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COVID-19 may affect a group of biochemical reactions called one-carbon metabolism

Jacob Scott

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). The SARS-CoV-2 infection has a wide range of symptoms, ranging from none to extremely critical symptoms.

The pathophysiology of COVID-19 is not well understood, even after more than two years; however, many scientists consider that critical and severe COVID-19 is related to the severity of the immune-inflammatory response.

A new International Journal of Molecular Sciences study addresses the relationship between SARS-CoV-2 to the metabolism of one-carbon molecules in the host, suggesting new therapeutic pathways.

Study: COVID-19 and One-Carbon Metabolism. Image Credit: atdigit / Shutterstock.com

Introduction

Earlier protein-based research in COVID-19 patients showed that several pathways were dysregulated, some of which include the complement and coagulation cascades, interactions between different cytokines, and cholesterol metabolism. Even as biomarkers were identified that indicated increased severity and mortality from COVID-19, these were found to be largely involved in inflammatory pathways.

Apart from acute COVID-19, ‘long COVID’ has become a recognized syndrome, though it is far from being clearly defined. The symptoms of long COVID may include neurological sequelae, chest pain, fatigue, dyspnea, respiratory symptoms, joint pain, and insomnia. These symptoms resemble those of pernicious anemia, which is a condition caused by the deficiency of vitamin B12 or cobalamine.

The underlying mechanism here is a one-carbon pathway of methylation, as B12 is a cofactor of vitamin B12-dependent methionine (Met) synthase (MS), which is a key enzyme in this pathway. MS is the source of methionine in the body and is required for the production of the universal methyl donor S-adenosylmethionine (SAM).

The one-carbon pathway is involved in many biological processes including purine and thymidine synthesis, nucleic acid synthesis, homeostasis of glycine, serine, and methionine, as well as the generation of glutathione through the homocysteine-cysteine pathway, wherein glutathione is an essential molecule for antioxidant activity in physiological processes. This pathway is also involved in the production of energy through adenosine triphosphate (ATP) generation within the mitochondria of the cell.

In the current study, scientists report that during the hijacking of host cell metabolism by SARS-CoV-2, transcription continues to occur for host metabolic enzymes but shows an overall reduction. ATP appears to be depleted, as shown by the expression of mitochondrial DNA.

Interconnections between metabolism of folate, one-carbon, and sulfur compounds. Indicated metabolites are discussed in the text. CysGly, a product of GSH catabolism, affected in COVID-19 and discussed in the text, is not shown.

Important changes in one-carbon pathways

Purine biosynthesis de novo appears to increase, with rising levels of intermediates and a reduction in intracellular folate. Notably, serine donates one-carbon units for this process, taking part in folate metabolism. Many other metabolites in the cell that participate in either sulfur-containing amino acid pathways or one-carbon metabolism also showed a reduction following SARS-CoV-2 infection.

Methionine levels

Within the infected cell, methionine and related sulfur amino acids showed a reduction. Conversely, such cells did not show any reductions in SAM, cysteine, and oxidized glutathione, all of which participate in one-carbon metabolism. The implication is that SARS-CoV-2 takes over folate and one-carbon pathways for its intracellular replication.

A rise in SAM levels, as well as a rise in SAM/S-adenosyl homocysteine (SAH), suggests lung damage has occurred, while the former is highest in critically ill patients but is linked to a better outcome. The level of dimethylglycine, which is produced from homocysteine during its conversion of methionine, did not show any association with the product concerned.

Some studies show methionine increasing, whereas others have reported its reduction; however, an increase in methionine levels is more common in patients with critical COVID-19, whereas its reduction is more often associated with mild illness. The reduction in methionine sulfoxide levels, which is seen consistently in COVID-19, indicates an increase in oxidant stress following infection.

Glutathione shifts

Glutathione levels are also affected in COVID-19, with low levels indicating oxidative stress and lung damage. This is the most important antioxidant in human physiology and is depleted in high-risk conditions for COVID-19. The level of SAM is also associated with a higher SAM to GSH ratio and higher homocysteine levels.

In some studies, cysteine was increased in serum, as Cys-Gly produced by the metabolism of GSH is lower with lung damage. Meanwhile, glycine, being a part of GSH biosynthesis, showed varying directions of change in these patients, as with cysteine.

Homocysteine changes

Homocysteine is elevated in COVID-19; however, there remains limited information regarding whether this effect is due to older age and male sex in COVID-19 cases as compared to controls remains unanswered. The MTHFR 677T gene is more common in certain ethnic groups that have a higher-than-expected incidence of COVID-19 and related mortality.

Homocysteine may trigger thrombosis or coagulopathy, both of which are complications common in COVID-19. Some researchers have suggested that genotyping COVID-19 for certain single nucleotide polymorphisms would help identify those with the highest risk of complications from clotting; however, this is currently not supported by experimental data.

Choline and MMA

In adults but not COVID-19 positive children, choline and its metabolites were found at lower levels.

Methylmalonic acid (MMA), which fell to 3% of the baseline level, is a catabolic product formed during the breakdown of certain amino acids and could play an antiviral and anti-inflammatory role. The reduction of MMA in adults fits thus supports a potential mechanism that causes increased severity of COVID-19 in adults.

Renin-angiotensin system

The renin-angiotensin system (RAS) is key to the regulation of cardiovascular function and renal health. It may also cause hypertension, diabetes, and obesity, all of which are risk factors for COVID-19. Angiotensin-converting enzyme (ACE) and RAS balance each other to prevent undesirable effects on the cardiovascular system. Moreover, high ACE2 levels at admission have been used to predict a higher risk of severe illness.

The one-carbon cycles linked to homocysteine act through the RAS system as well.

Folate cycle

The folate cycle is key to one-carbon metabolism. Drugs that inhibit dihydrofolate reductase, as well as other steps in one-carbon transfer, have been found to block viral replication.

Folic acid could also be a furin inhibitor, thus preventing SARS-CoV-2 infection as furin activity is required for the proteolytic cleavage of the viral spike protein that precedes lung cell entry by the virus.

Several treatment strategies suggested for COVID-19 are currently being examined. Interestingly, screening pathways indicate the potential utility of folic acid as an inhibitor of spike-ACE2 receptor binding. Indeed, this was the leading nutraceutical with this predicted activity.

Similarly, 5-methyltetrahydrofolate was found to be a ligand of the key viral enzyme PLpro, while folic acid derivatives bound to the NSP15 protein. In all these cases, binding energies were comparable or superior to currently known drugs that inhibit these pathways.

Comparatively, antifolate drugs such as methotrexate have been found to have an antiviral effect by blocking purine biosynthesis. This drug may act in synergy with remdesivir to block viral replication and the secretion of infectious virions.

Implications

The results of many studies regarding the relationship between one-carbon metabolism and SARS-CoV-2 replication within human host cells are often conflicting. However, these studies have demonstrated the potential role of glutathione, methionine sulfoxide, and choline in this process. These differences could be due to the confounding effects of non-matched age, sex, or ethnicity between cases and controls in various studies.

Another possible reason for inconsistent findings could be the difference in COVID-19 classification systems as to the severity of illness and differences in the time points at which samples were taken. For instance, one review found that SAM levels could differ in cases as compared to controls simply by manipulating the study selected by the classification system used.

Among potential therapeutic approaches, the three aforementioned metabolites that are potentially impacted by COVID-19 may be worthy of further study. Thus, measures to normalize their levels may mitigate the severity of COVID-19 and improve patient outcomes. This includes N-acetyl cysteine to increase glutathione levels, preferably with glycine as well.

The resulting antioxidant boost may help restore methionine sulfoxide levels to normal as well. More work will be needed to establish the therapeutic utility of these strategies.

Journal reference:
Perla-Kajan, J. & Jakubowski, H. (2022). COVID-19 and One-Carbon Metabolism. International Journal of Molecular Science. doi:10.3390/ijms23084181.

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Genetic bottlenecks could impact Wyoming toads’ ability to respond to new pathogens

Jacob Scott

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A new study from North Carolina State University examines immune system diversity in the critically endangered Wyoming toad and finds that genetic bottlenecks could impact a species’ ability to respond to new pathogens. The findings could inform captive breeding strategies for endangered animal populations.

The Wyoming toad, Anaxyrus baxteri, suffered a severe population decline throughout the latter part of the 20th century due to factors including habitat destruction and fungal infection. The toad was brought into a captive breeding program in the 1990s in order to save the species. Scientists estimate a current wild population of only 400 to 1,500 animals, meaning that the toad is considered critically endangered.

Population reduction in this species created a genetic bottleneck to begin with, meaning the level of genetic diversity is already very small. This is the first study to look specifically at genetic diversity in the immune systems of these toads and how it could impact them as a population.”

Jeff Yoder, professor of comparative immunology at NC State and co-corresponding author of paper

Yoder, with co-corresponding author Alex Dornburg of the University of North Carolina at Charlotte, performed RNA sequencing on immune tissues from three healthy, retired Wyoming toad breeders. Study co-author Michael Stoskopf, who was on the Wyoming Toad Recovery Implementation Team established in 2008, obtained the samples.

“We were focused specifically on sequences encoding toll-like receptors – TLRs – and the proteins of the major histocompatibility complex, or MHC, expressed in these tissues,” says Kara Carlson, first author of the study and current Ph.D. candidate at NC State. “These sets of genes are major components of the immune system.”

TLRs are the first responders of the immune system, and are similar, or well-conserved, between species. The MHC, on the other hand, is a large and diverse group of genes that varies between species and individuals. It can determine why one group is more resistant to a particular pathogen than another.

“MHC genes are some of the most rapidly evolving sequences in the genome,” Carlson says. “So in a healthy population there’s a lot of variety that gets passed along to descendants, enabling the species at large to adapt to different pathogens. However, if disease survivors do so because of their MHC, then that group would have a similar MHC.

“The Wyoming toads that were brought into captivity to save the species were all able to resist the fungus that had decimated the population, but that could mean that their immune diversity is reduced.”

The researchers compared the TLR and MHC of the three Wyoming toads to each other, as well as to samples from a common toad and a cane toad. Both the common toad and the cane toad showed more MHC diversity than the Wyoming toad, even though the cane toad underwent a similar genetic bottleneck.

“The small sample size in this study – which was unavoidable due to the endangered status of the toad – nevertheless lays an important framework for conservation,” Carlson says.

“Amphibians in general don’t have as many genomic resources as other organisms,” Yoder says. “And captive breeding from a small population further decreases genetic diversity. But while these toads may be better protected against the fungal infection that nearly wiped them out, they may not be equipped to deal with new pathogens down the road.”

“While we weren’t necessarily surprised by the lack of immunogenic diversity in the Wyoming toad, it does spark an important question,” Dornburg says. “How equipped are other species of conservation concern for a battle with an emergent pathogen?”

“By understanding the genetic diversity of the immune system we can inform captive breeding to increase the chance of a species to resist disease in the wild,” Yoder adds. “Studies like this one are invaluable for captive breeding practices going forward.”

Source:
Journal reference:

Carlson, K.B., et al. (2022) Transcriptome annotation reveals minimal immunogenetic diversity among Wyoming toads, Anaxyrus baxteri. Conservation Genetics. doi.org/10.1007/s10592-022-01444-8.

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Video conferencing hinders creativity

Jacob Scott

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In-person teamwork has now transformed into virtual collaboration due to the COVID-19 pandemic. But does this affect innovation and creativity?

An interesting study on virtual communication led by Dr. Melanie S. Brucks from Columbia University and Prof. Jonathan Levav from Stanford University is published in the journal Nature. The study examines whether videoconferencing affects creative idea generation.

Study: Virtual communication curbs creative idea generation. Image Credit: Andrey_Popov / Shutterstock

Communication and collaboration

Collaboration is essential for several workplace tasks. It leads to innovation and idea generation. Historically, these collaborations have been in-person and required sharing of the same physical space. The use of traditional communication technologies like letters, emails, and phone calls hinder the smooth exchange of information and limits collaboration.

Now, due to advances in audio-visual technology, face-to-face interaction is possible via videoconferencing, allowing virtual collaboration. Videoconferencing has replaced in-person interactions due to pandemic-driven social distancing. Video interaction and in-person interaction allow communication of the same information.

While videoconferencing replacing in-person interaction has been beneficial in the social scenario, does it come with a cost in the workplace scenario? For example, does it affect collaborative idea generation?

Experiments

The investigators performed a Laboratory experiment and a field experiment to test the difference between in-person interaction and videoconferencing in collaborative idea generation. First, they recruited participants and divided them into pairs: half of the pairs were assigned to an in-person setting, and the rest were assigned to a virtual setting.

Laboratory experiment

A total of 602 participants were recruited for the laboratory experiment and divided into pairs. The participants were in separate rooms in the virtual setting and communicated through videoconferencing. The pairs were allotted five minutes to generate creative uses for a frisbee (150 pairs) or bubble wrap (151 pairs) and then one minute to select their most innovative idea.

The pairs were evaluated by counting the number of creative ideas and ideas they generated. The virtual pairs generated significantly fewer total and creative ideas compared to in-person pairs.

So, virtual collaboration hampered creative ideas. This could be because the virtual space narrows the visual scope, which in turn narrows the cognitive scope. To assess the visual focus, two methods were used. Firstly, the participants had to recollect the individual props in the room and point them on a worksheet. Secondly, the participants’ eye gaze was recorded during the experiment.

The virtual pairs narrowed their focus to the screen. Compared to in-person pairs, they spent significantly more time looking directly at their partner and less time looking at the surrounding room, and remembered significantly fewer props in the surrounding room.

As a consequence, the virtual medium narrowed the visual focus and inhibited the generation of ideas.

However, these results are in the context of a controlled laboratory setting.

Field experiment

The experiment was repeated in ‘the field’ under actual work conditions within a large multinational telecommunications company to see if these results could be extrapolated to the real world. The field experiment was conducted in five country sites – in Europe, the Middle East, and South Asia. In this setting, the participants knew their partners and used video conferencing regularly for work. Moreover, it included domain experts highly invested in the outcome of the collaboration.

A total of 1,490 engineers were recruited to participate in an ideation workshop and randomly divided into pairs. The pairs were allotted an hour to generate product ideas and submit one idea as future product innovation for the company.

The engineer pairs who worked on the task virtually generated fewer total ideas and creative ideas than in-person pairs at all five sites.

However, the decision quality was not affected by virtual collaboration. The in-person pairs generated a significantly higher top-scoring idea, but the selected idea did not significantly differ in quality between the virtual pairs and in-person pairs.

Other reasons for reduced creativity

The could be other reasons why virtual collaboration negatively affected idea generation. Therefore, the investigators explored the alternative explanations.

More ideas

Since the in-person collaborators generated more total and creative ideas than the virtual collaborators, they could generate additional ideas similar to each other. However, upon semantic analysis, it was observed that they generated diverse and disconnected ideas.

Feelings of connection and trust

Studies have shown that feelings of connection and trust can foster team creativity. The virtual pairs may have reduced feelings of connection and trust toward their partner.

However, when assessed for subjective feelings of closeness, verbal and non-verbal behaviors, and mimicry, the virtual pairs were similar to in-person pairs in the laboratory experiment.

Thus, virtual and in-person interactions are very similar in terms of social connection or social behavior.

Communication coordination

Usually, there is a lack of coordination in a conversation in virtual interactions due to the absence of eye contact. However, it could not wholly explain the effect of virtual interaction on idea generation.

Interpersonal processes

This study also assessed the effect of interpersonal processes on idea generation. Interpersonal processes fear of evaluation, dominance, social facilitation, social loafing, social sensitivity, perceptions of performance, and production blocking were affected in virtual collaborations and these, in turn, affected idea generation.

Implications of the study

This study supports previous research suggesting that pairs perform better than large groups, both in-person and online. Therefore, this study recommends ideation in pairs and in person. Also, this study suggests that larger videoconferencing screens would not impact idea generation.

In-person collaborations offer a cognitive advantage. Now several workplaces are moving towards a hybrid setup. This study indicates that the creative idea generation should be reserved for in-person meetings.

Journal reference:
Brucks, M.S., Levav, J. (2022) Virtual communication curbs creative idea generation. Nature. https://doi.org/10.1038/s41586-022-04643-y, https://www.nature.com/articles/s41586-022-04643-y

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Gum Health Day 2022 calls for prevention, early detection, and effective treatment of gum diseases

Jacob Scott

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“Treat your gums” is the slogan for Gum Health Day 2022, a worldwide awareness campaign organized by the European Federation of Periodontology (EFP). The event aims to inform the public of the detrimental effects of gum diseases – gingivitis, periodontitis, peri-implant mucositis, and peri-implantitis – on both oral and overall health. The campaign calls for the prevention, early detection, and – where necessary – effective treatment of gum diseases.

Although still poorly acknowledged by the public, gum diseases are chronic inflammatory conditions affecting a high proportion of adults worldwide, causing tooth loss and other problems in the mouth. Crucially, gum diseases are also linked to major systemic health issues including diabetes mellitus, cardiovascular diseases, chronic kidney disease, adverse pregnancy outcomes, rheumatoid arthritis, Alzheimer’s disease, erectile dysfunction, certain forms of cancer, and more severe Covid-19 outcomes. This means that gum diseases and their prevention and treatment are of major importance not only for oral health, but also for the whole body.

This year’s campaign focuses heavily on the treatment part – we know that millions of people suffer from gum diseases that can be treated effectively. ‘Treat your gums’ calls for this treatment – with all the documented positive effects for the mouth and whole body – to actually happen.”

Moritz Kebschull, coordinator of Gum Health Day 2022

That is why the hashtag for the campaign is #TreatYourGums, and why the recent EFP-produced clinical practice guidelines on the treatment of periodontitis are a major part of the Gum Health Day 2022 initiative.

“The new EFP-produced clinical practice guidelines on the treatment of all four stages of periodontitis are a crucial development, as they are the first high-quality international guidelines to outline a structured and easily implemented pathway for the efficient and effective treatment of gum disease,” Prof. Kebschull says. “In a nutshell, gum disease treatment that works!”

He adds: “It is important to underline that gum disease is one of the most widespread chronic diseases in the worldwide adult population, and that it is usually painless, so its early detection and successful treatment depends heavily on how fast the patient takes action.”

A major innovation of Gum Health Day 2022 is an EFP-designed “customized content generator”, a feature that allows the federation’s 37 affiliated national societies of periodontology, their individual members – as well as practices, hospitals, and members of the public – to customise their own Gum Health Day 2022 materials, based on a series of graphic templates and catchphrases.

In the framework of Gum Health Day 2022, the EFP encourages periodontists, dentists, researchers, and other health-related professionals to sign and disseminate the EFP Manifesto: Perio and General Health, an international call to action for the prevention, early detection, and treatment of gum disease. Individuals and organisations are invited to endorse it and join the 1,200+ professionals, dental practices, companies, and universities that have so far supported it.


The European Federation of Periodontology (EFP, ww.efp.org) is a non-profit organization dedicated to promoting awareness of periodontal science and the importance of gum health. Its guiding vision is “periodontal health for a better life.”

Founded in 1991, the EFP is a federation of 37 national periodontal societies that represents more than 16,000 periodontists, dentists, researchers, and oral-health professionals from Europe and around the world. It supports evidence-based science in periodontal and oral health, and it promotes events and campaigns aimed at both professionals and the public.

The EFP organizes EuroPerio, the world’s leading congress in periodontology and implant dentistry, as well as other important professional and expert events such as Perio Master Clinic and Perio Workshop. The annual Gum Health Day on May 12, organized by the EFP and its member societies, brings key messages on gum health to millions of people across the world.

The EFP also organizes workshops and outreach campaigns with its partners: projects to date have covered the relationship between periodontal disease and diabetes, cardiovascular disease, and caries, as well as women’s oral health during pregnancy.

The EFP’s Journal of Clinical Periodontology is the most authoritative scientific publication in this field. The federation also publishes JCP Digest, a monthly digest of research, and the Perio Insight magazine, which features experts’ views and debates.

The EFP’s work in education is also highly significant, notably its accreditation programme for postgraduate education in periodontology and implant dentistry.

The EFP has no professional or commercial agenda.

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