scholarly journals Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

2021 ◽  
Author(s):  
Debra Van Egeren ◽  
Alexander Novokhodko ◽  
Madison Stoddard ◽  
Uyen Tran ◽  
Diane Joseph-McCarthy ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Viral Evolution ◽  
Herd Immunity ◽  
Point Mutations ◽  
Multiple Point ◽  
Random Events ◽  
Evolutionary Advantage ◽  
Low Probability ◽  
Rapid Emergence

The rapid emergence and expansion of novel SARS-CoV-2 variants is an unpleasant surprise that threatens our ability to achieve herd immunity for COVID-19. These fitter SARS- CoV-2 variants often harbor multiple point mutations, conferring one or more traits that provide an evolutionary advantage, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we explore the mechanism by which fitter variants of SARS-CoV-2 arise during long-term infections using a mathematical model of viral evolution and identify means by which this evolution can be slowed. While viral load and infection duration play a strong role in favoring the emergence of such variants, the overall probability of emergence and subsequent transmission from any given infection is low, suggesting that viral variant emergence and establishment is a product of random chance. To the extent that luck plays a role in favoring the emergence of novel viral variants with an evolutionary advantage, targeting these low-probability random events might allow us to tip the balance of fortune away from these advantageous variants and prevent them from being established in the population.

scholarly journals Controlling long-term SARS-CoV-2 infections can slow viral evolution and reduce the risk of treatment failure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Debra Van Egeren ◽  
Alexander Novokhodko ◽  
Madison Stoddard ◽  
Uyen Tran ◽  
Bruce Zetter ◽  
...  
Keyword(s):  
Viral Evolution ◽  
Herd Immunity ◽  
Point Mutations ◽  
Population Level ◽  
Multiple Point ◽  
Evolutionary Modeling ◽  
Modeling Framework ◽  
Stochastic Events ◽  
Risk Of Treatment

AbstractThe rapid emergence and expansion of novel SARS-CoV-2 variants threatens our ability to achieve herd immunity for COVID-19. These novel SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more evolutionarily advantageous traits, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we used a stochastic evolutionary modeling framework to explore the emergence of fitter variants of SARS-CoV-2 during long-term infections. We found that increased viral load and infection duration favor emergence of such variants. While the overall probability of emergence and subsequent transmission from any given infection is low, on a population level these events occur fairly frequently. Targeting these low-probability stochastic events that lead to the establishment of novel advantageous viral variants might allow us to slow the rate at which they emerge in the patient population, and prevent them from spreading deterministically due to natural selection. Our work thus suggests practical ways to achieve control of long-term SARS-CoV-2 infections, which will be critical for slowing the rate of viral evolution.

Is 3 years adequate for tracking completely occluded coiled aneurysms?

2020 ◽  
Vol 133 (3) ◽  
pp. 758-764
Author(s):  
Eung Koo Yeon ◽  
Young Dae Cho ◽  
Dong Hyun Yoo ◽  
Su Hwan Lee ◽  
Hyun-Seung Kang ◽  
...  
Keyword(s):  
De Novo ◽  
Careful Monitoring ◽  
Surveillance Period ◽  
Radiological Data ◽  
De Novo Aneurysm ◽  
Low Probability ◽  
Almost All ◽  
Annual Risk

OBJECTIVEThe authors conducted a study to ascertain the long-term durability of coiled aneurysms completely occluded at 36 months’ follow-up given the potential for delayed recanalization.METHODSIn this retrospective review, the authors examined 299 patients with 339 aneurysms, all shown to be completely occluded at 36 months on follow-up images obtained between 2011 and 2013. Medical records and radiological data acquired during the extended monitoring period (mean 74.3 ± 22.5 months) were retrieved, and the authors analyzed the incidence of (including mean annual risk) and risk factors for delayed recanalization.RESULTSA total of 5 coiled aneurysms (1.5%) occluded completely at 36 months showed recanalization (0.46% per aneurysm-year) during the long-term surveillance period (1081.9 aneurysm-years), 2 surfacing within 60 months and 3 developing thereafter. Four showed minor recanalization, with only one instance of major recanalization. The latter involved the posterior communicating artery as an apparent de novo lesion, arising at the neck of a firmly coiled sac, and was unrelated to coil compaction or growth. Additional embolization was undertaken. In a multivariate analysis, a second embolization for a recurrent aneurysm (HR = 22.088, p = 0.003) independently correlated with delayed recanalization.CONCLUSIONSAlmost all coiled aneurysms (98.5%) showing complete occlusion at 36 months postembolization proved to be stable during extended observation. However, recurrent aneurysms were predisposed to delayed recanalization. Given the low probability yet seriousness of delayed recanalization and the possibility of de novo aneurysm formation, careful monitoring may be still considered in this setting but at less frequent intervals beyond 36 months.

scholarly journals Transformed Canine and Murine Mesenchymal Stem Cells as a Model for Sarcoma with Complex Genomics

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1126
Author(s):  
Natasja Franceschini ◽  
Bas Verbruggen ◽  
Marianna A. Tryfonidou ◽  
Alwine B. Kruisselbrink ◽  
Hans Baelde ◽  
...  
Keyword(s):  
Copy Number ◽  
Point Mutations ◽  
Comparative Approach ◽  
Cell Of Origin ◽  
Mesenchymal Tumors ◽  
Spontaneous Transformation ◽  
Exon 2 ◽  
Species Analysis ◽  
Gains And Losses

Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in Tp53/Trp53 are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2-10 of Trp53 transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.

scholarly journals Public acceptance of COVID-19 vaccines: cross-national evidence on levels and individual-level predictors using observational data

BMJ Open ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. e048172
Author(s):  
Marie Fly Lindholt ◽  
Frederik Jørgensen ◽  
Alexander Bor ◽  
Michael Bang Petersen
Keyword(s):  
Health Communication ◽  
Herd Immunity ◽  
Geographical Location ◽  
Vaccine Acceptance ◽  
Total N ◽  
Individual Level ◽  
Health Authorities ◽  
Personal Consequences ◽  
Western Democracies

ObjectivesThe management of the COVID-19 pandemic hinges on the approval of safe and effective vaccines but, equally importantly, on high vaccine acceptance among people. To facilitate vaccine acceptance via effective health communication, it is key to understand levels of vaccine scepticism and the demographic, psychological and political predictors. To this end, we examine the levels and predictors of acceptance of an approved COVID-19 vaccine.Design, setting and participantsWe examine the levels and predictors of acceptance of an approved COVID-19 vaccine in large online surveys from eight Western democracies that differ in terms of the severity of the pandemic and their response: Denmark, France, Germany, Hungary, Sweden, Italy, UK and USA (total N=18 231). Survey respondents were quota sampled to match the population margins on age, gender and geographical location for each country. The study was conducted from September 2020 to February 2021, allowing us to assess changes in acceptance and predictors as COVID-19 vaccine programmes were rolled out.Outcome measureThe outcome of the study is self-reported acceptance of a COVID-19 vaccine approved and recommended by health authorities.ResultsThe data reveal large variations in vaccine acceptance that ranges from 83% in Denmark to 47% in France and Hungary. Lack of vaccine acceptance is associated with lack of trust in authorities and scientists, conspiratorial thinking and a lack of concern about COVID-19.ConclusionMost national levels of vaccine acceptance fall below estimates of the required threshold for herd immunity. The results emphasise the long-term importance of building trust in preparations for health emergencies such as the current pandemic. For health communication, the results emphasise the importance of focusing on personal consequences of infections and debunking of myths to guide communication strategies.

scholarly journals Long-term variation in influenza A virus prevalence and subtype diversity in migratory mallards in northern Europe

2014 ◽  
Vol 281 (1781) ◽  
pp. 20140098 ◽  
Author(s):  
Neus Latorre-Margalef ◽  
Conny Tolf ◽  
Vladimir Grosbois ◽  
Alexis Avril ◽  
Daniel Bengtsson ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Herd Immunity ◽  
Stopover Site ◽  
Virus Prevalence ◽  
Early Autumn ◽  
Temporal Occurrence ◽  
Wildlife Populations ◽  
Pronounced Peak

Data on long-term circulation of pathogens in wildlife populations are seldom collected, and hence understanding of spatial–temporal variation in prevalence and genotypes is limited. Here, we analysed a long-term surveillance series on influenza A virus (IAV) in mallards collected at an important migratory stopover site from 2002 to 2010, and characterized seasonal dynamics in virus prevalence and subtype diversity. Prevalence dynamics were influenced by year, but retained a common pattern for all years whereby prevalence was low in spring and summer, but increased in early autumn with a first peak in August, and a second more pronounced peak during October–November. A total of 74 haemagglutinin (HA)/neuraminidase (NA) combinations were isolated, including all NA and most HA (H1–H12) subtypes. The most common subtype combinations were H4N6, H1N1, H2N3, H5N2, H6N2 and H11N9, and showed a clear linkage between specific HA and NA subtypes. Furthermore, there was a temporal structuring of subtypes within seasons based on HA phylogenetic relatedness. Dissimilar HA subtypes tended to have different temporal occurrence within seasons, where the subtypes that dominated in early autumn were rare in late autumn, and vice versa. This suggests that build-up of herd immunity affected IAV dynamics in this system.

scholarly journals Plasticity in early immune evasion strategies of a bacterial pathogen

2018 ◽  
Vol 115 (16) ◽  
pp. E3788-E3797 ◽  
Author(s):  
Quentin Bernard ◽  
Alexis A. Smith ◽  
Xiuli Yang ◽  
Juraj Koci ◽  
Shelby D. Foor ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Bacterial Pathogen ◽  
Surface Protein ◽  
Innate Immune ◽  
Serum Complement ◽  
Term Survival ◽  
Evasion Strategy ◽  
Innate Immune Evasion ◽  
Novel Therapeutic

Borrelia burgdorferiis one of the few extracellular pathogens capable of establishing persistent infection in mammals. The mechanisms that sustain long-term survival of this bacterium are largely unknown. Here we report a unique innate immune evasion strategy ofB. burgdorferi, orchestrated by a surface protein annotated as BBA57, through its modulation of multiple spirochete virulent determinants. BBA57 function is critical for early infection but largely redundant for later stages of spirochetal persistence, either in mammals or in ticks. The protein influences host IFN responses as well as suppresses multiple host microbicidal activities involving serum complement, neutrophils, and antimicrobial peptides. We also discovered a remarkable plasticity in BBA57-mediated spirochete immune evasion strategy because its loss, although resulting in near clearance of pathogens at the inoculum site, triggers nonheritable adaptive changes that exclude detectable nucleotide alterations in the genome but incorporate transcriptional reprograming events. Understanding the malleability in spirochetal immune evasion mechanisms that ensures their host persistence is critical for the development of novel therapeutic and preventive approaches to combat long-term infections like Lyme borreliosis.

scholarly journals Structure of HIV-2 Nef reveals unique features distinct from HIV-1 involved in immune regulation

2019 ◽  
Author(s):  
Kengo Hirao ◽  
Sophie Andrews ◽  
Kimiko Kuroki ◽  
Hiroki Kusaka ◽  
Takashi Tadokoro ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Immune Regulation ◽  
Titration Calorimetry ◽  
Viral Control ◽  
Mhc I ◽  
Infected People ◽  
Sorting Motif ◽  
Α Helix ◽  
Hiv 1

SummaryThe HIV accessory protein Nef plays a major role in establishing and maintaining infection, particularly through immune evasion. Many HIV-2 infected people experience long-term viral control and survival, resembling HIV-1 elite control. HIV-2 Nef has overlapping but also distinct functions from HIV-1 Nef. Here we report the crystal structure of HIV-2 Nef core. The dileucine sorting motif forms a helix bound to neighboring molecules, and moreover, isothermal titration calorimetry demonstrated that the CD3 endocytosis motif can directly bind to HIV-2 Nef, ensuring AP-2 mediated endocytosis for CD3. The highly-conserved C-terminal region forms a α-helix, absent from HIV-1. We further determined the structure of SIV Nef harboring this region, demonstrating similar C-terminal α-helix, which may contribute to AP-1 binding for MHC-I downregulation. These results provide new insights into the distinct pathogenesis of HIV-2 infection.

Vaccination Against COVID-19: Emerging Issues and Future Prospects

2021 ◽  
Vol 76 (6) ◽  
pp. 652-660
Author(s):  
Gennadiy G. Onischenko ◽  
Tatiana E. Sizikova ◽  
Vitaliy N. Lebedev ◽  
Sergey V. Borisevich
Keyword(s):  
Effective Means ◽  
Herd Immunity ◽  
High Rate ◽  
Vaccination Rates ◽  
Actual Duration ◽  
Entire Duration ◽  
Mass Immunization ◽  
Emerging Issues ◽  
First Time

The most effective means of combating the COVID-19 pandemic s the formation of herd immunity, with the formation of an immune population to infection. Vaccination rates are continuously increasing. In early February 2021, WHO announced that the number of people vaccinated against the disease for the first time exceeded the number of infected. In early June 2021 the vaccinated number exceeded 2 billion which is more than 12 times the total number infected for the entire duration of the pandemic. The high rate of vaccination leads to the formulation of a number of questions concerning the effectiveness of vaccines currently used for mass immunization the level of herd immunity, necessary to stop the spread of the disease, the actual duration of the vaccination carried out, long-term prospects of the platforms, used in the creation of vaccines. The purpose of this paper is to substantiate reasoned answers to the questions posed.

Current COVID-19 vaccine epidemiology and dentistry

Dental Update ◽  
2021 ◽  
Vol 48 (10) ◽  
pp. 881-886
Author(s):  
Lakshman Samaranayake
Keyword(s):  
Herd Immunity ◽  
Vaccine Recipient ◽  
Vaccine Hesitancy ◽  
Endogenous Factors ◽  
Societal Factors ◽  
The Public ◽  
New Information ◽  
Current Vaccine ◽  
Strain Type

The coronavirus disease 2019 (COVID-19) vaccine story is continuously unfolding. Since our previous COVID-19 commentaries, much new information has transpired on the subject, and here we revisit this topic, which has practical implications for all stakeholders in dentistry, as well as the public. This article, on current vaccine epidemiology, provides an account of why vaccines fail in general, and the particular concerns in relation to the new Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related ‘variants of concern’. Issues related to vaccine failure are fundamentally dichotomous in nature, appertaining either to the vaccine strain (type) per se, and/or the numerous endogenous factors of the vaccine recipient/vaccinee. Societal factors such as vaccine hesitancy and its impact on herd immunity appear to overarch the long-term goal of total or partial global suppression of SARS-CoV-2, and its eventual endemicity. CPD/Clinical Relevance: To describe the reasons for the failure of currently administered COVID-19 vaccines, particularly in relation to the advent of the SARS-CoV-2 ‘variants of concern’, and discuss implications for clinical dental practice.

scholarly journals ACBE, a new base editor for simultaneous C-to-T and A-to-G substitutions in mammalian systems

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Jingke Xie ◽  
Xingyun Huang ◽  
Xia Wang ◽  
Shixue Gou ◽  
Yanhui Liang ◽  
...  
Keyword(s):  
Cytidine Deaminase ◽  
Genetic Diseases ◽  
Point Mutations ◽  
Hek293 Cells ◽  
Multiple Point ◽  
Nucleotide Polymorphisms ◽  
Spacer Length ◽  
Endogenous Gene ◽  
Base Editing ◽  
Fetal Fibroblasts

Abstract Background Many favorable traits of crops and livestock and human genetic diseases arise from multiple single nucleotide polymorphisms or multiple point mutations with heterogeneous base substitutions at the same locus. Current cytosine or adenine base editors can only accomplish C-to-T (G-to-A) or A-to-G (T-to-C) substitutions in the windows of target genomic sites of organisms; therefore, there is a need to develop base editors that can simultaneously achieve C-to-T and A-to-G substitutions at the targeting site. Results In this study, a novel fusion adenine and cytosine base editor (ACBE) was generated by fusing a heterodimer of TadA (ecTadAWT/*) and an activation-induced cytidine deaminase (AID) to the N- and C-terminals of Cas9 nickase (nCas9), respectively. ACBE could simultaneously induce C-to-T and A-to-G base editing at the same target site, which were verified in HEK293-EGFP reporter cell line and 45 endogenous gene loci of HEK293 cells. Moreover, the ACBE could accomplish simultaneous point mutations of C-to-T and A-to-G in primary somatic cells (mouse embryonic fibroblasts and porcine fetal fibroblasts) in an applicable efficiency. Furthermore, the spacer length of sgRNA and the length of linker could influence the dual base editing activity, which provided a direction to optimize the ACBE system. Conclusion The newly developed ACBE would expand base editor toolkits and should promote the generation of animals and the gene therapy of genetic diseases with heterogeneous point mutations.

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