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Selective sequencing on an industrial scale
No full textThe production of real-time sequence data from native, long single-molecule Deoxyribonucleic acid and Ribonucleic acid is unique to Oxford Nanopore Technologies sequencers. Real-time analysis can guide the application of both run-until and read-until, which increases the efficiency of sequencing runs. Run-until allows users to stop a sequencing run at certain thresholds, preserving flow cell health. Read-until,
or adaptive-sampling, can focus genome-wide sequencing onto specific regions of interest enriching coverage over these targets. In Chapter 1, we discuss the development and application of our fully-customisable nanopore simulator, which allowed us to test these tools whilst avoiding the costs of performing real sequencing.
In Chapter 2 we discuss a real-life application of real-time adaptive-sampling: viral pathogenomic surveillance. We describe a framework that optimises sequencing: it can provide adaptive-sampling targets for amplicon-based viral sequencing, increase the speed and efficiency of a run, and further preserve flow cell health via metrics that determine when all samples have produced enough data.
The highest throughput device that Oxford Nanopore Technologies currently offers is PromethION, designed at a scale that further optimises, and lowers the cost of, sequencing. As described in Chapter 3, by developing mappy-rs, a Rust-based extension to minimap2, we further developed and refactored readfish (a previously developed open source adaptive-sampling tool) to permit its use with PromethION scale sequencing. Mappy-rs increases the speed of alignments to enable processing of PromethION output.
To demonstrate the combination of ultra-long, high-throughput PromethION sequencing with adaptive-
sampling, we attempted to close the gaps in a de novo, nanopore-only genome assembly of the NA12878 cell line. This approach shows promise for the creation of haplotyped Telomere to Telomere assemblies using nanopore sequencing in the future
Beyond bars: examining suicide risk amongst people on probation
Get PDFObjective: The thesis broadly explores suicide risk in the probation population, with a predominant focus on risk factors, preventative intervention and risk assessment.
Methods: The thesis includes a systematic review regarding risk factors for suicide amongst individuals on probation (Chapter Two), empirical research paper discerning differences between individuals on probation who experience suicidal ideation, suicide attempt and no history of suicidal thoughts or behaviour (Chapter Three), a single case study of a male on probation who demonstrated a historical suicide attempt and experienced suicidal ideation at the time of intervention (Chapter Four), and critique of the Depression, Hopelessness and Suicide (DHS) Screening Form.
Results: Chapter Two presents 10 references that were systematically identified, of which highlights the scarcity of research regarding suicide risk factors for the probation population. Chapter Three attempts to expand on existing literature and presents sociodemographic, criminogenic and clinical differences between men on probation who have; attempted suicide, experienced solely suicidal ideation and have not experienced suicidal thoughts or behaviour. Findings also present a tool that is comprised of routinely assessed risk factors within the probation setting to identify vulnerabilities to suicidality and indicate individuals who may require a suicide assessment. Chapter Four proposes Cognitive Behavioural Therapy (CBT; Beck & Beck, 2020) and Dialectical Behavioural Therapy (DBT; Linehan, 2014) could be considered in reducing the presence of suicidal ideation amongst the probation population and findings add further validity to the tool developed from the primary research paper, of which identified vulnerabilities to suicidality. Chapter Five indicated psychometric properties of the DHS are satisfactory when utilised with forensic populations. Although, the DHS should be utilised with caution in light of outlined limitations that must be addressed in practice.
Conclusion: Clinical risk factors are critical when assessing and managing suicide risk in probation populations. However, additional risk factors that can mediate suicide risk outcomes should also be considered. However, probation do not have surplus resources to manage these problems. Therefore, responsibility must be shared with probation, prison and community services to provide integrated, quality resettlement support and care for those on probation. The thesis supports the use of risk factors in identifying vulnerabilities for suicidality, and indicates that when risk factors are more prevalent ideation may transcend into attempt. However, as Chapter Three is retrospective in nature, the validity of the tool should be treated with caution and used in conjunction with clinical judgement when assessing suicide risk. Finally, each case should be formulated individually with support from psychology professionals to identify suitable intervention, and observational and collateral information should be utilised in addition to screening tools for risk assessment
The molecular basis of atypicality in antipsychotic drug action
Get PDFDopamine D2 receptor (D2R) antagonism is thought to be the pharmacological mechanism behind the clinical efficacy of antipsychotic drugs (APDs) in treating the positive symptoms of schizophrenia. Unfortunately, D2R antagonism is also associated with extrapyramidal symptoms (EPS) that encompass a range of motor side effects. More recently developed APDs are termed ‘atypical’ based on their low propensity to cause EPS. Despite several suggested hypotheses, no single mechanism has yet to account for all cases of atypicality in clinically prescribed APDs. This thesis explored two promising molecular mechanisms recently proposed to account for APD atypicality: (1) the reduced rebinding of atypical APDs to D2R resulting in surmountable D2R antagonism and (2) the low efficacy of atypical APDs as pharmacological chaperones of D2R, resulting in reduced D2R upregulation to the cell surface.
First, in-solution reads of fluorescent APDs with differing binding kinetics at D2R, spiperone-d2 and clozapine-Cy5, were optimised using the advanced spectroscopy technique, fluorescence correlation spectroscopy (FCS). In addition, the variable expression of SNAP-D2R in a CHO tetracycline-inducible SNAP-D2R cell line was characterised using confocal imaging and FCS. FCS was also used to investigate the membrane dynamics of SNAP-D2R within CHO tetracycline-inducible SNAP-D2R cells which revealed that a small percentage of receptors may form clusters on the plasma membrane.
Subsequently, the rebinding effects of these fluorescent APDs at D2R were investigated by measuring their concentration above cells with a range of SNAP-D2R expression levels. A high concentration of spiperone-d2 was found near the upper membrane of D2R-expressing cells which decreased further away from cells into the bulk aqueous solution. Interestingly, spiperone-d2 formed concentration gradients above cells that were dependent on the level of SNAP-D2R expression at the plasma membrane. These concentration gradients were indicative of spiperone-d2 rebinding to D2R and provided evidence of drug rebinding in vitro. In contrast, clozapine-Cy5, which has a slower association rate, showed negligible concentrating effects above D2R-expressing cells. When an added concentration of 0.2 x Kd of each fluorescent APD was used, the concentrating effect at 3 μm above the membrane of high D2R- expressing cells was 95-fold greater for spiperone-d2 in comparison to clozapine-Cy5. This is consistent with the association rate of APDs at D2R being the driver for APD rebinding, resulting in sustained D2R antagonism leading to higher EPS risks.
The APD-induced trafficking of D2R to various cellular compartments was next investigated using a bystander BRET-based D2R trafficking assay and confocal imaging. Most notably, APDs showed differing efficacies as pharmacological chaperones of D2R by increasing D2R trafficking from the endoplasmic reticulum to the plasma membrane. Interestingly, APDs that showed high efficacy for D2R chaperoning were also associated with high EPS risks. However, the APD-induced upregulation of D2R at the plasma membrane was also shown to be acutely reversible in vitro.
Finally, the optimisation of the primary culture of striatal neurones from SNAP-D2R mice was carried out with the aim of extending studies into more therapeutically relevant cells. Determining the molecular basis behind the atypicality of APDs would enable better prediction of the EPS risks of future APDs, ultimately leading to the improved treatment of schizophrenia and other psychiatric disorders where psychosis is a primary symptom
The influence of executive characteristics on corporate social innovation
No full textFirms can integrate innovative products or services into business strategies to solve social problems and provide economic returns through corporate social innovation (CSI). It is important for businesses to consider profits and solve social problems with their products or services to be sustainable. CSI is an emerging research area where literature suggests that different aspects of organisations can influence CSI. Though previous literature provided insights into the importance and evolution of CSI, there is a knowledge gap in theory regarding the concept and resources of CSI. It is argued that CSI is a strategic decision that requires effective resource allocation (financial, human, and organisational resources) and the capability or characteristics of a CEO (such as education, experience, tenure, social networks, and connections). These background characteristics of a CEO can be influential factors in initiating CSI as these factors are used to indicate their social skills, knowledge, or abilities. This study has given an opportunity to fill the gap and contribute to knowledge by examining the characteristics of CEOs that can influence CSI. I incorporated stakeholder theory, upper-echelon theory, social capital and human capital theory in this research to contribute to the CSI literature. These theories described why and how the differences in the individual’s ability, skills and characteristics can provide different strategic and innovative outcomes. As my research questions are related to the top management resources, skills, and abilities as well as strategic decision-making processes like CSI, the interconnection of these theories guided me to address my research questions and assist me in achieving the research objectives.
I adopted a sequential mixed methodology (qualitative followed by quantitative) in my PhD thesis. I have conducted a qualitative study to identify the perception of top management regarding CSI, the role of top management in CSI, and the CEO characteristics that can influence the CSI strategic decision consecutively. To achieve these objectives, I have conducted 21 interviews with different top-level management employees and experts in the financial sector of Bangladesh as an emerging economy. I also conducted five additional interviews with top-level managers of the financial sector in Malaysia and one top-level executive from Thailand to validate my qualitative study results. The financial sector, especially banking operations, mainly assists in exploring opportunities by utilising financial resources in social development, such as education, health, and entrepreneurship, reducing income inequality, which is an essential agenda for sustainable development goals. The financial sector reflects an economy's economic functions and strength. So, the financial industry of these countries is an appropriate context for this study.
I selected these countries because of their similar emerging economies and cultural proximity, which can provide the generalisability of the research. I have performed phenomenography and thematic analysis to analyse the results of my qualitative research. I have found four perspectives on CSI based on top management's perceptions. These are technological, sustainability, social development, and entrepreneurship perspectives.
The qualitative results also suggest that the CEO, as a top management team member, play a vital role in embedding social innovations in corporate strategy. The top management team or CEO act as an idea generator, communicator, risk taker, and implementor of CSI. My qualitative study also unveiled the top-level management or CEO characteristics which can play a role in initiating and implementing the CSI. I found that top-level managers' or CEOs' human capital, such as experience level, education, technological knowledge, and mindset, play critical roles in influencing CSI as strategic decisions. Moreover, as a source of social capital, the CEO's social network with non-profit organisations, other boards and government organisations can influence CSI. The results also suggest that CEO empathy as social capital can influence the CSI strategic decisions in the organisations.
For the quantitative part, I collected data from different sources of databases (Fitch connect, Orbis bank focus), annual reports, and companies' websites. This is the unique hand-collected dataset from which I examined the extent to which CEO characteristics influence CSI. There are 45 Bangladeshi banks, 19 Malaysian banks, and 8 Thai banks included in my observation. I have collected data from 2008 to 2020 to prepare the panel data set of 823 observations. I have used a negative binomial regression model as my dependent variable is count. I have compared Akaike's information criterion (AIC) and Bayesian information criterion (BIC) between different models to justify appropriate regression model selection. I also conducted a comparison test through the mean and variance of CSI (dependent variable). I have also done the overdispersion test to select an appropriate regression model. These test results suggested using negative binomial regression as an appropriate model for my data analysis.
I confirmed the results from the negative binomial models held using alternative, albeit less optimal model specifications (Poisson and OLS). My quantitative study reveals that CEO overseas education and experience level positively influence CSI, and CEO tenure negatively influences CSI. CEO overseas education positively moderates the relationships between CEO experience and CSI. Similarly, CEO overseas education positively moderates CEO tenure and CSI relationships. I also incorporated bank size (company size) as an organisational factor to investigate its effect on CSI. The study results suggest that company size positively moderates the relationship between CEO tenure and CSI. The results also suggest that CEO affiliation with non-profit organisations negatively influences the CSI. My research will contribute to corporate social innovation, sustainability, and responsible and ethical business literature. The managerial implication of my research contributes to the recruitment and selection of appropriate CEO and TMT members to compose efficient top management to initiate and implement the CSI.
Key Words: Corporate Social Innovation (CSI), CEO characteristics, Top-Management Team (TMT), Emerging econom
Investigating the effects of drug combinations and loss of the PRH/Hhex oncoprotein in CCA cells
Get PDFCholangiocarcinoma (CCA) is a group of malignancies that arises from the biliary epithelial cells that line the bile duct. Despite the emergence of new treatment modalities, patient prognosis is very poor and novel therapeutics are urgently needed. This project investigates Niclosamide, an anti-helminth drug, that was identified from a drug repurposing screen. In this thesis, I show that Niclosamide treatment over 72 hours can reduce CCA cell viability significantly more than normal Biliary Epithelial Cells (BECs). This reduction in cell viability is due in large part to Niclosamide-induced mitochondrial uncoupling that causes cellular stress and an imbalance in protein homeostasis. Niclosamide treatment is also shown to promote apoptosis after 24 hours of treatment and to have an anti-proliferative effect over 72 hours. The Proline Rich Homeodomain (PRH) protein, also known as the haematopoietically expressed homeobox (HHEX) protein, has recently been shown to act as an oncoprotein in CCA cells increasing cell proliferation and cell migration. Interestingly, Palbociclib was shown to abrogate cell proliferation in PRH-driven CCA cells through the inhibition of CDK4/6 activity. Here, Palbociclib is shown to selectively reduce the viability of CCA cell lines compared to BECs and to synergise with Niclosamide. At a phenotypic and protein level, the Niclosamide-Palbociclib combination is shown to effectively promote cell cycle arrest through multiple mechanisms. Thus, the combination of Niclosamide and Palbociclib is shown to provide a potent anti-CCA effect in 2D and 3D in vitro cancer models. PRH is substantially decreased by Niclosamide and Palbociclib dual therapy, which occurs through two independent mechanisms, whereby Niclosamide treatment induces PRH degradation by the proteasome, and PRH protein level also decreases upon Palbociclib-induced cell cycle arrest. Also, the drugs as single agents, and as a combination, are more effective in cells with high levels of PRH expression compared to cells with low levels of PRH expression. To understand the role of PRH in CCA further, the effects of PRH knockdown on CCA cells was studied through siRNA and shRNA protein knockdown and for the first time CRISPR-Cas mediated PRH knockout. These models shed light on the functions of the PRH protein in cell cycle and highlight previously undocumented roles of PRH in CCA cells in cell survival, cell metabolism and apoptosis. In conclusion, this thesis provides the first preclinical evaluation of Niclosamide-Palbociclib dual therapy for CCA and provides more information about the role of PRH in CCA biology that may lead to improved methods for the targeting of PRH in PRH-driven CCA
Transmedia authorship as a media industries practice
No full textThis thesis offers an analytical framework to investigate transmedia authorship within the context of the media industries. Through the case studies of the Wizarding World and Star Wars, it transcends the dichotomy, prevalent in media authorship research, between viewing authorship as tied to individual genius or to the collaborative effort of numerous contributors. Challenging current understandings of transmedia authorship as relying on a central authorial figure (Jenkins, 2006; Evans, 2011; Freeman, 2016), the case studies demonstrate that transmedia authorship is mutable, like the texts to which it relates.
The thesis uses paratextual analysis (Genette, 1997 [1987]; Gray, 2010), as well as the concept of performance in linguistics (Austin, 1975) and media authorship (Gray, 2010; Hadas, 2020), to show how a ‘transmedia author-function’ emerges from the performed relationships between a primary authorial figure and the other contributors to the fictional universe, as mediated through officially-branded material and public commentary by key creatives.
The crux of the study lies in recognising the media industries as a key player in the construction of authorship and its fluidity. Accordingly, the thesis demonstrates that the performed relationships serve as a mechanism through which authorial authority can be bestowed or limited. The case studies show how media corporations contribute to shifts in the transmedia author-function; by showcasing or sidelining different authorial figures, IP owners can encourage a more or less collaborative conception of authorship, with the aim of pursuing different strategic objectives for the future of the transmedia universe as brand
Computational pathology and deciphering the complexity of HER2 expression in breast cancer
Get PDFBackground
Breast cancer (BC) is the most common cancer and second leading cancer-related death in women. Despite significant advancement in the detection, prognostic and predictive classification of BC, there remains a proportion of
patients who recur and die of their disease. Further research on BC diagnosis and classification is needed. Digital pathology (DP) and molecular assays, including whole slide imaging (WSI), digital image analysis (DIA) and artificial intelligence (AI), are revolutionising BC diagnosis and treatment, enabling detailed cyto-morphometric assessments that enhance diagnostic accuracy, personalise treatment, and improve outcomes. Although the therapeutic roles of HER2 protein in BC have been defined for more than two decades, the spectrum of HER2 expression in BC is evolving, and therapeutic modalities are expanding. HER2-positive cases are candidates for targeted anti-HER2 therapy, but patient response varies, with recurrence rates ranging from 20-40%.
The introduction of HER2-Low BC and antibody-drug conjugates (ADCs) has
transformed the management of HER2-negative BC but added complexity to
HER2 assessment, particularly regarding the lower limits of ADC therapy eligibility.
This thesis evaluates the integration of computational pathology and advanced
molecular approaches in identifying novel BC prognostic parameters and deciphering the complexity of HER2 expression, including its biological and clinical characterisation. It highlights differential responses to targeted anti-HER2
therapies among HER2-positive classes, the role of hormone receptor (HR)
expression, and refines the definition of HER2-Low BC.
Methods and Results
A large cohort of 40,160 breast WSIs was analysed to assess the accuracy
and utility of WSI compared to traditional microscopy. The assessment focused
on the presence, frequency, location, and tissue type of missing tissue and its
clinical implications. Additionally, scanning time, specimen type, time to implement WSIs and quality control measures were evaluated. The results indicated
that while missing tissue's frequency, area, and location varied, all cases involved fat tissue, and none affected final diagnoses. Quality control measures
significantly improved image quality and reduced WSI failure rates by sevenfold.
We also used AI to identify novel prognostic parameters in breast cancer. All
slide images were analysed using AI-based DP tools to extract stromal and
tumour features, focusing on the tumour-stroma ratio and spatial distribution
of stromal cells. Deep learning algorithms were employed for feature extraction
and spatial analysis, following extensive annotation at the cellular and region
levels. The tumour-stroma ratio was found to be a significant prognostic factor,
with higher ratios associated with worse outcomes. AI-based spatial analysis
revealed patterns of stromal cell distribution that correlated with tumour aggressiveness and patient survival. This demonstrated the utility of AI in enhancing understanding of the tumour microenvironment and its impact on BC
prognosis.
A substantial BC cohort with clinical, transcriptional, and survival data was utilised to develop a HER2-driven morphometric signature reflecting HER2-positive tumours with active oncogenic signalling and better response to targeted
anti-HER2 therapy. WSIs of invasive BC cases with HER2-positive and HER2-
negative controls were analysed. Image acquisition, segmentation, and spatial
distribution analyses were performed using DIA algorithms. Statistical correlations between HER2-driven morphometric features and patient outcomes were
analysed. A total of 57 morphometric features were evaluated, with 22 significantly associated with HER2 positivity. HER2 IHC score 3+/oestrogen receptor
(ER) negative tumours were significantly associated with HER2-related morphometric features and showed the least intra-tumour morphological heterogeneity. The HER2-driven morphometric signature was validated on PAM50
HER2-Enriched molecular subtype (HER2-E) cases, correlating with prolonged distant metastasis-free survival (DMFS) post-adjuvant anti-HER2 therapy.
For deciphering the response of HER2-positive BC to targeted anti-HER2 therapy, we first compared both HER2-positive classes regarding clinicopathological features, pathological complete response (pCR), patient survival, and the
role of ER status on therapy response. Differentially expressed genes and molecular pathways within both classes were identified, with TAF10 and BCAT1
selected for further validation through transcriptomic and proteomic analyses.
Tissue microarray blocks were constructed, and IHC staining, scoring, and
analysis were performed. The value of concomitant use of multigene assays
that assess ERBB2, ESR1, PGR, and MKI67 (MammaTyper® assay) with
HER2 IHC for predictive stratification of HER2-positive BC patients to anti HER2 therapy was investigated. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue, quantified using RT-qPCR, and discordant HER2
status cases were validated through staining on excision specimens and patient record reviews.
Our results revealed that compared to HER2 IHC 3+ tumours, patients with
IHC 2+/Amplified BC had a significantly lower pCR rate (22% versus 57%,
p<0.001) and shorter survival regardless of HER2 gene copy number level. ER
positivity was significantly associated with decreased response to anti-HER2
therapy in IHC 2+/Amplified but not in HER2 IHC 3+ BC patients. Compared
to IHC 3+, HER2 IHC 2+/Amplified tumours were less frequently classified as
HER2-E molecular subtype (16% versus 49%, p<0.001), with downregulation
of HER2 oncogenic pathway genes, upregulation of trastuzumab resistance
genes, and enrichment in ER signalling pathway genes.
TAF10 mRNA expression was significantly associated with HR-positive and
HER2-positive tumours, particularly the HER2-E molecular subtype (p<0.001).
High TAF10 mRNA expression correlated with prolonged breast cancer-specific survival (BCSS) in both the TCGA and METABRIC cohorts (p<0.008 and
p<0.001, respectively). Multivariate Cox regression confirmed TAF10 mRNA
as an independent predictor of better survival, which was also validated at the
protein level. High TAF10 protein expression levels predicted a better response
to trastuzumab-based chemotherapy, whereas in chemotherapy-only treated
HER2-positive patients, high TAF10 expression had no predictive role. TAF10
mRNA significantly correlated with low PIK3CA, mTOR, RICTOR and MIB1
mRNA expression, known resistance genes to trastuzumab therapy. At the
same time, BCAT1 showed a poor prognostic and predictive role in HER2-
positive BC cases with high expression associated with short BCSS and DMFS
in trastuzumab-treated patients.
Regarding the role of multigene assays in predicting response to anti-HER2
therapy, ERBB2 mRNA identified 251/287 (87.5%) cases as HER2-positive,
10.8% (31/287) as HER2-Low, and 1.7% (5/287) as HER2-negative. According
to the MammaTyper® assay, ERBB2-positive patients treated with anti-HER2
therapy had significantly prolonged 5-year disease free survival (DFS) and
DMFS (HR=0.56, p=0.003 and HR=0.62, p=0.023, respectively). MammaTyper®-defined HER2-E subtype showed a better response to anti-HER2
therapy compared to IHC-defined subtypes, with significant prolongation in
both 5-year DFS and BCSS. For ERBB2-negative patients, there were no significant differences in survival rates between those treated with trastuzumab
and those who received only chemotherapy (p > 0.05). Validation analysis revealed that 11/36 ERBB2-negative cases were IHC 2+/ISH positive with very
low gene amplification levels.
For HER2-Low tumours, we refined this category by integrating IHC scoring
with mRNA levels and artificial neural network (ANN) models to achieve a refined scoring algorithm with high concordance. HER2 staining intensity, pattern, and subcellular localisation were assessed in detail, and inter-observer
concordance in scoring HER2-Low class according to current guidelines was
evaluated. ANN analysis successfully distinguished HER2 score 0 from 1+ with
high sensitivity and specificity, improving the consistency of HER2 scoring and
pathologist concordance. The study provided a clearer definition of HER2-Low
BC, facilitating better patient stratification for ADC therapy. Most HER2-Low
tumours were HR-positive, enriched with luminal intrinsic molecular subtype,
lacking significant HER2 oncogenic signalling gene expression, and exhibiting
favourable clinical behaviour compared to HER2-negative BC. In HR-positive
BC, no significant prognostic differences were detected between HER2-Low
and HER2-negative tumours. However, in HR-negative BC, HER2-Low tumours were less aggressive, with longer patient survival. Transcriptomic data
showed that most HR-negative/HER2-Low tumours were luminal androgen receptor (LAR) intrinsic subtypes, enriched with T-helper lymphocytes, activated
dendritic cells, and tumour-associated neutrophils, while most HR-negative/HER2-negative tumours were basal-like, enriched with tumour-associated
macrophages.
Conclusion
The research demonstrated the efficacy of integrating DP, including WSI and
AI, in enhancing diagnostic accuracy and identifying novel BC prognostic parameters. HER2 protein overexpression is the primary oncogenic driver and
the main predictor of response to anti-HER2 therapy in HER2-positive BC. ER
signalling pathways are more dominant in BC with equivocal HER2 expression
compared to HER2 3+ tumours. The differential response to anti-HER2 therapy based on IHC classes should inform treatment decisions for HER2-positive BC patients. The concomitant use of multigene assays with IHC could improve the prediction of therapeutic response to anti-HER2 therapies. A more
precise definition of HER2-Low BC was established, integrating protein expression levels and mRNA data. This refined definition aids in identifying patients who may benefit from novel therapies, such as ADCs. Integrating computational pathology and molecular approaches offers a pathway to more precise and effective clinical management of HER2-positive and HER2-Low BC
patients
An inquiry into the production and material-reality of hybridity through an analysis of where and when
No full textIn this thesis, I assemble my inquiry into hybrid work in becoming inspired by new materialist thought, and thereafter in being moved along different directions. Structuring the thesis into three parts, each of which connect to each other laterally rather than hierarchically, I seek to map the inquiry which unfolded in a similar multi-directional, non-hierarchical way. And so, while this thesis contributes to academic scholarship on hybrid work, and more broadly, new ways of working, and in so doing, develops organisation theory on space and time, the writing of this inquiry hopes to leave that which is produced from its reading open-ended.
I situate the inquiry with/in the post-pandemic world of work whereby hybrid work, commonly referred to as a way of working which entails splitting working at the office and home using technology, has been hailed as the ‘future of work’. In encountering only limited academic scholarship relating to hybrid work specifically, I move my inquiry towards developing an empirically informed understanding of hybrid work. Turning to related telework and broader new ways of working literature, I encountered recent sociomaterial perspectives which overcome dualist drawbacks of focusing either on people or technology by examining how both are entangled with each other in enactments of such ways of working. In seeking to continue the sociomaterial stream of research in my own inquiry into hybrid work, I encounter new materialist scholarship which extends an understanding of materiality beyond that of technology through a complete ontological (re)turn to matter. Through a new materialist perspective, I approach hybrid work as a phenomenon of human-nonhuman relations, and therein, seek to understand the materiality of hybrid work – how it is produced, and the material-realities it produces.
In commencing my empirical research into the material-reality of hybrid work in one UK-based organisation called MCorp (a pseudonym), my inquiry unfolds across different directions through both my empirical encounters and further wanderings across different regions of literature. Specifically, my inquiry moves along the directions of space and time. Accordingly, I seek to understand the material production of hybrid work by addressing where hybrid work materialises and the time and temporality of how hybrid work unfolds in everyday life. Empirical inquiry was performed according to, what I have referred to as, an assemblage ethnography, which was informed by considerations of a post qualitative inquiry. This approach, which emphasises the intra-actions between the researcher and the researched for producing knowledge (Barad, 2003; 2007), was developed along the way as I realised a ‘pure’ traditional ethnography would not align with my ‘hybrid’ phenomenon of inquiry. And so, an emergent analysis of the space and time of hybrid work unfolded through my inquiry, details of which I assemble in my two empirical chapters.
Accordingly, I render an analysis of MCorp’s spatial system of hybrid work according to Law and Mol’s (1994; 2001) topological shapes of region, network, fluid, and fire. This puts forth an understanding of hybrid spatiality of work which is produced by human-nonhuman agencies taking different shapes. Hybrid space, therefore, not only involves both fixing and moving work but also contingently transforming the materiality with/in which work takes place and making visible centres of presence through absence of certain relations. Along the temporal dimension, I render an analysis of four times: mechanical, elastic, infrastructured, and viscous, which emerges in MCorp, and consequently, affects how working and organising unfolds in their everyday hybrid organisational life through micropolitical dynamics between them. Such empirical analysis is put into conversation with existing organisation studies literature and theory on telework, new ways of working, space, and time for producing different understandings about these matters. Specifically, I propose that hybrid work is produced by the organising of paradoxes across topological shapes of hybrid space, through the micropolitics between different materialisations of time, which affect the everyday unfolding of material-realities of hybridity
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