The S-band Linear Collider Test Facility

Synthetic mRNAs; Their Analogue Caps and Contribution to Disease

“…The frequent presence of O' 2 methylation on the ribose of the second transcribed nucleotide "the so-called cap 2 formation", and the first nucleotide, adenosine N-6 methylation, prognosticate for the differential translation efficiency in different cell lineages and under specific stimuli [18,19]. In the experimentation by Holtkamp S et al 2006, quite rightly the authors conclude that an evident enhanced RNA stability and translational efficiency was devoted to the presence of globin untranslated regions (UTRs) and also to the concurrent presence of a 120-length poly A tail incorporated to the synthetic mRNAs and not to the presence of the cap O structures that had been inserted to the tested synthetic mRNAs [24]. In this experimentation, [24] which is considered as fundamental for the optimization of synthetic mRNA technology, [12,13] the detection of optimum synthetic mRNA expression was measured by means of antigen presentation on EL4 mouse malignant T-cell lymphoma cells.…”

“…In the experimentation by Holtkamp S et al 2006, quite rightly the authors conclude that an evident enhanced RNA stability and translational efficiency was devoted to the presence of globin untranslated regions (UTRs) and also to the concurrent presence of a 120-length poly A tail incorporated to the synthetic mRNAs and not to the presence of the cap O structures that had been inserted to the tested synthetic mRNAs [24]. In this experimentation, [24] which is considered as fundamental for the optimization of synthetic mRNA technology, [12,13] the detection of optimum synthetic mRNA expression was measured by means of antigen presentation on EL4 mouse malignant T-cell lymphoma cells. This can also be a misguidance as these cancer cells are often used in these kind of experimentations because they stably express fluorescent proteins and are thus a useful experimental tool for cancer biology research than may not reflect normal conditions (personal communication).…”

“…For example, the elF4E efficient binding to the mRNA caps recruits the elF4G and elF4A proteins to form the elF4F binding complex. Once the elF4F complex becomes intact, the translation of mRNAs, especially those mRNAs that are equipped with the highly stable structures of 5' UTRs stabilizing the β-globin gene translation [29] and which are fundamentally used in the manufacturing of synthetic mRNAs used for vaccination [24], becomes highly efficient [12,13,24]. The increased binding affinity of caps used in synthetic mRNAs [17,18,19,20] and thereafter the increase in translation efficiency of synthetic mRNAs of vaccines means that the elF4E is rendered to become more readily bound to the elF4F complex for a prolonged time than normal and also that may avoid forming complex with the 4E binding proteins (4EBPs).…”

“…For example, the translation of ferritin heavy chain 1 (Fth1) is highly sensitive to elF4E expression levels in a dose depended manner [27]. Moreover the synthetic mRNAs are modified structurally to carry the 5' untranslated repeats (URTs) of β-globin gene in order to confer translational efficiency and stability [12,13,17,20,24]. The above normal limits regular presence of 5' UTRs and the overwhelming attractiveness by the long lasting presence of p-elF4E through the regular binding of iron-responsive element binding protein / iron regulatory protein (IRE/IRP) regulatory network, could also possibly drive the activation of nuclear erythroid-derived 2-like 2 (NRF2) transcription factor targeting the gene of FTH1 [38,40,41], According to specific cellular vulnerabilities [38]), this may also cause a disturbance in the cellular iron availability and in the regulation of ferroptosis of the cells that are induced to prolong translation by the synthetic mRNAs as illustrated in figure 1.…”

On the higher order mode coupler design for damped accelerating structures

“…The re¯ected energies will move downstream and ®nally be trapped in the cavities where the group velocities are zero. To damp the TM 11 modes in a detuned structure via a few HOM couplers is the main idea of the so-called damped detuned structure currently adopted in the S-Band linear collider main linac design [5]. To demonstrate the behaviour of a HOM coupler let's assume that at the beginning of a detuned structure a HOM coupler (four waveguides) is installed and is matched to the ith TM 11 mode.…”