scholarly journals Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2

2021 ◽  
Author(s):  
Samuel J Dicken ◽  
Matthew J Murray ◽  
Lucy G Thorne ◽  
Ann-Kathrin Reuschl ◽  
Calum Forrest ◽  
...  
Keyword(s):  
Protein Function ◽  
Virus Entry ◽  
Mitigation Measures ◽  
Evolutionary Trajectory ◽  
Immune Resistance ◽  
Recent Emergence ◽  
Model Cell ◽  
Evolutionary Trajectories ◽  
Evolutionary Tuning ◽  
The Uk

The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARS-CoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.

scholarly journals Heterogeneous Mental Health Development During the COVID-19 Pandemic in the United Kingdom

2021 ◽  
Author(s):  
Lea Ellwardt ◽  
Patrick Praeg
Keyword(s):  
United Kingdom ◽  
Psychological Distress ◽  
Latent Class ◽  
Mitigation Measures ◽  
Social Lives ◽  
The United Kingdom ◽  
Policy Measures ◽  
Nationally Representative ◽  
The Uk

Aim. The COVID-19 pandemic and the mitigation measures by governments have upended the economic and social lives of many, leading to widespread psychological distress. However, how distress developed during the pandemic and who was most affected is poorly understood. We explore heterogeneity in trajectories of psychological distress during the first six months of the pandemic in the United Kingdom and relate this heterogeneity to socio-demographic and health factors. Subjects and Methods. We analyze six waves of longitudinal, nationally representative survey data from the UK Household Longitudinal Study (N = 15,218), covering the first lockdown in 2020. First, latent class mixture modelling (LCCM) is used to identify trajectories of psychological distress. Second, associations of the trajectories with covariates are tested with multinomial logistic regressions. Results. We find four different trajectories of distress: continuously low, continuously moderate, temporarily elevated, and continuously elevated distress. One-fifth of the population experienced severely elevated risks of distress. Long-term exposure was highest among younger people, women, those who lost income, and those with previous health conditions or COVID-19 symptoms. Conclusion. Given the threat of persistent stress on health, policy measures should be sensitized to the unintended yet far-reaching consequences of non-pharmaceutical interventions.

COVID-19 IMPACTS ON DESTITUTION IN THE UK

2020 ◽  
Vol 253 ◽  
pp. R77-R85 ◽  
Author(s):  
Arnab Bhattacharjee ◽  
Elena Lisauskaite
Keyword(s):  
Adverse Effects ◽  
The Elderly ◽  
Mitigation Measures ◽  
Aggregate Level ◽  
Multiple Impacts ◽  
Number Of Children ◽  
The United Kingdom ◽  
The Uk ◽  
The Unemployed ◽  
Very High

We use microsimulation combined with a model of the COVID-19 impacts on individuals and households to obtain projections of households in destitution in the United Kingdom. The projections are estimated at two levels: aggregate quarterly for the UK, for all quarters of 2020; and annual for 2020 differentiated by region, sector and household demographics. At the aggregate level, destitution is projected to be about three times higher than the non-COVID counterfactual level in 2020Q2, as well as substantially higher than the non-COVID case for the remainder of the year. This increased destitution is initially largely due to the effect on the self-employed, and as the Furlough scheme is drawn down, also on the unemployed. Impacts upon different regions and sectors vary widely, and so do variations across different household types. The sectors particularly affected are construction and manufacturing, while London and its closely connected regions (South East and the Midlands) are most severely affected. Single adult households suffer the most, and the adverse effects increase with number of children in the household. That the effects upon youth remain high is a particularly worrying sign, and very high increases in destitution are also projected for 25–54 year olds and the elderly (75 years and older). Further, severe adverse effects are projected for sections of society and the economy where multiple impacts are coincident. Robust and sustained mitigation measures are therefore required.

scholarly journals Does aquatic foraging impact head shape evolution in snakes?

2016 ◽  
Vol 283 (1837) ◽  
pp. 20161645 ◽  
Author(s):  
Marion Segall ◽  
Raphaël Cornette ◽  
Anne-Claire Fabre ◽  
Ramiro Godoy-Diana ◽  
Anthony Herrel
Keyword(s):  
Aquatic Environment ◽  
Anterior Part ◽  
Three Dimensional ◽  
Shape Evolution ◽  
Head Shape ◽  
Evolutionary Trajectory ◽  
Biomechanical Models ◽  
Historical Factors ◽  
Evolutionary Trajectories ◽  
Do So

Evolutionary trajectories are often biased by developmental and historical factors. However, environmental factors can also impose constraints on the evolutionary trajectories of organisms leading to convergence of morphology in similar ecological contexts. The physical properties of water impose strong constraints on aquatic feeding animals by generating pressure waves that can alert prey and potentially push them away from the mouth. These hydrodynamic constraints have resulted in the independent evolution of suction feeding in most groups of secondarily aquatic tetrapods. Despite the fact that snakes cannot use suction, they have invaded the aquatic milieu many times independently. Here, we test whether the aquatic environment has constrained head shape evolution in snakes and whether shape converges on that predicted by biomechanical models. To do so, we used three-dimensional geometric morphometrics and comparative, phylogenetically informed analyses on a large sample of aquatic snake species. Our results show that aquatic snakes partially conform to our predictions and have a narrower anterior part of the head and dorsally positioned eyes and nostrils. This morphology is observed, irrespective of the phylogenetic relationships among species, suggesting that the aquatic environment does indeed drive the evolution of head shape in snakes, thus biasing the evolutionary trajectory of this group of animals.

scholarly journals Evaluating Integrated Surveillance for Antimicrobial Use and Resistance in England: A Qualitative Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Houda Bennani ◽  
Laura Cornelsen ◽  
Katharina D. C. Stärk ◽  
Barbara Häsler
Keyword(s):  
Data Collection ◽  
Qualitative Study ◽  
Surveillance System ◽  
Companion Animals ◽  
Mitigation Measures ◽  
Antimicrobial Use ◽  
Surveillance Systems ◽  
Structured Interviews ◽  
A Value ◽  
The Uk

Integrated surveillance systems for antimicrobial use (AMU) and antimicrobial resistance (AMR) require regular evaluation to ensure the effectiveness and efficiency of the system. An important step in the evaluation is to choose an appropriate tool for the purpose of the evaluation. The “Integrated Surveillance System Evaluation” (ISSE) framework is a conceptual framework that was developed to evaluate One Health (OH) integration in surveillance system for AMU/AMR. This study aimed to evaluate the performance and value of integrated surveillance system for AMU/AMR in England by applying the ISSE framework, which was used to develop data collection protocols and define the study design. A qualitative study using semi-structured interviews was conducted to collect the data and analyse it thematically. Eighteen stakeholders from human, animal, food and environment sectors that are involved in AMU/AMR surveillance were interviewed. Four main themes emerged from the analysis: (1) Cross-sectoral integration in the surveillance system for AMU/AMR; (2) Production of OH outputs and outcomes; (3) Drivers and barriers to cross-sectoral collaboration; and 4) Need for more cross-sectoral collaboration. The findings showed that there were links between integrated surveillance information, decision making and interventions. However, there were only few OH examples, such as the UK AMR contingency plan, where the potential of cross-sectoral collaboration was fully exploited. A lot of the benefits described were related to the generation of information and increase in knowledge and understanding without links to how the information generated was used. While these intangible benefits have a value on their own, being able to link surveillance information and mitigation measures would help to enhance the value of integrated surveillance. In terms of improvement, the main areas identified were the development of more harmonised methods for data collection and analysis, provision of resources dedicated to cross-sectoral collaboration, improved coordination, and collection of surveillance data from the environment and from companion animals. By identifying links between OH surveillance information produced and various outputs and outcomes; this study helped to understand the wider benefits of integrated surveillance for AMU/AMR in England and provided insights on how the system could be improved and efficiency increased.

scholarly journals Covid-19 testing strategies and lockdowns: the European closed curves, analysed by “skew-normal” distributions, the forecasts for the UK, Sweden, and the USA, and the ongoing outbreak in Brazil

2020 ◽  
Author(s):  
Stefano De Leo
Keyword(s):  
Early Stage ◽  
Spreading Rate ◽  
European Countries ◽  
Mitigation Measures ◽  
Local Authorities ◽  
Normal Distributions ◽  
Testing Strategies ◽  
The Usa ◽  
The Uk ◽  
Skew Normal

AbstractAs the number of Covid-19 infections worldwide overtakes 6 millions of Total Confirmed Cases (TCC), the data reveal almost closed outbreaks in many European countries. Using the European data as a basis for our analysis, we study the spreading rate of Covid-19 and model the Daily Confirmed Cases and Deaths per Million (DCCpM and DDpM) curves by using “skew-normal” probability density functions. The use of these asymmetrical distributions allows to get a more realistic prediction of the end of the disease in each country and to evaluate the effectiveness of the local authorities strategies in facing the European outbreak. The initial stage of the Brazilian disease is compared with the early phase of the European one. This is done by using the weekly spreading rate of Covid-19. For Sweden, UK, and USA, we shall give a forecast for the end of pandemic and for Brazil the prediction of the peak of DDpM. We also discuss additional factors that could play an important role in the fight against Covid-19, such as the fast response of the local authorities, the testing strategies, the number of beds in the intensive care units, and, last but not least, the measures of isolation adopted. The Brazilian mitigation measures can be placed between the strict lockdown of many European countries and the Swedish approach, but clearly much comparable to the European ones (in particular to the Netherlands).MethodsFor Brazil, the weekly spreading rates of Covid-19, as more people are getting infected, was used to compare the outbreak in these countries with the ones of the European countries when they were at the same stage of infection. In the early stage of the disease, normal distributions have been used to obtain what we call a dynamic prediction of the peaks. After reaching the peak of daily infections and/or deaths, skew-normal distributions are required to correctly fit the asymmetrical DCCpM and DDpM curves and get a realistic forecast of the pandemic end.FindingsThe European data analysis shows that the spreading rate of Covid-19 increased similarly for all countries in its initial stage, but it changed as the number of TCCpM in each country grew. This was caused by the different timely action of the authorities in adopting isolation measures and/or massive testing strategies. The early stage of the outbreak in the USA and Brazil shows for their α factor (DCCpM) a behaviour similar to Italy and Sweden, respectively. For the β factor (DDpM), the American spreading is similar to the one of Switzerland, whereas the Brazilian factor is greater than the ones of Portugal, Germany, and Austria (which showed, in terms of TDpM, the best results in Europe) but, at the moment, it is lower than the other European countries.InterpretationThe fitting skew parameters used to model the DCCpM and DDpM curves allow a more realistic prediction of the end of the pandemic and give us the possibility to compare the mitigation measures adopted by the local authorities by analysing their respective skew normal parameters (mean, mode, standard deviation, and skewness). In Europe, Sweden and the UK show the greatest asymmetries, a kind of marathon instead of the sprint of other European countries (as observed by Swedish authorities). This also happens for the USA. The Brazilian weekly spreading rate for deaths is lower than most of the European countries at the same stage of the outbreak.FundingIndividual grants by CNPq (2018/303911) and Fapesp (2019/06382–9).

scholarly journals Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

2021 ◽  
Author(s):  
Pengfei Wang ◽  
Manoj S. Nair ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk ◽  
Antibody Resistance

The COVID-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1–3, with more in the pipeline4–7. Furthermore, multiple vaccine constructs have shown promise8, including two with ~95% protective efficacy against COVID-199,10. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. The recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a few mAbs to the receptor-binding domain (RBD). It is not more resistant to convalescent plasma or vaccinee sera. Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals Covid-19 testing strategies and lockdowns: the European closed curves, analysed by ``skew-normal'' distributions, the forecasts for the UK, Sweden, and the USA, and the ongoing outbreak in Brazil (Preprint)

2020 ◽  
Author(s):  
Stefano De Leo
Keyword(s):  
Early Stage ◽  
Spreading Rate ◽  
European Countries ◽  
Mitigation Measures ◽  
Local Authorities ◽  
Normal Distributions ◽  
Testing Strategies ◽  
The Usa ◽  
The Uk ◽  
Skew Normal

BACKGROUND As the number of Covid-19 infections worldwide overtakes 6 millions of Total Confirmed Cases (TCC), the data reveal almost closed outbreaks in many European countries. Using the European data as a basis for our analysis, we study the spreading rate of Covid-19 and model the Daily Confirmed Cases and Deaths per Million (DCCpM and DDpM) curves by using ``skew-normal'' probability density functions. OBJECTIVE The use of these asymmetrical distributions allows to get a more realistic prediction of the end of the disease in each country and to evaluate the effectiveness of the local authorities strategies in facing the European outbreak. The initial stage of the Brazilian disease is compared with the early phase of the European one. This is done by using the weekly spreading rate of Covid-19. For Sweden, UK, and USA, we shall give a forecast for the end of pandemic and for Brazil the prediction of the peak of DDpM. We also discuss additional factors that could play an important role in the fight against Covid-19, such as the fast response of the local authorities, the testing strategies, the number of beds in the intensive care units, and, last but not least, the measures of isolation adopted. The Brazilian mitigation measures can be placed between the strict lockdown of many European countries and the Swedish approach, but clearly much comparable to the European ones (in particular to the Netherlands). METHODS For Brazil, the weekly spreading rates of Covid-19, as more people are getting infected, was used to compare the outbreak in these countries with the ones of the European countries when they were at the same stage of infection. In the early stage of the disease, normal distributions have been used to obtain what we call a dynamic prediction of the peaks. After reaching the peak of daily infections and/or deaths, skew-normal distributions are required to correctly fit the asymmetrical DCCpM and DDpM curves and get a realistic forecast of the pandemic end. RESULTS The European data analysis shows that the spreading rate of Covid-19 increased similarly for all countries in its initial stage, but it changed as the number of TCCpM in each country grew. This was caused by the different timely action of the authorities in adopting isolation measures and/or massive testing strategies. The early stage of the outbreak in the USA and Brazil shows for their $\boldsymbol{\alpha}$ factor (DCCpM) a behaviour similar to Italy and Sweden, respectively. For the $\boldsymbol{\beta}$ factor (DDpM), the American spreading is similar to the one of Switzerland, whereas the Brazilian factor is greater than the ones of Portugal, Germany, and Austria (which showed, in terms of TDpM, the best results in Europe) but, at the moment, it is lower than the other European countries. CONCLUSIONS The fitting skew parameters used to model the DCCpM and DDpM curves allow a more realistic prediction of the end of the pandemic and give us the possibility to compare the mitigation measures adopted by the local authorities by analysing their respective skew normal parameters (mean, mode, standard deviation, and skewness). In Europe, Sweden and the UK show the greatest asymmetries, a kind of marathon instead of the sprint of other European countries (as observed by Swedish authorities). This also happens for the USA. The Brazilian weekly spreading rate for deaths is lower than most of the European countries at the same stage of the outbreak.

scholarly journals Auditors and regulatory work (1987–2013)

2019 ◽  
Vol 32 (7) ◽  
pp. 2088-2113
Author(s):  
David Collins ◽  
Ian Dewing ◽  
Peter Russell
Keyword(s):  
Financial Services ◽  
Design Methodology ◽  
Financial Regulation ◽  
Analytical Framework ◽  
Content Type ◽  
Documentary Sources ◽  
Recent Emergence ◽  
The Uk ◽  
Intensive Reading

Purpose The purpose of this paper is to investigate the jurisdictional expansion of audit into the area of UK financial regulation. The paper draws on the analytical framework of new audit spaces (Andon et al., 2014, 2015), which built on the concept of regulatory space (Hancher and Moran, 1989), and characterises this new audit space as regulatory work. Design/methodology/approach Through an intensive reading of a variety of publicly available documentary sources, the paper investigates the role of auditors and accountants in the reporting accountants’ and skilled persons’ regimes in the UK under the Banking Act 1987 and the Financial Services and Markets Act 2000. Findings The paper identifies a new audit space characterised as regulatory work, which is made up of three distinct phases (and suggests the recent emergence of a fourth phase), and considers the extent to which these phases of regulatory work share common themes across new audit spaces identified by Andon et al. (2015) as independence, reporting, accreditation and mediating. Originality/value The paper identifies a further jurisdictional expansion of audit into a new audit space, characterised as regulatory work.

scholarly journals ATP1A1-Mediated Src Signaling Inhibits Coronavirus Entry into Host Cells

2015 ◽  
Vol 89 (8) ◽  
pp. 4434-4448 ◽  
Author(s):  
Christine Burkard ◽  
Monique H. Verheije ◽  
Bart L. Haagmans ◽  
Frank J. van Kuppeveld ◽  
Peter J. M. Rottier ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Crucial Role ◽  
Influenza A ◽  
Hepatitis Virus ◽  
Early Stage ◽  
Virus Entry ◽  
Host Cells ◽  
Α Subunit ◽  
Src Signaling ◽  
Recent Emergence

ABSTRACTIn addition to transporting ions, the multisubunit Na+,K+-ATPase also functions by relaying cardiotonic steroid (CTS)-binding-induced signals into cells. In this study, we analyzed the role of Na+,K+-ATPase and, in particular, of its ATP1A1 α subunit during coronavirus (CoV) infection. As controls, the vesicular stomatitis virus (VSV) and influenza A virus (IAV) were included. Using gene silencing, the ATP1A1 protein was shown to be critical for infection of cells with murine hepatitis virus (MHV), feline infectious peritonitis virus (FIPV), and VSV but not with IAV. Lack of ATP1A1 did not affect virus binding to host cells but resulted in inhibited entry of MHV and VSV. Consistently, nanomolar concentrations of the cardiotonic steroids ouabain and bufalin, which are known not to affect the transport function of Na+,K+-ATPase, inhibited infection of cells with MHV, FIPV, Middle East respiratory syndrome (MERS)-CoV, and VSV, but not IAV, when the compounds were present during virus inoculation. Cardiotonic steroids were shown to inhibit entry of MHV at an early stage, resulting in accumulation of virions close to the cell surface and, as a consequence, in reduced fusion. In agreement with an early block in infection, the inhibition of VSV by CTSs could be bypassed by low-pH shock. Viral RNA replication was not affected when these compounds were added after virus entry. The antiviral effect of ouabain could be relieved by the addition of different Src kinase inhibitors, indicating that Src signaling mediated via ATP1A1 plays a crucial role in the inhibition of CoV and VSV infections.IMPORTANCECoronaviruses (CoVs) are important pathogens of animals and humans, as demonstrated by the recent emergence of new human CoVs of zoonotic origin. Antiviral drugs targeting CoV infections are lacking. In the present study, we show that the ATP1A1 subunit of Na+,K+-ATPase, an ion transporter and signaling transducer, supports CoV infection. Targeting ATP1A1 either by gene silencing or by low concentrations of the ATP1A1-binding cardiotonic steroids ouabain and bufalin resulted in inhibition of infection with murine, feline, and MERS-CoVs at an early entry stage. Infection with the control virus VSV was also inhibited. Src signaling mediated by ATP1A1 was shown to play a crucial role in the inhibition of virus entry by ouabain and bufalin. These results suggest that targeting the Na+,K+-ATPase using cardiotonic steroids, several of which are FDA-approved compounds, may be an attractive therapeutic approach against CoV and VSV infections.

Sign in / Sign up

Export Citation Format

Share Document