Category Archives: Biology

Researchers Shed Light On The Mechanism Of Magnetic Sensing in Birds (Biology)

Humans perceive the world around them with five senses – vision, hearing, taste, smell and touch. Many other animals are also able to sense the Earth’s magnetic field. For some time, a collaboration of biologists, chemists and physicists centred at the Universities of Oldenburg (Germany) and Oxford (UK) have been gathering evidence suggesting that the magnetic sense of migratory birds such as European robins is based on a specific light-sensitive protein in the eye. In the current edition of the journal Nature, this team demonstrate that the protein cryptochrome 4, found in birds’ retinas, is sensitive to magnetic fields and could well be the long-sought magnetic sensor.

First author Jingjing Xu, a doctoral student in Henrik Mouritsen’s research group in Oldenburg, took a decisive step toward this success. After extracting the genetic code for the potentially magnetically sensitive cryptochrome 4 in night-migratory European robins, she was able, for the first time, to produce this photoactive molecule in large quantities using bacterial cell cultures. Christiane Timmel’s and Stuart Mackenzie’s groups in Oxford then used a wide range of magnetic resonance and novel optical spectroscopy techniques to study the protein and demonstrate its pronounced sensitivity to magnetic fields.

The team also deciphered the mechanism by which this sensitivity arises – another important advance. “Electrons that can move within the molecule after blue-light activation play a crucial role”, explains Mouritsen. Proteins like cryptochrome consist of chains of amino acids: robin cryptochrome 4 has 527 of them. Oxford’s Peter Hore and Oldenburg physicist Ilia Solov’yov performed quantum mechanical calculations supporting the idea that four of the 527 – known as tryptophans – are essential for the magnetic properties of the molecule. According to their calculations, electrons hop from one tryptophan to the next generating so-called radical pairs which are magnetically sensitive. To prove this experimentally, the team from Oldenburg produced slightly modified versions of the robin cryptochrome, in which each of the tryptophans in turn was replaced by a different amino acid to block the movement of electrons.

Using these modified proteins, the Oxford chemistry groups were able to demonstrate experimentally that electrons move within the cryptochrome as predicted in the calculations – and that the generated radical pairs are essential to explain the observed magnetic field effects.

The Oldenburg team also expressed cryptochrome 4 from chickens and pigeons. When studied in Oxford, the proteins of these species, which do not migrate, exhibit similar photochemistry to that of the migratory robin, but appear markedly less magnetically sensitive.

“We think these results are very important because they show for the first time that a molecule from the visual apparatus of a migratory bird is sensitive to magnetic fields” says Mouritsen. But, he adds, this is not definitive proof that cryptochrome 4 is the magnetic sensor the team is looking for. In all experiments, the researchers examined isolated proteins in the laboratory. The magnetic fields used were also stronger than the Earth’s magnetic field. “It therefore still needs to be shown that this is happening in the eyes of birds” Mouritsen stresses. Such studies are not yet technically possible.

However, the authors think the proteins involved could be significantly more sensitive in their native environment. In cells in the retina, the proteins are probably fixed and aligned, increasing their sensitivity to the direction of the magnetic field. Moreover, they are also likely to be associated with other proteins that could amplify the sensory signals. The team is currently searching for these as yet unknown interaction partners.

Hore says “if we can prove that cryptochrome 4 is the magnetic sensor we will have demonstrated a fundamentally quantum mechanism that makes animals sensitive to environmental stimuli a million times weaker than previously thought possible”.

The cooperation between Oldenburg and Oxford is funded by a 6-year Synergy Grant from the European Research Council (ERC) with the title ‘QuantumBirds’. The collaboration is also a key part of the Collaborative Research Center, ‘Magnetoreception and Navigation in Vertebrates’ (SFB 1372) funded by the German Research Foundation (DFG), and Ilia Solov’yov is a Lichtenberg Professor funded by the Volkswagen Stiftung.

Featured image: Migratory birds such as European robins can sense the Earth’s magnetic field. Now researchers show for the first time that a molecule from their visual apparatus is sensitive to magnetic field. © Corinna Langebrake and Ilia Solov’yov


Reference: Xu, J., Jarocha, L.E., Zollitsch, T. et al. Magnetic sensitivity of cryptochrome 4 from a migratory songbird. Nature 594, 535–540 (2021). https://doi.org/10.1038/s41586-021-03618-9


Provided by University of Oldenburg

Immune Cells in the Human Biliary System Mapped (Biology)

Researchers at Karolinska Institutet have analysed and described in detail the immune cells residing in the human bile duct. The findings may pave the way for new treatment strategies against disorders of the bile duct, which are often linked to immunological processes. The study is published in the journal Science Translational Medicine.

Over the last decade, our understanding of the composition of immune cells across most tissues has increased immensely. However, the human biliary tract has remained one of few unexplored immunological niches because of difficulties in accessing this site. The biliary system, which includes the bile duct connecting the liver with the intestine, is an organ often affected by serious inflammatory and malignant diseases.

Dismal prognosis

Portrait of Niklas Björkström.
Niklas Björkström. Photo: Markus Marcetic

“Difficulties in studying this organ has hampered our understanding of biliary diseases, many of which are severe with dismal prognosis,” says Niklas Björkström, physician and immunology researcher at the Center for Infectious Medicine, the Department of Medicine, Huddinge, Karolinska Institutet, who led the study.

To overcome this, the researchers at Karolinska Institutet, in close collaboration with clinical scientists at the Karolinska University Hospital, employed a novel clinical examination method for retrieving and studying immune cells localised in the biliary system. With this method, they managed to retrieve immune cells from the bile duct of 125 patients and in detail characterise each of these immune cells.

The researchers compared immune cells from patients with primary sclerosing cholangitis (PSC), a severe inflammatory disease of the biliary system, with immune cells from non-inflammatory controls. PSC patients had a high infiltration of immune cells called neutrophils and T cells in their bile ducts that seemed to cooperate in causing an inflammatory environment.

Resource for future studies

“Our study sheds new light on the immunological processes involved in PSC,” says Niklas Björkström. “It also helps uncover the immunological niche of human bile ducts, which is a major step forward and will provide an important resource for future studies of the immune response in biliary disorders.”

The research was funded by the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Cancer Research Foundations of Radiumhemmet, Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, the Center for Innovative Medicine at Karolinska Institutet, Region Stockholm, and Karolinska Institutet. The authors declare that there is no conflict of interest.

Publication

“A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells”. Christine L. Zimmer, Erik von Seth, Marcus Buggert, Otto Strauss, Laura Hertwig, Son Nguyen, Alicia Y. W. Wong, Chiara Zotter, Lena Berglin, Jakob Michaëlsson, Marcus Reuterwall Hansson, Urban Arnelo, Ernesto Sparrelid, Ewa C. S. Ellis, Johan D. Söderholm, Åsa V. Keita, Kristian Holm, Volkan Özenci, Johannes R. Hov Jeff E. Mold, Martin Cornillet, Andrea Ponzetta, Annika Bergquist, and Niklas K. BjörkströmScience Translational Medicine, online 23 June, 2021, doi: 10.1126/scitranslmed.abb3107.

Featured image credit: Getty images


Provided by Karolinska Institute

Researchers Discover How To Reverse Cardiac Scarring And How This Could Treat Heart Failure (Biology)

A healthy heart is a pliable, ever-moving organ. But under stress—from injury, cardiovascular disease, or aging—the heart thickens and stiffens in a process known as fibrosis, which involves diffuse scar-like tissue. Slowing or stopping fibrosis to treat and prevent heart failure has long been a goal of cardiologists.

Now, researchers at Gladstone Institutes have discovered a master switch for fibrosis in the heart. When the heart is under stress, they found, the gene MEOX1 is turned on in cells called fibroblasts, spurring fibrosis. Their new study, published in the journal Nature, suggests that blocking this gene could prevent fibrosis in the heart—and other organs that can similarly fail from stiffening over time.

“With these findings, we may have an entirely new way to stop that slow but steady progression of heart failure that affects 24 million people worldwide,” says Deepak Srivastava, MD, president and senior investigator at Gladstone and senior author of the study. “Right now, we don’t have any drugs that effectively prevent fibrosis.”

Deepak Srivastava, senior investigator at Gladstone Institutes
Deepak Srivastava and his team hope to identify a new approach to prevent the detrimental development of scar-like tissue in the heart and other organs. ©Gladstone Institutes

Fibroblasts are key to normal organ repair and integrity; they’re the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function.

Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn’t clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity.

“To treat a heart failure patient with a BET inhibitor is a sledgehammer approach, because we might prevent fibrosis, but we’d likely also disrupt many other critical cellular functions throughout the body in the process,” says Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). “Our hope was that if we could understand the precise mechanism through which BET works in the heart, we could home in on a narrower target with fewer side effects.”

Srivastava’s group studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics—which can reveal which genes in a cell are accessible and being turned on at any given time—to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function.

These technologies allowed the researchers to analyze thousands of cells at once, and separate them based on their specific cell type. Thanks to a close collaboration with the laboratory of Katie Pollard, PhD, at Gladstone, they developed new computational methods to learn from the vast amount of data generated by their analysis.

While the scientists didn’t find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart.

In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor. Moreover, the levels of MEOX1 correlated with activation of the fibroblasts; when the gene was switched on, the fibroblasts were better at making scar tissue. In fact, MEOX1 seemed to be a “master regulator” of fibroblast activation, controlling thousands of other genes that contribute to fibrosis.

MEOX1 is a gene known to be important in early development, but not much was known about it in adult disease, so our findings were quite surprising,” says Michael Alexanian, PhD, a Gladstone postdoctoral scholar and first author of the new study.

Michael Alexanian, postdoc at Gladstone Institutes
Michael Alexanian, the study’s first author, showed that deleting a small part of DNA blocks the activation of fibroblasts. © Gladstone Institutes

The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress.

The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor—it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts.

“Fibrosis is much broader than just the heart; it affects many other organs,” says Srivastava. “We hope this discovery provides an avenue to slow down or stop fibrosis in many settings.”

More studies are needed to show whether blocking MEOX1 could have therapeutic value in humans. Srivastava and his colleagues are now conducting additional studies to better understand the long-term role of MEOX1 in heart disease and heart failure.

“In a coordinated effort to design novel therapies for heart failure, researchers are looking for molecular clues to use as therapeutic targets,” says Bishow Adhikari, PhD, a program officer in the heart failure and arrhythmias branch, located within the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute. “These findings are highly informative and bring researchers closer to advancing new therapeutic strategies to better predict and treat heart disease.”

About the Study

The paper “A Transcriptional Switch Governs Fibroblast Activation in Heart Disease” was published by the journal Nature on June 23, 2021.

Other authors are: Pawel Przytycki, Arun Padmanabhan, Lin Ye, Bárbara Gonzàlez Teràn, Ana Catarina Silva, Qiming Duan, Sanjeev Ranade, Franco Felix, Clara Yougna Lee, Nandhini Sadagopan, Angelo Pelonero, Yu Huang, Casey Gifford, and Saptarsi Haldar of Gladstone; Rudi Micheletti and Michael Rosenfeld of UC San Diego; Joshua Travers and Timothy McKinsey of University of Colorado; Ricardo Linares-Saldana, Li Li and Rajan Jain of University of Pennsylvania; and Gaia Andreoletti of UCSF.

The work at Gladstone was supported by the Swiss National Science Foundation, the National Institutes of Health (P01 HL098707, HL098179, R01 HL127240, P01 HL146366, R01 HL057181, R01 HL015100, C06 RR018928), the San Simeon Fund, the Tobacco‐Related Disease Research Program, A.P. Giannini Foundation, Michael Antonov Charitable Foundation Inc., Sarnoff Cardiovascular Research Foundation, the American Heart Association, the Roddenberry Foundation, the L.K. Whittier Foundation, Dario and Irina Sattui, and the Younger Family Fund.

Featured image: Michael Alexanian, a postdoc in the Srivastava Lab, helped discover a gene that could prevent fibrosis in the heart. © Gladstone Institutes


Provided by Gladstone Institutes

Asian Elephants Do More Than Just Trumpet- They Buzz Their Lips to Squeak (Biology)

The animals’ sound production does not only come from the trunk

Communication is crucial for elephants that live in complex multi-tiered social systems. Apart from their iconic trumpets uttered through the trunk, Asian elephants also produce species-specific squeaks by buzzing their lips. This demonstrates once again the elephant’s flexibility in sound production. These results are presented in a publication in “BMC Biology” by behavioural biologist Veronika Beeck from the University of Vienna and colleagues.

Everybody from a child knows that elephants trumpet. Over the past decades research in general and at the University of Vienna has mainly studied the elephants low-frequency rumble. Its fundamental frequency reaches into the infrasonic range below the human hearing threshold. This call is produced by the elephant´s massive vocal folds. Much less was known about how elephants produce their higher pitched sounds, trumpets and squeaks.

The following rule generally applies to sound production in mammals: the larger the vocal fold, the lower the calls fundamental frequency. Conversely the size of the vocal folds sets an upper limit to the fundamental frequencies that can be reached. The high-pitched squeak only Asian but not African elephants produce when aroused, do not fit within that spectrum.

In her recent study Veronika Beeck, who is part of the FWF doctorate school Cognition and Communication at the Department of Behavioural and Cognitive Biology at the University of Vienna and her supervisor Angela Stöger, together with Gunnar Heilmann and Micheal Kerscher from gfai tech, Berlin, studied the squeak sounds of Asian elephants in Nepal.

The researchers used an acoustic camera with an array of 48 microphones that visualises sounds in colours similar to a thermic camera. In this way the sound source was precisely located. “Our images clearly demonstrate that the squeaks are emitted by the mouth and not the trunk”, Veronika Beeck explains. 

According to the researcher’s theory the Asian elephants produce squeaks by pressing air through their tensed lips inducing the lip´s vibration. This technique equals the human brass players lip buzzing to produce a complex sound whose harmonic overtones are subsequently resonated by the instrument, resulting in its characteristic brassy sound. “Apart from human brass players this technique of lip buzzing to produce sounds has, to our knowledge, not been described in any other animal species and is thus considered unique in the animal kingdom”, says Veronika Beeck.

The elephants iconic trumpet on the other hand is produced by a blast of air through the trunk. Here again, however, the vibrating anatomic sound source is not yet conclusively studied.

This new evidence further highlights the elephant´s flexibility in sound production. A few years ago, Angela Stöger-Horwath showed that elephants are capable of learning novel sounds. An Asian elephant in a Korean Zoo, by imitating his trainer, learned to speak some words in Korean. Since only a few elephants in this recent study squeaked the researchers suggest that squeaks might be learned, too.

Featured image: With the acoustic camera´s star-shaped array of microphones placed in front of the elephant the researchers are waiting patiently for her to vocalize while night falls. (© Gunnar Heilmann)


Publication in BMC Biology:

  • A novel theory of Asian elephant high-frequency squeak production.
  • Veronika C. Beeck, Gunnar Heilmann, Michael Kerscher, Angela S. Stoeger
  • DOI: BMCB-D-20-01049

Provided by University of Wien

Geckos Might Lose Their Tails, But Not Their Dinner (Biology)

Ability to capture prey unaffected by defensive tail detachment

 UC Riverside study finds geckos are fierce hunters whether or not their tails are attached to their bodies. 

Geckos and other lizards can distract predators by quickly dropping their tails. The tail vertebrae are perforated, making it easier to disconnect them without any formation of scar tissue or loss of blood. Though this ability can keep lizards from being eaten, the maneuver is performed at a cost.  

“Other studies have documented the negative effects of tail loss on lizards’ ability to run, jump, mate, and reproduce,” said UCR biologist Marina Vollin, lead author of the study. “However, few have examined their ability to capture food when they lose their tails, which is critical for regenerating the tail and for overall survival.”

To help fill this gap in understanding, Vollin and Tim Higham, an associate professor in UCR’s Department of Evolution, Ecology, and Organismal Biology, observed intact and newly tailless geckos on the hunt. Their work is published in a recent Integrative and Comparative Biology journal article. 

western banded gecko
The Western banded gecko, as seen in San Bernardino County, California. (Connor Long)

The researchers found that geckos successfully captured crickets about 77% of the time both before and after losing tails — a surprising retention of accuracy since tails appear to help stabilize gecko body positions during and after a strike.

“The geckos were much slower without tails, and their attack strikes much more awkward,” Vollin said.

Western banded geckos, native to the southwestern U.S. and Mexico, are one of the few reptiles that help control scorpion populations. 

In this study, the geckos were observed hunting crickets in artificial enclosures. Vollin and Higham are planning future studies in which they hope to observe geckos hunting in the wild and feeding on other small insects. 

“It is very possible that geckos suffer a loss in feeding performance and success following autotomy in nature given the complexity of the habitat and more room for the prey to escape,” Higham said. 

They’ll also study whether geckos are able to fully regain their agility once their tails have regenerated, which can take up to a month.

Newly tail-less gecko capturing cricket prey. (Marina Vollin/UCR)

“It’s important to get a sense of how they operate in nature, where additional elements could affect whether they have more difficulty capturing prey,” Vollin said.

Understanding how lizards like the Western banded gecko are able to survive carries a significance beyond the lizards themselves. Though they eat a variety of small insects, they also serve as a key food source for birds, snakes, and other predatory mammals. 

“I’ve heard them referred to as ‘nature’s popcorn,’ because other animals can eat a bunch of them at once, they’re abundant, and easy to acquire,” Vollin said. “They’re a big part of the base of the food chain.”


Provided by University of California Riverside

How Does the One-humped Arabian Camel Survive Without Drinking? (Biology)

Research led by scientists at the University of Bristol has shed new light on how the kidneys of the one-humped Arabian camel play an important role in helping it to cope with extremes.

In a new paper published today in the journal Communications Biology, they have studied the response of the camel’s kidneys to dehydration and rapid rehydration stresses.

Camelus dromedarius is the most important livestock animal in the arid and semi-arid regions of North and East Africa, the Arabian Peninsula and Iran, and continues to provide basic needs to millions of people.

Thought to have been domesticated 3,000 to 6,000 years ago in the Arabian Peninsula, the camel has been used as a beast of burden, for riding and sport, and to produce milk, meat and shelter, and they are still used today for the same purposes.

This animal is so incredibly well adapted to the desert environment that can endure weeks without access to water. A very well-developed kidney is the key to produce highly concentrated urine and assure water is never wasted.

In the current context of advancing desertification and climate change, there is renewed interest in the adaptations of camels. Further, advanced laboratory techniques allow to study the underlying genetic mechanisms of these adaptations.

However, there was not to date, a freely available and comprehensive study of the genes implicated in coping with dehydration in the kidney of the camel.

This project was born in 2015 with the onset of a fruitful collaboration between Professor David Murphy’s Lab at University of Bristol and Professor Abdu Adem’s Lab at United Arab Emirates University.

The team analysed how thousands of genes changed in the camel kidney as a consequence of dehydration and rehydration and suggested that the amount of cholesterol in the kidney has a role in the water conservation process. They used different techniques to further validate these results.

Lead authors Fernando AlviraI Iraizoz and Benjamin T. Gillard from the University of Bristol’s Medical School, said: “A decrease in the amount of cholesterol in the membrane of kidney cells would facilitate the movement of solutes and water across different sections of the kidney – a process that is required to efficiently reabsorb water and produce a highly concentrated urine, thus avoiding water loss.

“This is, to the best of our knowledge, the first time that the level of cholesterol has been directly associated with water conservation in the kidney. Thus, we describe a novel role for this lipid that may be of interest when studying other species.”

The team also presents an immense source of information that, as mentioned by one of the reviewers, is very valuable in the context of climate change and thus will help scientists to understand the mechanisms of water control in dehydration.

Following the publication of this research, the team are now looking at how the camel brain responds to the same stimuli and how other species, such as jerboas and Olive mice, adapt to life in the deserts.

Further information

‘Multiomic analysis of the Arabian camel (Camelus dromedarius) kidney reveals a role for cholesterol in water conservation’ by Fernando Alvira-Iraizoz, Benjamin T. Gillard, Panjiao Lin, Alex Paterson, Audrys G. Pauža, Mahmoud A. Ali, Ammar H. Alabsi, Pamela A. Burger, Naserddine Hamadi, Abdu Adem, David Murphy, Michael P. Greenwood in Communications Biology


Provided by University of Bristol

MicroRNAs May Play A Role in COVID-19 (Biology)

New research published in the Journal of Cellular and Molecular Medicine indicates that SARS-CoV-2, the virus that causes COVID-19, produces microRNAs that can have impacts on infected cells. MicroRNAs are genetic molecules that prevent the production of particular proteins by binding to and destroying messenger RNAs that code for those proteins.

Investigators found that the virus’ microRNAs affect individuals’ respiratory system, immune response, and vitamin D pathways. Understanding these impacts could provide new insights related to SARS-CoV-2 infection, pathogenesis, and treatment.

“Our finding highlighted genes’ involvement in three crucial molecular pathways and may help develop new therapeutic targets related to SARS-CoV-2,” the authors wrote.


Reference: Karimi, E, Azari, H, Yari, M, Tahmasebi, A, Hassani Azad, M, Mousavi, P. Interplay between SARS-CoV-2-derived miRNAs, immune system, vitamin D pathway and respiratory system. J Cell Mol Med. 2021; 00: 1– 15. https://doi.org/10.1111/jcmm.16694


Provided by Wiley

Engineering Nanobodies As Lifesavers When SARS-CoV-2 Variants Attack (Biology)

In lab, molecules inhibit effectively, access nooks too small for human antibodies

Scientists are pursuing a new strategy in the protracted fight against the SARS-CoV-2 virus by engineering nanobodies that can neutralize virus variants in two different ways.

In lab studies, researchers identified two groups of molecules that were effective against virus variants. Using different mechanisms, nanobodies in each group bypassed mutations and disabled the virus’s ability to bind to the receptor that lets it enter host cells.

Though vaccination is enabling the resumption of some pre-pandemic activities in parts of the world, SARS-CoV-2 is rapidly working its way around vaccines by mutating itself. In this study, the nanobodies neutralized three emerging variants: Alpha, Beta and Gamma.

“Companies have already started introducing the variants of concern into the construct of booster shots of the existing vaccines,” said Kai Xu, assistant professor of veterinary biosciences at The Ohio State University and a co-lead author of the research. “But the virus is constantly mutating, and the speed of mutation may be faster than we can capture. Therefore, we need to utilize multiple mechanisms to control the virus spread.”

An accelerated article preview of the study is published online in Nature.

Nanobodies are antibodies derived from immunization of camelid mammals – such as camels, llamas and alpacas – that can be re-designed into tiny molecules that mimic human antibody structures and functions.

For this work, the researchers immunized llamas to produce single-chain antibodies against SARS-CoV-2. They also immunized “nanomice,” transgenic mice with a camelid gene that had been engineered by research fellow Jianliang Xu in the lab of Rafael Casellas, senior investigator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), to generate nanobodies similar to those produced by camelids.

The team enhanced the nanobodies’ power by immunizing the animals first with the receptor binding domain (RBD), a part of the viral surface spike protein, and following with booster shots containing the entire spike protein.

“By using this sequential immunization strategy, we generated nanobodies that can capture the virion by recognizing the receptor binding domain with very high affinity,” Xu said.

The scientists tested different nanobodies’ neutralization capacity, mapping the surface of the RBD, conducting functional and structure analyses, and measuring the strength of their affinity to narrow the candidate molecules from a large library to six.

The coronavirus is highly infectious because it binds very tightly to the ACE2 receptor to gain access to lung and nasal cavity cells in humans, where it makes copies of itself to infect other cells. The receptor binding domain on the spike protein is fundamental to its success in attaching to ACE2.

“That RBD-ACE2 interface is on the top of the receptor binding domain – that region is the primary target for the protective human antibodies, generated by vaccination or previous infection, to block the viral entry,” Xu said. “But it is also a region frequently mutated in the variants.”

The way mutants have emerged so far suggests long-term reliance on current vaccines will eventually be compromised, the researchers say, because antibody effectiveness is affected significantly by those mutants at the interface.

“We found that certain nanobodies can recognize a conserved region of the receptor binding domain, a hidden location that is too narrow for human antibodies to reach,” Xu said. And attaching at this location, even though it is some distance away from where RBD connects to ACE2, still accomplishes what is intended – blocking SARS-CoV-2 from entering a host cell.

The other group of nanobodies, attracted to the RBD-ACE2 interface, while in their original form could not neutralize certain variants. However, when the researchers engineered this group to be homotrimers – three copies linked in tandem – the nanobodies achieved potent neutralization of the virus. Altering the structure of the nanobodies that attached to the conserved region of RBD in the same way enhanced their effectiveness as well.

There is much more research ahead, but the findings suggest nanobodies could be promising tools to prevent COVID-19 mortality when vaccines are compromised, Xu said.

“Our future plan is to further isolate antibodies specifically against emerging variants for therapeutic development, and to find a better solution for vaccines by learning from those antibodies,” he said.

An HIV vaccine researcher at the NIH before joining Ohio State, Xu collaborated with multiple labs on this research. Jianliang Xu and Rafael Casellas of NIAMS, and Peter Kwong of the National Institute of Allergy and Infectious Diseases, are also equal contributors on the study. In addition to numerous NIH agencies, co-author institutions include Rockefeller University, the Aaron Diamond AIDS Research Center at Columbia University and the Frederick National Laboratory for Cancer Research.

This work was supported by NIAMS, the National Cancer Institute, NIH Helix Systems, NIAID and the Frederick National Laboratory for Cancer Research.

Featured image: Though vaccination is enabling the resumption of some pre-pandemic activities in parts of the world, SARS-CoV-2 is rapidly working its way around vaccines by mutating itself. The study findings suggest nanobodies could be promising tools to prevent COVID-19 mortality when vaccines are compromised.Photo: Shutterstock.com


Reference: Xu, J., Xu, K., Jung, S. et al. Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants. Nature (2021). https://doi.org/10.1038/s41586-021-03676-z


Provided by OSU

Study Clarifies Why Some Proteins “Flock Together” in the Nucleus (Biology)

The nucleus is much more than a storage compartment for chromosomes: It also contains the complex machinery that produces transcripts of the genes that are currently needed and releases them into the cell body. Some of the proteins involved herein are not evenly distributed in the nucleus, but cluster at specific sites. A study by the universities of Würzburg, Heidelberg and Bonn with the help of Evotec SE at the Martinsried site now shows how these “flash mobs” are regulated. In the long term, the results could also yield new therapeutic approaches for spinal muscular atrophy. They are published in the journal Cell Reports.

Almost all cells in our body contain a nucleus: a somewhat spherical structure that is separated from the rest of the cell by a membrane. Each nucleus contains all the genetic information of the human being. So it serves as a kind of library – but one with strict requirements: If the cell needs the building instructions for a protein, it won’t simply borrow the original information. Instead, a transcript of it is made in the nucleus.

The machinery required for this is very complex, not least because the transcripts are not simple copies. In addition to essential information, genes also contain numerous passages of meaningless “garbage”. They are removed when the transcript is made. Biologists call this editorial revision “splicing”.

“An important role in splicing is played by the SMN complex, a ‘molecular machine’ consisting of nine different proteins,” explains Prof. Dr. Oliver Gruss from the Institute of Genetics at the University of Bonn, who is also a member of the university’s transdisciplinary research area “Life and Health”. “Interestingly, these machines are not evenly distributed in the nucleus. Instead, they accumulate at specific sites called Cajal bodies.” However, there are no transport mechanisms in the cell nucleus that bring the SMN complexes to Cajal bodies. Instead, the SMN proteins themselves have certain properties that are responsible for their aggregation. Which ones these are, was unclear until now.

SMN complexes carry an unusually large number of phosphate groups

SMN complexes have a prominent feature: They carry an unusually large number of phosphate groups, which are small molecular residues with a phosphorus atom in the center. “We suspected that this phosphorylation promotes their mass clustering into Cajal bodies,” explains Dr. Maximilian Schilling from the research group around Oliver Gruss.

Prof. Dr. Oliver Gruß
Prof. Dr. Oliver Gruss – from the Institute of Genetics at the University of Bonn.© Barbara Frommann/Uni Bonn

Phosphate groups are not part of the actual blueprint of a protein – they are added later and can also be removed again. This is often how the cell regulates the activity of the respective protein. The phosphate group is attached in this process by certain enzymes, the kinases. “We have now inhibited each of the hundreds of human kinases individually and looked at how that affects the formation of Cajal bodies,” Schilling says.

In this way, they encountered a network of kinases, which, when inhibited, caused the Cajal bodies to largely disappear. Further analyses showed that in the absence of these kinases, phosphorylation of SMN complexes at specific sites decreased sharply. This then causes the flash mobs in the nucleus to cease – the Cajal bodies disintegrate. The finding is particularly interesting because the kinases identified not only regulate splicing, but also the translation of the gene transcripts edited in this way into proteins. These are therefore enzymes that are crucial for various steps in this vital process.

Mutation causes severe disease

The SMN complex is known to human geneticists not only for its role in splicing: Individual mutations in its blueprint result in a serious disease, spinal muscular atrophy, in those affected. One in about 6,000 newborns is born with this genetic defect. Treatment is extremely expensive; the cost per patient runs into millions. “Some of the gene defects that cause spinal muscular atrophy are near the phosphorylation sites of the SMN complex,” explains Gruss. “Affected individuals may therefore have impaired attachment of phosphate groups to these sites, and consequently also impaired formation of Cajal bodies. We suspect that this causes splicing to be impaired, which subsequently results in the disease symptoms.”

The kinases identified may therefore also be suitable as a starting point for new therapies. Preliminary results from mouse model cells for human spinal muscular atrophy show that agents that increase kinase activity also improve Cajal body formation. “It is completely unclear whether these agents also ameliorate pathological changes in a complex organism,” cautions Gruss against inflated expectations. “That new treatment options will eventually emerge from this is therefore still speculation at this stage.”

Participating institutions and funding:
The universities of Bonn, Würzburg and Heidelberg were involved in the study. It was funded by the German Research Foundation (DFG) and the US-American CURE SMA Foundation.

Publication: Maximilian Schilling, Archana B. Prusty, Björn Boysen, Felix S. Oppermann, Yannick L. Riedel, Alma Husedzinovic, Homa Rasouli, Angelika König, Pradhipa Ramanathan, Jürgen Reymann, Holger Erfle, Henrik Daub, Utz Fischer and Oliver J. Gruss: TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis; Cell Reports; DOI: 10.1016/j.celrep.2021.109277 Link to the study: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00644-6

Featured image: SMN is concentrated – in the Cajal bodies (left, red) in the nucleus of human cells (blue). If phosphorylation of SMN is inhibited, the concentration ceases and Cajal bodies disappear.© AG Gruss / University of Bonn


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