cell types.  

“This is happening in natural killer cells, T cells, dendritic cells from human skin, and epidermal stem cells in mice,” says Samantha B. Larsen, a former graduate student in the laboratory of Elaine Fuchs at The Rockefeller University. “The similarities in mechanism are striking, and may explain the remitting and relapsing nature of chronic inflammatory disorders in humans.” 

Uncelebrated immunity 

When thinking about our immune system, we default to specific immunity—that cadre of T cells and B cells trained, by experience or vaccination, to remember the specific contours of the last pathogen that broke into our bodies. But there’s a less specific strategy available to many cells, known as trained immunity. The impact is shorter-lived, but broader in scope. Trained immunity allows cells to respond to entirely new threats by drawing on general memories of inflammation. 

Scientists have long suspected that even cells that are not traditionally involved in the immune response have the rudimentary ability to remember prior insults and learn from experience. The Fuchs lab drove this point home in a 2017 study published in Nature by demonstrating that mouse skin that had recovered from irritation healed 2.5 times faster than normal skin when exposed to irritation at a later date.  

One explanation, the Fuchs team proposed, could be epigenetic changes to the skin cell genome itself. During inflammation, regions of DNA that are usually tightly coiled around histone proteins unravel to transcribe a genetic response to the attack. Even after the dust settles, a handful of these memory domains remain open—and changed. Some of their associated histones have been modified since the assault, and proteins known as transcription factors have latched onto the exposed DNA. A once naïve cell is now raring for its next fight.  

But the molecular mechanism that explained this process, and how the cell could use it to respond to types of inflammation and injury that it had never seen before, remained a mystery. 

Inside a memory domain 

So the Fuchs lab once again exposed mice skin to irritants, and watched as stem cells in the skin changed. “We focused on the regions in the genome that become accessible during inflammation, and remain accessible afterwards,” says Christopher Cowley, a graduate student in the Fuchs lab. “We call these regions memory domains, and our goal was to explore the factors that open them up, keep them open and reactivate them a second time.”  

They observed about 50,000 regions within the DNA of the stem cells that had unraveled to respond to the threat, but a few months later only about 1,000 remained open and accessible, distinguishing themselves as memory domains. Interestingly, many of these memory domains were the same regions that had unraveled most prodigiously in the early days of skin inflammation. 

The scientists dug deeper and discovered a two-step mechanism at the heart of trained immunity. The process revolves around transcription factors, proteins which govern the expression of genes, and hinges on the twin transcription factors known as JUN and FOS. 

The stimulus-specific STAT3 transcription factor responds first, deployed to coordinate a genetic response to a particular genre of inflammation. This protein hands the baton to JUN-FOS, which perches on the unspooled genetic material to join the melee. The specific transcription factor that sounded the original alarm will eventually return home; FOS will float away as the tumult quiets down. But JUN stands sentinel, guarding the open memory domain with a ragtag band of other transcription factors, waiting for its next battle. 

When irritation strikes again, JUN is ready. It rapidly recruits FOS back to the memory domain, and the duo charges into the fray. This time, no specific transcription factor is necessary to respond to a particular type of inflammation and get the ball rolling. The system unilaterally activates in response to virtually any stress—alacrity that may not always benefit the rest of the body. 

Better off forgotten 

Trained immunity may sound like a boon to human health. Veteran immune cells seem to produce broader immune responses; experienced skin cells should heal faster when wounded.  

But the same mechanism that keeps cells on high alert may instill a sort of molecular paranoia in chronic inflammation disorders. When the Fuchs lab examined data collected from patients who suffer from systemic sclerosis, for instance, they found evidence that JUN may be sitting right on the memory domains of affected cells, itching to incite an argument in response to even the slightest disagreement. 

“These arguments need not always be disagreeable, as animals benefit by healing their wounds quickly and plants exposed to one pathogen are often protected against others,” says Fuchs. “That said, chronic inflammatory disorders may owe their painful existence to the ability of their cells to remember, and to FOS and JUN, which respond universally to stress.”  

The scientists hope that shedding light on one possible cause of chronic inflammatory disease may help researchers develop treatments for these conditions. “The factors and pathways that we identify here could be targeted, both in the initial disease stages and, later, during the relapsing stages of disease,” says Cowley. Larsen adds: “Perhaps these transcription factors could be used as a general target to inhibit the recall of the memories that cause chronic inflammation.” 

Featured image: Inflamed mouse stem cells located in the basal layer (red) of the epidermis and FOS (green), a near-universal stress response factor essential to inflammatory memory. Credit: Christopher Cowley.


Provided by Rockefeller University

Three Dwarf Spheroidal Galaxies Are Found To Rotate (Cosmology)

An international team of astrophysicists from the Instituto de Astrofísica de Canarias (IAC), the University of La Laguna (ULL) and the Space Telescope Science Institute (STScI, USA) has discovered the presence of transverse rotation (in the plane of the sky) in three dwarf spheroidal galaxies, a very faint type of galaxies and difficult to observe, which are orbiting round the Milky Way; this helps to trace their evolutionary history. The finding was made using the most recent data from the GAIA satellite of the European Space Agency. The results of the study have just been published in the journal Monthly Notices of the Royal Astronomical Society (MNRAS).

Dwarf galaxies have a particular interest for cosmology. The standard cosmological model suggests that this type of galaxies was the first to form. Many of them, the majority, have been destroyed and cannibalized by large galaxies such as the Milky Way. However, those that remain can be studied and contain valuable information about the early Universe.

One subclass of dwarf galaxies are the dwarf spheroidals. They are very diffuse, with low luminosity, they contain large proportions of dark matter and little or no gas. Since their discovery they have been deeply studied. However, their internal kinematics are still little known, due to the technical difficulties needed for their detailed study.

Various previous studies have shown that the dwarf spheroidals do not have patterns of internal rotation, but their stars move on random orbits predominantly towards and away from the centre of the galaxy. But the galaxies within the other major sub-class of dwarfs, the irregulars, have large quantites of gas, and in some cases do have internal rotation. These differences suggest a different origin for the two types of dwarfs, or to a very different evolutionary history in which interactions with large galaxies, in our case with the Milky Way, have played a crucial role in eliminating the internal rotation of the spheroidals.

To carry out their present research, the team of astrophysicists form the IAC and the STScI have used the latest data from ESA’s Gaia to study the internal kinematics of six dwarf spheroidal galaxies, satellites of the Milky Way, and have discovered the presence of transverse rotation (in the plane of the sky) in three of them: Carina, Fornax, and Sculptor.  These are the first detections of this type of rotation in dwarf spheroidal galaxies, except for the Sagittarius spheroidal, which is strongly distorted by the gravitational potential of the Milky Way, and is therefore not representative of its type.

“The importance of this result is because, in general, the internal kinematics of galaxies, in this case their rotation, is an important tracer of their evolutionary history, and of the conditions in which the system was formed”, explains Alberto Manuel Martínez-García, doctoral student at the IAC and the ULL, and first author of the article.

“Although the standard model of cosmology assumes that the dwarf galaxies were the first to form, it is not clear if they are simple systems or whether those we observe are formed by the agglomeration of other even simpler systems, smaller and older. The presence of rotation suggests the second option. It also suggests a common origin for all dwarf galaxies, those that are  at present rich in gas (the irregulars) and those which are not (the spheroidals)”, explains Andrés del Pino, researcher at the STScI and a co-author of the article.

“The Gaia satellite has revolutionised our knowledge of the Milky Way and its neighbourhood, giving us very precise measurements of the positions and motions of almost two thousand million stars.  Although the data from Gaia are used mainly to study our Galaxy, this ESA mission has also opened a new window on the study of the satellite galaxies of the Milky Way, giving specific access to their internal kinematics”, says Antonio Aparicio, a researcher at the IAC and the ULL and a co-author of the article.

Even so, according to the researchers, studies based on Gaia data entail many technical difficulties. In the first place, one must determine which of the stars in the database really belong to the satellite galaxies, and which to the Milky Way itself, as the latter tend to contaminate the sample. The problem is that although the data to be analysed are limited to the region and the angular size of the spheroidal under study, which is the equivalent of one quarter of the angular diameter of the Moon, the vast majority of the stars detected in this area belong to the Milky Way and therefore indeed contaminate the sample.

In addition, the distance of the spheroidals studied, which is up to some half a million light-years, and the low intrinsic luminosity of their stars, imply that the measurements are affected by a considerable level of noise. For all these reasons the analysis of the data requires a thorough filtration and a deep analysis of the different observational parameters to be able to reach reliable conclusions.

Members of the research team involved in this study, which forms a part of the doctoral thesis of Alberto Manuel Martínez-García, include Andrés del Pino Molina (STScI, director of the thesis), Antonio Aparicio Juan (IAC-ULL, director of the thesis), Roeland P. van der Marel (STScI, Center for Astrophysical Sciences, at the Johns Hopkins University) and Laura L. Watkins (ESA mission to AURA, STScI).

Featured image: Fornax dwarf spheroidal galaxy. Credit: ESO/Digitized Sky Survey 2.


Article: Alberto Manuel Martínez-García, Andrés del Pino, Antonio Aparicio, Roeland P. van der Marel, Laura L. Watkins. “Internal rotation of Milky Way dwarf spheroidal satellites with Gaia Early Data Release 3”. Monthly Notices of the Royal Astronomical Society, July 8, 2021. DOI: https://doi.org/10.1093/mnras/stab1568


Provided by IAC

Bioprinted 3D Cardiac Patches Could Reverse Scar Formation, Promote Myocardial Regeneration After Heart Attacks (Medicine)

Cardiovascular diseases account for 32% of global deaths. Myocardial infarction, or heart attacks, play a large part in heart diseases and the necrosis of cardiac tissue after blood supply is decreased or stopped.

In APL Bioengineering, researchers from Pohang University of Science and Technology in South Korea take stock of stem cell-laden 3D-bioprinted cardiac patch technologies and their efficacy as a therapeutic and regenerative approach for ischemic cardiomyopathy in reversing scar formation and promoting myocardial regeneration.

“Currently available therapeutics are not sufficient for the complete treatment of myocardial infarction,” said author Jinah Jang. “The development of a new, advanced modality, such as reducing adverse cardiac remodeling, promoting myocardial functions, and correcting molecular or genetic defects, is urgently required.”

The researchers explore various types of candidate stem cells that possess cardiac regenerative potential, explaining their applications and limitations. They share updates on the challenging implementation of the state-of-the-art 3D-bioprinting approach to fabricate a cardiac patch and highlight different strategies to implement vascularization and augment cardiac functional properties with respect to electrophysiological similarities to native tissue.

Following a myocardial infarction, myocardial tissues and vasculatures are equally and severely damaged. Therefore, therapeutic or regenerative approaches should be planned to target both of them concurrently to achieve a successful cardiac repair, because the heart has very little ability to regenerate cardiomyocytes or heart cells by itself.

Employing a 3D-bioprinting strategy to geometrically control the spatial patterning and using dual stem cell therapy as its co-culture can play an important role in promoting and synergistically improving vascularization as well as cardiac function following myocardial infarction.

Currently applied patch-based stem cell therapies have shown advanced efficacy, rather than using single-component therapies, by providing a tissue-friendly environment during the time of host-graft integration.

“It would be helpful for tracing cells of the printed patch to investigate the mode of action for the transplanted patch,” said author Sanskrita Das.

“Although there are still inherent limitations for the clinical study, the suggested stem cell delivery platform technology provides a practical therapeutic perspective for various tissue engineering applications,” said author Hyoryung Nam.

As enthusiasm for cardiac regeneration charges and science continues to advance, 3D-bioprinted cardiac patches will soon become an increasingly feasible, viable, and functional option, unblocking the barriers to achieve cardiomyocytes properties. This will open new avenues for cardiac research, paving the way for new treatments for patients with cardiovascular disease.null

Featured image: Jinah Jang, Reprinted from Biomaterials, Vol 112, Jinah Jang et al., 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair, Pages 264-274, Copyright (2017), with permission from Elsevier. Schematic illustration of a pre-vascularized stem cell patch having multiple stem cell-laden bioinks. © AIP


Reference: Sanskrita Das et al, 3D bioprinting of stem cell-laden cardiac patch: A promising alternative for myocardial repair, APL Bioengineering (2021). DOI: 10.1063/5.0030353


Provided by American Institute of Physics

Study Identifies Biomarker For Breast Cancer Response To Immunotherapy (Medicine)

A biomarker that has proven to be a predictor for response to immunotherapies in melanoma patients also has clinical relevance for breast cancer patients, according to a new study published in Clinical Cancer Research.

The study demonstrated that this biomarker, a molecule called the Major Histocompatibility Complex Class II protein (MHC-II), has the potential to be a predictor of immunotherapy benefit with two types of breast cancer—early-stage, triple negative breast cancer (TNBC) and high-risk, estrogen receptor-positive breast cancer (HR+) when expressed on breast cancer cells. Although immunotherapies are likely to soon be prescribed along with chemotherapies for these breast cancers before surgery, most patients don’t require the addition of immunotherapy to achieve treatment response. Without an optimal biomarker, clinicians don’t have a reliable way to discern which patients need immunotherapy and which ones don’t.

Clinical tests for MHC-II expression could shield breast cancer patients who don’t need the immunotherapy from possible treatment complications and additional costs. Immunotherapies are expensive and associated with significant toxicity.

Justin Balko, PharmD, Ph.D., associate professor of Medicine and Pathology, Microbiology and Immunology, conceived and designed the study.

“These findings are particularly exciting for us, because if validated, they could provide a better way to personalize therapy for breast cancer patients. So far, the typical biomarkers like PD-L1 expression and the numbers of immune cells in the tumor have not done a good job of identifying patients who need immunotherapy,” said Balko, the study’s senior author.

Paula Gonzalez Ericsson, the study lead author, added, “the test can be easily performed on patient’s tissue samples obtained for diagnosis without the need of additional intervention.”

Balko and colleagues analyzed tissue samples donated by three cohorts of patients:

  • patients with non-immunotherapy-treated breast cancers
  • patients with TNBC treated with the immunotherapy durvalumab and standard chemotherapy
  • patients with HER2-negative breast cancer treated with either standard chemotherapy or the standard chemotherapy plus the immunotherapy pembrolizumab.

They determined that MHC-II is expressed in a subgroup of primary TNBC and HR+ breast cancers, and that tumor MHC-II expression is associated with response to standard chemotherapy plus durvalumab or pembrolizumab, but not to standard neoadjuvant chemotherapy alone.

“The findings of the association with response in early-stage high-risk HR+ patients suggests that MHC-II may be a useful tool in a broader context for breast cancer and this area would benefit from further study,” said co-senior author, Kim Blenman, Ph.D., MS, assistant professor of Medicine at Yale University.

The study is believed to be the first to evaluate and demonstrate the predictive capacity of tumor MHC-II for immunotherapy-specific benefit in patients with breast cancer. The researchers also noted that MHC-II has the potential to be a pan-cancer biomarker predictor for anti-PD-1 or anti-PD-L1 immunotherapies since its clinical relevance has been demonstrated with melanoma, breast cancer and Hodgkin’s lymphoma in this study and previous studies. However, they call for a large, randomized controlled trial to validate their findings with breast cancer, which was based on a retrospective tissue-based analysis.


Reference: Paula I Gonzalez-Ericsson et al, Tumor-specific major histocompatibility-II expression predicts benefit to anti-PD-1/L1 therapy in patients with HER2-negative primary breast cancer, Clinical Cancer Research (2021). DOI: 10.1158/1078-0432.CCR-21-0607


Provided by Vanderbilt University Medical Center

Scientists Uncover How Decisions About What We See Are Relayed Back Through the Brain (Neuroscience)

NIH study in monkeys finds that in visual decision-making, information relevant to the decision is broadcast widely

Researchers at the National Institutes of Health have discovered that decisions based on visual information, which involve a complex stream of data flowing forward and backwards along the brain’s visual pathways, is broadcast widely to neurons in the visual system, including to those that are not being used to make the decision. Feedback—such as information about a decision traveling back to neurons detecting visual features like color or shape—is thought to help the brain focus on visual information that is relevant to decision-making. The study, by scientists at the National Eye Institute (NEI), was published in Nature Communications.

“Why and how decision-making information is relayed back into the visual processing parts of the brain is an open question. Some theories posit that this type of feedback should be selective – only affecting those neurons that are involved in the decision,” said Hendrikje Nienborg, Ph.D., chief of the NEI Unit on Visual Decision Making and lead author of the study. “This study shows that decision-related feedback is spatially unselective, affecting neurons much more broadly than one might suppose.”

Feedback is used by the brain in many ways and many systems. When a decision is based on what we see, information about expectation or attention—such as where the object is, or about its features—is fed back to brain regions involved in the visual process, raising the activity of neurons involved in seeing the object or event in question.

An example of this type of expectation might be keeping an eye out for a pedestrian at a crosswalk while driving through an intersection. Neurons specialized in detecting objects to your right might receive an extra bit of signal due to your attention. If you were trying to decide whether the person was your red jacket-clad child, neurons specializing in detecting the color red might receive feedback.

Researchers have hypothesized that feedback may help the brain focus in on hard-to-see features, or perhaps help stabilize the decision as it’s being made. Some scientists have thought that decision-related feedback is selective, raising the activity of only the neurons involved in the decision, and not irrelevant neurons.

However, scientists wondered what happens when two different types of information are relevant to a decision at the same time. Is there feedback for each type of information, and is that feedback selective for the decision?

To answer this question, Katrina Quinn, a graduate student in Nienborg’s lab and first author of the study, and colleagues trained monkeys to distinguish whether an object on a screen in a particular location looked concave or convex, while ignoring objects in irrelevant locations. While the animals were performing the task, the researchers recorded the activity of neurons involved in processing visual information. The animals were good at the task, efficiently distinguishing objects in the correct locations and ignoring objects in irrelevant locations.

To see whether the decision-related feedback was selective for both pieces of relevant information, such as location and depth, the researchers recorded activity from neurons that detect depth information and spatial location in the visual cortex, the part of the brain that specializes in visual processing.

Despite the animals’ stellar performance, the researchers discovered an unexpectedly nuanced picture of feedback in the visual system. Similar to previous studies, they found that location feedback is selective, but location feedback didn’t vary depending on the decision the animal made, it was only associated the location that the animal was paying attention to. Conversely, feedback related to the object’s depth was associated with the decision, but was spatially unselective, meaning that even depth-sensing neurons that couldn’t possibly be used to make the decision got extra decision-related feedback anyway.

“You would think that this kind of feedback is always tailored to the task at hand, but it turns out we can’t make that assumption,” said Quinn.

“This study may point towards a feedback mechanism that generalizes across tasks, but in some ways, these findings raise more questions than they answer,” said Nienborg.

The study was funded by the NEI Intramural program, the European Research Council, the German Research Foundation, and the National Science Foundation.

Featured image: Decision-signals about feature information, like object depth, are broadcast widely in the visual cortex via feedback during visual decision-making. Image credit: National Eye Institute


Reference: Quinn KR, Seillier L, Butts DA, and Nienborg H. “Decision-related feedback in visual cortex lacks spatial selectivity.” Nat Comm. July 22, 2021. https://doi.org/10.1038/s41467-021-24629-0


Provided by NEI

Novel Discovery Describes The Mechanisms of Wound Detection in the Body (Medicine)

THE IDEA

A new study from Vanderbilt University researchers has established a novel way to understand how the body discovers and responds to wounds. The research was led by graduate student James O’Connor and Professor Andrea Page-McCaw in the Department of Cell and Developmental Biology, and Shane Hutson, chair of the Department of Physics and Astronomy and professor of physics and biological sciences.

Aaron Stevens
Aaron Stevens © Vanderbilt University
Andrea Page-McCaw
Andrea Page-McCaw © Vanderbilt University

Cells that cover the body and its organs, known as epithelial cells, must be able to heal wounds, as they are uniquely subjected to all kinds of insults and abrasions. “When these cells detect a wound nearby, they change their behaviors,” said Page-McCaw. “They transition from stationary, nondividing, noninvasive cells to cells that migrate, divide and invade.” This also describes the behaviors of cancer cells, which adopt wound-healing behaviors without any wound.

The trans-institutional team of scientists started by looking into the earliest known response of epithelial cells to a nearby wound: an increase in calcium levels. This increase typically occurs within a minute of wounding.

“We were able to connect the response of these cells directly to the cellular damage inherent in wounding,” Page-McCaw said. “We found that wounds destroy cells, causing them to leak or even burst, and some of their contents gets out. Outside of cells, tissues have a detector molecule ready to sense these cellular contents. When they do, proteases in the cellular contents chop up the detector molecule into smaller pieces, which spread to nearby cells. This activates receptors on the cells’ surfaces, giving them the information that a wound is nearby.”

James O'Connor
James O’Connor © Vanderbilt University

The multidisciplinary collaboration with Hutson’s lab brought the convergence of experimental biology and theoretical mathematical modeling together. “James O’Connor led the experiments,” Page-McCaw said, “and we worked collaboratively with the Hutson lab to analyze the data quantitatively. Aaron Stevens, graduate student in the Hutson lab, generated a mathematical model that showed this scenario is plausible if the cells release their contents slowly, rather than all at once. This finding was an interesting aspect that we had not noticed, but we were able to go back and see evidence for such a slow release.”

WHY IT MATTERS

Successful and efficient wound healing is an important aspect of bodily recovery from trauma or surgery. This research brings us closer to a full mechanistic understanding of how wounds are recognized by epithelial cells and how this leads to wound healing. A foundational understanding of this behavior is essential to developing therapeutics that can address this health issue.

Model of epithelial wound detection. Destroyed cells at the center of wounds release proteases, cleaving extracellular pro-Gbp into its active form, which diffuses to distal cells to activate a calcium response through the receptor Mthl10. © Vanderbilt University

Slow wound healing time can be caused by many factors, leading to infection and declining health. Healogics, the nation’s leading provider of advanced wound care, sponsors an annual Wound Care Awareness Week in June that recognizes the “nearly 7 million people in the United States living with a nonhealing wound.” Healogics notes that “the prevalence of chronic wounds is growing in tandem with an aging population and increasing rates of diseases, such as diabetes and heart disease.”

Additionally, by figuring out how to downregulate these wound-healing behaviors in combination with other cancer interventions, this work offers insights that could help combat cancer’s adoption of this mechanism.

WHAT’S NEXT

Shane Hutson
Shane Hutson © Vanderbilt University

Page-McCaw and Hutson will focus on how cells use the information they receive about the presence of a wound, specifically how the information is encoded in the calcium signal dynamics and then converted into migration, proliferation and changes in cell- and tissue-level mechanics. “Now that we have a solid understanding of how the presence of a wound is first signaled to nearby cells, we can ask a lot of interesting follow-up questions,” said Hutson. “How much information is present in those signals? Can cells interpret the signals to know how large the wound is or how far they are from the wound? Do they use the way the dynamic signals change with time to make that measurement? What are the detailed mechanisms by which the signals then get turned into cellular actions?” Through those and other questions, this research will contribute to a stronger foundational understanding of cell behavior that can be translated to impact human health.

FUNDING

This work was supported by the National Institute of General Medical Sciences, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Cancer, the National Institute of Child Health and Human Development, and the American Heart Association.

GO DEEPER

The article “Proteolytic activation of Growth-Blocking Peptides triggers calcium responses through the GPCR Mthl10 during epithelial wound detection” was published in the journal Developmental Cell on July 16.


Provided by Vanderbilt University

HKUMed Develops Inhaled Dry Powder Formulation of Broad-spectrum Antiviral Against COVID-19 and Influenza (Medicine)

The collaborative research team formed by the Department of Pharmacology and Pharmacy and Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has developed an inhalable dry powder formulation of tamibarotene, a repurposed drug that exhibits broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV and influenza A H1N1 virus following pulmonary delivery. The work has been published online in Advanced Therapeutics [link to publication] in June 2021. A provisional application has been filed to the United States Patent and Trademark Office based on this work.

Background

In response to the unpredictable epidemic and pandemic outbreaks of influenza and coronavirus, early administration of a broad-spectrum antiviral agent could be an effective strategy to control the spread of respiratory infections. The HKUMed research team has previously reported that a retinoid derivative, AM580, demonstrated broad-spectrum antiviral activity against coronaviruses (MERS-CoV, SARS-CoV and SARS-CoV-2) and influenza virus (Nature Communication 2019Viruses 2020).

An analogue of AM580, tamibarotene, is an orally active retinoid derivative for the treatment of acute promyelocytic leukemia currently marketed in Japan. With an antiviral activity comparable to AM580, tamibarotene has an established safety profile in human with milder adverse effects than other retinoid derivatives. Tamibarotene is available as an oral tablet, which is difficult to achieve robust antiviral activity in the respiratory tract due to inadequate lung distribution following oral administration. When high dose is administered to compensate the insufficient lung distribution, toxic side effects are expected because of the extensive systemic exposure.

Photos of ‘spray-freezing’ step in spray freeze drying process. Liquid is fed into a nozzle and atomised into fine droplets. Those droplets fall into liquid nitrogen (inside the white styrofoam container) and become frozen. © University of Hong Kong

By contrast, pulmonary delivery is a non-invasive administration route that can maximise local concentration in the lung and reduce systemic exposure, thereby reducing the risk of adverse effects and improving therapeutic efficacy. Inhaled powder formulation of broad-spectrum antiviral drug can be used on outpatient basis due to the ease of (self-)administration as prophylaxis and treatment for respiratory viral infections.

Study method and findings

Inhaled dry powder formulation of tamibarotene was prepared by spray freeze drying, a particle engineering technique that combines spray freezing and freeze drying to produce particles with excellent aerosol properties for inhalation. The HKUMed research team found that a prophylactic dose of tamibarotene powder delivered by intratracheal administration significantly reduced virus titer and viral RNA load of SARS-CoV-2 in the hamsters’ lungs, and the antiviral efficacy was comparable to intratracheally administered remdesivir. The broad-spectrum anti-coronavirus activity of inhaled tamibarotene powder was also demonstrated in MERS-CoV-infected mice model as pre-challenge prophylaxis. Moreover, remarkable anti-influenza activity of tamibarotene powder formulation was demonstrated by the improved survival rate of mice and alleviated disease severity when administered either intratracheally as prophylaxis or intranasally as treatment.

Research implications

‘Currently, there is no inhaled powder formulation of antiviral available on the market for COVID-19 treatment. Tamibarotene dry powder with broad-spectrum antiviral activity presents a new strategy for COVID-19 management, especially as prophylaxis and treatment for outpatients when in-patient healthcare cannot be provided,’ said Dr Jenny Lam, Associate Professor, Department of Pharmacology and Pharmacy, HKUMed, who initiated the study. ‘With the favourable safety profile of tamibarotene and based on the findings in the present study, clinical trials evaluating inhaled tamibarotene for its safety and as at-home treatment for COVID-19 could be considered.’

Since tamibarotene exerts its antiviral activity by targeting lipid metabolism in the host cells, it is advantageous in responding to mutated or drug-resistant virus strains. More importantly, by demonstrating antiviral efficacy against SARS-CoV-2 and H1N1 virus in respective animal models, inhaled tamibarotene presents a possible solution for COVID-19 and influenza co-infection.

Featured image: SEM image of ‘inhaled tamibarotene powder formulation’ at x5,000 magnification. © University of Hong Kong


Provided by University of Hong Kong