Tag Archives: Genetic

The E484K mutation is potentially linked to SARS-CoV-2 adaptive fitness | Instant News


A team of Brazilian scientists recently conducted a genomic and phylogenetic analysis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome to better understand the process of viral evolution. Their analysis revealed that the E484K mutation variant of SARS-CoV-2 was present in three different lineages in four regions of Brazil and that the mutation could serve as a general solution for viral evolution. Studies are currently available at bioRxiv* preprint server.

Background

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes Coronavirus disease 2019 (COVID-19), is a member of the Coronaviridae family, which is enveloped in positive sense single-strand RNA viruses with a larger genome size of about 30 kb. Since its appearance in December 2019 in China, researchers around the world have sequenced nearly 4.10,000 SARS-CoV-2 genomes and have shared information in the Global Initiative on Sharing All Influenza Data (GISAID) database.

Several epidemiological studies of the SARS-CoV-2 genomics have been conducted, with the majority focusing on viral mutations. spike protein, surface glycoproteins SARS-CoV-2 is responsible for binding to the host angiotensin-converting enzyme 2 (ACE2) and initiating viral entry. Current research mainly focuses on three viral lineages, B.1.1.7, B.1.351, and P.1. because of its significant impact on viral transmission and pathogenicity. From this lineage, the P.1 lineage is prevalent in Brazil with three mutations (K417T, E484K, and N501Y) in the spike receptor binding (RBD) domain. In Brazil, many viral genomes harbor the E484K mutation, which is associated with increased viral transmission and immune evasion.

In the current study, scientists evaluated mutation characteristics and phylogenetic relationships in currently known lineages in Brazil to understand the adaptive evolutionary process of SARS-CoV-2.

A mutation histogram frequently observed in the Brazilian SARS-CoV-2 genome which stores the E484K mutation.  The red label above the bar indicates the absolute nucleotide position and the blue label indicates the effect of this mutation on the corresponding protein.  Since P.1 has only 19 represented genomes and a handful of mutations, only the major mutations of concern were highlighted.  UTR: Areas that have not been translated;  Syn: Synonym substitution;  del: deletion;  ORF: Open Reading Frame;  Nsp: Non-structural protein;  S: Surge;  E: Envelope;  M: Membrane;  N: Nucleocapsid.

A mutation histogram frequently observed in the Brazilian SARS-CoV-2 genome that stores the E484K mutation. The red label above the bar indicates the absolute nucleotide position and the blue label indicates the effect of this mutation on the corresponding protein. Since P.1 has only 19 represented genomes and a handful of mutations, only the major mutations of concern were highlighted. UTR: Areas that haven’t been translated; Syn: Synonym substitution; del: deletion; ORF: Open Reading Frame; Nsp: Non-structural protein; S: Surge; E: Envelope; M: Membrane; N: Nucleocapsid.

An important observation

The results revealed that the SARS-CoV-2 variant with the E484K mutation was widespread in many regions in Brazil. This mutation was introduced in Brazil in October 2020. Because the E484K mutation was found in different viral lineages at the same time as other mutations, scientists suggest that this particular amino acid substitution could act as a general driver for viral evolution in different genetic variants of SARS. -CoV-2. In the E484K mutation, a negatively charged amino acid (glutamic acid) is replaced by a positively charged amino acid (lysine). Thus, it is hoped that mutations will have a significant impact on viral survival and adaptive evolution.

Structural analysis revealed that a new site for ACE2 (75 amino acid) binding was generated due to the E484K mutation. This appears to create a significantly stronger interaction between ACE2 and the native binding site located at the RBD and ACE2 interface (amino acid 501).

A very diverse range of genetic mutations was observed in all Brazilian lineages with the E484K mutation. On average, about 19 and 30 mutations were observed in lineages B.1.1.33 and P.1, respectively. Further genomic analysis of the most recently emerging P.2 lineage showed that the P.1 and P.2 lineages were rapidly developing and had been circulating in Brazil for a longer period.

A new specific single substitution analysis was also carried out in this study. One such mutation, A27V, is present in the N-terminal domain (NTD) of the spike protein. Research has suggested that mutations in the NTD spike can allosterically change the dynamics of the spike RBD-ACE2 interaction and facilitate immune evasion. In addition, evidence suggests that viral lineages carrying the E484K mutation are associated with increased escape from antibody-mediated neutralization. Although the true impact of E484K and other substitutes on immune avoidance remains unclear, scientists argue that the E484K mutation is associated with improved viral fitness under pressure of natural selection.

Learn significance

Overall, the study suggests that the E484K mutation acts as an important evolutionary event for different viral lineages in terms of increased viral fitness. The E484K mutation has the potential to increase the infectivity and immune-avoidance potential of SARS-CoV-2. According to scientists, further research investigating the effectiveness of human serum anti-SARS-CoV-2 against the E484K mutation variant of SARS-CoV-2 is urgently needed.

* Important Notice

bioRxiv publishes a preliminary scientific report that is not peer reviewed and, therefore, should not be construed as a conclusion, a guide to health-related clinical / behavioral practice, or be treated as prescribed information

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The new N501 SARS-CoV-2 mutation may have been circulating in Italy since August 2020 | Instant News


A recent study published in Lancet Infectious Disease The journal suggests that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain mutated by substitution at position 501 may have been circulating unnoticed even before the end of September 2020, when the rapid emergence of the B.1.1.7 lineage (carrying the N501Y mutation) was initially reported.

On 14 December 2020, British authorities reported to the World Health Organization (WHO) that a new variant of SARS-CoV-2, the causative agent for the ongoing coronavirus disease 2019 (COVID-19) pandemic, was identified through the viral genome sequence.

This variant is often referred to as SARS-CoV-2 VUI 202012/01 (Variant Under Investigation, 2020, month 12, variant 01), was shown to spread more easily among people, although there was no significant association with symptom severity or vaccines efficacy.

However, the mutation is a viral spike type glycoproteins characteristics for this variant, with N501Y a major concern as it involves one of the six major amino acid residues which is responsible for the close contact between the SARS-CoV-2 receptor-binding domain (RBD) and cellular angiotensin-converting enzyme 2 (ACE2). receptors.

As a result, a group of researchers, led by Dr. Simona Fiorentini of the Department of Molecular and Translational Medicine at the University of Brescia in Italy, performed a detailed metagenomic sequencing and bioinformatic analysis to take an in-depth look at Italian isolates.

Detailed genetic characterization

In November 2020, a 59-year-old man with a history of SARS-CoV-2 infection continued to undergo molecular testing. After laboratory confirmation of the infection, genetic characterization of the virus in the November or MB61-Nov samples (but also the previous sample from August 2020, known as MB61-August) was carried out by metagenomic sequencing.

The two complete genomes obtained were then compared with the complete viral genomes freely available at GISAID platform, which is an open source of access to genome data for the influenza virus and SARS-CoV-2.

Strains with the N501Y mutation in spike RBD, recently characterized in Italy and Great Britain as belonging to the rapidly emerging B.1.1.7 lineage, were included in the analysis. Finally, sequence alignment and detailed editing are also carried out to get a complete picture.

The N501T variant arrived in early August

In summary, the bioinformatic analysis in this study revealed that the MB61-Aug SARS-CoV-2 isolate had accumulated ten amino acid changes compared to the initial Italian isolate; In addition, three more have appeared as it evolves until the end of November 2020.

It should be noted that the substitution of N501T was found in the MB61-Aug and MB61-Nov SARS-CoV-2 isolates, which leads to the conclusion that mutations in the key amino acid 501 residue have been spreading in Italy since August 2020..

Our maximum possible time scale tree shows that the N501T variant of this spike appeared in early August in northern Italy, and therefore the SARS-CoV-2 strain having a substitution at position 501 may have been circulating unnoticed even before the end of September 2020, when the Lineage A rapidly emerging B.1.1.7 (carrying the N501Y mutation) was first reported, “the study authors said.

The need for massive research efforts

Recent discoveries regarding the evolution of SARS-CoV-2, particularly in RBD, require massive scientific efforts to pinpoint new variants with the potential for increased spread of the virus, but also with a tendency to exhibit evasive behavior towards strains of infection or vaccines. induced neutralizing immunity.

This study is one step in that direction, and also compares the Wuhan reference strain with the two MB61 variants. The variant actually carries four mutations and one deletion to the glycoprotein spike – two of which are located within the RBD.

Nonetheless, more complex and lengthy studies requiring collaboration between different research groups will be needed in the future. In this regard, the recently established WHO SARS-CoV-2 Virus Evolution Working Group is a way to increase understanding of this timely problem.

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Scientists are beginning to better understand how space travel affects the body | Instant News



Space travel has been one of the greatest achievements of the last century. Indeed, putting humans in space took a lot of time, effort, dedication, and planning. However, there is still a lot to learn. Recently, scientists have gained a better understanding of how space travel specifically affects the body at the molecular level, providing insight into the potential long-term effects it will have on an individual’s health. According to a recent NASA statement, scientists are now starting to understand that “a possible underlying factor of these impacts [is] the powerhouse of the cell, called the mitochondria, [which] undergoes changes in activity during space flights. This full view of the International Space Station was photographed from Space Shuttle Discovery … [+] during the STS-114 return flight mission, following the undocking of the two spacecraft. getty The statement says this preliminary belief stems from decades of research conducted on the International Space Station and samples from around 59 astronauts. The findings are based on a larger compendium of research by several principal investigators, studies and scientific efforts that take a closer look at how space affects human health. Afshin Beheshti, who is one of the key scientists, says, “We have found a universal mechanism that explains the types of changes we are seeing in the body in space, and in a place that we did not expect. […] Everything is turned upside down and it all starts with the mitochondria. Beheshti continues: “When we started to compare the tissues of mice transported on separate space missions, we noticed that mitochondrial dysfunction continued to emerge. […] Whether we were looking at eye or liver problems, the same mitochondrial pathways were causing the problem. CAP CANAVERAL, FL – NOVEMBER 15: NASA astronauts, vehicle pilot Victor Glover (front L), commander … [+] Mike Hopkins (front R), mission specialist Shannon Walker (rear L) and Japan Aerospace Exploration Agency (JAXA) mission specialist, astronaut Soichi Noguchi (rear R) exit the operations building and aircraft en route to the SpaceX Falcon 9 rocket with the Crew Dragon spacecraft on Launch Pad 39A at the Kennedy Space Center November 15, 2020 in Cape Canaveral, Florida. This will mark the second astronaut launch from American soil by NASA and SpaceX and the first operational mission named Crew-1 to the International Space Station. (Photo by Red Huber / Getty Images) Getty Images The press release further states that “NASA data on humans has confirmed this hypothesis. The changes identified in the immune system of astronaut Scott Kelly during his year in space from 2015 can also be explained by the changes observed in the activity of his mitochondria. Blood and urine samples from dozens of other astronauts have shown additional evidence that in various cell types being in space results in altered mitochondrial activity. Evagelia C. Laiakis, PhD, associate professor of oncology at Georgetown said that “although we have each studied different tissues, we have all come to the same conclusion: that mitochondrial function has been adversely affected by travel in l ‘space.” Regardless, the disease related to mitochondrial dysfunction is a broad area of ​​study, which has some level of understanding in both physiological and pathological contexts. So, Beheshti states that perhaps “We can look at the countermeasures and drugs that we are already using to treat mitochondrial disorders on Earth to see how they might work in space, to begin with. Indeed, this crucial finding reaffirms that more research needs to be done in this area to continue examining the short and long term health effects of space travel on humans. Only then can humanity truly unlock and explore the full potential that space has to offer. .



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Mobile phone contamination can be part of the SARS-CoV-2 chain of transmission in hospitals, the Brazilian case study suggests | Instant News


Researchers conducting the study at the 2019 coronavirus disease (COVID-19) intensive care unit (ICU) in São Paulo, Brazil, have warned that infection control guidelines need to include a universal policy regarding the disinfection of cell phones in hospitals.

A team from the University of São Paulo, Brazil, conducted a cross-sectional study in the ICU to investigate health workers’ knowledge of cross-contamination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent responsible for COVID-19.

Although most workers understand the importance of cross-transmission and the importance of adhering to hand hygiene and mobile phone disinfection practices, SARS-CoV-2 ribonucleic acid (RNA) – the genetic material for the virus – is still being detected in some devices, said Evelyn Patricia Sanchez Espinoza and colleagues.

The researchers said the finding that healthcare workers’ cell phones could be contaminated with SARS-CoV-2 suggests these devices could be part of a chain of transmission in health care settings.

“Implementation of official hospital policies to guide health workers [healthcare workers] regarding disinfection and personal MP care [mobile phones] is needed, ”the team warned.

A preprinted version of the paper is available at medRxiv* server when articles undergo peer review.

Worries about cell phone in hospital

Espinoza and colleagues say that cell phones are now generally considered a working tool in hospitals.

However, although SARS-CoV-2 has been detected on the cell phones belonging to patients with COVID-19, the devices have not been identified as a potential source of transmission in a hospital setting.

At the same time, concerns are growing about cross-transmission of SARS-CoV-2, following recent descriptions of how the virus can survive on surfaces in hospitals, the team said.

“However, there is no official policy from the Centers for Disease Control and Prevention (CDC) about it [mobile phone] disinfection in health facilities, ”write the investigators. “Little is known about [the] viruses in MPs or their potential for cross-contamination. “

Investigate healthcare workers’ knowledge of the risks of cell phones

Espinoza and colleagues set out to investigate health workers’ knowledge of SARS-CoV-2 cross-transmission and whether they understand its potential to survive on their own cell phones and be part of the transmission chain.

They conducted a cross-sectional study involving staff members working in the adult ICU at a teaching hospital in São Paulo.

The ICU has 11 separate rooms for each patient. Health care staff use scrubs, N95 respirators and surgical caps as standard when working within the unit, and they also wear surgical gowns, face shields and gloves when entering patient rooms.

An educational campaign on cross-transmission of SARS-CoV-2 and mobile disinfection was launched at the start of the pandemic.

“Informative posters were left on units that had QR codes with access to campaign videos,” said Espinoza and the team.

In the video, health workers are advised to use 70% alcohol swabs to clean phones and screen protectors to keep the oleophobic coating. They are also advised to avoid using the device when providing patient care and while in the restroom.

Ten days after the campaign was held, researchers took participants’ cell phones and sent them for SARS-CoV-2 testing by reverse transcriptase-polymerase chain reaction (RT-PCR).

Electronic questionnaires on hand hygiene and mobile phone use and disinfection were also administered.

What did the research find?

Although most health care workers understood the importance of cross-transmission and increased their adherence to hand hygiene and mobile disinfection during the pandemic, SARS-CoV-2 RNA was still detected in two devices.

Fifty-one out of fifty-three staff members working in the unit participated in the survey and answered the questionnaire. Nine (18%) had covered their cell phones with kitchen plastic film in an effort to facilitate disinfection. Eleven (16%) said they did not remember the campaign and three (6%) said they had not changed their behavior.

Only four (8%) healthcare workers do not believe that the virus can survive on mobile phones and only one (4%) do not believe that the virus can survive on hand.

Ninety-eight percent of participants said they had washed their hands more since the start of the pandemic.

Of the fifty-one swabs collected from the cell phone, SARS-CoV-2 RNA was detected by RT-PCR on two devices.

There is a need for a universal policy regarding the care of electronic devices in hospitals

Espinoza and colleagues said the findings suggest that healthcare workers’ phones could be contaminated with SARS-CoV-2.

“So, maybe members of parliament [medical professionals] may be part of the chain of transmission of the virus in health care settings, ”they wrote.

“Our findings suggest the need for universal policies in infection control guidelines on how to care for electronic devices in hospitals,” the team concluded.

* Important Notice

medRxiv publishes preliminary scientific reports that are not peer reviewed and, therefore, should not be construed as conclusions, guidelines for health-related clinical / behavioral practice, or are treated as defined information.

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Simultaneous mutation of two nonessential genes can lead to the death of cancer cells | Instant News


Ludwig cancer research, has revealed a new instance in which simultaneous mutation of two nonessential genes;none of which are vital for the survival of cells can cause cancer cell death.

Headed by member of the Ludwig San Diego Richard Kolodner and published in the current The proceedings of the National Academy of Sciences, the study also shows that it is a deadly combination, or “synthetic lethality” can be reproduced in a drug-like molecule that can be used to treat cancer.

The development and FDA approval of a new generation of drugs called PARP inhibitors, for the treatment of malignant tumors with defects in tumor suppressor genes BRCA1 and BRCA2 that cause breast cancer, ovarian and many other cancers, have generated significant interest in using synthetic lethal interactions to develop cancer treatments.

Scientists, including group Kolodner, are on the hunt for other synthetic lethal interactions in cancers. “PARP inhibitors are a major step forward, but they are not perfect. Patients can become resistant to them, so there’s always a need for new and better treatments.”

Building from research done on yeast cells, Kolodner and his colleagues found that disabling or removing FEN1 gene of mammals, which is essential for DNA replication and repair, is fatal to cancer cells, mutated forms of the genes BRCA1 and 2.

We have provided information that should make people think FEN1 as a potential interesting therapeutic target and showed how yeast can be used to predict a number of synthetic lethal interactions, which can then be tested in a bona FIDE cancer cell lines with genetic instruments”.

Richard Kolodner, Professor, Professor, Department of cellular and molecular medicine, University of California, San Diego

In previous work with yeast Saccharomyces as a model to identify and study genes that maintain the integrity of the genome, Kolodner and his colleagues found that the RAD27 gene, and of synthetic lethal interactions with the 59 other nonessential genes of yeast.

Two such genes, it should be noted RAD51 and RAD52 play a role in recombination of DNA.

FEN1 is a close analogue or homologue, RAD27 in mammals. Based on their studies of yeast, Kolodner and his colleagues predicted that FEN1 synthetic lethal interactions with BRCA1 and BRCA2, which function in the same biochemical reactions in mammals, as RAD51 and RAD52 to do in yeast.

To test this hypothesis, they synthesized four FEN1-blocking molecules and used the best of them, S8, to suppress the activity of FEN1 in tumor cell lines with or without BRCA mutations. C8 proved to be an effective killer of BRCA-mutant cells.

Then they demonstrated that genetic disorders FEN1 expression had the same effect that S8 did for the breast cancer gene-mutant cells, confirming that the S8 worked, causing synthetic lethality.

Finally, the researchers instilled in C8-C8 sensitive and-resistant tumors in mice and showed that C8 significantly inhibited the growth of C8-sensitive tumors, but not in C8-resistant tumors.

Interestingly, not all cancer cell lines and tumors that responded to treatment C8 was deficient BRCA, K, indicating that FEN1 and synthetic lethal interactions with other genes as well.

These results reveal FEN1 as a novel target for drugs for the treatment of various malignant tumors by induction of synthetic lethality.

They also demonstrate that yeast-based screens provide a powerful tool to accelerate the discovery of synthetic lethal interactions for potential therapeutic value;it is an ongoing project in the laboratory Kolodner.

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