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Platelet-Activating Factor Receptors in the Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Whether there is involvement of inflammatory cells other than eosinophils in PAF-acether-induced airway hyperresponsiveness is still unclear. However, as shown in Figure 7, other cells are capable of releasing PAF-acether. There are conflicting reports about the role of platelets in PAF-induced bronchospasm. In rabbits and guinea pigs, bronchoconstriction induced by PAF is apparently a platelet-dependent process because PAF-induced bronchospasm was suppressed in animals treated with antiplatelet serum.180–182 Inhibition of platelet activation by prostaglandin I2 (PGI2)146 and inhibition of platelet release182 also suppressed the PAF-induced bronchospasm. These studies suggest that PAF induces a platelet-dependent bronchoconstriction by the release or secretion of as yet undefined contractile agents from platelets. Morley and colleagues183 have reported that platelets release factor(s) which may be involved in the genesis of airway hyperresponsiveness. Two such factors have been mentioned in the literature and have been termed “platelet-derived hyperreactive factor” (PDHF) and “platelet-derived growth factor” (PDGF). Whether these two factors are similar in nature is still unclear. However, PGDF can produce airway smooth muscle hyperplasia, which in turn may result in an increased bronchoconstriction.183
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
As reviewed exhaustively by Capecchi and Webster (1975), the experiments in which a release factor was specifically inactivated with antisera showed that the endogenous release factors followed the predicted pattern of response to the terminator codons in the RNAs from R17 or related mutants. Thus, only RF-1 mediated release of the hexapeptide in response to UAG within the coat protein gene, while only RF-2 mediated release of an R17 replicase fragment in response to a UGA codon within the replicase gene, and either RF-1 or RF-2 mediated release of intact coat protein in response to a UAA codon at the end of the coat gene. It remained unclear why UAA was followed by a second terminator codon, UAG, at the end of the coat protein gene. Since such tandem signals were not a general rule, it was speculated that the second codon acts as a safety device which can signal release in case the first codon is misread (Capecchi and Webster 1975).
The Thymus in the Regulation and Control of Cell Growth
Published in Nate F. Cardarelli, The Thymus in Health and Senescence, 2019
The effect of the thymus on hypothalamic endocrine function has been the subject of various studies. Rebar et al. have shown that thymosin stimulates the secretion of LH-release factor.132Pierpaoli and Basedowski postulated a regulatory role for the thymus in some neuroendocrine functions.129 Both oxytocin and neurophysin have been detected in the human thymus at molar ratios similar to that found in the hypothalamo-neurohypophyseal system.180 Materials are concentrated in the thymus, being at far higher levels than found in general circulation. Such concentrations decline as the thymus ages. Relationships between the neuroendocrine and immune system have been discovered in turtles and frogs.181
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
If an mRNA transcript containing a premature PTC escapes nonsense-mediated decay, during translation the PTC results in termination of the protein, leading to a truncated protein product. Normal binding of tRNA with its matching site on mRNA takes place within the ribosome ‘A’ site during translation. A cognate tRNA matches three of its mRNA base pairs, while a near-cognate tRNA matches only two. The normal levels of near-cognate tRNA matches compared to cognate tRNA are less than 0.1% in normal translation [78]. When a PTC exists, no cognate tRNA exists: instead, eukaryotic release factor 1 (eRF1) binds to the stop codon at the ‘A’ site and initiates release of the polypeptide from the ribosomal complex. Nonsense suppression therapy works by promoting read-through of transcripts with a PTC by promoting binding of near-cognate tRNAs at the PTC instead of eRF1. In clinical usage, aminoglycoside antibiotics exploit this mechanism by binding to bacterial ribosomes and causing fatal translational errors. Eukaryotic cells have greater resistance to the substitution of near-cognate tRNAs due to differences in ribosomal structure. Nonetheless, aminoglycosides such as gentamicin, paromomycin, streptomycin among others promote read-through at eukaryotic PTC sites. Moosajee et al. showed that in a zebrafish model of choroideremia, where homozygous REP1 knockout caused by chmru848 usually confers embryonic lethality, administration of gentamicin and paromomycin improved read-through and conferred a 1.5- to 1.7-fold improvement in survival [79].
Targeting p53 in chronic lymphocytic leukemia
Published in Expert Opinion on Therapeutic Targets, 2020
Riccardo Moia, Paola Boggione, Abdurraouf Mokhtar Mahmoud, Ahad Ahmed Kodipad, Ramesh Adhinaveni, Sruthi Sagiraju, Andrea Patriarca, Gianluca Gaidano
Approximately 10% of TP53 mutations are nonsense mutations leading to the insertion of a premature stop codon that causes the translation of a truncated protein [26,27]. Importantly, APR-246 acts by refolding mutant p53 protein but is not effective in cases of truncated proteins caused by nonsense mutations [78]. Nonsense mutations, therefore, would require drugs with a MoA different from that of APR-246 or other drugs that revert conformational mutants to the wild type p53 configuration [4]. In fact, when ribosome encounters a premature termination codon, release factor eRF1 and eRF3 bind to the nascent amino acid chain, and translation is terminated leading to the release of a truncated p53 protein. Readthrough induction allows the ribosome to continue translation until the physiological stop codon is encountered resulting in a full-length p53 protein [78]. Different molecules are able to rescue nonsense mutated p53. Initial evidence has demonstrated that aminoglycosides (i.e. G418, gentamicin and amikacin) restore the function of a p53 truncated protein with a mechanism that is not completely understood but is probably related to the binding of aminoglycosides to the ribosomal proteins [78,79]. The development of novel readthrough inducer molecules is ongoing.
Development of a high yielding expression platform for the introduction of non-natural amino acids in protein sequences
Published in mAbs, 2020
Gargi Roy, Jason Reier, Andrew Garcia, Tom Martin, Megan Rice, Jihong Wang, Meagan Prophet, Ronald Christie, William Dall’Acqua, Sanjeev Ahuja, Michael A Bowen, Marcello Marelli
Mammalian cells are the most common manufacturing platform, offering access to a large variety of protein classes. For the generation of antibodies, mammalian cells are the optimal expression system, as they produce properly folded, functional, and soluble proteins at high yield.68 Many of the strategies aimed at improving nnAA incorporation listed above are not practical, or simply not possible, in higher eukaryotes. For example, mammalian cells contain a single release factor protein (eRF1) (unlike bacteria which have two) that is essential and recognizes all three stop codons. Thus, stop codon suppression technologies in mammalian cells initially relied on overexpression of the aaRS or tRNA to increase nnAA incorporation efficacy. Studies using transient transfections of mammalian cells determined that high tRNA levels were key to improving nnAA incorporation levels.54,69,70 Further optimizations have aimed to improve the stability and cross-talk of the tRNA with the mammalian translational machinery,65,69-71 improve the introduction of the genetic components into cells,69,72 develop promoters to increase tRNA expression,54,71 identify permissive sequence context for more efficient amber suppression,63 as well as overexpress mutant eRF1 with reduced affinity for amber codons.70 These optimizations have led to significant improvements in the yields of mammalian cells, and more importantly identified key components that affect the efficiency of nnAA incorporation.