Turbulence-driven magnetic reconnection and the magnetic correlation length: observations from magnetospheric multiscale in Earth's magnetosheath

Turbulent plasmas generate a multitude of thin current structures that can be sites for magnetic reconnection. The Magnetospheric Multiscale (MMS) mission has recently enabled the detailed examination of such turbulent current structures in Earth's magnetosheath and revealed that a novel type of reconnection, known as electron-only reconnection, can occur. In electron-only reconnection, ions do not have enough space to couple to the newly reconnected magnetic fields, suppressing ion jet formation and resulting in thinner sub-proton-scale current structures with faster super-Alfvénic electron jets. In this study, MMS observations are used to examine how the magnetic correlation length (λC) of the turbulence, which characterizes the size of the large-scale magnetic structures and constrains the length of the current sheets formed, influences the nature of turbulence-driven reconnection. We systematically identify 256 reconnection events across 60 intervals of magnetosheath turbulence. Most events do not appear to have ion jets; however, 18 events are identified with ion jets that are at least partially coupled to the reconnected magnetic field. The current sheet thickness and electron jet speed have a weak anti-correlation, with faster electron jets at thinner current sheets. When ≲20 ion inertial lengths, as is typical near the sub-solar magnetosheath, a tendency for thinner current sheets and potentially faster electron jets is present. The results are consistent with electron-only reconnection being more prevalent for turbulent plasmas with relatively short λC and may be relevant to the nonlinear dynamics and energy dissipation in turbulent plasmas

EVALUATION AND RESPONSE TO EhVIRONMEl\TAL CHANGE

iii ACKNOWLEDGEMENT

Identification of molecular markers of delayed graft function based on the regulation of biological ageing

Introduction: Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications. Methodology: The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre-transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts. Results: Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (>90%) and specificity (>60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation. Conclusion: These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia

Imaging of cell membrane topography using Tamm plasmon coupled emission

Imaging of the cell membrane topography is important for a clear understanding of various biological activities of cells. We propose a technique for imaging the cell membrane topography that uses a metal-photonic crystal structure instead of a glass-water interface used in conventional polarized total internal reflection fluorescence microscopy (pTIRFM) techniques. Through the metal-photonic crystal of the proposed technique, the fluorophore labels on the cell membrane can be excited by both the p- and s-polarized excitation light, and in each case, the p- and s-polarized radiation from the excited fluorophores can be separated to form an image. We calculate the images of the cell membrane topography that is fusing a granule using the proposed technique and pTIRFM. The image obtained by the proposed technique shows a much greater contrast with respect to the background than that of the image obtained by pTIRFM. We also find that the structural similarity index of the image obtained by the proposed technique to a reference image is ~77%, which is only ~16% for the image obtained by pTIRFM. The proposed technique will help to obtain a clearer and more accurate image of the cell membrane topography, and hence, a deeper understanding of different biological activities

Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post- transplant serum creatinine when compared to “Gold Standard” clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future

Glycomacropeptide:long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU

In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined.AimA longitudinal, parallel, controlled study over 12months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36mg Phe per 20g protein equivalent.MethodsChildren with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52weeks. Nutritional biochemistry was studied at baseline and 26weeks only.ResultsAt the end of 52weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52weeks CGMP-AA2 provided a median of 75% (30-100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52weeks: [baseline to 26weeks; baseline Phe 270mol/L (170-430); 26weeks, Phe 300mol/L (125-485) p=0.06; baseline to 52weeks: baseline, Phe 270mol/L (170-430), 52weeks Phe 300mol/L (200-490),

THE THREE-DIMENSIONAL EVOLUTION OF ION-SCALE CURRENT SHEETS: TEARING AND DRIFT-KINK INSTABILITIES IN THE PRESENCE OF PROTON TEMPERATURE ANISOTROPY

We present the first three-dimensional hybrid simulations of the evolution of ion-scale current sheets, with an investigation of the role of temperature anisotropy and associated kinetic instabilities on the growth of the tearing instability and particle heating. We confirm the ability of the ion cyclotron and firehose instabilities to enhance or suppress reconnection, respectively. The simulations demonstrate the emergence of persistent three-dimensional structures, including patchy reconnection sites and the fast growth of a narrow-band drift-kink instability, which suppresses reconnection for thin current sheets with weak guide fields. Potential observational signatures of the three-dimensional evolution of solar wind current sheets are also discussed. We conclude that kinetic instabilities, arising from non-Maxwellian ion populations, are significant to the evolution of three-dimensional current sheets, and two-dimensional studies of heating rates by reconnection may therefore over-estimate the ability of thin, ion-scale current sheets to heat the solar wind by reconnection

Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties

Adrenomedullin (AM) is a peptide hormone with numerous effects in the vascular systems. AM signals through the AM1 and AM2 receptors formed by the obligate heterodimerization of a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity-modifying proteins (RAMP) 2 and 3, respectively. These different CLR-RAMP interactions yield discrete receptor pharmacology and physiological effects. The effective design of therapeutics that target the individual AM receptors is dependent on understanding the molecular details of the effects of RAMPs on CLR. To understand the role of RAMPs 2 and 3 on the activation and conformation of the CLR subunit of AM receptors we mutated 68 individual amino acids in the juxtamembrane region of CLR, a key region for activation of AM receptors and determined the effects on cAMP signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling of the full-length AM-bound AM1 and AM2 receptors predicted differences in the binding pocket, and differences in the electrostatic potential of the two AM receptors. Druggability analysis indicated unique features that could be used to develop selective small molecule ligands for each receptor. The interaction of RAMP2 or RAMP3 with CLR induces conformational variation in the juxtamembrane region, yielding distinct binding pockets, probably via an allosteric mechanism. These subtype-specific differences have implications for the design of therapeutics aimed at specific AM receptors and for understanding the mechanisms by which accessory proteins affect G protein-coupled receptor function

High temperature cycles result in maternal transmission and dengue infection differences between Wolbachia strains in Aedes aegypti

Environmental factors play a crucial role in the population dynamics of arthropod endosymbionts, and therefore in the deployment of Wolbachia symbionts for the control of dengue arboviruses. The potential of Wolbachia to invade, persist, and block virus transmission depends in part on its intracellular density. Several recent studies have highlighted the importance of larval rearing temperature in modulating Wolbachia densities in adults, suggesting that elevated temperatures can severely impact some strains, while having little effect on others. The effect of a replicated tropical heat cycle on Wolbachia density and levels of virus blocking was assessed using Aedes aegypti lines carrying strains wMel and wAlbB, two Wolbachia strains currently used for dengue control. Impacts on intracellular density, maternal transmission fidelity, and dengue inhibition capacity were observed for wMel. In contrast, wAlbB-carrying Ae. aegypti maintained a relatively constant intracellular density at high temperatures and conserved its capacity to inhibit dengue. Following larval heat treatment, wMel showed a degree of density recovery in aging adults, although this was compromised by elevated air temperatures