Why B.1.617 Variant Of SARS-CoV-2 Is Highly Transmissible Than Others? (Biology)

There are many variants of SARS-CoV-2, the virus which causes COVID-19, but why is B.1.617 variant of SARS-CoV-2 virus is highly transmissible among all others? Recent study done by Wendy Barclay and colleagues now answered this question. They provided experimental evidence that virus of the B.1.617 variant has enhanced spike (S) cleavage and this cleavage is enhanced by P681R monobasic mutant or by an enzyme furin. Their study recently appeared in bioRxiv.

Unlike SARS-CoV, the SARS-CoV-2 spike (S) protein contains a furin cleavage site at S1/S2 junction (as shown in figure above) that enhances SARS-CoV-2 replication in airway cells and contributes to virus pathogenicity and transmissibility. The Lineage B.1.617, also known as G/452R.V3, is one of the known variants of SARS-CoV-2, the virus that causes COVID-19. It was first identified in Maharashtra, India on 5 October 2020. As of May 2021, three sublineages/subvariants have been found. Despite its name, B.1.617.3 was the first sublineage of this variant to be detected, in October 2020 in India. This sublineage has remained relatively uncommon compared to the two other sublineages, B.1.617.1 and B.1.617.2, both of which were first detected in December 2020.

Now, Barclay and colleagues investigated whether the spike (S) protein of B.1.617 undergoes a higher degree of post translational cleavage at S1/S2 than previously circulating strains. In order to know, they isolated several B.1.617 lineage viruses (1 x B.1.617.1 and 2 x B.1.617.2) and compared their S1/S2 cleavage to that of a previously circulating strain of lineage B.1.238, which contains only D614G. They found that, B.1.617 lineage S proteins were all more highly cleaved (≥50% cleaved), with a higher proportion of cleaved S2 and a lower proportion of full-length S detectable than the control virus (~33% cleaved) (Figure 1 below).

Figure 1 – P681R results in enhanced furin cleavage of the SARS-CoV-2 B.1.617 spike protein: (left panel) Western blot analysis of spike cleavage of concentrated B.1.238 (D614G) and B.1.617 (P681R containing) SARS-CoV-2 isolates. Levels of nucleocapsid (N) protein shown as loading control. Right panel: Densitometry analysis of the western blot from part (b). Densitometry measured using J. Points indicate two technical repeats from the same concentrated virus stocks. © Barclay et al.

They also characterised which amino change in the B.1.617 S is responsible for its enhanced cleavage and suggested that P681R alone is responsible for the enhanced S cleavage seen in the B.1.617 lineages viruses.

They then performed assays to determine whether the optimised cleavage site found in the B.1.617 S enables better cleavage directly by furin (an enzyme that in humans is encoded by the FURIN gene). They showed that, P681R significantly enhanced the ability of furin to cleave the peptide confirming that the arginine substitution is responsible for the enhanced cleavage of the B.1.617 spike protein.

“The virus of the B.1.617 lineage has enhanced S cleavage, that enhanced processing of an expressed B.1.617 spike protein in cells is due to P681R, and that this mutation enables more efficient cleavage of a peptide mimetic of the B.1.617 S1/S2 cleavage site by recombinant furin.  Together, these data demonstrate viruses in this emerging lineage have enhanced S cleavage by furin which we hypothesise could be enhancing transmissibility and pathogenicity.”

Finally, they concluded that, enhanced S1/S2 cleavage seen in B.1.617 and B. 1.1.7, may be contributing to the enhanced transmissibility of these SARS-CoV-2 variants. As well as B.1.1.7 and B.1.617, several other emerging variants contain mutations in the furin cleavage site. They advise that these lineages be kept under close monitoring for any early evidence of more rapid transmission or higher pathogenesis.

Reference: Thomas P. Peacock, Carol M. Sheppard, Jonathan C. Brown, Niluka Goonawardane, Jie Zhou, Max Whiteley, PHE Virology Consortium, Thushan I. de Silva, Wendy S. Barclay, “The SARS-CoV-2 variants associated with infections in India, B.1.617, show enhanced spike cleavage by furin”, bioRxiv 2021.05.28.446163; doi: https://doi.org/10.1101/2021.05.28.446163

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Researchers Uncover The Embryonic Origin of the Heart (Biology)

Researchers from the Francis Crick Institute have studied the earliest point at which the heart forms during embryonic development and revealed, for the first time, that each part of the heart has a unique origin. Their study in mice, published in PLoS Biology today (Thursday), has implications for understanding congenital heart diseases.

As an embryo develops, cells become increasingly specialised to form different tissues and organs. A key period is known as gastrulation, which leads to the formation of the main tissues of body, including the heart. 

The team, a collaboration between two leading Crick developmental biology labs, identified the cells that form the heart during gastrulation and traced each individual cell’s destiny from this earliest stage until the heart had fully formed.

They found that the four chambers of the heart all have distinct spatial and temporal origins. The very first set of cells create the left ventricle, followed by cells forming the right ventricle and finally the two atria.

We can now envisage generating cells pre-determined to become specific parts of the heart and could use these to model disease or develop and test new regenerative therapies. Kenzo Ivanovitch

Jim Smith, head of the Crick’s Developmental Biology Laboratory, said: “Investigating how different types of cell in an embryo form at the right time and in the right place is crucial for understanding why this can sometimes go wrong. Congenital heart diseases affect around one in 180 babies worldwide and work like ours may help explain why just a single chamber of the heart is affected in heart defects such as left ventricle hypoplasia.”

In their study, the team first measured gene activity in individual cells, and concluded that distinct genes are active in the predecessors of the heart at very early stages of embryonic development. This means they would be allocated to distinct anatomical structures of the heart.

They then used an advanced imaging technique called multiphoton live-imaging to microscopically film mouse embryos developing outside the womb. They were able to follow the fate of individual cells as they migrated through the embryo to establish different parts of the heart.

Kenzo Ivanovitch, lead author and postdoctoral training fellow at the Crick, said: “Our finding that different parts of the heart arise in different locations may help researchers build better models using stem cells. Current methods produce a mix of atrial and ventricular cells which can make studying diseases that affect particular chambers of the heart more difficult. 

“We can now envisage generating cells pre-determined to become specific parts of the heart and could use these to model disease or develop and test new regenerative therapies.”

James Briscoe, head of the Crick’s Developmental Dynamics Laboratory, said: “Different heart cell populations having distinct origins may mean that each group is uniquely predisposed or sensitive to genetic or environmental changes.
“New technologies are giving us unprecedented insight into the make-up and behaviour of individual cells in developing tissues. This is offering a new understanding into the causes of congenital diseases and identifying targets for new treatments.”

Featured image: Picture of mouse embryo at gestational day 8. The heart is labelled in white. © Francis Crick Institute

Reference: Ivanovitch K, Soro-Barrio P, Chakravarty P, Jones RA, Bell DM, Mousavy Gharavy SN, et al. (2021) Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak. PLoS Biol 19(5): e3001200. doi:10.1371/journal.pbio.3001200

Provided by Francis Crick Institute

Why Some Children Develop Secondary Leukaemia After Neuroblastoma Treatment? (Neuroscience)

New study used whole genome sequencing to gain further understanding of why some children develop secondary leukaemia after neuroblastoma treatment

Scientists from the Wellcome Sanger Institute and the University of Cambridge found that in children with neuroblastoma – a cancer of immature nerve cells – treatment with platinum chemotherapy caused changes to the genome that could then cause leukaemia in some children later on.

The findings, published 27th May 2021 in Blood could lead to an ability to identify which children are more likely to develop the secondary cancer. This in turn could lead to changes in their treatment plan to either avoid these risks or take measures to prepare.

Secondary blood cancer is a challenging complication of childhood neuroblastoma cancer treatment. Every year around 100 children in the UK are diagnosed with neuroblastoma*, and those who had high-risk treatment are at an increased risk of developing secondary blood cancer – leukaemia – after neuroblastoma treatment.

Neuroblasoma often requires intense treatment including several chemotherapy drugs. These powerful drugs kill cancer cells very effectively but unfortunately also have side effects, including damaging the DNA of healthy cells, including bone marrow cells. In up to 7 per cent of childhood neuroblastoma survivors, damaged bone marrow cells go on to develop into secondary leukaemia.

In this new study, researchers from the Wellcome Sanger Institute and the University of Cambridge sequenced the whole genomes of bone marrow and blood samples of two children who both had developed blood cancer following high-risk neuroblastoma treatment.  They discovered that the seeds of secondary leukaemia were sown by neuroblastoma chemotherapy right at the beginning of treatment.

“We have been able to unravel the root of secondary leukaemia in these children which seems to lie in the early stages of neuroblastoma treatment. We hope to further investigate this to try to identify children at higher risk, and to inform a more tailored treatment plan to reduce the risk of secondary leukaemia.”

Dr Sam Behjati,co-lead author and group leader at the Wellcome Sanger Institute

The team found that in both patients the leukaemia had mutations that were caused by neuroblastoma chemotherapy. A wider analysis of 17 children treated for a variety of cancers then identified another child who had undergone neuroblastoma treatment and had developed pre-leukaemia seeds. In the future, it could be possible to identify the children who have a higher risk of developing secondary leukaemia by sequencing their genome and highlighting any genetic drivers that could be pre-cursors for blood cancer.

“This research would not have been possible without the contributions of the patients and their families, and we are indebted to them for their participation in this study. Understanding the reason why some childhood cancer survivors go on to develop secondary blood cancer is crucial if we are to find a way to help protect against this devastating complication.”

— Dr Grace Collord,joint first author from the Wellcome Sanger Institute

“Neuroblastoma can be an aggressive disease that requires intense chemotherapy treatment. Occasionally this chemotherapy can cause serious adverse effects such as leukaemia. So these findings are important to inform possible strategies for monitoring for secondary cancer and tailoring individual treatment plans. However, I should stress that it remains vital that children with high risk neuroblastoma continue to receive intense treatment for their cancer.”

Professor John Anderson of Great Ormond Street Hospital, who contributed to this study

This study included patients, research nursing teams, and laboratory staff from Addenbrooke’s Cambridge University Hospital and Great Ormond Street Hospital (London).


Tim H.H. Coorens, Grace Collord and Sam Behjati, et al. (2021) Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment. Blood. DOI:10.1182/blood.2020010150


This project is supported by Wellcome and St. Baldrick’s Foundation. Further support was provided by NIHR and Great Ormond Street Hospital Children’s Charity.

Featured image credit: Adobe stock

Provided by Wellcome Sanger Institute

Twitter Experiment Finds Correcting Misinformation Makes Problem Worse (Politics)

Correcting misinformation on Twitter may only make the problem worse, according to a new study.

In a Twitter field experiment, a research team from the University of Exeter Business School and MIT Sloan offered polite corrections, complete with links to solid evidence, in replies to flagrantly false tweets about politics.

But they found this had negative consequences, leading to even less accurate tweets and greater toxicity from those being corrected.

According to the study’s lead author Dr Mohsen Mosleh, Lecturer in Business Analytics at University of Exeter Business School, the findings were “not encouraging”.

“After a user was corrected they retweeted news that was significantly lower in quality and higher in partisan slant, and their retweets contained more toxic language,” said Dr Mosleh.

To conduct the experiment, the researchers identified 2,000 Twitter users, with a mix of political persuasions, who had tweeted out any one of 11 frequently repeated false news articles.

All of those articles had been debunked by the fact-checking website snopes.com. Examples include the incorrect assertion that Ukraine donated more money than any other nation to the Clinton Foundation, and the false claim that Donald Trump, as a landlord, once evicted a disabled combat veteran for owning a therapy dog.

The research team then created a series of Twitter bot accounts, all of which existed for at least three months and gained at least 1,000 followers, and appeared to be genuine human accounts.

Upon finding any of the 11 false claims being tweeted out, the bots would then send a reply along the lines of, “I’m uncertain about this article – it might not be true. I found a link on Snopes that says this headline is false.”

The reply would also link to the correct information.

The researchers observed that the accuracy of news sources the Twitter users retweeted promptly declined by roughly 1 percent in the 24 hours after being corrected.

Similarly, evaluating over 7,000 retweets with links to political content made by the Twitter accounts in the same 24 hours, the scholars found an upturn in the partisan lean of content and the “toxicity” of the language being used.

However, in all these areas – accuracy, partisan lean, and the language being used – there was a distinction between retweets and the primary tweets being written by the Twitter users.

Retweets, specifically, degraded in quality, while tweets original to the accounts being studied did not.

“Our observation that the effect only happens to retweets suggests that the effect is operating through the channel of attention,” said co-author Professor David Rand from the MIT Sloan School of Management, noting that on Twitter people seem to spend a relatively long time crafting primary tweets, and little time making decisions about retweets.

He added: “We might have expected that being corrected would shift one’s attention to accuracy. But instead, it seems that getting publicly corrected by another user shifted people’s attention awayfrom accuracy – perhaps to other social factors such as embarrassment.”

The effects were slightly larger when being corrected by an account that identified with the same political party as the user, suggesting that the negative response was not driven by animosity towards counter-partisans.

The findings seemingly run in contrary to a previous paper by Dr Mosleh and the research team, published in Nature in March, showing that neutral, non-confrontational reminders about the concept of accuracy can increase the quality of the news people share on social media.

“Unlike the subtle accuracy nudges, direct public corrections were found to make things worse. This shows how complicated the fight against misinformation is, and cautions against encouraging people to go around correcting each other online,” said Dr Mosleh. 

Perverse Downstream Consequences of Debunking: Being Corrected by Another User for Posting False Political News Increases Subsequent Sharing of Low Quality, Partisan, and Toxic Content in a Twitter Field Experiment,” is published online in CHI ’21: Proceedings of the 2021 Conference on Human Factors in Computing Systems.

Featured image: To conduct the experiment, the researchers identified 2,000 Twitter users, with a mix of political persuasions, who had tweeted out any one of 11 frequently repeated false news articles. © University of Exeter

Provided by University of Exeter

Tiny Lesions Found on US After Thyroid Cancer are Primarily Benign (Medicine)

Research shows that lesions smaller than 6 mm are minimal risk for malignancy

Although it’s common to find small lesions in and around the post-surgical thyroid bed in thyroid cancer patients, most of these lesions are not cancerous, according to a large, retrospective study published in Radiology.

“If tiny lesions are identified and reported on post-thyroidectomy ultrasound, patients and their doctors become understandably anxious and concerned,” said lead author Mary C. Frates, MD, a diagnostic radiologist at Brigham and Women’s Hospital, and professor of radiology at Harvard Medical School, both in Boston.

“Patients worry that the cancer has come back,” Dr. Frates continued. “They want the tiny lesion biopsied and sometimes even removed surgically. But if the lesion is not cancer, that amounts to a lot of unnecessary procedures.”

Dr. Frates, who focuses much of her clinical research on thyroid sonography, said that recent advances in ultrasound (US) equipment are making it possible to find increasingly smaller thyroid bed lesions.

“The goal of this study was to determine if ultrasound can differentiate all the tiny ‘nothings’ discovered in the thyroid bed from the important cancer recurrences,” Dr. Frates said.

Lesion Characteristics and Associations with Malignancy

Dr. Frates and colleagues searched a US reporting database at BWH for all patients imaged between July 2006 and June 2016 with an indication of post-thyroidectomy follow-up.

Frates © RSNA

Researchers analyzed 5,732 US studies in 1,885 patients, 79% of whom were females. Patient age ranged from 3 to 87 years, with a mean age of 48 years.

Recorded data included patient demographic characteristics, date of thyroidectomy, and thyroid cancer type. The vast majority of patients in the study — 82% — had papillary cancer, Dr. Frates said.

The researchers also evaluated the presence, size and US characteristics of thyroid bed lesions, as well as the results of fine-needle aspiration of those lesions (FNA).

Dr. Frates independently reviewed images of all lesions that underwent FNA. She evaluated the shape of thyroid bed lesions, and also looked for echogenicity and the presence of a cystic component, fatty hilum and punctate echogenicities.

Investigators determined that 40% of US examinations showed thyroid bed lesions following thyroidectomy; however, only 2.2% of these lesions proved to be malignant. Furthermore, only 0.2% of lesions in the thyroid bed smaller than 6 mm in maximum diameter were malignant.

“Only the presence of punctate echogenicities had a clear statistical association with malignancy,” Dr. Frates said. “The other characteristics were not helpful in differentiating benign from malignant lesions.”

Patients determined to have positive lymph nodes when they underwent initial thyroidectomy for thyroid cancer had a higher malignancy rate than those who did not have positive lymph nodes at initial surgery.

“Our large study confirms that most patients with thyroid cancer are unlikely to have clinically significant recurrence in the thyroid bed,” Dr. Frates said.

According to the researchers, reporting only lesions 5 mm or larger will simplify US reporting yet allow for appropriate comparison at follow up. Sampling should be considered for lesions 6 mm or larger with concerning features.

“If a lesion does not have punctate echogenicities, it would likely be safe to follow the lesion instead of doing a biopsy,” Dr. Frates said. “But any lesion with punctate echogenicities needs to be taken seriously, and possibly biopsied and removed.”

For More Information

Access the Radiology study, “Role of Sonographic Characteristics of Thyroid Bed Lesions Identified Following Thyroidectomy in the Diagnosis or Exclusion of Recurrent Cancer.”

Provided by RSNA

Fluoroscopic-Guided Technique Shows Promise for Migraine Relief (Medicine)

RSNA-funded grant demonstrates efficacy, cost-effectiveness of emerging procedure

A relatively simple fluoroscopic-guided procedure may provide relief for patients with chronic headaches including migraines but is not yet widely performed at U.S. medical centers. 

A recent RSNA grant recipient is exploring how to change that — and to get the word out to physicians and patients about the emerging procedure.

Migraines affect roughly one in six adults in the U.S., costing $20 billion annually in medical care and lost productivity.

With her 2018 RSNA Research Medical Student Grant, Amy E. Crumb, BA, and her colleagues and mentors at the Medical College of Wisconsin (MCW), sought to shed light on why fluoroscopic-guided sphenopalatine ganglion block (SPGB) is underutilized compared with medications and alternative procedures that are more commonly covered by insurance.

Researchers also did a cost analysis of fluoroscopic-guided SPGB and other medications and procedures used for migraine treatment.

Crumb reviewed medical records for 66 patients enrolled in a fluoroscopic-guided SPGB regimen at Milwaukee’s Froedtert Memorial Lutheran Hospital between 2017 and 2019. Ultimately, 37 patients were included in the study.

Crumb was excited about two findings in particular.

“First, no severe adverse events were experienced by our patients. Second, patients experienced improvement in their otherwise recalcitrant migraines after receiving this treatment,” she said. These two findings combined suggest fluoroscopic-guided SPGB has the potential to help patients who have largely exhausted their options, Crumb said. “Although fluoroscopic-guided SPGB may not work for every patient, the risks are minimal,” she said.

“We hope that the findings from this study make clinicians aware of this minimally invasive approach to treating migraines, that can positively impact patients’ lives with minimal associated risks.”

— Amy E. Crumb, BA

A Safe, Effective Alternative

Fluoroscopic-guided SPGB is performed with an intranasal catheter that is advanced into the nares and lidocaine is dripped posterior to bathe the sphenopalatine ganglion.

This results in neuromodulation and prevents the nerves from sending the headache signal. Patients often report near-immediate relief. Surprisingly, Crumb and colleagues found that 5% of patients reported complete resolution of their migraines at follow up. The mechanism behind the long-term effects is not fully understood, Crumb said.

Prior to initiating the SPGBs, patients experienced headaches for an average of 18 years, had tried at least eight preventative/abortive medications and had three alternative procedures. The data revealed that 54% of patients had relief after SPGB, while 43% experienced no relief and only 3% (one patient) had a negative effect. Sixteen patients reported at least one minor adverse effect, including rebound headache, dizziness, nausea, rhinitis and hyperosmia.

Because minimal adverse events were reported, fluoroscopic-guided SPGB performed in the interventional radiology (IR) setting may offer a safe and effective alternative to medical therapy for the treatment of chronic headaches, the researchers concluded.

“We hope that the findings from this study make clinicians aware of this minimally invasive approach to treating migraines, that can positively impact patients’ lives with minimal associated risks,” she said.

Crumb also determined that the cost of image-guided SPGB isn’t a significant factor compared to other therapies.

“Despite the perception that fluoroscopic-guided SPGB is an expensive therapy, a single image-guided-SPGB session is less expensive than an onabotulinum toxin A injection and of equivalent cost to common medication-based abortive procedures approved by insurance,” the authors said.

Research, Insurance Coverage Lacking

As part of the project, Crumb and colleagues built a HIPAA-secure, shareable database to analyze the safety and efficacy of the SPGB procedure.

She is hopeful that database will support the safety and efficacy of SPGB with the goal of persuading insurance companies to cover the technique as a viable option for migraine treatment.

One reason the procedure isn’t covered by insurance could be the lack of rigorous trials on fluoroscopic-guided SPGB, Crumb said.

“For that reason, many insurance companies therefore consider this an ‘experimental’ treatment,” Crumb said.

The team also developed educational materials on the SPGB procedure for distribution by interventional radiologists and referring clinicians.

RSNA Grant Advances Career in Interventional Radiology

Crumb said that the RSNA-funded grant provided an invaluable learning experience for her. She was surprised by some aspects of the study — namely, the complexity of the cost analysis between SPGB and medications and other procedures.

“I also hadn’t realized the broad range of medications patients could be prescribed for migraines, and there isn’t one standardized regimen,” she said.

Crumb said that this work wouldn’t have been possible without support from the RSNA grant and the guidance of her mentor, Sarah B. White, MD, an associate professor of radiology in the Division of Vascular Interventional Radiology at MCW and also a two-time RSNA research grant recipient.

“The RSNA grant helped me meet living expenses during the gap in federal loans between the summer months of my first and second years of medical school, so I was able to focus on the research instead of juggling a short-term, full-time job to make ends meet,” Crumb said.

She cites Dr. White’s mentorship and RSNA support for advancing her career in IR, which she says factored into her performance in the 2021 National Resident Matching Program.

“In March, I found out I matched into an integrated interventional radiology position for residency. This is a goal that I, until very recently, thought unattainable,” Crumb said. “I genuinely believe my early introduction to radiology research with help from RSNA, Dr. White and other mentors put me in a very favorable position to match into one of the most competitive residency fields.”

Her RSNA grant experience highlighted the importance of having a well-structured study design, especially when dealing with subjective or often poorly documented objective variables.

Crumb also gleaned some valuable advice to pass on to other medical students.

“It’s OK if your project does not produce positive results! Being able to say, for example, ‘We wanted to compare variables, but the results demonstrated that there was no difference.’ If that happens, it doesn’t mean that your work is useless, wasted or any less valid,” she said.

Provided by RSNA

Selenium-based Compounds Target SARS-CoV-2 With Unusual Inhibition Mechanism of its Main Protease (Medicine)

Scientists have discovered a new mechanism of inhibiting a critical enzyme of the SARS-CoV-2 virus, demonstrating the on-target engagement of novel selenium based compounds.

An international team of researchers led by the University of Liverpool has shown that a selenium-based drug-molecule called ebselen and a number of derivative compounds can halt SARS-CoV-2 replication by targeting its main protease Mpro. Their findings are published in the journal Nature Communications.

Global control of the COVID-19 pandemic replies on the availability of effective medicines and vaccines. Drug development for COVID-19 has been speeded up with repurposing numerous established therapeutic compounds for treating SARS-CoV-2.

SARS-CoV-2 replication in human is dependent on viral enzymes. Inhibiting one of those critical enzymes can stop coronavirus infection. SARS-CoV-2 main protease (Mpro) is one of the enzymes considered as an interesting target for the development of anti-coronaviral compounds.

A team of researchers from the University of Liverpool, ShanghaiTech University and Wuhan Institute of Virology have focused on the repurposing of ebselen and derivative compounds developed at Liverpool for COVID-19 treatment. They have demonstrated the potentials of the compounds to be lead candidates with strong inhibition against SARS-CoV-2 Mpro and potent ability to rescue SARS-CoV-2 infected primate cells. Moreover, the team also revealed unusual inhibition mechanism of this selenium-based compounds that donate selenium atom to inactivate Mpro function and eventually kill the virus.

Professor Samar Hasnain, Max Perutz Professor of Molecular Biophysics at the University of Liverpool, who led the international team of interdisciplinary experts said: “This is an important finding that helps understand how the compounds work with the target protein and could guide the future development of this class of compounds to be potent candidates in fighting COVID-19”.

Professor Paul O’Neill, University of Liverpool, who led the medicinal chemistry programme said: “Our medicinal chemistry approach, guided by protein-ligand crystallography studies, focused on the design of ebselen based analogues have produced sub micromolar inhibition of the key enzyme of the virus is good news with significant potential for the development of an effective drug.”

Professor Leike Zhang from Wuhan Institute and Professor Haitao Yang from ShanghaiTech added that “these compounds are some of the best compounds we have tested against the virus” and “this international collaboration is another important step to discover potent inhibitors against COVID-19.”

Lead author Dr Kangsa Amporndanai, a research associate at the University of Liverpool, said: “The fact that this new generation of organo-selenium compounds target cysteine of the main protease so effectively, arresting the virus ability to replicate is good news for boosting a second line of defence against this virus.”

The work was supported by the grant from Biotechnology and Biological Sciences Research Council (BBSRC)’s Impact Acceleration Account (IAA) scheme. Some development also arose from a grant from the ALS Association.

Research reference:

Amporndanai, K., Meng, X., Shang, W. et al. Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. Nat Commun 12, 3061 (2021). https://doi.org/10.1038/s41467-021-23313-7

Provided by University of Liverpool

Solving a Plant Cell “Parking Garage” Puzzle (Botany)

Biological organelles may be messy and crowded, but sometimes only an exact mathematical description will do

To design a multistory parking garage, you need to figure out how to pack the maximum number of cars into the smallest possible space while still allowing free passage between levels. Parking-garage-like structures in plant and animal cells evolved for similar purposes: Their thin, flat levels enable them to support large numbers of exposed molecules while continuous helical “ramps” connecting the layers facilitate the flow of various materials. In our cells, for example, they help create efficient assembly lines for protein production and folding; in plant cells, they house the complexes necessary for photosynthesis.

In parking garages, the architectural and engineering principles that guide the positioning of the helical ramps are permanently cast in concrete. Biological “parking garages,” however, are made of fluid membranes: embedded helical ramps can freely move around, repositioning themselves to optimize their elastic energy. Minute forces govern the arrangement of these biological structures, but to understand these springy structures, one must get an accurate description of their geometry. When Dr. Efi Efrati and postdoctoral fellow Dr. Luiz Da Silva of the Weizmann Institute of Science set out to do just that, they found that no appropriate mathematical tools existed, so they had to devise new ones.

Efrati is in the Physics of Complex Systems Department. His work spans a broad area connecting chemistry and the life sciences to physics and mathematics. Out of the entire range of physics – from elementary particles to the entire Universe – he has chosen to focus on the physics that takes place at the human scale: ranging from a few nanometers to a few meters. This field of study, called soft-matter physics, encompasses micron-wide lipid membranes and meter-wide soap films. Despite the differences in scale and chemical makeup, these both follow the same broad shaping principles and mathematical description. In particular, both systems form “minimal surfaces,” – surfaces of the smallest possible area that can span a given closed boundary. Minimal surfaces have been shown to minimize the surfaces’ bending energy, and they thus occur naturally in a variety of manmade and biological systems.

Embedded helical ramps can freely move around, repositioning themselves to optimize their elastic energy

Several years ago, Efrati began working with Prof. Ziv Reich of the Institute’s Biomolecular Sciences Department on garage-like structures called thylakoids, which are found in plant and green algal cells. Thylakoids house the photosynthetic complexes, and their structure lets them pack a lot of surface area – and hence lots of complexes – into a small space. In addition to their primary function – trapping light and using it to split water – thylakoids pump protons and facilitate the production of energy-storing molecules that emerge into the rest of the plant cell.

The electron microscopy reconstructions of thylakoids conducted in Reich’s group revealed that these organelles form minimal surfaces. They also found different embedded ramp structures, or “motifs,” that wound in different directions – some left- and others right-handed, each at a different slope, or pitch. Existing physical tools could describe the pitch of their slopes, but determining the spatial arrangement of the motifs, or understanding what determines their pitch ratio (that is, the slope compared to the diameter) required more delicate tools.

Three-dimensional model of a plant photosynthetic membrane network (color) generated from electron microscope images. Stacked thylakoid domains (yellow) are surrounded by garage-like structures formed by alternating left-handed helical junctions (purple) and right-handed helices (blue) © Weizmann Institute of Science

Minimal surfaces were discovered in the 18th century, and they are perhaps the most studied types of surfaces in the world of mathematics. Indeed, producing a minimal surface with one helical ramp follows a 250-year-old recipe. However, constructing a minimal surface that resembles the convoluted geometry of a thylakoid or the endoplasmic reticulum in our own cells is an entirely different story. “As physicists, we are exceptionally fond of approximations and idealization,” says Efrati. “We started with modeling the system using a common mathematical approximation to minimal surfaces.” This approximation allowed them to place the helical motifs at will and to construct arbitrarily complex parking-garage geometries, but the resulting structures were very far from being minimal surfaces. “We discovered that the approximation only applied when the motifs are very far apart. We had to find some way to produce an exact minimal surface.” Instead of starting from scratch, Da Silva and Efrati first tried to find a way to “amend” the approximation. “The approximation looked a lot like what we wanted, but with subtle differences, so we used it as a starting point for our calculation.” Da Silva and Efrati came up with a one-step “fix”: a distortion maneuver that considers the approximation for the entire surface and all its embedded helical ramps, and then calculates the lateral displacement for every point on the surface. The result is an exact minimal surface with the desired helical motifs embedded within. This allows an accurate construction of a minimal surface that has the complex geometry of the thylakoid structure.

The mathematical solution Efrati and Da Silva have created will give biological researchers the ability to conduct quantitative analyses of the physical organelles in cells. Because such parking-garage-like structures are found in many biological systems, this ability can further basic research, as well as that into disorders involving these structures; in the case of plants, it can foster improvements in their photosynthetic capabilities and energy management.

Featured image: Dr. Efi Efrati and Dr. Luiz Da Silva © Weizmann Institute of Science

Reference: Efi Efrati and Luiz Da Silva, “Construction of exact minimal parking garages: nonlinear helical motifs in optimally packed lamellar structures”, Proceedings of the Royal Society A, 2021. https://doi.org/10.1098/rspa.2020.0891

Provided by Weizmann Institute of Science

Study Confirms Longer-term Lung Damage After COVID-19 (Medicine)

A study by Sheffield and Oxford researchers using a cutting-edge method of imaging has identified persistent damage to the lungs of COVID-19 patients at least three months after they were discharged from hospital, and for some patients even longer.

  • Hyperpolarised xenon MRI detected lung damage which was not picked up by routine CT scans and clinical tests
  • The cutting-edge method of imaging pioneered at the University of Sheffield has identified persistent damage to the lungs of Covid-19 patients at least three months after they were discharged from hospital

A study by Sheffield and Oxford researchers using a cutting-edge method of imaging has identified persistent damage to the lungs of COVID-19 patients at least three months after they were discharged from hospital, and for some patients even longer.

This damage was not detected by routine CT scans and clinical tests, and the patients would consequently normally be told their lungs are normal.

Further early research by the team has shown that patients who have not been hospitalised with COVID-19 but who are experiencing long-term breathlessness may have similar damage in their lungs, and a larger study is needed to confirm this.

In a paper published in Radiology, the world’s leading radiology journal, the researchers from the University of Oxford and University of Sheffield said that hyperpolarised xenon MRI (XeMRI) scans had found abnormalities in the lungs of some COVID-19 patients more than three months – and in some cases, nine months – after leaving hospital, when other clinical measurements were normal.

“The 129Xe MRI is pinpointing the parts of the lung where the physiology of oxygen uptake is impaired due to long standing effects of COVID-19 on the lungs, even though they often look normal on CT scans.”

— Professor Jim Wild, Head of Imaging and NIHR Research Professor of Magnetic Resonance at the University of Sheffield

Professor Jim Wild Head of Imaging and NIHR Research Professor of Magnetic Resonance at the University of Sheffield, said: “The findings of the study are very interesting. The 129Xe MRI is pinpointing the parts of the lung where the physiology of oxygen uptake is impaired due to long standing effects of COVID-19 on the lungs, even though they often look normal on CT scans.

“It is great to see the imaging technology we have developed rolled out in other clinical centres, working with our collaborators in Oxford on such a timely and clinically important study sets a real precedent for multi-centre research and NHS diagnostic scanning with 129Xe MRI in the UK.”

The study’s Principal Investigator Professor Fergus Gleeson, Professor of Radiology at the University of Oxford and Consultant Radiologist at Oxford University Hospitals (OUH) NHS Foundation Trust, said: “Many COVID-19 patients are still experiencing breathlessness several months after being discharged from hospital, despite their CT scans indicating that their lungs are functioning normally.

“Our follow-up scans using hyperpolarised xenon MRI have found that abnormalities not normally visible on regular scans are indeed present, and these abnormalities are preventing oxygen getting into the bloodstream as it should in all parts of the lungs.”

The study, which is supported by the NIHR Oxford Biomedical Research Centre (BRC), has now begun testing patients who were not hospitalised with COVID-19 but who have been attending long COVID clinics.

“Although we are currently only talking about early findings, the XeMRI scans of non-hospitalised patients who are breathless – and 70 per cent of our local patients with Long COVID do experience breathlessness – may have similar abnormalities in their lungs. We need a larger study to identify how common this is and how long it will take to get better.” Professor Gleeson explained.

“We have some way to go before fully comprehending the nature of the lung impairment that follows a COVID-19 infection. But these findings, which are the product of a clinical-academic collaboration between Oxford and Sheffield, are an important step on the path to understanding the biological basis of long COVID and that in turn will help us to develop more effective therapies.”

The Pulmonary, Lung and Respiratory Imagining Sheffield (POLARIS) research group led by Professor Jim Wild at the University of Sheffield pioneered the methods, development and clinical applications of hyperpolarised gas lung MRI in the UK, performing the first clinical research studies in the UK and the world’s first clinical diagnostic scanning with this technology.

Additional information 

The study – C-MORE-POST in Oxford and MURCO in Sheffield – forms part of the University of Oxford’s C-MORE (Capturing the MultiORgan Effects of COVID-19) study, which feeds into the major national follow-up study PHOSP-COVID, led by the University of Leicester, which is investigating the long-term effects of COVID-19 on hospitalised patients.

Reference: James T. Grist, Mitchell Chen, Guilhem J. Collier, Betty Raman, Gabriele AbuEid, Anthony McIntyre, Violet Matthews, Emily Fraser, Ling-Pei Ho, Jim M. Wild, and Fergus Gleeson, “Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Participants 3 Months after COVID-19 Pneumonia: Preliminary Results”, RSNA, May 25 2021. https://doi.org/10.1148/radiol.2021210033

Provided by University of Sheffield