New Vaccine Blocks COVID-19 and Variants, Plus Other Coronaviruses (Medicine)

Study in animals identifies a potential way to build vaccines to fight future pandemics

A potential new vaccine developed by members of the Duke Human Vaccine Institute has proven effective in protecting monkeys and mice from a variety of coronavirus infections — including SARS-CoV-2 as well as the original SARS-CoV-1 and related bat coronaviruses that could potentially cause the next pandemic.

The new vaccine, called a pan-coronavirus vaccine, triggers neutralizing antibodies via a nanoparticle. The nanoparticle is composed of the coronavirus part that allows it to bind to the body’s cell receptors, and is formulated with a chemical booster called an adjuvant. Success in primates is highly relevant to humans.

The findings appear Monday, May 10 in the journal Nature.

“We began this work last spring with the understanding that, like all viruses, mutations would occur in the SARS-CoV-2 virus, which causes COVID-19,” said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “The mRNA vaccines were already under development, so we were looking for ways to sustain their efficacy once those variants appeared.

“This approach not only provided protection against SARS-CoV-2, but the antibodies induced by the vaccine also neutralized variants of concern that originated in the United Kingdom, South Africa and Brazil,” Haynes said. “And the induced antibodies reacted with quite a large panel of coronaviruses.”

Haynes and colleagues, including lead author Kevin Saunders, Ph.D., director of research at DHVI, built on earlier studies involving SARS, the respiratory illness caused by a coronavirus called SARS-CoV-1. They found a person who had been infected with SARS developed antibodies capable of neutralizing multiple coronaviruses, suggesting that a pan-coronavirus might be possible.

The Achilles heel for the coronaviruses is their receptor-binding domain, located on the spike that links the viruses to receptors in human cells. While this binding site enables it to enter the body and cause infection, it can also be targeted by antibodies.

The research team identified one particular receptor-binding domain site that is present on SARS-CoV-2, its circulating variants and SARS-related bat viruses that makes them highly vulnerable to cross-neutralizing antibodies.

The team then designed a nanoparticle displaying this vulnerable spot. The nanoparticle is combined with a small molecule adjuvant — specifically, the toll-like receptor 7 and 8 agonist called 3M-052, formulated with Alum, which was developed by 3M and the Infectious Disease Research Institute. The adjuvant boosts the body’s immune response. 

In tests of its effect on monkeys, the nanoparticle vaccine blocked COVID-19 infection by 100%. The new vaccine also elicited significantly higher neutralizing levels in the animals than current vaccine platforms or natural infection in humans. 

“Basically what we’ve done is take multiple copies of a small part of the coronavirus to make the body’s immune system respond to it in a heightened way,” Saunders said. “We found that not only did that increase the body’s ability to inhibit the virus from causing infection, but it also targets this cross-reactive site of vulnerability on the spike protein more frequently. We think that’s why this vaccine is effective against SARS-CoV-1, SARS-CoV-2 and at least four of its common variants, plus additional animal coronaviruses.”

“There have been three coronavirus epidemics in the past 20 years, so there is a need to develop effective vaccines that can target these pathogens prior to the next pandemic,” Haynes said. “This work represents a platform that could prevent, rapidly temper, or extinguish a pandemic.”

In addition to Haynes and Saunders, study authors include Esther Lee, Robert Parks1,5, David R. Martinez, Dapeng, Haiyan Chen, Robert J. Edwards, Sophie Gobeil, Maggie Barr, Katayoun Mansour, S. Munir Alam, Laura L. Sutherland, Fangping Cai, Aja M. Sanzone, Madison Berry, Kartik Manne, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Anyway B. Kapingidza, Mihai Azoitei, Longping V. Tse, Trevor D. Scobey, Rachel L. Spreng, R. Wes Rountree, C. Todd DeMarco, Thomas N. Denny, Christopher W. Woods, Elizabeth W. Petzold, Thomas H. Oguin III, Gregory D. Sempowski, Matthew Gagne, Daniel C. Douek, Mark A. Tomai, Christopher B. Fox, Robert Seder, Kevin Wiehe, Drew Weissman, Norbert Pardi, Hana Golding, Surender Khurana, Priyamvada Acharya, Hanne Andersen, Mark G. Lewis, Ian N. Moore, David C. Montefiori and Ralph S. Baric.

The study received funding from the State of North Carolina with funds from the federal CARES Act; the National Institutes of Health (AI142596, R01AI157155 U54 CA260543, F32 AI152296, T32 AI007151); the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund; and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award. COVID sample processing was performed in the Duke Regional Biocontainment Laboratory, which received partial support for construction from the NIH/NIAD (UC6AI058607) with support from a cooperative agreement with DOD/DARPA (HR0011-17-2-0069).


Provided by Duke Health

Spacing Pfizer COVID-19 Jabs Increases Antibodies in Older People (Medicine)

The second dose of the Pfizer COVID-19 vaccine produced a 3.5-times greater antibody response when given at 12 weeks, compared to three weeks, in people over 80.

The new study is supported by the UK Coronavirus Immunology Consortium. It was jointly funded by UK Research and Innovation and the National Institute for Health Research and supported by the British Society for Immunology.

To provide real-time information in the pandemic, these preliminary results will be posted on the medRxiv preprint server and submitted to a journal to undergo peer review.

175 people aged over 80

The study was led by the University of Birmingham in collaboration with Public Health England (PHE) and involved 175 people who were aged over 80 and living independently.

It is the first direct comparison of the immune response in any age group between those given the second Pfizer vaccine at a three-week interval and those at a 12-week interval.

The Pfizer vaccine was originally authorised for a three-week interval between doses. However several countries, including the UK, chose to expand this to a 12-week interval to allow a higher percentage of the population to receive one vaccine dose quicker.

Increased antibody response

The research found that extending the second dose interval to 12 weeks increased the peak SARS-CoV-2 spike specific antibody response 3.5-fold. This is compared to those who had the second vaccine at three weeks.

Although the peak cellular immune responses were lower after the delayed second vaccine, responses were comparable between the groups when measured at a similar time point following the first dose.

The team concluded that extending administration of the second Pfizer vaccine to 12 weeks potentially enhances and extends antibody immunity. This is believed to be important in virus neutralisation and prevention of infection.

Large-scale protection

First author Dr Helen Parry, at the University of Birmingham, said:

SARS-CoV-2 vaccines have been remarkably effective in providing large-scale protection against infection and symptomatic disease – but many questions remain regarding their optimal delivery for provision of effective and sustained immunity.

This is the first time antibody and cellular responses have been studied when the second vaccine is given after an extended interval. Our study demonstrates that peak antibody responses after the second Pfizer vaccine are markedly enhanced in older people when this is delayed to 12 weeks.

This research is crucial, particularly in older people, as immune responses to vaccination deteriorate with age. Understanding how to optimise COVID-19 vaccine schedules and maximise immune responses within this age group is vitally important.

Corresponding author Professor Paul Moss, at the University of Birmingham and principal investigator of the UK Coronavirus Immunology Consortium, added:

The enhanced antibody responses seen after an extended interval may help to sustain immunity against COVID-19 over the longer term and further improve the clinical efficacy of this powerful vaccine platform.

Our research findings may be important in the development of global vaccination strategy as extension of interval of the second vaccine dose in older people may potentially reduce the need for subsequent booster vaccines.

Blood samples for analysis

The research saw the team taking blood samples for analysis in the lab after participants’ first vaccine and then again two to three weeks after participants had received their second vaccine.

Of the cohort:

  • 99 participants had the second vaccine at three weeks
  • 73 had the second dose at 12 weeks.

Participants who had previous infection (10 in the three-week interval group and five in the 12-week interval group) were excluded from the analysis. Previous infection has been shown to have a major impact on the immune response to vaccination (University of Birmingham website).

After their second vaccine, spike-specific antibodies were detected in all participants no matter how far apart their doses were. However, after the second vaccine the average concentration of antibodies was 3.5 times higher in the 12-week interval group (4,030 U/ml) compared to the three-week interval group (1,138 U/ml).

Cellular immune response

The cellular (or T cell) immune response plays an important role in supporting and maintaining antibody production.

The team found that within the three-week interval group, 60% had a confirmed cellular response at two to three weeks following the second vaccine. Although this fell to only 15% eight to nine weeks later.

The proportion of participants showing a cellular response in the 12-week interval group was only 8% at five to six weeks after the first vaccine. This rose to 31% two to three weeks after the second vaccine.  Research is required to further explore these variations in responses.

Supportive evidence

Dr Gayatri Amirthalingam, Consultant Epidemiologist at PHE, said:

The higher antibody responses in people receiving two doses of the Pfizer vaccine using an extended 12-week interval provides further supportive evidence of the benefits of the UK approach to prioritise the first dose of vaccine. This analysis shows better antibody responses in those receiving their second dose at 12 weeks compared to the standard three-week schedule.

It is vital that you take up the offer of vaccination as it is the best way to protect yourself and your community and to help us out of the pandemic.

Professor Moss added:

Taking a collaborative approach to research through the UK Coronavirus Immunology Consortium and National Core Studies has allowed us to drive forward our knowledge at an incredible pace and build our understanding of how different components of the immune system respond to COVID vaccines. This knowledge will allow us to optimise vaccination protocols and maximise protection against SARS-CoV-2 within our population.

Top image: Credit: triloks/GettyImages


Provided by UKRI

Staring into Space: Physicists Predict Neutron Stars May Be Bigger Than Previously Imagined (Planetary Science)

When a massive star dies, first there is a supernova explosion. Then, what’s left over becomes either a black hole or a neutron star.

That neutron star is the densest celestial body that astronomers can observe, with a mass about 1.4 times the size of the sun. However, there is still little known about these impressive objects. Now, a Florida State University researcher has published a piece in Physical Review Letters arguing that new measurements related to the neutron skin of a lead nucleus may require scientists to rethink theories regarding the overall size of neutron stars.

In short, neutron stars may be larger than scientists previously predicted.

“The dimension of that skin, how it extends further, is something that correlates with the size of the neutron star,” said Jorge Piekarewicz, a Robert O. Lawton Professor of Physics.

Piekarewicz and his colleagues have calculated that a new measurement of the thickness of the neutron skin of lead implies a radius between 13.25 and 14.25 kilometers for an average neutron star. Based on earlier experiments on the neutron skin, other theories put the average size of neutron stars at about 10 to 12 kilometers.

Piekarewicz’s work complements a study, also published in Physical Review Letters, by physicists with the Lead Radius Experiment (PREX) at the Thomas Jefferson National Accelerator Facility. The PREX team conducted experiments that allowed them to measure the thickness of the neutron skin of a lead nucleus at 0.28 femtometers — or 0.28 trillionths of a millimeter.

An atomic nucleus consists of neutrons and protons. If neutrons outnumber the protons in the nucleus, the extra neutrons form a layer around the center of the nucleus. That layer of pure neutrons is called the skin.

It’s the thickness of that skin that has captivated both experimental and theoretical physicists because it may shed light on the overall size and structure of a neutron star. And though the experiment was done on lead, the physics is applicable to neutron stars — objects that are a quintillion (or trillion-million) times larger than the atomic nucleus.

Piekarewicz used the results reported by the PREX team to calculate the new overall measurements of neutron stars.

“There is no experiment that we can carry out in the laboratory that can probe the structure of the neutron star,” Piekarewicz said. “A neutron star is such an exotic object that we have not been able to recreate it in the lab. So, anything that can be done in the lab to constrain or inform us about the properties of a neutron star is very helpful.”

The new results from the PREX team were larger than previous experiments, which of course affects the overall theory and calculations related to neutron stars. Piekarewicz said there is still more work to be done on the subject and new advances in technology are constantly adding to scientists’ understanding of space.

“It’s pushing the frontiers of knowledge,” he said. “We all want to know where we’ve come from, what the universe is made of and what’s the ultimate fate of the universe.”

Piekarewicz’s co-authors are Brendan Reed and Charles Horowitz from Indiana University and Farrukh Fattoyev from Manhattan College.

This work is funded by the Department of Energy.

Featured image: A composite image of the supernova 1E0102.2-7219 contains X-rays from Chandra (blue and purple), visible light data from VLT’s MUSE instrument (bright red), and additional data from Hubble (dark red and green). A neutron star, the ultra dense core of a massive star that collapses and undergoes a supernova explosion, is found at its center. Photo courtesy of NASA.


Reference: Brendan T. Reed, F. J. Fattoyev, C. J. Horowitz, and J. Piekarewicz, “Implications of PREX-2 on the Equation of State of Neutron-Rich Matter”, Phys. Rev. Lett. 126, 172503 – Published 27 April 2021. DOI: https://doi.org/10.1103/PhysRevLett.126.172503


Provided by Florida State University

A Shortcut To Promising High-density Materials (Material Science)

International group establishes novel high-pressure experiment at the X-ray laser European XFEL

An international group of researchers has pioneered a new way of performing static high-pressure and high-temperature experiments, using so-called diamond-anvil cells at the X-ray laser European XFEL, and discovered a new, faster route to produce iron nitrides, promising candidates for high-density data storage and other applications. The scientists report their results in two publications.

Nitrides are compounds of nitrogen (N) and other elements. Nitrides of transition metals like iron (Fe) are an important group of industrially relevant materials because of their versatile magnetic, electrical and mechanical properties. “In particular iron nitrides have gained the interest of industry because of possible applications as high-density magnetic recording media as well as for use in catalysis and as high wear-resistant and corrosion-resistant material,” says Yongjae Lee from Yonsei University in South Korea. A team led by Lee has now found the new, extremely fast way to synthesize iron nitrides, as the scientists report in the Journal of Physical Chemistry Letters.

In their work, the researchers followed the reaction of an iron foil with nitrogen under X-ray bombardment at 50,000 times atmospheric pressure in diamond-anvil cells (DACs) – which use ultra-strong diamonds to squeeze matter during the experiments.

The reaction between the iron foil and the nitrogen was initiated by a series of ultra-bright X-ray pulses from the European XFEL. “The X-ray pulses can be used both to initiate and probe the chemical reaction,” explains lead author Huijeong Hwang. “We estimate that sample temperatures up to 5400 degrees Celsius were reached by varying the power and the repetition rate of the incident X-ray pulses.” Under the right pulse conditions, a chemical reaction between iron and nitrogen was initiated and the formation of the iron nitride designated ε-Fe3N1.33 was observed.

“The product, homogeneous iron nitride, took only hundreds of nanoseconds to form which is highly unusual,“ says co-author and high-pressure physics specialist Hanns-Peter Liermann from DESY. „Normally atomic nitrogen diffuses into solid iron at reaction times of hundreds of seconds to form iron nitride layers, and in heated diamond anvil cells di-iron nitride Fe2N was formed at similar timescales.” A nanosecond is a billionth of a second. So, the new path is roughly a billion times faster.

The X-ray pulses from the European XFEL come at intervals of 443 billionths of a second (nanoseconds) and heat the iron and nitrogen in the diamond anvil cell (green) so rapidly that iron nitride (bottom right) is formed in a few hundred nanoseconds. Credit: Yonsei University, Huijeong Hwang

“One pulse contains about a hundred billion photons and the cumulative energy over all the pulses reaching the sample and initiating the reaction amounted to about three millijoule,” calculates Liermann. The team has shown that intense X-ray laser pulses can be used to provide the necessary energy to initiate distinctive chemical reactions and be used in ‘pump-probe’ experiments to follow the evolution of reactions of solids surrounded by volatile media in high-pressure environments.

“Systematic exploration of chemical reactivity across a broad range of reactants with contrasting atomic numbers at extreme pressures and temperatures is expected to lead to the discovery of hitherto unknown pathways not only to industrially relevant compounds, but also to compounds that are needed to understand the chemistry of astrophysical objects and processes, for instance,” explains co-author Valerio Cerantola, local contact for the experiment and Instrument Scientist at European XFEL’s HED group.

The experiment is only one of a series of new static high-pressure experiments that an international group of more than 40 scientists from 22 institutions performed at the European XFEL, led by Stewart McWilliams from the University of Edinburgh. While performing these experiments, the team commissioned the new static high-pressure diamond anvil cell setup designed by the Helmholtz International Beamline for Extreme Fields (HIBEF) consortium for the High Energy Density (HED) instrument at European XFEL to create and study these extreme pressure and temperature conditions exploiting the unprecedented X-ray pulse time resolution of the European XFEL. The group describes the concepts for performing research with this novel experimental setup in the Journal of Synchrotron Radiation.

DESY is one of the founding institutions of the HIBEF consortium which is led by Helmholtz-Zentrum Dresden-Rossendorf (HZDR). The European XFEL X-ray laser in the Hamburg metropolitan region is an international research facility, powered by the world’s largest linear particle accelerator, starting at DESY. DESY is the main shareholder of the European XFEL non-profit company. At present, 12 countries have signed the European XFEL convention: Denmark, France, Germany, Hungary, Italy, Poland, Russia, Slovakia, Spain, Sweden, Switzerland, and the United Kingdom.

Featured image: View into the experimental chamber at the High Energy Density Instrument of the European XFEL. Credit: European XFEL


References:

(1) X‐ray Free Electron Laser-Induced Synthesis of ε‐Iron Nitride at High Pressures; Huijeong Hwang et al.; „Journal of Physical Chemistry Letters“, 2021; DOI: 10.1021/acs.jpclett.1c00150 (2) Novel experimental setup for megahertz X-ray diffraction in a diamond anvil cell at the High Energy Density (HED) instrument of the European X-ray Free-Electron Laser (EuXFEL); Hanns-Peter Liermann et al.; „Journal of Synchrotron Radiation“, 2021; DOI: 10.1107/S1600577521002551


Provided by DESY

Atomic Structure Of the Type 7 Secretion System of the Tuberculosis Pathogen Solved (Medicine)

In a new study, published in Nature, CSSB researchers and international collaborators reveal new insights into the structure of a key system of the tuberculosis pathogen:Type VII secretion systems are molecular machines that play key roles in the infection cycle of many pathogenic mycobacteria, including the notorious Mycobacterium tuberculosis. A deeper understanding of the structure and function of these systems can enable the development of novel therapies for the treatment of tuberculosis.

Prior to the corona virus pandemic, tuberculosis was the leading cause of death worldwide from a single infectious agent. Mistakenly considered by many to be a disease of the past, tuberculosis is a disease that still kills four thousand people every day (approximately 1.4 million every year). With the spotlight placed on combatting COVID-19, the fight against tuberculosis has now suffered additional difficulties, due to decreased options for testing and treatment during lockdown periods. WHO models are currently estimating an excess of half a million TB deaths in 2020 and a decade-long setback in the fight against TB.

To infect a human host cell, Mycobacterium tuberculosis must transport bacterial proteins across its own impermeable cell envelope. “The pathogen possesses an arsenal of dedicated molecular machines, called type VII secretion systems (T7SS), that facilitate this transport,” explains Wilbert Bitter from the Vrije Universiteit Amsterdam/Amsterdam UMC “In fact, the five different types of these systems in Mycobacterium tuberculosis are not only central for virulence but are also critical for nutrient uptake which makes them ideal drug targets to fight the disease.”

The high-resolution structure, created based on data collected by Jiri Wald at the CSSB cryo-EM facility, confirms that four components of T7SS do in fact form a six-sided star-shaped complex. The structural model also revealed that this complex is stabilized by an additional fifth component, the enzyme MycP, which the researchers discovered is essential for T7SS functioning. A group of three MycPs cap a dome-like chamber sitting at the top of T7SS’s star-shaped complex. Each MycP sits on top, like an inverted cherry, and provides stability by increasing the overall number of contact points. “In the absence of MycP the entire complex becomes more flexible, and the arms of the star begin to wobble,” explains CSSB researcher and first author Catalin Bunduc “The complex with MycP is like a stable suspension bridge and when the suspenders (MycP) are removed, the complex lacks support and sways like an unsteady footbridge.”

The data also provided new insights into how T7SSs could be able to secrete proteins in a controlled manner without allowing other molecules to leak in and out. Proteins are usually transported in an unfolded state, meaning that prior to traveling through a secretion channel the protein is untangled into a chain-like structure, reducing its width. T7SS, however, secretes proteins in at least a partially folded manner which requires a relatively large opening in the bacterial membrane. “The T7SS molecular machinery seems to form two communicating chambers, one on each side of the inner membrane which could potentially prevent leakage when a pore is opened.” notes CSSB researcher Dirk Fahrenkamp.

While tuberculosis can be treated with antibiotics, drug resistant strains are becoming increasingly more prevalent and in 2019 these represented 3.5% of new TB cases and 17.7% of previously treated cases. The structural insights gained by the researchers provide a starting platform for the identification of domains and interactions that could be targets for drug development. “Our results are a huge step forward in understanding T7SSs and Mycobacterium tuberculosis itself” explain the authors “we can now investigate potential drug binding sites that inhibit the function of T7SS and prevent the spread of infection.”

“This breakthrough not only reveals new possibilities in the fight against tuberculosis but also emphasizes the societal importance of fundamental research. Breakthroughs, like this one, can ultimately lead to practical applications that save lives,” emphasizes CSSB investigator Thomas Marlovits.

Featured image: Atomic structure of the complete type 7 secretion system of the tuberculosis pathogen Mycobacterium tuberculosis determined by cryo-electron microscopy (picture: CSSB).


Reference
Catalin M. Bunduc, Dirk Fahrenkamp, Jiri Wald, Roy Ummels, Wilbert Bitter, Edith N. G. Houben & Thomas C. Marlovits: Structure and dynamics of a mycobacterial type VII secretion system;  Nature 2021; DOI: 10.1038/s41586-021-03517-z


Provided by DESY

Brain Research Gets a Boost from Mosquitos (Neuroscience)

New versions of light-sensitive proteins could illuminate the dark corners of our brain’s communication pathways

Can a protein found in a mosquito lead to a better understanding of the workings of our own brains? Prof. Ofer Yizhar and his team in the Weizmann Institute of Science’s Neurobiology Department took a light-sensitive protein derived from mosquitos and used it to devise an improved method for investigating the messages that are passed from neuron to neuron in the brains of mice. This method, reported today in Neuron, could potentially help scientists solve age-old cerebral mysteries that could pave the way for new and improved therapies to treat neurological and psychiatric conditions.

Yizhar and his lab team develop so-called optogenetic methods – research techniques that allow them to “reverse engineer” the activity of specific brain circuits in order to better understand their function. Optogenetics uses proteins known as rhodopsins to control the activity of neurons in the mouse brain. Rhodopsins are light-sensing proteins – they are most known for their role in organs like the retina rather than in the dark inner reaches of the body. But the rhodopsins in the brains of Yizhar’s mice enable him to control the activity of specific neurons when he and his team shine a minuscule beam of light into the mouse’s brain. He is especially interested in communication between neurons: What signals are getting passed through the synapses, those gaps over which the brain’s signals move? “We can detect the presence of the various neurotransmitters, but different neurons ‘read’ those neurotransmitters differently,” he says. “Optogenetics enables us to not only see the ‘ink,’ but really to decipher the ‘message’.”

While optogenetic methods have produced a number of breakthrough results in labs around the world in recent years, they can be a bit finicky. In particular, the rhodopsins used for optogenetic studies tend to be imperfect when it comes to controlling the activity of synapses, the tiny junctions between neurons.

Rhodopsins are light-sensing proteins that are manipulated in optogenetic methods to reveal communication pathways in the brain

Yizhar and a large team of his trainees, including Dr. Mathias Mahn, Dr. Inbar Saraf Sinik and Pritish Patil, believed they could create a better version of the rhodopsins than those currently available. “We decided to look around and see what natural solutions exist out there,” says Yizhar. And nature, it turns out, contains a multitude of variations on the rhodopsin molecule – not only in animal eyes but also fish, insects, and even mammals carry them in various body parts; some possibly for regulating their circadian cycles, others for purposes as yet unknown. Thus, the team started out with a long list of potential rhodopsin proteins, and their first job involved assessing which ones were most likely to fill their experimental requirements, which primarily included light-gated proteins that are able to modulate synaptic activity. Eventually the researchers winnowed their list down to two – one taken from a pufferfish and one from a mosquito.

Segment of a mouse brain. The red illuminated areas – communication pathways between neurons that express the mosquito-derived protein. In blue – cells’ nuclei © Weizmann Institute of Science

It was the mosquito rhodopsin that turned out to be the most suitable. To evaluate the efficacy of the new mosquito-derived tool, the researchers tested their method against a drug that is known to reduce the strength of the communication between neurons in the brain. They found that the interference was just as effective, and much more stable with the mosquito rhodopsin.

More than that: Unlike a conventional drug that affects numerous parts of the brain and is hard to control, the researchers found that since only neurons that produce the mosquito sensor are affected by the light, the modulatory effect on the brain’s synapses can be precisely controlled in both space and time – just by switching the light on or off in specific brain regions. They then validated the utility of the new tool by using it to block the release of the neurotransmitter dopamine on one side of the brain only: Illuminating the hemisphere expressing the mosquito rhodopsin with green light led to a one-sided bias in the behavior of these mice. In other words, they had created a tool that was precise, selective, and controllable.

“One of the major advantages of the mosquito rhodopsin is that it’s bistable – that is, it does not need refreshing – and it is potentially very specific, so that we can control just the precise synapses in which we are interested,” says Yizhar. “This is a very exciting technology, since it will allow us to discover the roles of specific pathways in the brain in a way that was not possible before. We think this mosquito protein could open the way to developing a whole family of new optogenetic tools for use in neuroscience research.” These scientific endeavors will receive a great boost within the framework of the new Institute for Brain and Neural Sciences – Weizmann Institute’s flagship project that is expected to bring together leading research groups from various fields, which will join efforts to unfold the mysteries of the brain.

Illustration of the mosquito rhodopsin’s structure. Efficient and stable © Weizmann Institute of Science

At the beginning of 2021, Yizhar’s optogenetic research was included in Nature’s list of “Seven technologies to watch in 2021.”

Study authors also included Dr. Jonas Wietek, Dr. Julien Dine, Rivka Levy, Anna Litvin, Ido Davidi and graduate students Eyal Bitton, Shaked Palgi and Asaf Gat from Prof. Ofer Yizhar’s group – who worked alongside their European collaborators Dr. Simon Wiegert from the Center for Molecular Neurobiology in Hamburg, Dr. Benjamin Rost and Dr. Dietmar Schmitz at the Charite Research Hospital in Berlin, and Dr. Andreas Lüthi from the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel.

Prof. Ofer Yizhar is the incumbent of the Joseph and Wolf Lebovic Charitable Foundation Chair for Research in Neuroscience.

Prof. Yizhar’s research is supported by the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; and the Adelis Brain Research Award.

Featured image: A neuron with its dendritic extensions expressing the mosquito-derived protein © Weizmann Institute of Science


Reference: Mathias Mahn, Inbar Saraf-Sinik et al., “Efficient optogenetic silencing of neurotransmitter release with a mosquito rhodopsin”, Neuron, 2021. DOI: https://doi.org/10.1016/j.neuron.2021.03.013


Provided by Weizmann Institute of Science

The Triple Threat of Coronavirus (Medicine)

A new study exposes how SARS-CoV-2 tampers with the cell’s hardware to outsmart the immune system

Severe symptoms of COVID-19, leading often to death, are thought to result from the patient’s own acute immune response rather than from damage inflicted directly by the virus. Immense research efforts are therefore invested in figuring out how the virus manages to mount an effective invasion while throwing the immune system off course. A new study, published today in Nature, reveals a multipronged strategy that the virus employs to ensure its quick and efficient replication, while avoiding detection by the immune system. The joint labor of the research groups of Dr. Noam Stern-Ginossar at the Weizmann Institute of Science and Dr. Nir Paran and Dr. Tomer Israely of the Israel Institute for Biological, Chemical and Environmental Sciences, this study focused on understanding the molecular mechanisms at work during infection by SARS-CoV-2 at the cellular level.

During an infection, our cells are normally able to recognize that they’re being invaded and quickly dispatch signaling molecules, which alert the immune system of the attack. With SARS-CoV-2 it was apparent early on that something was not working quite right – not only is the immune response delayed, enabling the virus to quickly replicate, unhindered, but once this response does occur it’s often so severe that instead of fighting the virus it causes damage to its human host.

“Most of the research that has addressed this issue so far concentrated on specific viral proteins and characterized their functions. Yet not enough is known today about what is actually going on in the infected cells themselves,” says Stern-Ginossar, of the Molecular Genetics Department. “So we infected cells with the virus and proceeded to assess how infection affects important biochemical processes in the cell, such as gene expression and protein synthesis.”   

SARS-CoV-2 is able to take over the cell’s protein-making machinery in a matter of hours while evading the immune system

When cells are infected by viruses, they start expressing a series of specific anti-viral genes – some act as first-line defenders and meet the virus head on in the cell itself, while others are secreted to the cell’s environment, alerting neighboring cells and recruiting the immune system to combat the invader. At this point, both the cell and the virus race to the ribosomes, the cell’s protein synthesis factories, which the virus itself lacks. What ensues is a battle between the two over this precious resource.

The new study has elucidated how SARS-CoV-2 gains the upper hand in this battle: It is able to quickly, in a matter of hours, take over the cell’s protein-making machinery and at the same time to neutralize the cell’s anti-viral signaling, both internal and external, delaying and muddling the immune response.

Illustration of the proposed three-way strategy employed by SARS-CoV-2 during infection. 1 – Global reduction in translation; 2 – Degradation of cellular messenger RNA; 3 – Inhibition of nuclear export of messenger RNA © Weizmann Institute of Science

The researchers showed that the virus is able to hack the cell’s hardware, taking over its protein-synthesis machinery, by relying on three separate, yet complementary, tactics. The first tactic the virus uses is to reduce the cell’s capacity for translating genes into proteins, meaning that less proteins are synthesized overall. The second tactic is that it actively degrades the cell’s messenger RNAs (mRNA) – the molecules that carry instructions for making proteins from the DNA to the ribosomes – while its own mRNA transcripts remain protected. Finally, the study revealed that the virus is also able to prevent the export of mRNAs from the cell’s nucleus, where they are synthesized, to the cell’s main chamber, where they normally serve as the template for protein synthesis.

“By employing this three-way strategy, which appears to be unique to SARS-CoV-2, the virus is able to efficiently execute what we call ‘host shutoff’ – where the virus takes over the cell’s protein-synthesis capacity,” Stern-Ginossar explains. “In this way, messages from important anti-viral genes, which the cell rushes to produce upon infection, do not make it to the factory floor to be translated into active proteins, resulting in the delayed immune response we are seeing in the clinic.” The good news is that this study was also successful in identifying the viral proteins involved in the process of host shutoff by SARS-CoV-2, which could spell new opportunities for developing effective COVID-19 treatments.

Study authors also included Yaara Finkel, Avi Gluck, Aharon Nachshon, Dr. Roni Winkler, Tal Fisher, Batsheva Rozman, Dr. Orel Mizrahi and Dr. Michal Schwartz, who are all members of Dr. Noam Stern-Ginossar’s group; Dr. Yoav Lubelsky and Binyamin Zuckerman from Prof. Igor Ulitsky’s group in the Department of Biological Regulation; Dr. Boris Slobodin from the Department of Biomolecular Sciences – as well as Dr. Yfat Yahalom-Ronen and Dr. Hadas Tamir from the Israel Institute for Biological, Chemical and Environmental Sciences.

Dr. Noam Stern-Ginossar’s research is supported by Skirball Chair in New Scientists; Knell Family Center for Microbiology; American Committee for the Weizmann Institute of Science 70th Anniversary Lab; Ben B. and Joyce E. Eisenberg Foundation; Maurice and Vivienne Wohl Biology Endowment; and Miel de Botton.

Featured image: Microscopic images of cultured human lung cells infected with SARS-CoV-2. Blue (left) – staining of the cells’ nuclei; Green (center) – SARS-CoV-2 staining; Cyan (right) – cells infected with SARS-CoV-2 © Weizmann Institute of Science


Reference: Finkel, Y., Gluck, A., Nachshon, A. et al. SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis. Nature (2021). https://doi.org/10.1038/s41586-021-03610-3


Provided by Weizmann Institute of Science

What Is The Effect Of Plasma Therapy On Mortality Of Patients Having COVID-19? (Medicine)

Dr. Stephen Klassen and colleagues in their recent paper determined the effect of convalescent plasma therapy on mortality rate of patients with covid-19. They demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Their study recently appeared in Mayo Clinic Proceedings.

Convalescent plasma is a century-old passive antibody therapy that has been used to treat outbreaks of novel infectious diseases, including those affecting the respiratory system. At the onset of the pandemic, human convalescent plasma was used worldwide as it represented the only antibody-based therapy for coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Despite the emerging availability of monoclonal antibody therapies and vaccines for use in nonhospitalized patients through federal emergency authorization routes, convalescent plasma use has persisted (~100,000 units per month in the United States in early 2021) during subsequent waves of the COVID-19 pandemic because of surging hospitalizations and mortality rates. However, evidence for the efficacy of therapeutic COVID-19 convalescent plasma still requires definitive support from large randomized clinical trials (RCTs). As a result, there remains a lack of consensus on convalescent plasma use in hospitalized patients with COVID-19.

Now, Stephen Klassen and colleagues, by including 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies and 96 case reports or case series on pre-print servers or peer reviewed journals, investigated the impact of human convalescent plasma therapy on mortality of patients with covid-19.

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© Stephen Klassen et al.

They demonstrated that, the mortality rate of transfused patients with COVID-19 was lower than that of nontransfused patients with COVID-19 and suggested that early transfusion of high-titer plasma represents the optimal use scenario to reduce the risk of mortality among patients with COVID-19.

“Aggregation of mortality data from all controlled studies including RCTs and matched control studies indicated that patients transfused with convalescent plasma exhibited a 42% reduction in mortality rate compared with patients receiving standard treatment.”

— told Stephen Klassen, first author of the study

These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agents in hospitalized patients with COVID-19.

Text credit: Our author/editor: S. Aman


Reference: Stephen A. Klassen, Jonathon W. Senefeld, Patrick W. Johnson, Rickey E. Carter, Chad C. Wiggins, Shmuel Shoham, Brenda J. Grossman, Jeffrey P. Henderson, James Musser, Eric Salazar, William R. Hartman, Nicole M. Bouvier, Sean T.H. Liu, Liise-anne Pirofski, Sarah E. Baker, Noud van Helmond, R. Scott Wright, DeLisa Fairweather, Katelyn A. Bruno, Zhen Wang, Nigel S. Paneth, Arturo Casadevall, Michael J. Joyner, The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis, Mayo Clinic Proceedings, Volume 96, Issue 5, 2021, Pages 1262-1275, ISSN 0025-6196, https://doi.org/10.1016/j.mayocp.2021.02.008. (https://www.sciencedirect.com/science/article/pii/S0025619621001403)


Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author S. Aman or provide a link of our article

Bio-inspired Scaffolds Help Promote Muscle Growth (Medicine)

Rice University bioengineers adapt extracellular matrix for electrospinning

Rice University bioengineers are fabricating and testing tunable electrospun scaffolds completely derived from decellularized skeletal muscle to promote the regeneration of injured skeletal muscle.

Their paper in Science Advances shows how natural extracellular matrix can be made to mimic native skeletal muscle and direct the alignment, growth and differentiation of myotubes, one of the building blocks of skeletal muscle. The bioactive scaffolds are made in the lab via electrospinning, a high-throughput process that can produce single micron-scale fibers.

The research could ease the burden of performing an estimated 4.5 million reconstructive surgeries per year to repair injuries suffered by civilians and military personnel.

Current methods of electrospinning decellularized muscle require a copolymer to aid in scaffold fabrication. The Rice process does not.

“The major innovation is the ability to prepare scaffolds that are 100% extracellular matrix,” said bioengineer and principal investigator Antonios Mikos of Rice’s Brown School of Engineering. “That’s very important because the matrix includes all the signaling motifs that are important for the formation of the particular tissue.”

The scaffolds leverage bioactive cues from decellularized muscle with the tunable material properties afforded through electrospinning to create a material rich with biochemical signals and highly specific topography. The material is designed to degrade as it is replaced by new muscle within the body.

Experiments revealed that cells proliferate best when the scaffolds are not saturated with a crosslinking agent, allowing them access to the biochemical cues within the scaffold matrix.

Aligned fibers produced via electrospinning can be used to form a tunable scaffold for growing new muscle, according to Rice University bioengineers. These fibers were fabricated with decellularized skeletal muscle extracellular matrix on a mandrel spinning at 3,000 rotations per minute. Courtesy of the Mikos Research Group

Electrospinning allowed the researchers to modulate crosslink density. They found that intermediate crosslinking led to better retention of fiber alignment during cell culture.

Most decellularized matrix for muscle regeneration comes from such thin membranes as skin or small intestine tissue. “But for muscle, because it’s thick and more complex, you have to cut it smaller than clinically relevant sizes and the original material properties are lost,” said Rice graduate student and lead author Mollie Smoak. “It doesn’t resemble the original material by the time you’re done.

“In our case, electrospinning was the key to make this material very tunable and have it resemble what it once was,” she said.

“It can generate fibers that are highly aligned, very similar to the architecture that one finds in skeletal muscle, and with all the biochemical cues needed to facilitate the creation of viable muscle tissue,” Mikos said.

Mikos said using natural materials rather than synthetic is important for another reason. “The presence of a synthetic material, and especially the degradation products, may have an adverse effect on the quality of tissue that is eventually formed,” he said.

“For eventual clinical application, we may use a skeletal muscle or matrix from an appropriate source because we’re able to very efficiently remove the DNA that may elicit an immune response,” Mikos said. “We believe that may make it suitable to translate the technology for humans.”

Rice University graduate students Katie Hogan, left, and Mollie Smoak prepare to fabricate a scaffold with an electrospinner. The scaffolds derived from decellularized skeletal muscle are designed to promote regeneration of injured skeletal muscle. Photo by Jeff Fitlow

Smoak said the electrospinning process can produce muscle scaffolds in any size, limited only by the machinery.

“We’re fortunate to collaborate with a number of surgeons, and they see promise in this material being used for craniofacial muscle applications in addition to sports- or trauma-induced injuries to large muscles,” she said. “These would include the animation muscles in your face that are very fine and have very precise architectures and allow for things like facial expressions and chewing.”

Co-authors of the paper are Rice graduate student Katie Hogan and Jane Grande-Allen, the Isabel C. Cameron Professor of Bioengineering. Mikos is the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering.

The National Institutes of Health, the National Science Foundation and the Ford Foundation supported the research.

Read the abstract at https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abg4123.

Featured image: Aligned myotubes formed on electrospun extracellular matrix scaffolds produced at Rice University. The staining with fluorescent tags shows cells’ expression of myogenic marker desmin (green), actin (red) and nuclei (blue) after seven days of growth. Courtesy of the Mikos Research Group


Provided by Rice University