Cell Biology

Touch and taste? Its all in the suckers – ScienceBlog.com

We think because the molecules do not solubilize well, they could, for instance, be found on the surface of octopuses prey and [whatever the animals touch], saidNicholas Bellono, an assistant professor of molecular and cellular biology and the studys senior author. So, when the octopus touches a rock versus a crab, now its arm knows, OK, Im touching a crab [because] I know theres not only touch but theres also this sort of taste.

In addition, scientists found diversity in what the receptors responded to and the signals they then transmitted to the cell and nervous systems.

We think that this is important because it could facilitate complexity in what the octopus senses and also how it can process a range of signals using its semi-autonomous arm nervous system to produce complex behaviors, Bellono said.

The scientists believe this research can help uncover similar receptor systems in other cephalopods, the invertebrate family that also includes squids and cuttlefish. The hope is to determine how these systems work on a molecular level and answer some relatively unexplored questions about how these creatures capabilities evolved to suit their environment.

Not much is known about marine chemotactile behavior and with this receptor family as a model system, we can now study which signals are important for the animal and how they can be encoded, saidLena van Giesen, a postdoctoral fellow in theBellono Laband lead author of the paper. These insights into protein evolution and signal coding go far beyond just cephalopods.

Along with Giesen, other co-authors from the lab includePeter B. Kilian, an animal technician, andCorey A.H. Allard, a postdoctoral fellow.

The strategies they have evolved in order to solve problems in their environment are unique to them and that inspires a great deal of interest from both scientists and non-scientists alike, Kilian said. People are drawn to octopuses and other cephalopods because they are wildly different from most other animals.

The team set out to uncover how the receptors are able to sense chemicals and detect signals in what they touch, like an arm around a snail, to help them make choices.

Octopus arms are distinct and complex. About two-thirds of an octopuss neurons are located in their arms. Because the arms operate partially independently from the brain, if one is severed it can still reach for, identify, and grasp items.

People are drawn to octopuses and other cephalopods because they are wildly different from most other animals.

Peter B. Kilian

The team started by identifying which cells in the suckers actually do the detecting. After isolating and cloning the touch and chemical receptors, they inserted them in frog eggs and in human cell lines to study their function in isolation. Nothing like these receptors exists in frog or human cells, so the cells act essentially like closed vessels for the study of these receptors.

The researchers then exposed those cells to molecules such as extracts from octopus prey and others items to which these receptors are known to react. Some test subjects were water-soluble, like salts, sugars, amino acids; others do not dissolve well and are not typically considered of interest by aquatic animals. Surprisingly, only the poorly soluble molecules activated the receptors.

Researchers then went back to the octopuses in their lab to see whether they too responded to those molecules by putting those same extracts on the floors of their tanks. They found the only odorants the octopuses receptors responded to were a non-dissolving class of naturally occurring chemicals known as terpenoid molecules.

[The octopus] was highly responsive to only the part of the floor that had the molecule infused, Bellono said. This led the researchers to believe that the receptors they identified pick up on these types of molecules and help the octopus distinguish what its touching. With the semi-autonomous nervous system, it can quickly make this decision: Do I contract and grab this crab or keep searching?

While the study provides a molecular explanation for this aquatic touch-taste sensation in octopuses through their chemotactile receptors, the researchers suggest further study is needed, given that a great number of unknown natural compounds could also stimulate these receptors to mediate complex behaviors.

Were now trying to look at other natural molecules that these animals might detect, Bellono said.

This research was supported by the New York Stem Cell Foundation, the Searle Scholars Program, the Sloan Foundation, the Klingenstein-Simons Fellowship, the National Institutes of Health, and the Swiss National Science Foundation.

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Touch and taste? Its all in the suckers - ScienceBlog.com

Cell Biology

Touch and Taste? It’s All in The Octopus Tentacles – Technology Networks

Octopuses have captured the human imagination for centuries, inspiring sagas of sea monsters from Scandinavian kraken legends to TV's "Voyage to the Bottom of the Sea" and, most recently, Netflix's less-threatening "My Octopus Teacher." With their eight suction-cup covered tentacles, their very appearance is unique, and their ability to use those appendages to touch and taste while foraging further sets them apart.

In fact, scientists have wondered for decades how those arms, or more specifically the suction cups on them, do their work, prompting a number of experiments into the biomechanics. But very few have studied what is happening on a molecular level. In a new report, Harvard researchers got a glimpse into how the nervous system in the octopus' arms (which operate largely independently from its centralized brain) manage this feat.

The work published Thursday in Cell.

The scientists identified a novel family of sensors in the first layer of cells inside the suction cups that have adapted to react and detect molecules that don't dissolve well in water. The research suggests these sensors, called chemotactile receptors, use these molecules to help the animal figure out what it's touching and whether that object is prey.

"We think because the molecules do not solubilize well, they could, for instance, be found on the surface of octopuses' prey and [whatever the animals touch]," said Nicholas Bellono, an assistant professor of molecular and cellular biology and the study's senior author. "So, when the octopus touches a rock versus a crab, now its arm knows, 'OK, I'm touching a crab [because] I know there's not only touch but there's also this sort of taste.'"

In addition, scientists found diversity in what the receptors responded to and the signals they then transmitted to the cell and nervous systems.

"We think that this is important because it could facilitate complexity in what the octopus senses and also how it can process a range of signals using its semi-autonomous arm nervous system to produce complex behaviors," Bellono said.

The scientists believe this research can help uncover similar receptor systems in other cephalopods, the invertebrate family that also includes squids and cuttlefish. The hope is to determine how these systems work on a molecular level and answer some relatively unexplored questions about how these creatures' capabilities evolved to suit their environment.

"Not much is known about marine chemotactile behavior and with this receptor family as a model system, we can now study which signals are important for the animal and how they can be encoded," said Lena van Giesen, a postdoctoral fellow in the Bellono Lab and lead author of the paper. "These insights into protein evolution and signal coding go far beyond just cephalopods."

Along with Giesen, other co-authors from the lab include Peter B. Kilian, an animal technician, and Corey A.H. Allard, a postdoctoral fellow.

"The strategies they have evolved in order to solve problems in their environment are unique to them and that inspires a great deal of interest from both scientists and non-scientists alike," Kilian said. "People are drawn to octopuses and other cephalopods because they are wildly different from most other animals."

The team set out to uncover how the receptors are able to sense chemicals and detect signals in what they touch, like a tentacle around a snail, to help them make choices.

Octopus arms are distinct and complex. About two-thirds of an octopus's neurons are located in their arms. Because the arms operate partially independently from the brain, if one is severed it can still reach for, identify, and grasp items.

The team started by identifying which cells in the suckers actually do the detecting. After isolating and cloning the touch and chemical receptors, they inserted them in frog eggs and in human cell lines to study their function in isolation. Nothing like these receptors exists in frog or human cells, so the cells act essentially like closed vessels for the study of these receptors.

The researchers then exposed those cells to molecules such as extracts from octopus prey and others items to which these receptors are known to react. Some test subjects were water-soluble, like salts, sugars, amino acids; others do not dissolve well and are not typically considered of interest by aquatic animals. Surprisingly, only the poorly soluble molecules activated the receptors.

Researchers then went back to the octopuses in their lab to see whether they too responded to those molecules by putting those same extracts on the floors of their tanks. They found the only odorants the octopuses receptors responded to were a non-dissolving class of naturally occurring chemicals known as terpenoid molecules.

"[The octopus] was highly responsive to only the part of the floor that had the molecule infused," Bellono said. This led the researchers to believe that the receptors they identified pick up on these types of molecules and help the octopus distinguish what it's touching. "With the semi-autonomous nervous system, it can quickly make this decision: 'Do I contract and grab this crab or keep searching?'"

While the study provides a molecular explanation for this aquatic touch-taste sensation in octopuses through their chemotactile receptors, the researchers suggest further study is needed, given that a great number of unknown natural compounds could also stimulate these receptors to mediate complex behaviors.

"We're now trying to look at other natural molecules that these animals might detect," Bellono said.

This research was supported by the New York Stem Cell Foundation, the Searle Scholars Program, the Sloan Foundation, the Klingenstein-Simons Fellowship, the National Institutes of Health, and the Swiss National Science Foundation.

Reference:

Lena van Giesen. Corey A.H. Allard Nicholas W. et al. Molecular basis of chemotactile sensation in octopus. Cell, 2020 DOI: 10.1016/j.cell.2020.09.008

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Touch and Taste? It's All in The Octopus Tentacles - Technology Networks

Cell Biology

Foundational research shows early gene therapy prevents Angelman syndrome – BioWorld Online

Scientists working at the University of North Carolina, Chapel Hill reported in the Oct. 21, 2020, issue of Nature on the successful development of a one-time specific sequence-directed gene therapy approach using the combination of AAV with CRISPR technology that successfully prevented the presentation of Angelman syndrome throughout the lifetime of a mouse model.

Lifelong gene therapy has held promise for decades now as one of the only approaches that could possibly address many neurodevelopmental genetic disorders. But even after decades of research, gene therapy still possesses significant risks due to untoward random genomic insertions of vectors that could ultimately cause other genetic disorders.

Meanwhile, it has been known for decades now that adeno-associated virus (AAV) is a particularly powerful potential gene therapy vector because AAV integrates into the genome so well. However, the integration of AAV has always been random and so it inherently comes with significant risk.

This is the first time that a treatment for Angelman syndrome has been shown to correct this neurodevelopmental disorder.

Principal investigator, Mark Zylka, professor of Cell Biology and Physiology in the Neuroscience Center, University of North Carolina, Chapel Hill, told BioWorld Science, "The key really from what we can tell is going early in treatment. So for the animals that have the disorder we can identify them with genotyping. If you catch it early, you can treat them one time and it lasts forever as far as we can tell.

That longevity, he said, "contrasts with treatments that are in development using antisense technologies that usually have to be injected every 4 months or so, which is not ideal for a pediatric disorder that will last a lifetime."

Angelman syndrome is caused by loss of function of the maternal Ube3a allele, while the paternal allele is normally silenced by a very long antisense noncoding RNA known as Ube3a-ATS. Previously in a 2011 Nature publication Zylka and collaborators demonstrated that a class of drugs called topoisomerase inhibitors could reactivate the paternal allele by interfering with Ube3a-ATS. So Zylka knew that if the paternal copy of Ube3a can be turned on, this will provide the possibility of treating the condition.

Topoisomerase inhibitors, which include chemotherapy agents such as irinotecan and doxorubicin, are not a therapeutic option for Angelman syndrome due to their broad-spectrum nature and toxicity. But with the development of CRISPR combined with AAV, the researchers have now developed a tool to precisely hone in on specific regions of the genome.

First, the team screened 250 different RNA guided CRISPR/Cas9 constructs in cell culture until they identified the best one (Spjw33) reactivating the Ube3a-ATS allele. These clones had the good fortune to target Snord115 genes within the large Ube3a-ATS locus. The Snord genes are functionally redundant, with over 100 of them present in both mice and humans.

Ultimately the CRISPR/Cas9 with the cloned RNA guide was used to a specific region of the DNA, where DNA was inserted into the Snord115 gene of the Ube3a-ATS locus. The inserted DNA possessed a polyadenylation signal that caused the premature termination of the Ube3a-ATS noncoding RNA such that it no longer silenced the paternal expression of Ube3a.

With the Ube3a now made in the mouse, it fully developed and no longer presented with any phenotypes resembling Angelman syndrome throughout the life of the animal.

In short, instead of deleting the gene, this approach disrupted the Ube3a-ATS gene by stopping its full production prematurely. Only a small nonfunctioning part of the noncoding RNA was still produced in treated animals.

Earlier is better

The broad implications are that the study proves that Angelman syndrome can be treated and possibly prevented, if it is done early enough.

Previous studies showed that if turning on the paternal copy later, even within just a few days after birth in a mouse, this approach does not prevent Angelman syndrome.

Zylka said, "It is like with a building. You want to make sure the foundation is done correctly. Tons of time is put into the foundation. If there is a problem with the foundation, then when building on top of it, it is very hard and next to impossible to go back and fix the foundation. When the brain is developing, it is the initial foundation upon which the brain is built that is critical and you cannot really go back and fix it. So this study now shows that you can fix the problem if you catch it early enough by administering just a single treatment."

One encouraging result was the lack of gene therapy occurring in the mother. The team injected the vector into the fetus, but no gene therapy was detectable in the mother's liver and brain. Instead, the gene therapy was restricted to only the fetus. This was remarkable and very important since AAV is well known to particularly target the liver.

The technology to identify fetuses with the mutation that causes Angelman syndrome is already available and currently used in hospitals around the world. Techniques like amniocentesis, chorionic villus sampling, and even newer noninvasive technologies involving taking extra blood from the mom can now detect fetal DNA and cells to find out if there are any Angelman syndrome mutations.

However, there has not been a strong incentive to look for Angelman syndrome given that there are no therapeutic options at this point.

Zylka hopes to ultimately test the approach in the clinic. But first-time gene therapy technologies are often only given one shot in clinical trials and safety is of primary concern. So, extensive further research will be necessary to not throw away his shot (Wolter, J.M. et al. Nature 2020, Advanced publication).

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Foundational research shows early gene therapy prevents Angelman syndrome - BioWorld Online

Immunology

Analysis: What do waning COVID-19 antibodies tell us about immunity and vaccines? – Reuters

LONDON (Reuters) - Growing evidence that COVID-19 antibody levels can wane swiftly after someone is infected is not necessarily bad news for immunity, experts said on Thursday, and does not mean protection offered by coronavirus vaccines will be weak or short-lived.

FILE PHOTO: Convalescent plasma samples in vials are seen before being tested for COVID-19 antibodies at the Bloodworks Northwest Laboratory during the coronavirus disease (COVID-19) outbreak in Renton, Washington, U.S. September 9, 2020. Picture taken September 9, 2020. REUTERS/Lindsey Wasson/File Photo

Specialists in immunology and viruses warned against reading too much into studies of antibody levels in the blood of people previously infected with COVID-19, cautioning that antibody readings do not translate directly into levels of protective immunity.

The concentration of antibodies in your blood does not equal immunity, said Eleanor Riley, a professor of immunology and infectious disease at Britains University of Edinburgh.

She and other experts said reports earlier this week which suggested immunity to COVID-19 might decline in line with falling blood antibody levels failed to account for the many complexities in how the body builds immunity to infections.

Immunity is not something we can just wrap up in measuring an antibody or T-cell response, she told Reuters. Immunity is about the system working together so that next time you come across the infection, you either wont get it at all or wont get seriously ill from it. Thats protective immunity.

While antibodies induced by natural COVID-19 infection may start to decline in few months, as a study by researchers at Imperial College found on Tuesday, the many potential COVID-19 vaccines in development are designed to induce more durable immunity by invoking strong so-called immune memory.

Antibody responses are usually short-lived because once they have done their job you dont need them, said Jonathan Stoye, head of virology at Britains Francis Crick Institute.

But that doesnt mean that immunity, either induced by infection or by vaccination, is necessarily short-lived: Memory cells can respond to and combat a new infection.

Since SARS-CoV-2, the virus that causes COVID-19, is a new human virus, scientists dont yet know what levels of immunity will turn out to be protective. But many of the vaccine makers are touting both the antibody and T-cell responses, which are increasingly seen as important to lasting immunity.

The immune system is very complicated. We know antibodies are important, but theyre not the whole story, said Lawrence Young, a professor of molecular oncology at Britains Warwick University. The important thing here is immune memory.

Key to the process of immunity are memory cells known as T- and B-lymphocytes. Having made antibodies to a certain virus in an initial infection, the body uses these cells to remember that pathogen, so when you are next exposed to the virus, the antibody response kicks in much sooner, Young said.

With vaccines, a key feature is that scientists developing them can select as targets the most important bits of the pathogen - in COVID-19s case these include the so-called spike protein on the surface of SARS-CoV-2 virus - to get the strongest and most lasting memory responses from T and B lymphocytes.

Some vaccines also contain stimulators or boosters, known as adjuvants, which can supercharge the response, and others are designed to be given in multiple doses to ensure higher concentrations of antibodies will create stronger memories.

The idea is that while the natural infection may give you poor memory that may not last, the vaccine will give you strong memory that does last, said Danny Altmann, a professor of immunology at Imperial College London.

Reporting by Kate Kelland, editing by Kirsten Donovan

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Analysis: What do waning COVID-19 antibodies tell us about immunity and vaccines? - Reuters

Immunology

OSE Immunotherapeutics Presents OSE-230 as a Novel Agonist Monoclonal Antibody Therapy Triggering Resolution of Chronic Inflammation – BioSpace

The first presentation of new data characterizing the anti-ChemR23 antibody was at the FOCIS Virtual Annual Meeting held October 28-31, 2020

NANTES, France, Oct. 30, 2020 (GLOBE NEWSWIRE) -- OSE Immunotherapeutics (ISIN: FR0012127173; Mnemo: OSE) presented preclinical efficacy data for novel agonist monoclonal antibody therapy, OSE-230, at the 2020 Federation of Clinical Immunology Societies (FOCIS) Annual Meeting being held virtually on October 28-31, 2020. OSE-230 is an agonist antibody against ChemR23, also known as chemerin chemokine-like receptor 1 (CMKLR1), a G-protein coupled receptor (GPCR) expressed on myeloid immune cells known to modulate inflammation.

Persistent inflammation is a characteristic feature of all chronic inflammatory or autoimmune diseases and if not controlled or resolved, it can lead to further tissue damage and give rise to tissue fibrosis with eventual loss of organ function. Most anti-inflammatory agents act using a mechanism that blocks pro-inflammation pathways. In contrast, OSE Immunotherapeutics is developing OSE-230 as a first-in-class therapeutic agent with the potential to resolve chronic inflammation by driving affected tissues to complete the inflammation program and restore tissue integrity.

Nicolas Poirier, Chief Scientific Officer of OSE Immunotherapeutics, said: OSE-230 represents a disruptive concept in the resolution of inflammation, a failed process in potentially all chronic inflammatory diseases. The data presented show that OSE-230 is the first monoclonal antibody triggering the activation of specialized receptors of resolution to restore tissue homeostasis, integrity and functions. Chronic inflammatory diseases are the most significant cause of death worldwide* and their incidence is growing, highlighting the patientsneed for disruptive innovations to manage such complex diseases.Our findings provide strong evidence for the therapeutic potential of OSE-230 tobe developed in various chronic inflammation and autoimmune pathologies and reinforce OSEs position in the immunotherapy field targeting myeloid cellsin autoimmune and chronic inflammatory diseases andin immuno-oncology.

The oral presentation entitled Agonist anti-ChemR23 mAb blunts tissue neutrophil accumulation and triggers chronic colitis inflammation resolution shows efficacy results for OSE-230 in chronic inflammatory preclinical models and ex vivo human models. The main results from the presentation are as follows:

These results were based on OSEs key findings:

*Chronic Inflammation; Roma Pahwa , Amandeep Goyal, Pankaj Bansal, Ishwarlal Jialal; In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.; 2020 Aug 10.

ABOUT OSE ImmunotherapeuticsOSE Immunotherapeutics is an integrated biotechnology company focused on developing and partnering therapies to control the immune system for immuno-oncology and autoimmune diseases. The companys immunology research and development platform is focused on three areas: T-cell-based vaccination, Immuno-Oncology (focus on myeloid targets), Auto-immunity & Inflammation. Its balanced first-in-class clinical and preclinical portfolio has a diversified risk profile:

Vaccine platform

Immuno-oncology platform

Auto-immunity and inflammation platform

For more information:Click and follow us on Twitter and LinkedInhttps://twitter.com/OSEIMMUNOhttps://www.linkedin.com/company/10929673

Forward-looking statementsThis press release contains express or implied information and statements that might be deemed forward-looking information and statements in respect of OSE Immunotherapeutics. They do not constitute historical facts. These information and statements include financial projections that are based upon certain assumptions and assessments made by OSE Immunotherapeutics management in light of its experience and its perception of historical trends, current economic and industry conditions, expected future developments and other factors they believe to be appropriate.

These forward-looking statements include statements typically using conditional and containing verbs such as expect, anticipate, believe, target, plan, or estimate, their declensions and conjugations and words of similar import. Although the OSE Immunotherapeutics management believes that the forward-looking statements and information are reasonable, the OSE Immunotherapeutics shareholders and other investors are cautioned that the completion of such expectations is by nature subject to various risks, known or not, and uncertainties which are difficult to predict and generally beyond the control of OSE Immunotherapeutics. These risks could cause actual results and developments to differ materially from those expressed in or implied or projected by the forward-looking statements. These risks include those discussed or identified in the public filings made by OSE Immunotherapeutics with the AMF. Such forward-looking statements are not guarantees of future performance. This press release includes only summary information and should be read with the OSE Immunotherapeutics Universal Registration Document filed with the AMF on 15 April 2020, including the annual financial report for the fiscal year 2019, available on the OSE Immunotherapeutics website. Other than as required by applicable law, OSE Immunotherapeutics issues this press release at the date hereof and does not undertake any obligation to update or revise the forward-looking information or statements.

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OSE Immunotherapeutics Presents OSE-230 as a Novel Agonist Monoclonal Antibody Therapy Triggering Resolution of Chronic Inflammation - BioSpace

Immunology

Transforming coronavirus protein into a nanoparticle could be key to effective COVID-19 vaccine – UB Now: News and views for UB faculty and staff -…

A UB-led research team has discovered a technique that could help increase the effectiveness of vaccines against the novel coronavirus, the virus that causes COVID-19.

Jonathan F. Lovell, associate professor in the Department of Biomedical Engineering, is the primary investigator on the research, titled SARS-CoV-2 RBD Neutralizing Antibody Induction is Enhanced by Particulate Vaccination, which was published online today in Advanced Materials.

COVID-19 has caused a disruptive global pandemic, infecting at least 40 million worldwide and causing more than 220,000 deaths in the United States alone. Since it began spreading in early 2020, biomedical researchers have been in active pursuit of an effective vaccine.

According to Lovell, one answer might lie in designing vaccines that partially mimic the structure of the virus. One of the proteins on the virus located on the characteristic COVID spike has a component called the receptor-binding domain, or RBD, which is its Achilles heel. That is,he says, antibodies against this part of the virus have the potential to neutralize the virus.

It would be appealing if a vaccine could induce high levels of antibodies against the RBD, Lovell says. One way to achieve this goal is to use the RBD protein itself as an antigen; that is, the component of the vaccine that the immune response will be directed against.

The team hypothesized that by converting the RBD into a nanoparticle (similar in size to the virus itself) instead of letting it remain in its natural form as a small protein, it would generate higher levels of neutralizing antibodies and its ability to generate an immune response would increase.

Lovells team had previously developed a technology that makes it easy to convert small, purified proteins into particles through the use of liposomes, or small nanoparticles formed from naturally occurring fatty components. In the new study, the researchers included within the liposomes a special lipid called cobalt-porphyrin-phospholipid, or CoPoP. That special lipid enables the RBD protein to rapidly bind to the liposomes,forming more nanoparticles that generate an immune response, Lovell explains.The team observed that when the RBD was converted into nanoparticles, it maintained its correct, three-dimensional shape and the particles were stable in incubation conditions similar to those in the human body. When laboratory mice and rabbits were immunized with the RBD particles, high antibody levels were induced. Compared to other materials that are combined with the RBD to enhance the immune response, only the approach with particles containing CoPoP gave strong responses.

Other vaccine adjuvant technology does not have the capacity to convert the RBD into particle-form, Lovell notes.

We think these results provide evidence to the vaccine-development community that the RBD antigen benefits a lot from being inparticle format, he says. This could help inform future vaccine design that targets this specific antigen.

Lovells co-authors on the study include Wei-Chiao Huang, Shiqi Zhou, Xuedan He and Moustafa T. Mabrouk, all from the UB Department of Biomedical Engineering; Kevin Chiem and Luis Martinez-Sobrido, both from Texas Biomedical Research Institute; Ruth H. Nissly, Ian M. Bird and Suresh V. Kuchipudi, all from the Animal Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences at Pennsylvania State University; Mike Strauss and Joaquin Ortega from the Department of Anatomy and Cell Biology at McGill University; Suryaprakash Sambhara from the Immunology and Pathogenesis Branch of the U.S. Centers for Disease Control and Prevention; Elizabeth A. Wohlfert from the UB Department of Microbiology and Immunology; and Bruce A. Davidson from the Department of Anesthesiology and the Department of Pathology and Anatomical Sciences at UB.

Lovell founded the Lovell Lab at UB in 2012. It is focused on developing novel nanomedicine approaches to meet unmet needs in treating and preventing disease. He is also a co-founder of POP Biotechnologies Inc., a preclinical stage biotechnology company developing next-generation drug and vaccines products.

The study was supported by the U.S. National Institutes of Health and the Facility for Electron Microscopy Research (FEMR) at McGill University. FEMR is supported by the Canadian Foundation for Innovation, Quebec Government and McGill.

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Transforming coronavirus protein into a nanoparticle could be key to effective COVID-19 vaccine - UB Now: News and views for UB faculty and staff -...

Immunology

How a misconception about coronavirus immunity is causing thousand of needless deaths – Salon

The popular conceptionof a "vaccine" is that it is aninoculationthat makes you immune to a pathogen if not for life, at least for a very long time. On that principal, much of the world's hope for a return to a pre-pandemic normalcy has rested on avaccine for the novel coronavirus, the cause of COVID-19.

Yet that common conception of how vaccines work, it turns out, isn't entirely accurate. The reason relates to two concepts "transient immunity" and"durable immunity." Understanding these are the key to understanding how the pandemic will finally end.

First, a brief primer on the most common misconception about immunity: the idea that once you've contracted a virus, or once you've been vaccinated against it, you can no longer get said virus. Neither of those are necessarily true: there are viruses which people can contract multiple times, because the body's immune system essentially "forgets" how to create immunity to it after a period of time. Likewise, there are vaccines which only confer short-term immunity, and for which we have to get re-vaccinated for periodically.

Currently, we don't know for certain which category the novel coronavirus falls into although mounting evidence suggests that immunity against it won't last. Indeed, there are multiple cases of patients who have contracted the virus multiple times within a few months. While they could be outliers with poor immune systems, the more cases of re-infection that emerge suggest not.

But there's one more catch: Vaccines can actually confer different types of immunity than infections can say, long-term as opposed to short-term.

From a global public health standpoint, you can see how returning to any sense of normalcy depends on our understanding of coronavirus immunity. In other words, does coronavirus immunity last a lifetime, a year, or as short as a few months? Do those who have been infected already need a vaccine, or are they already immune?

It doesn't help that the science is constantly shifting on this, and month-to-month, scientific studies have slightly different conclusions.As Salon has previously reported, the data and research currently suggests that immunity isn't lifelong like the measles. However, it's hard to know how long immunity lasts because it's such a new virus, but here is everything that scientists currently know.

First, let's talk about immunity

There aremyriadways the human body can fight off a viral infection.Dr. Charles Chiu, a professor of infectious diseases at the University of CaliforniaSan Francisco, pointed Salon to three specific ones: passive immunity, neutralizing antibody immunity, and active immunity.

"The idea is that with any viral infection, including an infection from the novel SARS-CoV-2, is that patients who have intact or healthy immune systems will mount an immune response," Dr. Charles Chiu, a professor of infectious diseases at the University of CaliforniaSan Francisco, told Salon. This, he said, isknown as "passive immunity."

"That's really antibody-centered," Chiu said. "The idea is that the B cells, which are white blood cells in your blood, will react to the virus, and will produce antibodies."

These antibodies, Chiu said, can be used one of two different ways. One way is that the antibodies will be "neutralizing" and bind to the virus. Hence, the name, these antibodies will "neutralize," or inactivate, the coronavirus. This is called "neutralizing antibody immunity."

"The idea is that if you're immune, if there's a next time and you are reinfected, then those antibodies are already circulating and present in your blood and they will neutralize the virus immediately," Chiu explained. "So you will, you'll be less likely or you will not be reinfected."

However, not all antibodies are neutralizing. Chiu pointed to HIV (human immunodeficiency virus) as an example of a virus that creates antibodies that aren't neutralizing.

"You will make antibodies in response to a viral infection, but you may not necessarily make neutralizing antibodies that will prevent you from getting reinfected," Chiu noted.

Then, there's "active immunity," which is another type of immune response that's mediated by another type of white blood cells, T cells.

"T cells will actively react to [the virus], they're memory T cells that sort of remember when you've been infected before," Chiu said. "If you get exposed again, those T cells will then kick in and help to prevent you from getting reinfected."

Understanding "durable" and "transient" immunity

Immunologists are trying to figure out whether novel coronavirus infection confersdurable immunity or transient immunity. These termsreferto the strength and period of the type of immunity. For example, if the antibodies made due to a viral infectionare durable, that means immunity is long-lasting. If they're transient, that means they only last a short while.

As mentioned above, mounting evidence suggests that immunity to the novel coronavirusis transient. But just how transient? We don't know, but there is more evidence every week. In September, researchers published a study in the scientific journal Nature Medicine suggesting that people who contract the novel coronavirus and then become immune may stay that way for up to twelve months, based on studying four different seasonal coronaviruses.

However, as Chiu noted there are a couple of differences between the novel coronavirus (SARS-CoV-2)and the seasonal ones. One is that they've been around longer, meaning they're more diverse because they've had more time to mutate.

"It hasn't had the time to mutate widely and to become very divergent," Chiu said. "And what that means is that it's possible that vaccines that are directed specifically against SARS-CoV-2 are more likely to be durable; they're more likely to last longer and be effective longer, perhaps because there's less divergence within this particular strain versus the other seasonal coronaviruses."

What does this mean for COVID-19?

There have been several studies on antibodies and SARS-CoV-2. In one study, researchers tracked COVID-19 patients over time and found that the amount of their antibodies peaked following the onset of symptoms and then began to decline. For some study participants, the antibodies were almost all undetectable within three months. A more recent study of patients in Britain showed a similar trend. But as Nature explained in an article, it could just take minute numbers of antibodies to prevent a reinfection and fight off the coronavirus again.

Most importantly, however, vaccines can confer different types of immunity than actually contracting the virus. Indeed, immunologists note that a vaccine could have durable immunity even if the natural response is transient.

"The vaccine doesn't have to mimic or mirror the natural infection," Shane Crotty, a virologist at the La Jolla Institute for Immunology, told the New York Times.

Immunologists have been pointing to the human papillomavirus (HPV) as an example of a virus that has a poor immune response and weak antibodies, but a durable vaccine immune response that lasts for at least a decade.

Considering that the coronavirus likely has transient immunity, this would make it harder for countries and cities to achieve herd immunitythrough letting the virus spread.

"It really depends on how transient it is, and how rapidly we can really ramp up to be able to vaccinate a sufficient proportion of the population to develop herd immunity," Chiu said, adding that vaccine hesitancy is another barrier if the coronavirus vaccine requires multiple doses to be effective. "We already have issues right now with adherence to the flu vaccine, and there's no reason to think that it's going to be different."

That means that humanity's best bet forachieving durable immunity is still through a vaccine. Relying on a strategy of waiting for herd immunity to be achieved is "flawed," according to a paper by a group of researcherspublished in The Lancet.

"There is no evidence for lasting protective immunity to SARS-CoV-2 following natural infection, and the endemic transmission that would be the consequence of waning immunity would present a risk to vulnerable populations for the indefinite future," the researchers wrote. "Such a strategy would not end the COVID-19 pandemic but result in recurrent epidemics, as was the case with numerous infectious diseases before the advent of vaccination."

In other words, political leaders who have pinned hopes of defeating the virus on achieving herd immunity will not only fail, but will needlessly kill their citizens in the process. President Donald Trump as well as UK Prime Minister Boris Johnson have both touted a strategy of achieving herd immunity through deliberate public health inaction in order to let the virus run its course through citizens.

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How a misconception about coronavirus immunity is causing thousand of needless deaths - Salon

Cell Biology

University of Michigan’s Yukiko Yamashita discusses the mechanisms of long-term genomic maintenance – The Brown Daily Herald

Elementary schoolers learn that DNA is the instruction manual for life the immutable blueprints that cells follow to build proteins and stay alive.

But DNA is a physical molecule which can change over time. So how do cells, especially the ones which produce offspring, ensure that these blueprints stay safe and functional?

In a virtual seminar hosted Wednesday by the Graduate Program in Molecular Biology, Cell Biology and Biochemistry, titled Asymmetric Stem Cell Division and Germ-line Immortality, Yukiko Yamashita, a professor of life sciences at the University of Michigan, explained how her research resulted in a serendipitous connection between two fields of cell biology.

Yamashita typically studies asymmetric cell division, the process by which a daughter cell will split off from the original cell to specialize for a certain function, while the original cell will remain a stem cell capable of any function.

But a series of deductions and experiments on this process led Yamashita to an insight on the mechanisms of germline immortality.

Germline immortality refers to the fact that certain cells act as vessels for storing and passing down genetic information. Since these cells will carry similar genomes across generations, they can be thought of as immortal, Yamashita said. However, the mechanisms that protect this immortality are currently poorly understood. Yamashita hopes to change that through her research.

Yamashita started by working to answer a simple question: When a stem cell divides, how is the fate of the divided cells determined?

Using fruit flies testes as a model to examine stem cells and differentiated cells, which will specialize into different functions like sperm or other tissue, Yamashitas lab began by examining the latter.

They first determined that a common feature of asymmetric stem cell division was the presence of a mother centrosome, a cellular component which regulates the destination of genetic material during division.

Swathi Yadlapalli, who is currently an assistant professor at Michigans Department of Cell and Developmental Biology but worked in Yamashitas lab at the time, then determined that chromosomes, which would typically assort randomly between the divided cells, were in this case dividing non-randomly.

Specific chromosomes, the X and Y sex chromosomes, would regularly assort toward the mother cell, thereby breaking a fundamental rule of cell division: chromosomes assort randomly. Investigation of these oddly assorted chromosomes found a specific region vital to this activity.

Surprisingly, this region was composed of ribosomal DNA, the coding regions for parts of ribosomes, which are responsible for synthesis of proteins.

If you look at any of your cells, any transcriptionally active cell, 60 percent or more of the entire transcription activity is from ribosomal DNA, Yamashita said. You cant do that high demand of transcription off just a single copy of the gene. For that reason, ribosomal DNA genes are repeated hundreds of hundreds of times in our genome.

rDNA is inherently unstable. As cells age, the rDNA will decay, decreasing the availability of ribosome production sites and ultimately impacting the cells function.

For germ cells, which must preserve genetic information to pass on through generations, this erosion poses a threat to long-term reproductive viability. But organisms have demonstrated the capacity to somehow recover from this loss and produce offspring with more rDNA sites than the previous generation.

Yamashitas lab proposed a mechanism by which the odd non-random assortment observed earlier could replenish rDNA sites, ultimately increasing the cells ability to pass on their genes.

Typically, chromatids, pairs of identical chromosomes, align equally during division. An event called crossing over results in the random swapping of material on two parallel chromatids.

Yamashita realized that chromatids were purposely misaligning and crossing over.

That was a thunderstrike moment for us, Yamashita remembered. This is the asymmetry we have been looking (at) for quite some time. Probably, when we say non-random chromatid segregation, this copy-number asymmetry might be what can explain this.

While Yamashitas lab has yet to prove this mechanism, they can detect an unequal crossing over of these regions, as well as hypothesize as to the origins of the signal which leads to the intentional misalignments.

Yamashita related that her labs advances were due to a willingness to listen to the data, as she puts it.

Yamashita added that, oftentimes, scientists will run experiments repeatedly, each time encountering the same, implausible data. If you keep getting that data, multiple times, that is the moment that data is screaming at you, Yamashita told The Herald. You are wrong! You are on the wrong track. You really have to face this puzzling data.

Germline immortality was not the typical work of the Yamashita Lab, but after following the breadcrumbs left by investigation of asymmetric cell division, she found herself on the path toward new conclusions.

Thats the way I do my science, she said. If theres data thats puzzling (and) controversial but you cannot ignore it, you have to tackle it.

Over 60 audience members virtually attended the hour-long seminar. Questions bubbled in the chat throughout the talk.

Although Yamashita reflected that a virtual environment can lead to difficulties for newcomers to assimilate into the scientific community, she pointed to cost and time benefits making virtual scientific events much more accessible.

Mark Johnson, director of the Graduate Program in Molecular Biology, Cell Biology and Biochemistry, also pointed to the benefits of a virtual seminar. We find that some students and participants feel more comfortable asking questions by chat than they would in person, Johnson said. Virtual events can also bring in a much more diverse and interesting audience, without having the expense of time and travel.

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University of Michigan's Yukiko Yamashita discusses the mechanisms of long-term genomic maintenance - The Brown Daily Herald

Cell Biology

Cell biologists and bioimaging expert team up to solve fourth dimension secrets – News-Medical.net

Reviewed by Emily Henderson, B.Sc.Oct 29 2020

Cell biologists at the University of Illinois at Urbana-Champaign and Bar-Ilan University at Israel and a bioimaging expert at the University of Central Florida are teaming up in what they hope may lead to a major breakthrough in the understanding of the three-dimensional organization of the nucleus over time and their role in certain diseases.

The dream team was recently awarded a National Institutes of Health $4.2 million grant. The five-year grant is part of the NIH's 4D Nucleome Program (4DN). The program aims to spur the development of technologies that will advance the understanding of how DNA is arranged within cells in space and time and how this affects cellular functions in health and disease.

UCF optics and photonics Assistant Professor Kyu Young Han will develop new multifunctional high-performance microscopes that UIUC's Professor Andrew Belmont and other 4DN researchers will use to map proteins and genes and observe their dynamics in the fourth dimension.

Better understanding of what happens in these tiny places will likely lead to answers for diseases that currently have no treatment and perhaps even cures to others. The challenge is current microscopes lack the kind of power necessary to see detail researchers need in the cell's nucleus.

There are microscopes researchers use right now, but for fulfilling the goals of the 4DN, we need a new type of microscope. They are expensive as well. My team and I are building something that will have several key features, including high-resolution and high-throughput but gentle imaging that doesn't break the bank."

Kyu Young Han, Assistant Professor of Optics and Photonics, University of Central Florida

Han says the two new microscopes will allow Belmont to see proteins and chromosomes within the nucleus moving around in real-time, which will lead to a better understanding of what is going on in gene expression.

Han has an extensive background in chemistry and optical microscopy. He also has some experience in creating new technology with biomedical applications. In 2018 he developed a highly inclined swept tile (HIST) microscope, which can be used for single-molecule imaging in a very large imaging area.

Belmont, from the School of Molecular and Cellular Biology, has been conducting pioneering work in the movement and organization of chromosomes within the nucleus.

Belmont's lab suspects there may be at least two compartments in the nucleus of a cell that are involved in increasing gene expression. One is the nuclear speckle periphery. There may be other places that are critical. To know for sure, they need to be able to observe what is going on, which is why the microscope is so important.

Also on the team, is Yaron Shav-Tal, a researcher at Bar-Ilan University. He will lend his expertise in RNA movement and transport within cells. Together they plan to shed new light on nuclear dynamics and their impact on the biology of gene regulation.

Han is an assistant professor in the College of Optics and Photonics. This is Han's second NIH grant in less than 30 days. Earlier this month he became the university's first faculty member to be awarded the National Institutes of Health's Maximizing Investigators' Research Award for early-stage investigators.

Before joining UCF in 2016, Han worked at the Max Planck Institute in Germany where he studied super-resolution fluorescence imaging.

His postdoctoral research, at the University of Illinois at Urbana-Champaign, focused on designing new optical tools for biological applications, such as studying DNA-protein interactions, RNA imaging in live-cells, and revealing nuclear structure in mammalian cells. He has one patent, which was commercialized by Leica.

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Cell biologists and bioimaging expert team up to solve fourth dimension secrets - News-Medical.net

Cell Biology

Interdisciplinary work highlighted at COVID-19 Research Symposium – The Mix

One participant said, It seems like weve done 10 years of work in seven months!

Kevin Harrod, Ph.D.Jeanne Marrazzo, M.D., director of Infectious Diseases, got a text at the end of Wednesdays four-hour School of Medicine COVID-19 Research Symposium that highlighted the broad and breakneck work done at the University of Alabama at Birmingham since March 2020.

It seems like weve done 10 years of work in seven months! she told participants.

Presentations by eight leading UAB researchers buoyed that sentiment. Among the work:

One hallmark of all eight presentations? An extreme interdisciplinary collaboration of researchers and clinicians across the hospital and university campus, that co-convener Etty Tika Benveniste, Ph.D., called remarkable. Research presented by Fran Lund, Ph.D., for example, involved eight different labs and 30 researchers.

Here are brief highlights of each presentation.

The first two presenters, Lund and Paul Goepfert, M.D., looked at how two kinds of the immune systems white blood cells respond in patients with COVID-19.

Lund, an international expert in B cell biology, was able to isolate B cells from patients that made antibodies against the SARS-CoV-2 virus spike protein. Her team found that many of these antibodies were cross-reactive against the spike proteins from SARS or MERS, which suggested that the antibody protection might wane. She also briefly mentioned her work to test the Altimmune Inc. intranasal vaccine candidate that would be the first intranasal vaccine for COVID-19 and might be effective at preventing transmission.

Steven Rowe, M.D.Goepferts team found a surprising result: Peripheral T follicular helper cells against SARS-CoV-2 continue to increase during convalescence, and they are more activated in severe patients who are in intensive care.

Immunologic studies like those of Lund and Goepfert are vital for understanding how the body responds to SARS-CoV-2 infection, as a prelude to learning how to better treat the disease.

In the section on optimizing diagnosis and treatment, Erdmann talked about several other clinical trials besides the remdesivir trial. He noted that UAB has been quite successful in minority enrollment for inpatient trials, and said UAB researchers have been able to enroll 159 convalescent patients and 846 hospitalized patients for donations of high-quality biological samples like peripheral blood monocytes, blood plasma, urine and oral saline rinses.

After he finished, Marrazzo said, You highlighted the absolutely herculean efforts to do this exceptionally collaborative work at UAB.

Besides the creation and expansion of the UAB COVID-19 test, Leal described how his team was able to adapt that test to screen 250,000 students who were returning to Alabama colleges in August, by using a pooled-sample method. Now, as flu season approaches, the clinical lab is adjusting its test to detect both SARS-CoV-2 and seasonal influenza in a single test. They are also beginning to incorporate prognostic tests of things like interferon-beta or various cytokines into the COVID-19 test. The goal is being able to identify those who are more at risk for severe disease.

In Harrods drug screening, he identified tocopherol polyethylene glycol succinate (TPGS) an existing drug that is a Vitamin E precursor as a drug that acts in synergy with remdesivir. This is important because the TPGS could then lessen the amount of remdesivir needed to treat patients. Remdesivir is in short supply. Intriguingly, his team also found that ivacaftor, a cystic fibrosis drug, is effective against SARS-CoV-2 in the cell culture assays, opening the door to studying its mechanism of action.

The second presenter in basic science discovery, along with Harrod, was Steven Rowe, M.D., director of the Gregory Fleming James Cystic Fibrosis Research Center at UAB. He is testing ferrets as an animal model of severe COVID-19 disease, to fill the urgent need for such a model. His team has found that infection with SARS-CoV-2 disrupts mucociliary clearance in the ferret trachea, as measured by micro-optical coherence tomography, which is similar to the laser eye test that creates a profile of a patients retina. This test is now being adapted to quantify mucociliary clearance the escalator-like movement of mucus from the lungs to the throat in patients with COVID-19.

Paul Goepfert, M.D.,Nathan Erdmann, M.D., Ph.D., and Fran Lund, Ph.D.The final section of the symposium focused on COVID-19 and health disparities.

Mona Fouad, M.D., noted that COVID-19 deaths are higher in African Americans and Hispanics than whites, and she said that, as the pandemic arrived, the UAB Minority Health and Health Disparities team pivoted to COVID-19. They created a Community Mobile Testing Model with three parts: engaging and educating communities about COVID-19 and dispelling myths; bringing mobile testing to vulnerable communities; and creating patient navigators to help people with COVID-19. Navigators are people who have had experiences similar to those of the communitys people and understand their needs.

Jefferson County CARES Act funding expanded the program to 33 test sites in 18 communities in the county. Of the adults tested, Hispanics had a 29 percent positivity rate, African Americans 9 percent and whites 5 percent.

The final UAB presenter was Selwyn Vickers, M.D., dean of the UAB School of Medicine. He said a meeting he had with 13 Black medical leaders nationwide identified COVID-19 as a crisis within a crisis. African Americans already had health disparities, caused in part by disparities in education and socio-economic determinants, before the added burden of a pandemic.

The deadly combination of COVID-19 with the preexisting social determinants was like throwing gasoline on a fire, he said, a combination of smoldering chronic disease and an acute respiratory infection. Even more than African Americans, the worst-hit in the United States are Native Americans.

To help address disparities, Vickers said we need to prepare for a second surge of COVID-19, ensure equitable treatment and vaccine availability, invest in public health, and invest in reducing the social determinants of health disparities.

Mona Fouad, M.D., Selwyn Vickers, M.D., andSixto Leal, M.D., Ph.D.At UAB, Marrazzo is the C. Glenn Cobbs, M.D., Endowed Professor in Infectious Diseases and a professor in the Department of Medicine; Benveniste is the senior vice dean for Basic Sciences in the School of Medicine, the Charlene A. Jones Endowed Chair in Neuroimmunology, and professor, Department of Cell, Developmental and Integrative Biology; Lund is the Charles H. McCauley Professor and chair, Department of Microbiology; Goepfert is director of the Alabama Vaccine Research Clinic and professor, Department of Medicine, Division of Infectious Diseases; and Erdmann is an assistant professor, Department of Medicine, Division of Infectious Diseases.

Also, Leal is assistant professor, Department of Pathology; Harrod is the Benjamin Monroe Carraway Endowed Chair and professor, Department of Anesthesiology and Perioperative Medicine; Rowe is professor, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine; Fouad is senior associate dean of Diversity and Inclusion, professor, Department of Medicine, and director, Division of Preventive Medicine; and Vickers is the James C. Lee Jr. Endowed Chair, senior vice president for Medicine and dean, School of Medicine.

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Interdisciplinary work highlighted at COVID-19 Research Symposium - The Mix