Leon Boyd (pagetree05)

RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (m6A), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like (TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m2,2G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNAAla(AGC) isodecoders at position 26. Using a cellular in vitro model that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes may play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.This study analyses three additively manufactured canine implants designed for angular limb deformity correction procedure through probabilistic numerical analysis. These implants have produced excellent results in-vivo and are operational to-date. Therefore, this study uses finite element analysis in conjunction with statistical analysis in order to further validate these implants from a numerical perspective. Due to uncertainties associated with boundary conditions for a bespoke implant geometry, the analyses in this study were conducted on a range of input values. An interrogation of these parameters through sensitivity analysis enabled in identifying the vital inputs. These inputs were then employed to conduct robustness analysis in order to determine the mean value of stress on which these implants ideally operate. These mean values were then compared with the associated safety and failure limit to obtain the probability of reaching these limits through different reliability techniques. A low probability of failure computed from numerical analysis in combination with the continued performance of these implants, suggests a successful integration of the methodology in the design phase of bespoke implants. To investigate the prevalence of arm-involvement in Klippel-Trénaunay syndrome (KTS)-patients and to describe the venous anatomy and/or venous aberrations present in the arm, and if possible, their relationship to complaints (pain, congestion and thromboembolic events). A retrospective cohort-study was performed with data from medical records of a large KTS-cohort (n = 173) from a tertiary referral center. Within this cohort, a descriptive study (n = 12) was performed on the KTS-patients with arm involvement and who had been examined with Colour Duplex Ultrasonography (CDU). Our KTS-cohort (n = 173) comprised 43 patients (24.9%) with arm-involvement; in nineteen patients (11.0%) the arm was the only affected limb. Of those KTS patients investigated with CDU, 9 out of 12 (75%) had an aberrant venous anatomy. Future research needs to clarity whether the complaints of KTS-patients in general are caused by an aberrant venous anatomy, coagulation alterations and/or other fac