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Contemporary organizations are currently exploring the possibilities of using digital technologies for business benefits while meeting external and internal demands for increased sustainability (George et al., 2021). Emerging at the intersection of these somewhat contradictory objectives, practitioners have recently recognized digital sustainability as a potential solution to their, and ultimately ours, sustainability problems. In the information systems (IS) field, digital sustainability has been identified as an opportunity for IS sustainability scholars to contribute to the organizational push towards a digitalization and sustainability convergence. By focusing on how to leverage digital technologies for sustainability purposes, this discourse assumes that IS sustainability research will make a positive contribution to sustainable development (Kotlarsky et al., 2023). While the encouraging findings of this one-sided exploration might encourage organizations to pursue digital sustainability in practice, this dissertation argues that it might also expose organizations to the risk of prioritizing the opportunities of digitalization (Chatterjee & Sarker, 2024) while ignoring the contradictions, tensions and challenges that also comes with the organizational pursuit for digital sustainability (Schoormann et al., 2025).

This dissertation identifies this one-sidedness as a research limitation in the digital sustainability discourse. To remedy this gap in literature, and consistent with recent calls for research (Veit & Thatcher, 2023; Fors et al., 2024), this dissertation adopts a nuanced and holistic sustainability lens to advance our current understanding of the opportunities and challenges that comes with digital sustainability. In addition, this dissertation adopts an explorative and interpretative research approach to explore digital sustainability in practice. By drawing upon the findings of an extensive literature review and four empirical case studies, this dissertation makes the following research contributions. Firstly, this dissertation presents a new definition for digital sustainability. Secondly it develops an integrated, holistic and non-technology-deterministic sustainability lens for IS sustainability research. Thirdly, it presents four characteristics of digital sustainability practices and the organizational conditions that supports them. Finally, it presents a sustainability-first approach to move beyond a digital first agenda in research and in practice. Accordingly, this dissertation advances our understanding of digital sustainability on an organizational level and provides new and important insights for IS sustainability scholars and practitioners.

Background:

Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are Philadelphia-negative myeloproliferative neoplasms (MPN). These relatively rare hematologic malignancies are characterized by clonal hematopoiesis. Patients with MPN have an increased risk of vascular complications, including both arterial and venous thrombosis, as well as hemorrhagic events. The objective of study I was to determine the frequency of elevated blood counts among patients presenting with thromboembolic events and to evaluate whether underlying etiologies influence the risk of recurrence. Studies II–IV examined treatment patterns, assessed the incidence and risk factors for arterial and venousthrombosis, major bleeding, and all-cause mortality (ACM) in patients diagnosed with PV, ET, and MF.

Methods and material:

Study I included all adult patients diagnosed with different subtypes of arterial and venousthrombosis thrombosis in the county of Norrbotten during 2017–2018.The cohort used in studies II–IV consists of all adult patients diagnosed with PV, ET, or MF who were registered in the Swedish MPN Register between 1 January 2008 and 29 December 2021, along with a matched control cohort randomly selected from the Population Register by Statistics Sweden. By linking several Swedish healthcare registries, data on clinical outcomes, treatment patterns, and mortality were obtained.

Results:

Among the 3931 patients included in study I, 30.4% of the patients had elevated blood values fulfilling the 2016 revised WHO diagnostic thresholds for PV or ET. Of these, 411 patients had no identifiable secondary cause of erythrocytosis or thrombocytosis and therefore required further evaluation to exclude an underlying MPN. Patients with unexplained thrombocytosis and those with secondary erythrocytosis exhibited the highest recurrence rates of thromboembolic events. In study II, patients with PV and ET demonstrated significantly increased rates of venous thromboembolism, major bleeding, and ACM per 100 treatment-years compared with matched controls. Additionally, PV patients experienced higher rates of arterial thrombosis and all-cause stroke than their respective controls. The MF patients included in study III had significantly higher rates of thromboembolic events, major bleeding, and ACM compared with matched controls. Treatment with JAK inhibitors (JAKi), use of low-molecular weight heparin (LMWH), a history of arterial or venous thrombosis, and advanced age were identified as independent predictors of new events. The observed association between JAKi therapy and thrombosis may partly reflect Swedish treatment guidelines, which restrict JAKi use to patients with high or intermediate-2 risk disease. Similarly, LMWH is often used in contexts such as postoperative care and immobilization, potentially contributing to its association with thrombotic events. A prior venousevent, elevated leukocyte count at diagnosis, and JAKi therapy were also associated with an increased risk of major bleeding. In study IV, analysis of treatment strategies in PV and ET revealed that most high-risk patients were treated in accordance with established guidelines. Unexpectedly, a large proportion of low-risk patients also received cytoreductive therapy during follow-up, likely reflecting the transition to high-risk status upon reaching 60 years of age. Older age and leukocytosis at diagnosis were predictors of thrombotic complications, major bleeding, and ACM in both PV and ET. Treatment with HU and interferon (IFN) was associated with reduced ACM, and HU further demonstrated a protective effect against thromboembolism and major hemorrhage.

Conclusions:

Elevated blood values are common among patients presenting with thromboembolic events, and determining the underlying cause is essential for reducing the risk of recurrence. Patients with PV, ET, and MF experience substantially higher rates of thromboembolic events, major bleeding, and ACM compared with matched population controls, and these risks vary across treatment groups. Several risk factors for vascular complications, major bleeding, and ACM in MPN have been identified.

Gene co-expression networks (GCNs) are a powerful approach for exploring transcriptional regulation by identifying functionally related genes through their expression patterns across various conditions. The inference of GCNs can be achieved by various computational algorithms, each with distinct merits and limitations. The choice of algorithm can influence the network structure and the biological interpretation derived from it. By using a combination of different methods, biases can be minimised providing more robust and complementary insights. These methodologies are particularly valuable for non-model species, a challenge exemplified by Norway spruce and Scots pine. With ongoing climate change, drought and cold stresses are becoming increasingly important factors shaping the survival of these boreal conifers. Boreal regions are experiencing more frequent and prolonged drought periods, alongside greater variability in early spring, including sudden freeze-thaw events and episodes of extreme cold. Understanding the genetic regulation through which species such as Norway spruce and Scots pine, perceive, respond to, and potentially recover from drought and cold is therefore of high importance. 

In this thesis I have used an extensive collection of transcriptomic data generated from boreal tree species under abiotic stress conditions to infer GCNs to reveal coordinated patterns of gene expression responses to environmental challenges. In addition, comparative analyses of GCNs enabled the systematic assessment of conservation and divergence of co-expression among these species, identifying both shared regulatory circuits and species-specific adaptations. Analyses uncovered down-regulated modules of developmental processes, up-regulated modules of abiotic stress response, and several candidate transcription factors directly connected to these stress-responsive pathways. Comparison with boreal angiosperms revealed divergent responses in core cold-regulatory processes, most notably in the regulation and representation of C- repeat Binding Factor (CBF) transcription factors. The abiotic stress response patterns of both cold and drought were largely shared between the two conifer species, indicating a high degree of conservation in their transcriptional responses. This conservation extended to the organisation of topologically associated domains, where a subset of highly conserved co-expressed orthologs were found at the same location in the genomes of these conifers. 

Together, these analyses demonstrated the utility of comparative co-expression networks as a tool for understanding both conserved and diverged regulatory mechanisms, while offering new perspectives on the resilience of conifers in the context of environmental change.

Background: Age-related cognitive and physiological decline can in part be mitigated by increasing older adults’ physical exercise, but individuals respond differently, for example in cognitive domains such as working memory (WM). This thesis examines how high intensity exercise affects cognitive, neural, and physiological measures in older adults and explores how clinical findings can be translated into real world settings. 

Methods: This thesis includes four papers, and is based on the Umeå HIT study, which compared supramaximal high intensity interval training (HIT) to moderate intensity training (MIT) for older adults. Papers I-III used data from the Umeå HIT randomized controlled trial (RCT), while Paper IV used data from the Umeå HIT Home Study. The Umeå HIT RCT assessed the effects of 12 weeks of twice-weekly supramaximal HIT (20 minutes total, including 10 x 6 second intervals) compared to MIT (40 minutes total, including 3 x 8-minute bouts) among non-exercising older adults (n = 68, 66-79 years old, 56% women). Exercise intensity was individualized and controlled. Specifically, Paper I assessed cognitive, physiological, well-being and adverse event outcomes, of supramaximal HIT vs MIT. Paper II assessed effects of supramaximal HIT vs MIT on a functional magnetic resonance imaging WM task and examined the relationship between improved leg strength and WM manipulation task-related blood oxygen level dependent (BOLD) response and performance in an MRI subsample. Paper III tested baseline- and change-factors related to WM improvement. Paper IV, based on the Umeå HIT Home study (n = 11, 69-74 years old, 55% women) explored how the original supramaximal HIT protocol could be adapted to home use through a co-creation study involving participants who had exercised in the supramaximal HIT-group of the RCT. 

Results: Paper I found that irrespective of group, cardiorespiratory fitness and systolic and diastolic blood pressure were significantly improved, while global cognitive function was not affected. A significant group x time interaction was found in WM performance and isometric leg extensor strength in favor of supramaximal HIT. Paper II found that increased isometric leg extensor strength in the supramaximal HIT group was positively related to dorsolateral prefrontal cortex  BOLD response, which in turn was related to increased WM performance. Paper III showed that the link between increased isometric leg extensor strength and improved WM also applied to a broader WM composite and the relationship was found in both exercise groups. It further showed that baseline white matter lesion load did not limit WM improvements following supramaximal HIT, unlike MIT. Upregulated brain derived neurotrophic factor was related to WM improvements, but differed by group, suggesting a stronger relationship in MIT. Paper IV identified alternative modalities to stationary bicycling and several adaptations to the supramaximal HIT protocol, including extending intervals to ten seconds, using an audio metronome to control intensity, and a mobile application for exercise delivery. Of the suggested modalities, chair stand intervals elicited similar acute physiological responses to supramaximal HIT on a stationary bicycle, intensity could be systematically modulated using a metronome, and the modality was considered safe.  

Conclusion: This thesis found that supramaximal HIT elicits similar- to superior effects on physiological and cognitive outcomes compared to MIT, despite half the exercise time. Furthermore, leg strength improvements were related to increased BOLD response in a key WM area, which in turn was related to improved WM performance in supramaximal HIT. Leg strength gains were further related to broader WM improvements irrespective of exercise group, indicating that muscular adaptations may be an important target for future exercise-cognition studies. Unlike MIT, supramaximal HIT-related WM gains were not limited by baseline white matter lesion load, and future studies should test this hypothesis directly. Adapting HIT for home use, especially with chair stand intervals, appears promising for future implementation, potentially enabling both cardiorespiratory and muscular gains. Future research should test the feasibility and effects of home-based supramaximal chair stand, as a step toward future implementation to real-world settings for older adults.

Mitochondria are essential organelles in eukaryotic cells. They contain their own genome that encodes proteins of the OXPHOS complexes essential for cellular ATP production. Failure to maintain mitochondrial DNA (mtDNA) integrity, therefore, can impair energy production and lead to mitochondrial dysfunction, which consequently results in a wide range of diseases, including rare genetic mitochondrial disorders and neurodegeneration. 

In human mitochondria, the genome is replicated by a unique enzymatic machinery including the mitochondrial replicative DNA Polymerase Gamma (Polγ). Polγ is a holoenzyme consisting of a catalytic Polγ α subunit and two accessory Polγ β subunits. The catalytic subunit Polγ α has both DNA polymerase and exonuclease activities that are required for high-fidelity mtDNA replication. A precise cooperation of the two activities of Polγ during mtDNA replication is therefore critical to ensure proper mtDNA integrity. In our study, we investigated the mechanism by which the pathogenic mutation Y951N induces replication stalling and a loss of mtDNA in patient cells. Our findings showed that the Y951N mutation in the polymerase domain disrupts Polγ’s ability to switch between its polymerase and exonuclease activities, leading to severe mtDNA replication stalling and eventually mtDNA depletion. Identifying Polγ residues critical for this intramolecular switching mechanism provides insights into how various pathogenic mutations affect the maintenance of the mitochondrial genome. 

In response to mitochondrial dysfunction that alters the cellular energy state, particularly in the context of mitochondrial DNA depletion, AMP-activated protein kinase (AMPK), a key energy sensor and metabolic regulator can be activated to restore energy homeostasis. However, the degree of severity of mitochondrial dysfunction required to induce AMPK activation, as well as how mitochondrial biogenesis can be restored following stimulation of AMPK activity, remains to be elucidated. To address this, we used a cell model of mtDNA depletion syndromes (MDS) in which the expression of a pathogenic Polγ variant causes severe mtDNA loss, leading to progressive mitochondrial dysfunction. We observed that the activation of mitochondria-associated AMPK occurs during the early stages of advancing mitochondrial dysfunction. Moreover, our results showed that stimulation of AMPK activity using a specific agonist, A-769662, can mitigate impaired mitochondrial phenotypes and partially restore mtDNA levels. These findings contribute to our understanding of the impacts of specific activators of AMPK on mitochondrial and cellular function as well as their potential applications in mitochondrial diseases. 

In addition to defects in nuclear genes involved in mtDNA replication, mutations in the mitochondrial genome that arise from errors during mtDNA replication or from repair of damaged mtDNA can also result in a loss of mitochondrial genetic integrity, e.g. due to an accumulation of large-scale mtDNA deletions. Many of these mtDNA deletion breakpoints were recently suggested to occur at sequence motifs with potential to form secondary DNA structures, G-quadruplexes (G4s). In our study, by developing a novel tool for mapping G4s in living cells, we were able to determine mtDNA G4 formation in human cells under different cellular conditions. Our results indicated that replication stalling enhances G4 formation, which in turn blocks the replication fork progression and causes mtDNA loss, potentially leading to mitochondrial disease. The new mtG4-ChiP tool will enable future research to further investigate the factors involved in G4 formation and resolution, as well as the mechanistic roles of G4s in the generation of pathogenic mtDNA deletions. 

In parallel with studying mechanisms of mtDNA deletions and depletion, we investigated how cells tolerate mitochondrial genome damage to preserve mtDNA integrity. PrimPol, a primase–polymerase that can restart stalled mtDNA replication, requires stimulation by Polymerase δ–interacting protein 2 (PolDIP2) for efficient DNA synthesis. While characterizing this interaction, we unexpectedly found that PolDIP2 forms disulfide-linked homodimers, a process that is enhanced under oxidative stress. Notably, PolDIP2 interacts with coiled-coil-helix-coiled-coil-helix domain–containing protein 2 (CHCHD2), a mitochondrial protein implicated in maintaining cristae structure and dynamics. Our findings suggest that redox-sensitive PolDIP2 dimerization may influence mitochondrial function by modulating its interaction with CHCHD2 during oxidative stress. 

In summary, the findings presented here provided valuable insights into molecular mechanisms of mitochondrial genome instability caused by pathogenic mutations and cellular responses to mitochondrial dysfunctions, as well as the involvement of potential factors in mitochondrial DNA maintenance. 

This thesis investigates the meanings and uses of Russian converbs, with particular focus on resultant state meanings and teleological relations between converbs and matrix predicates. The study adopts a contrastive, corpus-based approach, using Swedish prepositional constructions as search cues to identify corresponding meanings expressed by converbs in Russian.

The analysis is grounded in Boguslavskij’s (1977) distinction between ‘manner adverbials’, which are interpreted within the temporal domain of the matrix predicate, and ‘temporal adverbials’, which introduce a temporal domain for the matrix. This distinction is compared, where relevant, with Klein’s (1994) notion of ‘topic time’.

The first part of the thesis examines converbs expressing ‘resultant states’. It is shown that these usages function as ‘depictives’ in the sense of Schultze-Berndt and Himmelmann (2005), patterning with predicatively used comitatives and participles and denoting temporary properties with continuous relevance to the subject. These constructions are analysed as manner-type adverbials: the converb does not introduce its own temporal domain but is interpreted using the time of the matrix predicate. Such readings are favoured by intransitive configurations and by constructions that establish reference to the subject’s body, including inalienable body parts and functionally equivalent items.

The second part of the thesis analyses converbs involved in a teleological division of labour between means and end (‘instrumental action’ and ‘purpose’). It is argued that these relations fall within the domain of ‘complementary coincidence’ (Růžička 1980). Instrumental converb constructions are shown to vary with respect to temporal interpretation: some behave like manner adverbials, specifying the method by which an action is carried out, while others pattern more closely with temporal adverbials by providing a correlate for an evaluative or interpretative judgment expressed by the matrix predicate.

The interpretation as either ‘means’ (method/effective factor) or ‘end’ (purpose/consequence) depends on the relative method-neutrality of either the converb or the matrix predicate. This also accounts for the observed convertibility between ‘means’ and ‘end’ interpretations in translation.

Overall, the thesis provides new corpus-based evidence for previously underdescribed converb constructions in Russian and proposes constructional generalisations that integrate semantic, temporal, and teleological dimensions of converb meaning.