New methodologies and scenarios for evaluating tidal current energy potential

Transition towards a low carbon economy raises concerns of loss of security of supply with high penetrations of renewable generation displacing traditional fossil fuel based generation. While wind and wave resources are increasingly forecastable, they are stochastic in nature. The tidal current resource, although variable has the advantage of being deterministic and truly predictable. With the first Crown Estate leasing round complete for wave and tidal current energy, plans are in place to install 1000 MW of tidal capacity in the Pentland Firth and Orkney waters. The aim of the work presented in this thesis is to examine the role tidal current energy can realistically play in the future electricity mix. To achieve this objective it was first necessary to develop new methodologies to capture the temporal and spatial variability of tidal current dynamics over long timescales and identify metrics relevant in a tidal energy context. These methodologies were developed for project scale resource characterisation, and provided a basis for development of a national scale dataset. The creation of project and national scale tidal datasets capture spatial and temporal variability at a level beyond previous insight, as demonstrated in case studies of three important early stage tidal current energy development sites. The provision of a robust national scale dataset enabled the development of realistic scenarios for the growth of the tidal current energy sector in UK waters. Assessing the various scenarios proposed indicates that first-generation technology solutions have the potential to generate up to 31 TWh/yr (over 8% of 2009 UK electricity demand). However, only 14 TWh/yr can be sensibly generated after incorporating realistic economic and environmental limitations proposed in this study. The preceding development of methodologies, datasets and scenarios enabled statistical analysis of the matching characteristics of future tidal energy generation potential with the present UK electricity demand and trends of electricity usage. This analysis demonstrated that the UK tidal current energy resource is much more in phase than has previously been understood, highlighting the flaws in previous studies suggesting that a combined portfolio of sites around the UK can deliver firm power. As there is negligible firm production, base-load contribution is insignificant. However, the time-series generated from this analysis identifies the role tidal current energy can play in meeting future energy demand and offer significant benefit for the operation of the electricity system as part of an integrated portfolio

Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing

Etelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In addition to binding to the calcium-sensing receptor, etelcalcetide is biotransformed by disulfide exchange in whole blood to predominantly form a covalent serum albumin peptide conjugate (SAPC). Key factors anticipated to affect the pharmacokinetics and disposition of etelcalcetide in chronic kidney disease patients on hemodialysis are the drug’s intrinsic dialytic properties and biotransformation kinetics. Methods: These factors were investigated using in vitro methods, and the findings were modeled to derive corresponding kinetic rate constants. Results: Biotransformation was reversible after incubation of etelcalcetide or SAPC in human whole blood. The rate of SAPC formation from etelcalcetide was 18-fold faster than the reverse process. Clearance of etelcalcetide by hemodialysis was rapid in the absence of blood and when hemodialysis was initiated immediately after addition of etelcalcetide to blood. Preincubation of etelcalcetide in blood for 3 hours before hemodialysis resulted in formation of SAPC and decreased its clearance due to the slow rate of etelcalcetide formation from SAPC. Etelcalcetide hemodialysis clearance was >16-fold faster than its biotransformation. Discussion: These results indicate that etelcalcetide should be administered after hemodialysis to avoid elimination of a significant fraction of the dose

A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function

<div><p>Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.</p></div

The G55R mutation increases the ability of 4R tau but not 3R tau to nucleate microtubule assembly.

<p>(A) Microtubule assembly in reactions containing a 1∶30 tau:tubulin dimer molar ratio were assayed by light scattering as a function of time. (B) Co-sedimentation assays demonstrate that the G55R mutation does not affect the ability of tau to assemble MT mass at steady-state, nor does it affect the ability of tau to bind to microtubules. Statistical significance was determined by comparing each mutant to its corresponding WT using two-tailed t-tests. Data in both panels represent the mean ± SEM from three independent experiments.</p

A. The family tree of the affected family shows the pattern of inheritance.

<p>The proband is the black oval on the left side of the figure (II:1), marked with an arrow. Tau haplotypes of sequenced individuals are also noted. “aoo” corresponds to age of onset; “aod” corresponds to age of death; black filling indicates persons possessing the G55R mutation; gray filling corresponds to diagnosed dementia of unknown origin (presumed to be G55R but inadequate medical records exist). Proband's son III:1 (from first marriage) is 36 years old and a carrier of G55R. Proband's second son III:2 (from second marriage) is 31 and also a G55R carrier. The other two sons (III:3 and III:4; from the second marriage) are not G55R carriers and are 29 and 28 years old. <b>B. The tau sequence in the region of the G55R mutation is extremely highly conserved across species lines.</b> The glycine at position 55 is completely conserved in seven species ranging from humans to lizards. Color coding emphasizes conserved nature of acidic (red), basic (blue), hydrophilic/polar (orange), hydrophobic (green) and proline (peach) positions.</p

Schematic map of the six CNS tau isoforms.

<p>Exons 2 (E2), 3 (E3) and 10 (E10) are alternatively spliced to generate all six possible combinations. Arrowheads denote the position of the G55R mutation, present in four of the six isoforms. R1, R2, R3 and R4 denote the four imperfect repeats in the MT binding region.</p