scholarly journals SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: a Computational Model of Epitope Loss in Variants of Concern

2021 ◽  
Author(s):  
Alice Triveri ◽  
Stefano A. Serapian ◽  
Filippo Marchetti ◽  
Filippo Doria ◽  
Silvia Pavoni ◽  
...  
Keyword(s):  
Epitope Prediction ◽  
Antibody Binding ◽  
Published Data ◽  
S Protein ◽  
Potential Impact ◽  
Protein Mutations ◽  
Protein Variants ◽  
Viral Surface ◽  
Selection Of ◽  
Prediction Strategy

The SARS-CoV-2 spike (S) protein is exposed on the viral surface and is the first point of contact between the virus and the host. For these reasons it represents the prime target for Covid-19 vaccines. In recent months, variants of this protein have started to emerge. Their ability to reduce or evade recognition by S-targeting antibodies poses a threat to immunological treatments and raises concerns for their consequences on vaccine efficacy. To develop a model able to predict the potential impact of S-protein mutations on antibody binding sites, we performed unbiased multi-microsecond molecular dynamics of several glycosylated S-protein variants and applied a straightforward structure-dynamics-energy based strategy to predict potential changes in immunogenic regions on each variant. We recover known epitopes on the reference D614G sequence. By comparing our results, obtained on isolated S-proteins in solution, to recently published data on antibody binding and reactivity in new S variants, we directly show that modifications in the S-protein consistently translate into the loss of potentially immunoreactive regions. Our findings can thus be qualitatively reconnected to the experimentally characterized decreased ability of some of the Abs elicited against the dominant S-sequence to recognize variants. While based on the study of SARS-CoV-2 Spike variants, our computational epitope-prediction strategy is portable and could be applied to study immunoreactivity in mutants of proteins of interest whose structures have been characterized, helping the development/selection of vaccines and antibodies able to control emerging variants.

scholarly journals Perspectives on the development of neutralizing antibodies against SARS-CoV-2

2020 ◽  
Vol 3 (2) ◽  
pp. 109-114 ◽  
Author(s):  
Mitchell Ho
Keyword(s):  
Neutralizing Antibodies ◽  
Respiratory Infections ◽  
Human Cells ◽  
Primary Target ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Single Domain Antibodies ◽  
Viral Membrane Fusion ◽  
Viral Surface ◽  
Selection Of

Abstract SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective.

scholarly journals Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

2013 ◽  
Vol 60 (4) ◽  
Author(s):  
Miroslaw Bik-Multanowski ◽  
Lukasz Kaluzny ◽  
Renata Mozrzymas ◽  
Mariusz Oltarzewski ◽  
Ewa Starostecka ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Continuous Treatment ◽  
Published Data ◽  
Complementary Approach ◽  
Trial Treatment ◽  
Potential Impact ◽  
Classical Phenylketonuria ◽  
Pah Gene ◽  
Selection Of Patients ◽  
Selection Of

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region.

scholarly journals Tetracycline-Resistant Bacteria Selected from Water and Zebrafish after Antibiotic Exposure

2021 ◽  
Vol 18 (6) ◽  
pp. 3218
Author(s):  
Ana Rita Almeida ◽  
Marta Tacão ◽  
Joana Soares ◽  
Inês Domingues ◽  
Isabel Henriques
Keyword(s):  
Statistical Significance ◽  
Recovery Period ◽  
Antibiotic Resistance Genes ◽  
Antibiotic Use ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Potential Impact ◽  
Susceptibility Profiles ◽  
Selection Of ◽  
Significant Mortality

The emergence of antibiotic-resistant pathogens due to worldwide antibiotic use is raising concern in several settings, including aquaculture. In this work, the selection of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) was evaluated after exposure of zebrafish to oxytetracycline (OTC) for two months, followed by a recovery period. The selection of ARB in water and fish was determined using selective media. The abundance of tetA genes was estimated through qPCR. Higher prevalence of ARB was measured in all samples exposed to the antibiotic when compared to control samples, although statistical significance was only achieved five days after exposure. Isolates recovered from samples exposed to the antibiotic were affiliated with Pseudomonas and Stenotrophomonas. Various antibiotic susceptibility profiles were detected and 37% of the isolates displayed multidrug resistance (MDR). The selection of the tetA gene was confirmed by qPCR at the highest OTC concentration tested. Two MDR isolates, tested using zebrafish embryos, caused significant mortality, indicating a potential impact on fish health and survival. Overall, our work highlights the potential impact of antibiotic contamination in the selection of potential pathogenic ARB and ARGS.

scholarly journals Potential impact of biocide adaptation on selection of antibiotic resistance in bacterial isolates

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Engy Elekhnawy ◽  
Fatma Sonbol ◽  
Ahmed Abdelaziz ◽  
Tarek Elbanna
Keyword(s):  
Antibiotic Resistance ◽  
Cross Resistance ◽  
Main Body ◽  
Bacterial Isolates ◽  
New Agents ◽  
Biocidal Products ◽  
Potential Impact ◽  
Emergence Of Resistance ◽  
Vital Factor ◽  
Selection Of

Abstract Background Antibiotic resistance in pathogenic bacterial isolates has increased worldwide leading to treatment failures. Main body Many concerns are being raised about the usage of biocidal products (including disinfectants, antiseptics, and preservatives) as a vital factor that contributes to the risk of development of antimicrobial resistance which has many environmental and economic impacts. Conclusion Consequently, it is important to recognize the different types of currently used biocides, their mechanisms of action, and their potential impact to develop cross-resistance and co-resistance to various antibiotics. The use of biocides in medical or industrial purposes should be monitored and regulated. In addition, new agents with biocidal activity should be investigated from new sources like phytochemicals in order to decrease the emergence of resistance among bacterial isolates.

scholarly journals Effects of Selection of Inlet Perturbations, Multiphase and Turbulence Equations on Slug Flow Characteristics Using Altair® AcuSolve™

Processes ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 2152
Author(s):  
Mohammad Sobir Abdul Basith ◽  
Nabihah Sallih ◽  
William Pao King Soon ◽  
Shinji Thomas Shibano ◽  
Ramesh Singh ◽  
...  
Keyword(s):  
Level Set ◽  
Slug Flow ◽  
Fluid Dynamic ◽  
Flow Characteristics ◽  
Convective Transport ◽  
Experimental Result ◽  
Internal Boundary ◽  
Published Data ◽  
Level Set Function ◽  
Selection Of

Selection of inlet perturbations, multiphase equations, and the turbulence equation may affect the development of slug flow using computational fluid dynamic simulation tools. The inlet perturbation, such as sinusoidal and random perturbations, play an essential role in inducing slug formation. Multiphase equations such as volume of fluid and level set methods are used to track and capture the gas-liquid immiscible interface. Similarly, turbulence equations such as Spalart Allmaras (SA), Detached Eddy Simulations (DES), k-omega, and k-epsilon can be used to predict the evolution of turbulence within the flow. At present, no direct comparison is available in the literature on the selection of (i) types of inlet perturbations, (ii) the choice of multiphase equations, and (iii) the turbulence equation on the development of slug flow using the Altair computational package. This article aims to compare the effects of the selection of inlet perturbations, multiphase models and turbulence equations on slug flow characteristics using Altair® AcuSolve™. The findings by Altair® simulation were compared to published experimental data and simulation works using ANSYS and STAR-CCM+. The slug flow characteristics of interest include slug morphology, a body length-to-diameter ratio, velocity, frequency, and pressure gradient. It was found that the slug flow could be developed for all combinations of settings. Although level set approach in Altair® can track fluid motion successfully, it has a limitation in modelling the convective transport of the multiphase mixture well, unlike ANSYS and STAR-CCM+. Compared to the standard level set method, the coupling of back-and-forth error compensation and correction with the level set function helps to capture the internal boundary more accurately by reducing errors caused by numerical diffusion in the transport of the level set. It was revealed that the Spalart Allmaras turbulence equation could mimic published experimental result better than DES as it produced the closest slug translational velocity. Since the frequency of the slugs for the developed models showed a good agreement with the published data, the models could be sufficient for the investigation of fluid-structure interaction.

scholarly journals Oral Fluoroquinolone or Trimethoprim-Sulfamethoxazole vs ß-Lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis

2019 ◽  
Vol 6 (10) ◽  
Author(s):  
Chitra Punjabi ◽  
Vivian Tien ◽  
Lina Meng ◽  
Stan Deresinski ◽  
Marisa Holubar
Keyword(s):  
Systematic Review ◽  
Oral Treatment ◽  
Meta Analysis ◽  
Published Data ◽  
All Cause Mortality ◽  
Dosing Regimens ◽  
Step Down ◽  
Selection Of ◽  
Infection Recurrence

Abstract Background Using published data, we sought to compare outcomes in patients transitioned to either oral fluoroquinolones (FQs) or trimethoprim-sulfamethoxazole (TMP-SMX) vs ß-lactams (BLs) after an initial intravenous (IV) course for gram-negative rod (GNR) bacteremia. Methods We conducted a systematic review of PubMed and EMBASE and published IDWeek abstracts. We included studies that reported all-cause mortality and/or infection recurrence in patients transitioned to oral FQ/TMP-SMX and BLs. Results Eight retrospective studies met inclusion criteria with data for 2289 patients, of whom 65% were transitioned to oral FQs, 7.7% to TMP-SMX, and 27.2% to BLs. Follow-up periods ranged from 21 to 90 days. All-cause mortality was not significantly different between patients transitioned to either FQ/TMP-SMX or BLs (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69–1.87). Overall recurrence of infection, either bacteremia or the primary site, occurred more frequently in patients transitioned to oral BLs vs FQs (OR, 2.05; 95% CI, 1.17–3.61). Analysis limited to recurrent bacteremia was similarly suggestive, although limited by small numbers (OR, 2.15; 95% CI, 0.93–4.99). However, based on known pharmacokinetics/pharmacodynamics, prescribed ß-lactam dosing regimens were frequently suboptimal. Conclusions In the step-down IV to oral treatment of GNR bacteremia, we found insufficient data regarding outcomes after oral TMP-SMX; however, selection of an FQ over commonly utilized ß-lactam regimens may reduce chances of infection recurrence. Although this may be a class effect, it may simply be the result of inadequate dosing of ß-lactams. Additional investigations are warranted to determine outcomes with TMP-SMX and optimized oral ß-lactam dosing regimens.

Fictional German governesses in Edwardian popular culture: English responses to German militarism and modernity

2019 ◽  
Vol 28 (2) ◽  
pp. 194-213 ◽  
Author(s):  
Susan Bayley
Keyword(s):  
Short Stories ◽  
Popular Culture ◽  
Radclyffe Hall ◽  
Dorothy Richardson ◽  
Avant Garde ◽  
Mixed Feelings ◽  
Potential Impact ◽  
Selection Of

Historians have tended to focus on propaganda when assessing Edwardian attitudes towards Germans, but a shift of focus to fiction reveals a rather different picture. Whereas propaganda created the cliché of ‘the Hun’, fiction produced non- and even counter-stereotypical figures of Germans. An analysis of German governess characters in a selection of short stories, performances, novels, and cartoons indicates that the Edwardian image of Germans was not purely negative but ambivalent and multifarious. Imagined German governesses appeared as patriots and spies, pacifists and warmongers, spinsters and seducers, victims and evil-doers. A close look at characterisations by Saki [H. H. Munro], M. E. Francis [Margaret Blundell], Dorothy Richardson, D. H. Lawrence, Radclyffe Hall, Frank Hart and others reveals not only their variety but also their metaphorical use as responses to Germany’s aggressive militarism and avant-garde modernity. Each governess figure conveyed a positive, negative or ambivalent message about the potential impact of German militarism and modernity on England and Englishness. The aggregate image of German governesses, and by inference Germans, was therefore equivocal and demonstrates the mixed feelings of Edwardians toward their ‘cousin’ country.

In-vitro Selection of Highly Stabilized Protein Variants with Optimized Surface

2001 ◽  
Vol 309 (3) ◽  
pp. 717-726 ◽  
Author(s):  
Andreas Martin ◽  
Volker Sieber ◽  
Franz X. Schmid
Keyword(s):  
In Vitro Selection ◽  
Protein Variants ◽  
Selection Of

scholarly journals The epidemiology of mumps in the UK: a preliminary study of virus transmission, herd immunity and the potential impact of immunization

1987 ◽  
Vol 99 (1) ◽  
pp. 65-84 ◽  
Author(s):  
R. M. Anderson ◽  
J. A. Crombie ◽  
B. T. Grenfell
Keyword(s):  
Herd Immunity ◽  
Virus Transmission ◽  
Epidemiological Data ◽  
Mumps Virus ◽  
Mass Vaccination ◽  
Vaccine Uptake ◽  
Published Data ◽  
Epidemic Period ◽  
Potential Impact ◽  
Mumps Infection

SUMMARYMathematical models and statistical analyses of epidemiological data are employed to assess the potential impact of mass vaccination on the incidences of cases of mumps infection and cases of mumps related complications. The analyses reveal that in the United Kingdom the average age at infection with the mumps virus is currently between 6–7 years and that the inter-epidemic period of the infection is approximately 3 years. The critical level of vaccine uptake to eliminate mumps virus transmission is predicted to be approximately 85% of each cohort of boys and girls by the age of 2 years. Analyses of published data show that the risk of complication arising from mumps infection is markedly age- and sex-related. Model predictions suggest that the incidence of orchitis will be increased, over the level pertaining prior to mass vaccination, by levels of vaccine uptake (by 2 years of age) that are less than 70% of each yearly cohort of boys and girls. Moderate (over 00%) to high (75%) levels of vaccine uptake, however, are predicted to reduce the overall incidence of cases of mumps related complications (especially those with CNS involvement).

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