scholarly journals Shortening Epitopes to Survive: The Case of SARS-CoV-2 Lambda Variant

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1494
Author(s):  
Stefano Pascarella ◽  
Massimo Ciccozzi ◽  
Martina Bianchi ◽  
Domenico Benvenuto ◽  
Marta Giovanetti ◽  
...  
Keyword(s):  
Bioinformatics Analysis ◽  
Adaptation Strategy ◽  
Spike Protein ◽  
South American ◽  
Glycosylation Sites ◽  
Immunogenic Epitope ◽  
In Silico Study ◽  
The Us ◽  
Potential Impact ◽  
The Stability

Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic parameters affecting the stability of the Spike protein and its Receptor Binding Domain. We report here an in silico study on the potential impact of the Spike protein mutations on the immuno-escape ability of the Lambda variant. Bioinformatics analysis suggests that a combination of shortening the immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy, potentially allowing this emerging viral variant to escape from host immunity.

scholarly journals Cutting epitopes to survive: the case of lambda variant

2021 ◽  
Author(s):  
Stefano Pascarella ◽  
Massimo Ciccozzi ◽  
Martina Bianchi ◽  
Domenico Benvenuto ◽  
Roberto Cauda ◽  
...  
Keyword(s):  
In Silico ◽  
Adaptation Strategy ◽  
Host Immunity ◽  
Spike Protein ◽  
Viral Variant ◽  
Glycosylation Sites ◽  
Immunogenic Epitope ◽  
In Silico Study ◽  
Potential Impact ◽  
Protein Mutations

This manuscript concisely reports an in-silico study on the potential impact of the Spike protein mutations on immuno-escape ability of SARS-CoV-2 lambda variant. Biophysical and bioinformatics data suggest that a combination of shortening immunogenic epitope loops and generation of potential N-glycosylation sites may be a viable adaptation strategy potentially allowing this emerging viral variant escaping host immunity.

scholarly journals Immune Evasion of SARS-CoV-2 Emerging Variants: What Have We Learnt So Far?

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1192
Author(s):  
Ivana Lazarevic ◽  
Vera Pravica ◽  
Danijela Miljanovic ◽  
Maja Cupic
Keyword(s):  
Immune Evasion ◽  
Human Population ◽  
Evolutionary Rate ◽  
Spike Protein ◽  
Close Monitoring ◽  
Global Level ◽  
Therapeutic Application ◽  
Neutralization Capacity ◽  
Rapid Transmission ◽  
Potential Impact

Despite the slow evolutionary rate of SARS-CoV-2 relative to other RNA viruses, its massive and rapid transmission during the COVID-19 pandemic has enabled it to acquire significant genetic diversity since it first entered the human population. This led to the emergence of numerous variants, some of them recently being labeled “variants of concern” (VOC), due to their potential impact on transmission, morbidity/mortality, and the evasion of neutralization by antibodies elicited by infection, vaccination, or therapeutic application. The potential to evade neutralization is the result of diversity of the target epitopes generated by the accumulation of mutations in the spike protein. While three globally recognized VOCs (Alpha or B.1.1.7, Beta or B.1.351, and Gamma or P.1) remain sensitive to neutralization albeit at reduced levels by the sera of convalescent individuals and recipients of several anti-COVID19 vaccines, the effect of spike variability is much more evident on the neutralization capacity of monoclonal antibodies. The newly recognized VOC Delta or lineage B.1.617.2, as well as locally accepted VOCs (Epsilon or B.1.427/29-US and B1.1.7 with the E484K-UK) are indicating the necessity of close monitoring of new variants on a global level. The VOCs characteristics, their mutational patterns, and the role mutations play in immune evasion are summarized in this review.

scholarly journals Bioinformatics Analysis of Allele Frequencies and Expression Patterns of ACE2, TMPRSS2 and FURIN in Different Populations and Susceptibility to SARS-CoV-2

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1041
Author(s):  
Mohammad Tarek ◽  
Hana Abdelzaher ◽  
Firas Kobeissy ◽  
Hassan A. N. El-Fawal ◽  
Mohammed M. Salama ◽  
...  
Keyword(s):  
Immune Response ◽  
Genetic Factors ◽  
Bioinformatics Analysis ◽  
Expression Patterns ◽  
Spike Protein ◽  
Target Cells ◽  
Health Crisis ◽  
Expression Levels ◽  
Different Populations ◽  
Shed Light

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2’s receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN’s potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.

The great Chinese surprise: the rupture with the United States is real and is happening

2020 ◽  
Vol 96 (2) ◽  
pp. 419-437
Author(s):  
Xiangfeng Yang
Keyword(s):  
United States ◽  
The United States ◽  
Donald Trump ◽  
Ample Evidence ◽  
Pendulum Swing ◽  
The Us ◽  
Methodological Problems ◽  
Trade War ◽  
The Stability ◽  
The Individual

Abstract Ample evidence exists that China was caught off guard by the Trump administration's onslaught of punishing acts—the trade war being a prime, but far from the only, example. This article, in addition to contextualizing their earlier optimism about the relations with the United States under President Trump, examines why Chinese leaders and analysts were surprised by the turn of events. It argues that three main factors contributed to the lapse of judgment. First, Chinese officials and analysts grossly misunderstood Donald Trump the individual. By overemphasizing his pragmatism while downplaying his unpredictability, they ended up underprepared for the policies he unleashed. Second, some ingrained Chinese beliefs, manifested in the analogies of the pendulum swing and the ‘bickering couple’, as well as the narrative of the ‘ballast’, lulled officials and scholars into undue optimism about the stability of the broader relationship. Third, analytical and methodological problems as well as political considerations prevented them from fully grasping the strategic shift against China in the US.

scholarly journals Pre-Drawn Syringes of Comirnaty for an Efficient COVID-19 Mass Vaccination: Demonstration of Stability

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1029
Author(s):  
Francesca Selmin ◽  
Umberto M. Musazzi ◽  
Silvia Franzè ◽  
Edoardo Scarpa ◽  
Loris Rizzello ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Real Life ◽  
Storage Conditions ◽  
Lipid Nanoparticles ◽  
Mass Vaccination ◽  
Hydrodynamic Diameter ◽  
The Us ◽  
Real Mass ◽  
The Stability ◽  
And Storage

Moving towards a real mass vaccination in the context of COVID-19, healthcare professionals are required to face some criticisms due to limited data on the stability of a mRNA-based vaccine (Pfizer-BioNTech COVID-19 Vaccine in the US or Comirnaty in EU) as a dose in a 1 mL-syringe. The stability of the lipid nanoparticles and the encapsulated mRNA was evaluated in a “real-life” scenario. Specifically, we investigated the effects of different storing materials (e.g., syringes vs. glass vials), as well as of temperature and mechanical stress on nucleic acid integrity, number, and particle size distribution of lipid nanoparticles. After 5 h in the syringe, lipid nanoparticles maintained the regular round shape, and the hydrodynamic diameter ranged between 80 and 100 nm with a relatively narrow polydispersity (<0.2). Samples were stable independently of syringe materials and storage conditions. Only strong mechanical stress (e.g., shaking) caused massive aggregation of lipid nanoparticles and mRNA degradation. These proof-of-concept experiments support the hypothesis that vaccine doses can be safely prepared in a dedicated area using an aseptic technique and transferred without affecting their stability.

scholarly journals Unraveling the stability landscape of mutations in the SARS-CoV-2 receptor-binding domain

2020 ◽  
Author(s):  
Mohamed Raef Smaoui ◽  
Hamdi Yahyaoui
Keyword(s):  
Receptor Binding ◽  
Single Point ◽  
Protein Structures ◽  
Point Mutations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Point Mutant ◽  
The Stability ◽  
Spike Proteins

Abstract The interaction between the receptor-binding domain of the SARS-CoV-2 spike glycoprotein and the ACE2 enzyme is believed to be the entry point of the virus into various cells in the body, including the lungs, heart, liver, and kidneys. The current focus of several therapeutic design efforts explore attempts at affecting the binding interaction between the two proteins to limit the activity of the virus and disease progression. In this work, we analyze the stability of the spike protein under all possible single-point mutations in the receptor-binding domain and computationally explore mutations that can affect the binding with the ACE2 enzyme. We unravel the mutation landscape of the receptor region and assess the toxicity potential of single and multi-point mutations, generating insights for future vaccine efforts on potential mutations that might further stabilize the spike protein and increase its infectivity. We developed a tool, called SpikeMutator, to construct full atomic protein structures of the mutant spike proteins and shared a database of 3,800 single-point mutant structures. We analyzed the recent 65,000 reported spike sequences across the globe and observed the emergence of stable multi-point mutant structures. Using the landscape, we searched through 7.5 million possible 2-point mutation combinations and report that the (R355D K424E) mutation produces one of the strongest spike proteins that therapeutic efforts should investigate for the sake of developing an effective vaccine.

scholarly journals Making of fusion genes in cancer: An in-silico study of mechanism of chromosomal translocations

2018 ◽  
Author(s):  
Kiran Lalwani ◽  
Shivani Sheth ◽  
Inayatullah Sheikh ◽  
Afzal Ansari ◽  
Fulesh Kunwar ◽  
...  
Keyword(s):  
Dna Sequences ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Fusion Gene ◽  
Genetic Material ◽  
Chromosomal Translocations ◽  
In Silico Study ◽  
Clinical Consequences ◽  
The Stability ◽  
Genomic Regions

Chromosomal translocations involve exchange of genetic material between non- homologous chromosomes leading to the formation of a fusion gene with altered function. The clinical consequences of non-random and recurrent chromosomal translocations have been so well understood in carcinogenesis that they serve as diagnostic and prognostic markers and also help in therapy decisions, mainly in leukemia and lymphoma. However, the molecular mechanisms underlying these recurrent genetic exchanges are yet to be understood. Various approaches employed include the extent of the vicinity of the partner chromosomes in the nucleus, DNA sequences at the breakpoints, etc. The present study addresses the stability of DNA sequences at the breakpoint regions using in-silico approach in terms of physicochemical properties such as; AT%, flexibility, melting temperature, enthalpy, entropy, stacking energy and free energy. Changes in these properties may lead to instability of DNA which could affect gene expression in particular and genome organization in general. Our study indicates that the fusion sequences are comparatively more unstable and hence, more prone to breakage. Current study along with others could lead to developing a model for predicting breakage prone genomic regions using this novel in-silico approach.

scholarly journals Dissecting Molecular Determinants of Mutational Escape Mechanisms in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Atomistic Simulations and Ensemble-Based Deep Mutational Scanning of Protein Stability and Binding Interactions

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Conformational Dynamics ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Binding Interactions ◽  
Mutational Profiling ◽  
Neutralizing Capacity ◽  
The Stability ◽  
Protein Response

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit, we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

Uncertainty of law as a factor in the stability of legal system (historical example of the USA)

2021 ◽  
pp. 235-243
Author(s):  
Nataliia S. Latypova
Keyword(s):  
Public Relations ◽  
Legal System ◽  
Legal Regulation ◽  
Gradual Transition ◽  
American Constitution ◽  
Historical Continuity ◽  
American Model ◽  
The Us ◽  
The Usa ◽  
The Stability

Certainty in law is a category that is ambiguously perceived by the scientific legal community. We make an attempt to analyze the meaning and role of the category of certainty in the process of creating a stable legal system with historical continuity. On the example of the US and France legislation, we give polar examples of the implementation of certainty of lawprinciple. We conclude about the undoubted usefulness and necessity of preserving this principle in the Russian legal system. However, a study of the French experience of legal regulation has shown that the desire for certainty, achieved through an overly detailed regulation of public relations, only cre-ates additional problems of interpretation and law enforcement, strengthening legal nihilism and citizens' distrust of law. At the same time, the American model, implying some uncertainty of law, has shown its effectiveness in its historical example. The ambiguity and framework nature of the American Constitution and basic federal laws makes it possible to interpret and concretize their provisions in judicial precedents in different ways, depending on the era and socio-political situation, which contributes to the flexibility and stability of the US legal system. In conclusion, it is noted that domestic legislators need to strive for a gradual transition to the American model of implementing the principle of certainty of law, while providing for detailed regulation of public relations at the level of bylaws. Such an approach will preserve the historical continuity and existence of basic normative acts for several decades, preserve the stability and predictability of legal regulation.

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