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The use of multimethodology in operational research practice supporting strategic decision-making: prevalence, methods, designs, and causal mechanisms
No full textRecently, there has been renewed and significant interest amongst both operational research (OR) academics and practitioners in how qualitative analysis methods (such as problem structuring methods) can be used with quantitative analysis methods (such as optimization and simulation) to address complex, strategic issues with stakeholders. However, multimethodology - a term commonly used in OR and systems thinking to describe the use of multiple methods or methodologies within the same project or intervention - is a critical aspect of OR where there is a persistent gap between OR literature and OR practice in non-academic settings. While OR is widely used to tackle important problems in UK government, and it is claimed that UK government practitioners commonly combine qualitative and quantitative OR analysis methods, this is an area of practice where we have few published examples. Further, OR literature sets out a range of influences on practitioner method choice and several reasons (benefits and rationales) for using multimethodology, as well as barriers and challenges. However, there is a lack of empirical evidence of the process by which practitioners choose and combine methods, including the extent to which they use the many theoretical frameworks and typologies for multimethodology found in OR literature. In this dissertation, I present a new review of the prevalence of use of qualitative with quantitative OR, report a new set of six multimethodological designs (forms of multimethodology) that may be more widely applicable across OR practice and mixed methods research, and enhance understanding of the use of multimethodology in OR practice by investigating over 100 decision support interventions supporting strategic decision-making for or on behalf of the UK government. I present and analyse, using descriptive statistics and thematic analysis, 104 cases of multimethod intervention from a survey of 54 practitioners conducted for understanding the research context. I then present a multiple case study, with in-depth, comparative study of five interventions using a multimethod approach that includes insights from project documents and 50 interviews with practitioners and their clients and collaborators. Overall, this applied research provides understanding of theoretical frameworks and terminology for multimethodology, and empirical evidence from this research context of the prevalence of multimethodology, methods used and not used, how, and why, all of which can be employed to ground scholarship on multimethodology, and to support and inform future OR practice, training, apprenticeships, and education. The research adds unique, empirical insights to the growing body of evidence that multimethod practice is commonplace in non-academic settings, and necessary for addressing complex, real-world issues. Moreover, for the multiple case study, and for the first time as far as I am aware, I operationalize critical realism for evaluating the practice of multimethodology in OR. I develop a new, theory-informed, critical realist analysis of a generic multimethodological OR intervention, synthesizing existing empirical research and theories in OR and recent developments in philosophy and social science. I employ the theoretical framework in aiming towards a more theory-informed, causal understanding of why OR practitioners use the methods and methodological designs they do, explaining the context and complex process of practitioners' methodological decisions using rich description, and structural and causal analysis. This new theoretical and methodological approach for evaluating multimethodological practice, developed and employed through the dissertation, can be extended in future in OR to investigate causal mechanisms leading to other individual and collective actions, and intervention outcomes including intervention success. It can also be used across other disciplines to theorize research design and evaluate mixed methods research projects, including their complexity and practical utility
Investigating the Characteristics of Dark Web Markets and Their Security Implications
Get PDFThe dark web and the markets on it are often shrouded in mystery. However, the fact that they are little known does not mean that they have no impact on society. On the contrary, these markets have evolved into platforms that may even facilitate cybercriminal activities. Furthermore, dark web markets take advantage of technology to hide themselves on the hard-to-trace dark web, making the fight against criminal activity increasingly challenging. Despite the rapid development of modern dark web markets in recent years, knowledge about them remains limited and needs to be expanded urgently.
Therefore, the research presented in this thesis aims to expand the understanding of dark web markets and explore their characteristics. To achieve this, a custom crawler was developed to help collect data from 21 dark web markets (over different time periods), including quantitative and qualitative data and information.
An in-depth analysis of the current status of the English and Chinese dark web markets was conducted, indicating that markets in different languages could be influenced by cultural factors. Following, security mechanisms on dark web markets were further examined and documented, which not only laid the groundwork for encountering the challenges of data collection in this area but also discussed the role and impact of the market's security mechanisms as a key part of the market's operation. Additionally, an analysis of data and events before and after the closure of markets was conducted, offering deeper insights into the perspectives of market operators, vendors, and users, as well as the impact of this phenomenon. A case study was also carried out focusing on the availability of child sexual abuse material on dark web markets, obtaining evidence of the sale/distribution of this specific serious criminal material on the dark web market. While it is fortunately not found in the mainstream English dark web markets, there are indications that it is widely available on the Chinese dark web markets.
Overall, the dark web market continues to be an active, often dynamic, and unpredictable environment. Despite the fact that the dark web market has been around for many years (even decades), the lack of up-to-date information and a clear vision of it has meant that we have always been one step behind the criminals. This thesis provides a thorough investigation of the current state of dark web markets in both English and Chinese contexts. It highlights how cultural differences affect market operations, summarises the common security mechanisms employed, and offers insights for effective data collection. Additionally, it categorises three types of market closures and examines the role and impact of dark web markets in facilitating specific criminal activities
Insights into the genomics, evolution, and conservation of antelopes
No full textGenomic advancements have increased the feasibility of generating chromosome-level genomes for non-model animals, enabling evolutionary and conservation related research of understudied species. Here, we focus on antelopes, in the ruminant subfamily Bovidae, and explore their chromosome evolution, 3D genome organisation, and population genomics. Antelopes have diploid chromosome numbers ranging between 2n = 30 and 2n = 60, predominantly due to Robertsonian fusions of acrocentric chromosomes. Additionally, some species have chromosome fusions that have remained polymorphic within species. One example of this is the waterbuck (Kobus ellipsiprymnus), with chromosome polymorphisms within and between two recognised subspecies, causing karyotypes of between 2n = 50 and 2n = 54. To explore inter- and intra-species genomics of antelopes we firstly sequenced and assembled a chromosome-level genome for the waterbuck using PacBio HiFi long-reads and Hi-C. We then extracted DNA and whole genome sequenced (WGS) 24 historical waterbuck samples and combined this with WGS data for 119 modern samples to explore the population genomics and chromosome rearrangements of waterbuck. Lastly, we combined the newly assembled waterbuck genome and Hi-C with published chromosome-level genomes and Hi-C data to investigate chromosome evolution and 3D genome organisation across antelopes. This study provides a highly contiguous and complete genome assembly for the waterbuck. At the population level we support previous studies by showing genomic differences between and within the two subspecies, with strong barriers to gene flow, but also varying degrees of admixture. We identified multiple regions of high genomic differentiation between the two subspecies, several of them near chromosome fusions, suggesting putative signatures of these rearrangements, with these regions containing genes that may be involved in speciation. Between species, we reconstructed the chromosomes of two bovid ancestors and explored chromosome fusions. We found that commonly fused chromosomes were not found to be located closer within the 3D genome organisation of the nucleus in species without the fusion. This was also the case for the polymorphic chromosome fusion in waterbuck. This study provides an overview of the genomics and evolution of antelopes, raising important questions on how we conserve species with variable karyotypes and in early speciation, and with ongoing hybridisation
Developing a Set of Key Principles for Care Planning Within Older Adult Care Homes: A Modified Delphi Survey
Get PDFBackground: Older adult care homes in England must develop care plans on behalf of their residents and make them available to care providers. There is currently a lack of formal agreement around the key principles that should inform the care planning process. Objective: The study aimed to develop a set of key principles for care planning in older adult care homes in England. Methods: We developed 78 evidence‐based items and presented them to a panel of health and social care professionals with experience of care planning. We used two online rounds of Delphi to generate consensus (≥ 75%) on items to include in a set of key principles for care planning. Results: A set of key principles, comprising 81 items, were developed. One‐hundred participants completed Round 1, and 80 participated in Round 2. Three percent (n = 4/78) of the Round 1 statements did not reach agreement. Revisions primarily related to the terminology used, clarification of language and an increased emphasis on care home residents' consent and autonomy. Agreement was achieved on all statements (n = 78/78) in Round 2. Conclusion: Substantial agreement was achieved regarding the document's content. Future research should (a) look to develop a resource for the family and friends of care home residents to enhance their participation in care planning and (b) explore how these principles can be put into practice. Reporting Method: Study reporting was guided by the Conducting and REporting of DElphi Studies (CREDES) framework. Patient or Public Contribution: Two public involvement advisers with lived experience of caring for a relative living in a care home worked with researchers to develop the key principles and Delphi survey, recruit panel members, interpret the results from the two rounds and assist with revising the items
Distinct adaptive strategies to cisplatin, vinblastine and gemcitabine in a panel of chemoresistant bladder cancer cell lines
Get PDFAim: Urinary bladder cancer (UBC) often develops chemoresistance, reducing treatment effectiveness. This study aimed to investigate diverse molecular mechanisms underlying acquired resistance by establishing and characterizing a comprehensive panel of UBC cell lines resistant to common chemotherapeutics.
Methods: Fifteen UBC cell lines were examined: three parental lines (RT-112, TCC-SUP, UMUC-3) and twelve derived sublines adapted to cisplatin, vinblastine, or gemcitabine. Drug sensitivity was assessed using the SRB assay. Resistance mechanisms were explored via quantitative real-time PCR (targeting genes including ABCB1, dCK, hENT1, ECHDC1, TUBB3), Western blotting (assessing proteins such as p21, Cyclin B, and Mcl-1), and biochemical assessment of glutathione levels and redox state.
Results: The adapted sublines exhibited distinct resistance profiles and cross-resistance patterns. Gene expression and protein analyses revealed drug- and lineage-specific alterations, involving factors such as p21, Cyclin B, and Mcl-1. Changes in glutathione metabolism were also associated with resistance. Notably, no single, universal mechanism accounted for resistance across the entire panel.
Conclusion: UBC cells develop diverse, context-dependent adaptive strategies to resist cisplatin, vinblastine, and gemcitabine. These findings highlight the complexity of chemoresistance mechanisms. The characterized cell line panel represents a valuable resource for future studies aimed at understanding and overcoming drug resistance in bladder cancer, suggesting that personalized therapeutic approaches may be necessary
Structural and molecular differentiation of cultured human neurons is accompanied by alterations of spontaneous and evoked calcium dynamics
Get PDFDuring development, neuronal precursors transform from a pluripotent state into specialized neurons. While much research has been conducted into morphological and molecular changes, there is a pressing need to define accompanying functional alterations. We used immunofluorescence microscopy and live imaging in SH-SY5Y-derived human neurons to elucidate the relationship between structural and molecular differentiation with evoked and spontaneous Ca2+ dynamics. In the undifferentiated state expressing trace amounts of neuronal markers, SH-SY5Y cells maintain spontaneous high-amplitude slow Ca2+ oscillations, with their stimulation by carbochol activating low-amplitude Ca2+ transients. Driving SH-SY5Y cells into the 2CL state by retinoic acid facilitated the outgrowth of neurites and expression of neuron-specific proteins. These changes are accompanied by the abolition of Ca2+ oscillations. Differentiating SH-SY5Y cells into definitive neurons by a cocktail of retinoic acid and BDNF induced their polarization and enrichment with specific neuronal markers, accompanied by a resurgence of spontaneous Ca2+ oscillations but with faster kinetics. The carbachol-induced rise of Ca2+ in these cells showed a higher peak and biphasic decay. At all developmental stages, Ca2+ transients in response to ionomycin were indistinguishable. These findings lead us to conclude that a switch of Ca2+ dynamics accompanies structural and molecular differentiation of SH-SY5Y cell-derived human neurons, contributing to the developmental process
A Hundred and Two Just-So Stories: Exploring the lay evolutionary hypotheses of the manosphere
No full textThe manosphere is a collection of online antifeminist men’s groups whose ideologies often invoke Darwinian principles and evolutionary psychological research. In the present study, we reveal that the manosphere generates its own untested and speculative evolutionary hypotheses, or “just-so stories”, about men, women, and society. This is a unique phenomenon, where lay (i.e., non-expert) individuals creatively employ evolutionary reasoning to explain phenomena in accordance with their particular worldview. We thus assembled the first dataset of lay evolutionary just-so stories extracted from manosphere content (n = 102). Through qualitative analysis, we highlight the particularity of the manosphere’s lay evolutionism. It is a collective bottom-up endeavor, which often leads to practical advice and exhibits a male gender bias. We further show that 83.3% of manosphere just-so stories pertain to sex differences, and that only 36.3% explicitly signal that they are speculative. Given this evidence that lay communities collectively engage in evolutionary hypothesizing, we reflect on implications for evolutionary scholars and for the field as a whole, in terms of ethics and public image. Lastly, we issue a call for renewed discussion and reflection on evolutionary hypothesizing, a central yet somewhat neglected feature of evolutionary behavioral science
Manipulating the impact of interest intensity on autistic and neurotypical child conversation.
No full textA Trip To L-Ala-L-Ala Land: the characterisation of AlaE, an amino acid efflux protein from Escherichia coli
No full textE. coli pathogenic strains are known to cause serious diseases in both humans and animals, sometimes leading to fatal complications. The growing challenge of treating these infections stems from multidrug resistance, which is enhanced by the bacteria's genetic adaptability and the protective nature of biofilm structures. AlaE, an L-alanine efflux pump, plays a critical role in biofilms by transporting L-alanine to nutrient-deprived regions, promoting colony growth under resource-limited conditions. The alaE-deficient mutant strain JW2645-5 (ΔalaE), exhibits bacteriostatic effects under high concentrations of L-alanine and its peptides, making AlaE a promising target for developing efflux pump inhibitors (EPIs). However, AlaE's function and structure remain poorly characterised.
In this study, we hypothesised the deletion of alaE to lead to impaired efflux of L-alanine and its peptides, resulting in growth inhibition under specific conditions. Furthermore, we predicted that the tripeptide L-alanyl-L-alanyl-alanine (Ala-Ala-Ala) is an additional inhibitory substrate, accumulating to toxic levels causing growth inhibition in the absence of AlaE. Micro-growth assays in defined M9 medium confirmed ΔalaE susceptibility to L-alanyl-L-alanine, displaying phenotypic delays and impaired growth at higher concentrations. Notably, ΔalaE was completely inhibited by the tripeptide L-alanyl-L-alanyl-alanine at lower concentrations. In restrictive media lacking carbon and nitrogen, ΔalaE metabolised Ala-Ala for growth, though with a 3-hour delay, while nutrient-rich LB alleviated inhibition, highlighting AlaE's inessentiality in these conditions. Using AlaE plasmid constructs, we rescued the ΔalaE phenotype and identified H10, D14, D84, and D133 as essential residues through site-directed mutagenesis. Alanine substitutions at these sites resulted in loss of AlaE function, restoring the ΔalaE phenotypic delay.
These findings are consistent with a role for AlaE in the export of alanine and alanine-containing peptides, contributing to both efflux and biofilm survival. Additionally, they highlight critical residues that could serve as antimicrobial targets, advancing the development of EPIs to combat multidrug-resistant E. coli, and providing a foundation for future studies into AlaE's structural and functional characterisation
Adaptation of Candida albicans to osmotic and oxidative stress drives innate immune evasion through distinct pathways
No full textCandida albicans is an opportunistic fungal pathogen causing superficial and systemic infections in humans. To survive in the host, C. albicans must evade attack from the human immune system, which it achieves through various mechanisms such as the remodelling of its cell wall and the recruitment of host regulatory factors, such as Factor H. The fungus regulates its immune evasion mechanisms in response to environmental factors such as lactate, hypoxia and iron limitation, which induce masking of cell wall β glucan, as well as oestrogen, which promotes the recruitment of Factor H to the cell surface through the action of the Factor H binding protein Gpd2. Here, we provide evidence that oxidative and osmotic stress are also environmental cues regulating immune evasion. To explore the mechanisms underlying these responses, as well as the previously described response to oestrogen, molecular and cellular assays are employed to measure factors such as gene expression, protein expression, protein localisation, cell wall composition and Factor H recruitment, in both wild type and genetically modified strains. It is demonstrated that, similarly to the response to oestrogen, oxidative stress induced immune evasion requires Gpd2. However, unlike the oestrogen response, Gpd2 is not required for Factor H recruitment, meaning it must play another role, such as promoting Factor H activity. The response to osmotic stress, on the other hand, appears entirely novel. Although the transcription factor Cap1 has been identified as an essential component of this response, the mechanisms driving evasion under this condition remain elusive. The data described here contributes to the growing body of evidence that C. albicans possesses a varied armoury of immune evasion mechanisms, which are tightly regulated in response to environmental stimuli. Increasing the understanding of these mechanisms, and the factors driving them, is vital for informing the development of additional drugs and treatment strategies
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