Tabu search for ship routing and scheduling

This thesis examines exact and heuristic approaches to solve the Ship Routing and Scheduling Problem (SRSP). The method was developed to address the problem of loading cargos for many customers using heterogeneous vessels. Constraints relate to delivery time windows imposed by customers, the time horizon by which all deliveries must be made and vessel capacities. The objective is to minimise the overall operation cost, where all customers are satisfied. Two types of routing and scheduling are considered, one called single-cargo problem, where only one cargo can be loaded into a ship, and the second type called multi-cargo problem, where multiple products can be carried on a ship to be delivered to different customers. The exact approach comprises two stages. In the first stage, a number of candidate feasible schedules is generated for each ship in the fleet. The second stage is to model the problem as a set partitioning problem (SPP) where the columns are the candidate feasible schedules obtained in the first stage. The heuristic approach uses Tabu Search (TS). Most of the TS operations, such as insert and swap moves, tenure, tabu list, intensification, and diversification are used. The results of a computational investigation are presented. Solution quality and execution time are explored with respect to problem size and parameters controlling the tabu search such as tenure and neighbourhood size. The results showed that the average of the solution gap between TS solution and SPP solution is up to 28% (for small problems) and up to 18% for large problems. However, obtaining an optimal solution requires a large amount of computer time to produce the solution compared to obtaining approximate solutions using the TS approach. The use of Tabu Search for SRSP is novel and the results indicate that it is viable approach for large problems.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Magnetic resonance imaging of placentome development in the pregnant Ewe

INTRODUCTION: Novel imaging measurements of placental development are difficult to validate due to the invasive nature of gold-standard procedures. Animal studies have been important in validation of magnetic resonance imaging (MRI) measurements in invasive preclinical studies, as they allow for controlled experiments and analysis of multiple time-points during pregnancy. This study characterises the longitudinal diffusion and perfusion properties of sheep placentomes using MRI, measurements that are required for future validation studies. METHODS: Pregnant ewes were anaesthetised for a MRI session on a 3T scanner. Placental MRI was used to classify placentomes morphologically into three types based on their shape and size at two gestational ages. To validate classification accuracy, placentome type derived from MRI data were compared with placentome categorisation results after delivery. Diffusion-Weighted MRI and T2-relaxometry were used to measure a broad range of biophysical properties of the placentomes. RESULTS: MRI morphological classification results showed consistent gestational age changes in placentome shape, as supported by post-delivery gold standard data. The mean apparent diffusion coefficient was significantly higher at 110 days gestation than at late gestation (~140 days; term, 150 days). Mean T2 was higher at mid gestation (152.2 ± 58.1 ms) compared to late gestation (127.8 ms ± 52.0). Significantly higher perfusion fraction was measured in late gestation placentomes that also had a significantly higher fractional anisotropy when compared to the earlier gestational age. DISCUSSION: We report baseline measurements of techniques common in placental MRI for the sheep placenta. These measurements are essential to support future validation measurements of placental MRI techniques

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors

Self-assembled peptide habitats to model tumor metastasis

Metastatic tumours are complex ecosystems; a community of multiple cell types, including cancerous cells, fibroblasts, and immune cells that exist within a supportive and specific microenvironment. The interplay of these cells, together with tissue specific chemical, structural and temporal signals within a three-dimensional (3D) habitat, direct tumour cell behavior, a subtlety that can be easily lost in 2D tissue culture. Here, we investigate a significantly improved tool, consisting of a novel matrix of functionally programmed peptide sequences, self-assembled into a scaffold to enable the growth and the migration of multicellular lung tumour spheroids, as proof-of-concept. This 3D functional model aims to mimic the biological, chemical, and contextual cues of an in vivo tumor more closely than a typically used, unstructured hydrogel, allowing spatial and temporal activity modelling. This approach shows promise as a cancer model, enhancing current understandings of how tumours progress and spread over time within their microenvironment. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Future-Proofed Energy Design Approaches for Achieving Low-Energy Homes: Enhancing the Code for Sustainable Homes

Under the label “future-proofing”, this paper examines the temporal component of sustainable construction as an unexplored, yet fundamental ingredient in the delivery of low-energy domestic buildings. The overarching aim is to explore the integration of future-proofed design approaches into current mainstream construction practice in the UK, focusing on the example of the Code for Sustainable Homes (CSH) tool. Regulation has been the most significant driver for achieving the 2016 zero-carbon target; however, there is a gap between the appeal for future-proofing and the lack of effective implementation by building professionals. Even though the CSH was introduced as the leading tool to drive the “step-change” required for achieving zero-carbon new homes by 2016 and the single national standard to encourage energy performance beyond current statutory minima, it lacks assessment criteria that explicitly promote a futures perspective. Based on an established conceptual model of future-proofing, 14 interviews with building practitioners in the UK were conducted to identify the “feasible” and “reasonably feasible” future-proofed design approaches with the potential to enhance the “Energy and CO2 Emissions” category of the CSH. The findings are categorised under three key aspects; namely: coverage of sustainability issues; adopting lifecycle thinking; and accommodating risks and uncertainties and seek to inform industry practice and policy-making in relation to building energy performance

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)