scholarly journals Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 734
Author(s):  
Xuhua Xia
Keyword(s):  
Codon Usage ◽  
Translation Initiation ◽  
Mrna Stability ◽  
Stop Codon ◽  
Translation Termination ◽  
Critical Evaluation ◽  
Immunization Programs ◽  
Translation Elongation ◽  
Different Types ◽  
Similarities And Differences

The design of Pfizer/BioNTech and Moderna mRNA vaccines involves many different types of optimizations. Proper optimization of vaccine mRNA can reduce dosage required for each injection leading to more efficient immunization programs. The mRNA components of the vaccine need to have a 5’-UTR to load ribosomes efficiently onto the mRNA for translation initiation, optimized codon usage for efficient translation elongation, and optimal stop codon for efficient translation termination. Both 5’-UTR and the downstream 3’-UTR should be optimized for mRNA stability. The replacement of uridine by N1-methylpseudourinine () complicates some of these optimization processes because is more versatile in wobbling than U. Different optimizations can conflict with each other, and compromises would need to be made. I highlight the similarities and differences between Pfizer/BioNTech and Moderna mRNA vaccines and discuss the advantage and disadvantage of each to facilitate future vaccine improvement. In particular, I point out a few optimizations in the design of the two mRNA vaccines that have not been performed properly.

scholarly journals Destabilization of Eukaryote mRNAs by 5′ Proximal Stop Codons Can Occur Independently of the Nonsense-Mediated mRNA Decay Pathway

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 800 ◽  
Author(s):  
Barbara Gorgoni ◽  
Yun-Bo Zhao ◽  
J. Krishnan ◽  
Ian Stansfield
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Closed Loop ◽  
Stop Codon ◽  
Translation Termination ◽  
Translation System ◽  
Translation Elongation ◽  
Reading Frame ◽  
Stop Codons ◽  
Nonsense Mediated Mrna Decay

In eukaryotes, the binding of poly(A) binding protein (PAB) to the poly(A) tail is central to maintaining mRNA stability. PABP interacts with the translation termination apparatus, and with eIF4G to maintain 3′–5′ mRNA interactions as part of an mRNA closed loop. It is however unclear how ribosome recycling on a closed loop mRNA is influenced by the proximity of the stop codon to the poly(A) tail, and how post-termination ribosome recycling affects mRNA stability. We show that in a yeast disabled for nonsense mediated mRNA decay (NMD), a PGK1 mRNA with an early stop codon at codon 22 of the reading frame is still highly unstable, and that this instability cannot be significantly countered even when 50% stop codon readthrough is triggered. In an NMD-deficient mutant yeast, stable reporter alleles with more 3′ proximal stop codons could not be rendered unstable through Rli1-depletion, inferring defective Rli1 ribosome recycling is insufficient in itself to trigger mRNA instability. Mathematical modelling of a translation system including the effect of ribosome recycling and poly(A) tail shortening supports the hypothesis that impaired ribosome recycling from 5′ proximal stop codons may compromise initiation processes and thus destabilize the mRNA. A model is proposed wherein ribosomes undergo a maturation process during early elongation steps, and acquire competency to re-initiate on the same mRNA as translation elongation progresses beyond the very 5′ proximal regions of the mRNA.

scholarly journals Translation Initiation Factors eIF3 and HCR1 Control Translation Termination and Stop Codon Read-Through in Yeast Cells

PLoS Genetics ◽  
2013 ◽  
Vol 9 (11) ◽  
pp. e1003962 ◽  
Author(s):  
Petra Beznosková ◽  
Lucie Cuchalová ◽  
Susan Wagner ◽  
Christopher J. Shoemaker ◽  
Stanislava Gunišová ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Stop Codon ◽  
Translation Termination ◽  
Yeast Cells ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Control Translation

scholarly journals Translational accuracy of a tethered ribosome

2020 ◽  
Author(s):  
Celine Fabret ◽  
Olivier Namy
Keyword(s):  
Translation Initiation ◽  
Messenger Rna ◽  
Stop Codon ◽  
Translation Termination ◽  
Large Subunit ◽  
Covalent Attachment ◽  
Ribonucleoprotein Complexes ◽  
Covalently Linked ◽  
Internal Translation ◽  
Large Subunit Rrna

AbstractRibosomes are evolutionary conserved ribonucleoprotein complexes that function as two separate subunits in all kingdoms. During translation initiation, the two subunits assemble to form the mature ribosome, which is responsible for translating the messenger RNA. When the ribosome reaches a stop codon, release factors promote translation termination and peptide release, and recycling factors then dissociate the two subunits, ready for use in a new round of translation. A tethered ribosome, called Ribo-T, in which the two subunits are covalently linked to form a single entity, was recently described in Escherichia coli1. A hybrid ribosomal RNA (rRNA) consisting of both the small and large subunit rRNA sequences was engineered. The ribosome with inseparable subunits generated in this way was shown to be functional and to sustain cell growth. Here, we investigated the translational properties of Ribo-T. We analyzed its behavior in −1 or +1 frameshifting, stop codon readthrough, and internal translation initiation. Our data indicate that covalent attachment of the two subunits modifies the properties of the ribosome, altering its ability to initiate and terminate translation correctly.

scholarly journals The Deleterious Effect of an Insertion Sequence Removing the Last Twenty Percent of the Essential Escherichia coli rpsA Gene Is Due to mRNA Destabilization, Not Protein Truncation

2007 ◽  
Vol 189 (17) ◽  
pp. 6205-6212 ◽  
Author(s):  
Patricia Skorski ◽  
Florence Proux ◽  
Chainez Cheraiti ◽  
Marc Dreyfus ◽  
Sylvie Hermann-Le Denmat
Keyword(s):  
Translation Initiation ◽  
Mrna Stability ◽  
Deleterious Effect ◽  
Insertion Sequence ◽  
Slow Growth ◽  
Stop Codon ◽  
Critical Role ◽  
Wild Type ◽  
Mrna Destabilization

ABSTRACT Ribosomal protein S1, the product of the essential rpsA gene, consists of six imperfect repeats of the same motif. Besides playing a critical role in translation initiation on most mRNAs, S1 also specifically autoregulates the translation of its own messenger. ssyF29 is a viable rpsA allele that carries an IS10R insertion within the coding sequence, resulting in a protein lacking the last motif (S1ΔC). The growth of ssyF29 cells is slower than that of wild-type cells. Moreover, translation of a reporter rpsA-lacZ fusion is specifically stimulated, suggesting that the last motif is necessary for autoregulation. However, in ssyF29 cells the rpsA mRNA is also strongly destabilized; this destabilization, by causing S1ΔC shortage, might also explain the observed slow-growth and autoregulation defect. To fix this ambiguity, we have introduced an early stop codon in the rpsA chromosomal gene, resulting in the synthesis of the S1ΔC protein without an IS10R insertion (rpsA ΔC allele). rpsA ΔC cells grow much faster than their ssyF29 counterparts; moreover, in these cells S1 autoregulation and mRNA stability are normal. In vitro, the S1ΔC protein binds mRNAs (including its own) almost as avidly as wild-type S1. These results demonstrate that the last S1 motif is dispensable for translation and autoregulation: the defects seen with ssyF29 cells reflect an IS10R-mediated destabilization of the rpsA mRNA, probably due to facilitated exonucleolytic degradation.

scholarly journals Premature translation termination mediates triosephosphate isomerase mRNA degradation.

1988 ◽  
Vol 8 (2) ◽  
pp. 802-813 ◽  
Author(s):  
I O Daar ◽  
L E Maquat
Keyword(s):  
Amino Acids ◽  
Mrna Stability ◽  
Half Life ◽  
Triosephosphate Isomerase ◽  
Stop Codon ◽  
Translation Termination ◽  
Mrna Structure ◽  
Mrna Half Life ◽  
Premature Translation Termination

We characterized an anemia-inducing mutation in the human gene for triosephosphate isomerase (TPI) that resulted in the production of prematurely terminated protein and mRNA with a reduced cytoplasmic half-life. The mutation converted a CGA arginine codon to a TGA nonsense codon and generated a protein of 188 amino acids, instead of the usual 248 amino acids. To determine how mRNA primary structure and translation influence mRNA stability, in vitro-mutagenized TPI alleles were introduced into cultured L cells and analyzed for their effect on TPI RNA metabolism. Results indicated that mRNA stability is decreased by all nonsense and frameshift mutations. To determine the relative contribution of the changes in mRNA structure and translation to the altered half-life, the effects of individual mutations were compared with the effects of second-site reversions that restored translation termination to normal. All mutations that resulted in premature translation termination reduced the mRNA half-life solely or mainly by altering the length of the mRNA that was translated. The only mutation that altered translation termination and that reduced the mRNA half-life mainly by affecting the mRNA structure was an insertion that shifted termination to a position downstream of the normal stop codon.

Premature translation termination mediates triosephosphate isomerase mRNA degradation

1988 ◽  
Vol 8 (2) ◽  
pp. 802-813 ◽  
Author(s):  
I O Daar ◽  
L E Maquat
Keyword(s):  
Amino Acids ◽  
Mrna Stability ◽  
Half Life ◽  
Triosephosphate Isomerase ◽  
Stop Codon ◽  
Translation Termination ◽  
Mrna Structure ◽  
Mrna Half Life ◽  
Premature Translation Termination

We characterized an anemia-inducing mutation in the human gene for triosephosphate isomerase (TPI) that resulted in the production of prematurely terminated protein and mRNA with a reduced cytoplasmic half-life. The mutation converted a CGA arginine codon to a TGA nonsense codon and generated a protein of 188 amino acids, instead of the usual 248 amino acids. To determine how mRNA primary structure and translation influence mRNA stability, in vitro-mutagenized TPI alleles were introduced into cultured L cells and analyzed for their effect on TPI RNA metabolism. Results indicated that mRNA stability is decreased by all nonsense and frameshift mutations. To determine the relative contribution of the changes in mRNA structure and translation to the altered half-life, the effects of individual mutations were compared with the effects of second-site reversions that restored translation termination to normal. All mutations that resulted in premature translation termination reduced the mRNA half-life solely or mainly by altering the length of the mRNA that was translated. The only mutation that altered translation termination and that reduced the mRNA half-life mainly by affecting the mRNA structure was an insertion that shifted termination to a position downstream of the normal stop codon.

Working Together

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Randi Veiteberg KVELLESTAD ◽  
Ingeborg STANA ◽  
VATN Gunhild
Keyword(s):  
Design Education ◽  
Critical Evaluation ◽  
Business Environment ◽  
Arts And Crafts ◽  
Action Research Project ◽  
Student Groups ◽  
Different Types ◽  
Working Together ◽  
Personal Qualities ◽  
Manual Skills

Teamwork involves different types of interactions—specifically cooperation andcollaboration—that are necessary in education and many other professions. The differencesbetween cooperation and collaboration underline the teacher’s role in influencing groupdynamics, which represent both a foundation for professional design education and aprequalification for students’ competences as teachers and for critical evaluation. As a testcase, we focused on the Working Together action-research project in design education forspecialised teacher training in design, arts, and crafts at the Oslo Metropolitan University,which included three student groups in the material areas of drawing, ceramics, and textiles.The project developed the participants’ patience, manual skills, creativity, and abilities,which are important personal qualities for design education and innovation and representcornerstones in almost every design literacy and business environment. The hope is thatstudents will transform these competences to teaching pupils of all ages in their futurecareers.

scholarly journals Asteroid and Comet Surveys

1994 ◽  
Vol 161 ◽  
pp. 385-400
Author(s):  
B.G. Marsden
Keyword(s):  
Logical Sequence ◽  
Different Types ◽  
The Future ◽  
Ecliptic Latitude ◽  
Similarities And Differences

Past surveys are described in the logical sequence of (1) comets visually, (2) asteroids visually, (3) asteroids photographically and (4) comets photographically. Plots show the evolution of asteroid surveys in terms of visual discovery magnitude and ecliptic latitude, and similarities and differences between surveys for the different types of body are discussed. The paper ends with a brief discussion of more recent discovery methods and some thoughts on the future.

Gene Overexpression as a Tool for Identifying New trans-Acting Factors Involved in Translation Termination in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 585-594
Author(s):  
Olivier Namy ◽  
Isabelle Hatin ◽  
Guillaume Stahl ◽  
Hongmei Liu ◽  
Stephanie Barnay ◽  
...  
Keyword(s):  
Protein Transport ◽  
Stop Codon ◽  
Translation Termination ◽  
Spindle Pole Body ◽  
Spindle Pole ◽  
Release Factor ◽  
Lacz Reporter Gene ◽  
Pole Body ◽  
Secondary Phenotypes ◽  
Termination Process

Abstract In eukaryotes, translation termination is dependent on the availability of both release factors, eRF1 and eRF3; however, the precise mechanisms involved remain poorly understood. In particular, the fact that the phenotype of release factor mutants is pleiotropic could imply that other factors and interactions are involved in translation termination. To identify unknown elements involved in this process, we performed a genetic screen using a reporter strain in which a leaky stop codon is inserted in the lacZ reporter gene, attempting to isolate factors modifying termination efficiency when overexpressed. Twelve suppressors and 11 antisuppressors, increasing or decreasing termination readthrough, respectively, were identified and analyzed for three secondary phenotypes often associated with translation mutations: thermosensitivity, G418 sensitivity, and sensitivity to osmotic pressure. Interestingly, among these candidates, we identified two genes, SSO1 and STU2, involved in protein transport and spindle pole body formation, respectively, suggesting puzzling connections with the translation termination process.

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