Development of the bill of lading : its future in the maritime industry

Merged with duplicate record (10026.1/796) on 03.01.2017 by CS (TIS)This is a digitised version of a thesis that was deposited in the University Library. If you are the author please contact PEARL Admin ([email protected]) to discuss options.This Thesis will consider the development of the traditional bill of lading from its origins, which appear to be much older than previously considered, up to the present day. The development of the bill of lading will be examined in order to answer basic questions: what is a traditional bill of lading, and what functions does it perform. In Part I of the Thesis the development of the three main functions of the traditional bill will be considered, namely receipt, contract, document of title. It will conclude with observations on the nature of the traditional bill of lading and how it differs from the early form of the bill of lading. Part II of the Thesis will then consider the development and nature of related shipping documents (charterparty bills, received for shipment bills, non-transferable bills), how far these documents perform the functions of the traditional bill of lading, and whether they can be truly described as bills of lading. Part II will then go on to consider the development and nature of electronic bills of lading and assess how well such bills perform the functions of the traditional bill of lading. The Thesis will conclude that although most of the functions of the traditional bill are in effect performed by electronic bills, electronic bills are in fact a new type of bill of lading and not merely a traditional bill in an electronic format. Conclusions will then be drawn as to what effect the development of new types of bill of lading will have on the future of the traditional bill of lading in the maritime industry

EscapED: A Framework for Creating Educational Escape Rooms and Interactive Games to For Higher/Further Education

Game-based learning (GBL) is often found to be technologically driven and more often than not, serious games for instance, are conceptualised and designed solely for digital platforms and state of the art technologies. To encourage a greater discussion on the potential benefits and challenges of a more holistic approach to developing GBL that promote human centered interactions and play for learning, the authors present the escapED programme. The escapED programme was conceived following the recent entertainment trend of escape rooms and is used for developing non-digital GBL approaches within education. escapED aids the design and creation of educational Escape Rooms and Interactive Gaming Experiences for staff and students in further/higher education settings. The paper first presents a pilot study that was used to assess the feasibility and acceptance of University teaching staff of embedding interactive GBL into a higher education environment. The authors then present the escapED theoretical framework that was used to create the prototype game for the pilot study as a tool to aid future design and development of on-site interactive experiences. The paper also presents an external developer report of using the escapED framework to develop a prototype game for teaching research methods to Southampton University students. Finally, the authors present a discussion on the use of the escapED framework so far and plans for future work and evaluation in order to provide engaging alternatives for learning and soft skills development amongst higher education staff andstudents

Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation.

The adenomatous polyposis coli (Apc) protein regulates diverse effector pathways essential for tissue homeostasis. Truncating oncogenic mutations in Apc removing its Wnt pathway and microtubule regulatory domains drives intestinal epithelia tumorigenesis. Exuberant cell proliferation is one well-established consequence of oncogenic Wnt pathway activity; however, the contribution of other deregulated molecular circuits to tumorigenesis has not been fully examined. Using in vivo and organoid models of intestinal epithelial tumorigenesis we found that Wnt pathway activity controls intestinal epithelial villi and crypt structure, morphological features lost upon Apc inactivation. Although the Wnt pathway target gene c-Myc (also known as Myc) has critical roles in regulating cell proliferation and tumorigenesis, Apc specification of intestinal epithelial morphology is independent of the Wnt-responsive Myc-335 (also known as Rr21) regulatory element. We further demonstrate that Apc inactivation disrupts the microtubule cytoskeleton and consequently localisation of organelles without affecting the distribution of the actin cytoskeleton and associated components. Our data indicates the direct control over microtubule dynamics by Apc through an independent molecular circuit. Our study stratifies three independent Apc effector pathways in the intestinal epithelial controlling: (1) proliferation, (2) microtubule dynamics and (3) epithelial morphology.This article has an associated First Person interview with the first author of the paper

Introducing an automated high content confocal imaging approach for Organs-on-Chips

Organ-Chips are micro-engineered systems that aim to recapitulate the organ microenvironment. Implementation of Organ-Chips within the pharmaceutical industry aims to improve the probability of success of drugs reaching late stage clinical trial by generating models for drug discovery that are of human origin and have disease relevance. We are adopting the use of Organ-Chips for enhancing pre-clinical efficacy and toxicity evaluation and prediction. Whilst capturing cellular phenotype via imaging in response to drug exposure is a useful readout in these models, application has been limited due to difficulties in imaging the chips at scale. Here we created an end-to-end, automated workflow to capture and analyse confocal images of multicellular Organ-Chips to assess detailed cellular phenotype across large batches of chips. By automating this process, we not only reduced acquisition time, but we also minimised process variability and user bias. This enabled us to establish, for the first time, a framework of statistical best practice for Organ-Chip imaging, creating the capability of using Organ-Chips and imaging for routine testing in drug discovery applications that rely on quantitative image data for decision making. We tested our approach using benzbromarone, whose mechanism of toxicity has been linked to mitochondrial damage with subsequent induction of apoptosis and necrosis, and staurosporine, a tool inducer of apoptosis. We also applied this workflow to assess the hepatotoxic effect of an active AstraZeneca drug candidate illustrating its applicability in drug safety assessment beyond testing tool compounds. Finally, we have demonstrated that this approach could be adapted to Organ-Chips of different shapes and sizes through application to a Kidney-Chip.</p

Serological evidence of a pararubulavirus and a betacoronavirus in the geographically isolated Christmas Island flying-fox (Pteropus natalis)

Due to their geographical isolation and small populations, insular bats may not be able to maintain acute immunizing viruses that rely on a large population for viral maintenance. Instead, endemic transmission may rely on viruses establishing persistent infections within hosts or inducing only short-lived neutralizing immunity. Therefore, studies on insular populations are valuable for developing broader understanding of viral maintenance in bats. The Christmas Island flying-fox (CIFF; Pteropus natalis) is endemic on Christmas Island, a remote Australian territory, and is an ideal model species to understand viral maintenance in small, geographically isolated bat populations. Serum or plasma (n = 190), oral swabs (n = 199), faeces (n = 31), urine (n = 32) and urine swabs (n = 25) were collected from 228 CIFFs. Samples were tested using multiplex serological and molecular assays, and attempts at virus isolation to determine the presence of paramyxoviruses, betacoronaviruses and Australian bat lyssavirus. Analysis of serological data provides evidence that the species is maintaining a pararubulavirus and a betacoronavirus. There was little serological evidence supporting the presence of active circulation of the other viruses assessed in the present study. No viral nucleic acid was detected and no viruses were isolated. Age-seropositivity results support the hypothesis that geographically isolated bat populations can maintain some paramyxoviruses and coronaviruses. Further studies are required to elucidate infection dynamics and characterize viruses in the CIFF. Lastly, apparent absence of some pathogens could have implications for the conservation of the CIFF if a novel disease were introduced into the population through human carriage or an invasive species. Adopting increased biosecurity protocols for ships porting on Christmas Island and for researchers and bat carers working with flying-foxes are recommended to decrease the risk of pathogen introduction and contribute to the health and conservation of the species

Endocytic profiling of cancer cell models reveals critical factors influencing lipid nanoparticle mediated mRNA delivery and protein expression

Lipid nanoparticles have great potential for delivering nucleic acid-based therapeutics, but low efficiency limits their broad clinical translation. Differences in transfection capacity between in vitro models used for nanoparticle pre-clinical testing is poorly understood. To address this, using a clinically relevant lipid nanoparticle (LNP) delivering mRNA we highlight specific endosomal characteristics in in vitro tumour models that impact on protein expression. A 30-cell line LNP-mRNA transfection screen identified three cells lines having low, medium and high transfection that correlated with protein expression when they were analysed in tumour models. Endocytic profiling of these cell lines identified major differences in endolysosomal morphology, localisation, endocytic uptake, trafficking, recycling, and endolysosomal pH, identified using a novel pH probe. High transfecting cells showed rapid LNP uptake and trafficking through an organised endocytic pathway to lysosomes or rapid exocytosis. Low transfecting cells demonstrated slower endosomal LNP trafficking to lysosomes, and defective endocytic organisation and acidification. Our data establishes that efficient LNP-mRNA transfection relies on an early and narrow endosomal escape window prior to lysosomal sequestration and/or exocytosis. Endocytic profiling should form an important pre-clinical evaluation step for nucleic acid delivery systems to inform model selection and guide delivery system design for improved clinical translation

Biomarker Driven Antifungal Stewardship (BioDriveAFS) in acute leukaemia—a multi-centre randomised controlled trial to assess clinical and cost effectiveness: a study protocol for a randomised controlled trial

BACKGROUND: Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). METHODS: BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. DISCUSSION: The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. TRIAL REGISTRATION: ISRCTN11633399. Registered 24/06/2022

Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles

Poor understanding of intracellular delivery and targeting hinders development of nucleic acid‐based therapeutics transported by nanoparticles. Utilizing a siRNA‐targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3‐LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE‐ID). A cell‐based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data‐rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid‐phase endocytosis as a productive cellular entry route. With this new knowledge, MC3‐LNP is re‐engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE‐ID approach can be broadly applicable for optimizing nanomedicine‐based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid‐based therapeutics