A Governance Perspective for System-of-Systems

The operating landscape of 21st century systems is characteristically ambiguous, emergent, and uncertain. These characteristics affect the capacity and performance of engineered systems/enterprises. In response, there are increasing calls for multidisciplinary approaches capable of confronting increasingly ambiguous, emergent, and uncertain systems. System of Systems Engineering (SoSE) is an example of such an approach. A key aspect of SoSE is the coordination and the integration of systems to enable ‘system-of-systems’ capabilities greater than the sum of the capabilities of the constituent systems. However, there is a lack of qualitative studies exploring how coordination and integration are achieved. The objective of this research is to revisit SoSE utility as a potential multidisciplinary approach and to suggest ‘governance’ as the basis for enabling ‘system-of-systems’ coordination and integration. In this case, ‘governance’ is concerned with direction, oversight, and accountability of ‘system-of-systems.’ ‘Complex System Governance’ is a new and novel basis for improving ‘system-of-system’ performance through purposeful design, execution, and evolution of essential metasystem functions.

mHealth hyperspectral learning for instantaneous spatiospectral imaging of hemodynamics

Hyperspectral imaging acquires data in both the spatial and frequency domains to offer abundant physical or biological information. However, conventional hyperspectral imaging has intrinsic limitations of bulky instruments, slow data acquisition rate, and spatiospectral tradeoff. Here we introduce hyperspectral learning for snapshot hyperspectral imaging in which sampled hyperspectral data in a small subarea are incorporated into a learning algorithm to recover the hypercube. Hyperspectral learning exploits the idea that a photograph is more than merely a picture and contains detailed spectral information. A small sampling of hyperspectral data enables spectrally informed learning to recover a hypercube from an RGB image. Hyperspectral learning is capable of recovering full spectroscopic resolution in the hypercube, comparable to high spectral resolutions of scientific spectrometers. Hyperspectral learning also enables ultrafast dynamic imaging, leveraging ultraslow video recording in an off-the-shelf smartphone, given that a video comprises a time series of multiple RGB images. To demonstrate its versatility, an experimental model of vascular development is used to extract hemodynamic parameters via statistical and deep-learning approaches. Subsequently, the hemodynamics of peripheral microcirculation is assessed at an ultrafast temporal resolution up to a millisecond, using a conventional smartphone camera. This spectrally informed learning method is analogous to compressed sensing; however, it further allows for reliable hypercube recovery and key feature extractions with a transparent learning algorithm. This learning-powered snapshot hyperspectral imaging method yields high spectral and temporal resolutions and eliminates the spatiospectral tradeoff, offering simple hardware requirements and potential applications of various machine-learning techniques.Comment: This paper will appear in PNAS Nexu

Reframing systems integration: a process perspective on projects

The delivery of large-scale technical systems is achieved through project organizing. The concept of systems integration, with its distinct focus on the systems that projects deliver, is theoretically important as projects become more complex and face significant uncertainty. We reframe systems integration in interorganizational projects as a flexible and adaptive process of making constituent parts of systems work together. This process involves boundary-spanning structures and activities to address emergent complexity and uncertainty (that are both technological and organizational in nature). We discuss implications and highlight areas for further research on projects

Complex System Governance as a Framework for Asset Management

Complex system governance (CSG) is an emerging field encompassing a framework for system performance improvement through the purposeful design, execution, and evolution of essential metasystem functions. The goal of this study was to understand how the domain of asset management (AsM) can leverage the capabilities of CSG. AsM emerged from engineering as a structured approach to organizing complex organizations to realize the value of assets while balancing performance, risks, costs, and other opportunities. However, there remains a scarcity of literature discussing the potential relationship between AsM and CSG. To initiate the closure of this gap, this research reviews the basics of AsM and the methods associated with realizing the value of assets. Then, the basics of CSG are provided along with how CSG might be leveraged to support AsM. We conclude the research with the implications for AsM and suggested future research

Parameterizing the Spillage Left Behind: Datafication, Machine Learning Algorithms, and the Question of Ecological Agency

With “datafication” practices becoming more common in digital ecologies, humans have become increasingly reliant on emerging technologies and other actors that can store, comprehend, and analyze information. This thesis offers a proposed model of mediative agency to address the importance of interrogating how non-human actors interpret and make meaning from data. Mediative agents contribute to the disbursement of rhetoric, as well as our understanding of information, by granting visibility and assigning value to data. These processes effectively play a role in shaping reality through agents’ parameterization of data broadly, allowing non-human actors to take on a complex agency that can alter rhetorical trajectories. In interrogating the structures of power that contribute to the dissemination of rhetoric within digital ecologies, mediative agency acts as a speculative modeling approach that allows rhetors to theorize various functions of agency and anticipate how non-human agency might further develop as technological environments change in the immediate future

From human genetics to radiobiology : in vitro radiosensitivity in individuals with a germline defect in DNA damage response genes

All currently known high to intermediate risk “breast cancer genes”, including BRCA1 and BRCA2, are involved in the DNA damage response pathway. Heterozygous germline mutations in these genes predispose to breast and ovarian cancer. In addition, such mutations may also result in enhanced radiosensitivity mediated by chromosomal instability after exposure to ionizing radiation, leading to a higher risk to develop radiation-induced breast cancer. However, results of currently available clinical studies evaluating carcinogenesis and in vitro studies comparing chromosomal radiosensitivity in mutation carriers and non-carriers are inconclusive. Nevertheless, insights into the radiosensitive phenotype of healthy tissues of mutation carriers is of the utmost importance for the safe use of ionizing radiation for diagnostic purposes or radiotherapy treatment. In this thesis, we evaluated in vitro radiosensitivity in carriers of a mutation in DNA damage response genes by means of two different assays. The first assay, the G2 micronucleus assay, is a cytogenetic assay in which MN are analyzed in cells irradiated in the G2 phase of the cell cycle. This assay was developed to evaluate radiosensitivity in cells with a heterozygous BRCA1 or BRCA2 mutation. BRCA1 and BRCA2 have a function in homologous recombination (HR), the main DNA double strand break repair pathway activated in late S and G2 phase of the cell cycle. Furthermore, BRCA1 is also involved in the G2/M cell cycle checkpoint. The G2 micronucleus assay allows evaluation of both functions by means of two distinct endpoints: (1) the radiation-induced micronucleus yield, which reflects DNA double strand break repair capacity and (2) the G2/M checkpoint efficiency ratio, which allows evaluation of the G2 arrest capacity. Before applying the G2 micronucleus assay on BRCA mutation carriers, the assay was validated in a patient with Ataxia Telangiectasia (AT). AT patients are characterized by a manifest increased radiosensitivity. AT patients show biallelic inactivation of ATM, involved in both DNA double strand break repair by means of HR and G2/M checkpoint activation. We demonstrated a severely increased radiosensitivity with both endpoints when applying the G2 micronucleus assay in lymphocytes of this AT patient. In lymphocytes of healthy relatives with a heterozygous ATM mutation the radiosensitivity observed with this assay was intermediate between the AT patient and the control cohort. When applying the G2 micronucleus assay on lymphocytes of healthy BRCA1/2 mutation carriers, we demonstrated significantly enhanced radiation-induced MN yields in both BRCA1 and BRCA2 germline mutation carriers, pointing to an impaired DNA double strand break repair capacity in both groups. Furthermore, an impaired G2 arrest capacity was observed in BRCA1 mutation carriers. In healthy relatives who did not inherit the familial mutation, no enhanced radiosensitivity was observed. Although a significantly enhanced radiosensitivity was demonstrated for the cohort of BRCA1 and BRCA2 mutation carriers compared to the control cohort, individual radiosensitivity evaluation was less straightforward due to overlap in micronucleus yields between both cohorts. Therefore, a scoring system to evaluate individual radiosensitivity was implemented. As both BRCA1 and BRCA2 are involved in HR, we evaluated if the accumulation of RAD51, a key protein involved in this pathway, at the double strand break site can be used to assess HR functionality and radiosensitivity. To this end, a radiation-induced RAD51 foci assay was optimized in a breast epithelial cell line (MCF10A) expressing ±50% reduced BRCA1 and BRCA2 protein levels, obtained by RNA interference. RAD51 foci were analyzed in cells synchronized in S phase by aphidicolin as HR is upregulated during this phase of the cell cycle. We demonstrated significantly reduced RAD51 foci formation, and thus impaired HR capacity, in response to the induction of radiation-induced double strand breaks in the BRCA knockdown cells compared to control cells. As no overlap in RAD51 foci distribution is observed between knockdown and control cells, we think that this assay could better differentiate between normal cells and cells with a heterozygous BRCA1 or BRCA2 mutation than the G2 micronucleus assay. This will be further explored in synchronized lymphocytes of heterozygous germline mutation carriers. In addition to the detection of unequivocal deleterious mutations in BRCA1 and BRCA2, variants of unknown clinical significance (VUS) are detected during diagnostic screening. The associated breast cancer risk is unknown, which creates a challenge for genetic counselling. mRNA analysis to assess variants that might impair proper RNA splicing, a highly regulated process, are widely used. We evaluated the outcome at cDNA level of 21 putative splicing variants in BRCA1 and BRCA2 and demonstrated aberrant splicing for 12 variants, suggesting that these are likely pathogenic. Furthermore, we demonstrated that in silico prediction tools might assist in the evaluation of these putative splicing variants. However, further optimization is warranted to allow reliable application outside the highly conserved consensus splice sites. The results obtained in this thesis may indicate that care should be taken when applying ionizing radiation for diagnostic or therapeutic purposes in individuals with a germline mutation in BRCA1 or BRCA2 as they may be at higher risk of developing radiation-induced breast cancer

Characterising Chinese Hamster Ovary Cell Line Stability in Bioproduction of Therapeutic Proteins

No abstract

System Governance Analysis of Complex Systems

The purpose of this research was to develop and deploy a systems-based framework for analysis of complex governance systems using a multimethodology research design. Two research gaps motivated this research: (1) lack of an integrated conceptualization of a system governance construct, (2) an absence of studies that consider both the governed and governing systems as well as the emergent interactions that arise from within complex governance systems. The research focused on three primary questions: (1) What are the distinctive characteristics of governance?; (2) What system-based framework can be developed for analysis of governance in complex systems?, and (3) What results from deployment of the framework in a field setting? The multimethodology research design that guided the effort included three primary phases. First, the literature was synthesized to derive a set of governance elements. This synthesis was accomplished across an extensive and multidisciplinary literature set by a novel method of content document clustering analysis to reveal important elements of governance. Second, a conceptual framework for analysis of system governance was constructed from the confluence of extant governance literature and systems theory. This governance system analysis framework was informed by Bunge\u27s (2003) system perspective to advance the understanding of governance that will be meaningful in a given practice. Finally, a case based application of the analysis framework was conducted to examine implications of the framework from a field perspective. The original research provided contributions to theory, methodology, and practice. From a theoretical perspective, the research contributed to the body of knowledge by providing: (1) a literature derived set of generalizable elements of governance, and (2) the development of a systems-based framework to be used to analyze complex governance systems. From a methodological stand-point, the research advanced an integrated multimethodology research design that featured: (1) a novel content analysis approach for synthesis of diverse literature; (2) the development of an integrated systems analysis method; and (3) a rigorous single-case study application within the engineering management discipline. Lastly, from a practical perspective, the systems framework provided a foundation for derivative approaches to enhance practices related to system governance