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Coming dissertations at Uppsala university

  • Volterra Modeling and Estimation of the Human Smooth Pursuit Author: Viktor Bro Link: Publication date: 2022-01-13 08:49

    This thesis treats the mathematical modeling of the human smooth pursuit system using Volterra-Laguerre models. The smooth pursuit system allows for tracking of moving objects. Since it is a complex system including the muscles of the eye, nerves and certain parts of the brain, the system may be impaired if some part is compromised.

    Eye tracking involves tracking the point of the gaze. When recorded, such coordinates may be used for mathematical modeling of the system controlling the gaze. Volterra models allow for modeling of smooth nonlinear dynamical systems, such as the smooth pursuit system. The input of the system is the position of the tracked object and the output of the system is the point of the gaze. The problem of overparametriztion in Volterra models may be alleviated by expansion of the kernels in some orthonormal basis. Choosing this basis as the set of Laguerre functions yields a Volterra-Laguerre model.

    This thesis expands on the development of Volterra-Laguerre models for modeling of smooth pursuit in several ways. An approach for finding a minimal model structure using sparse estimation is studied. This allows for a parsimonious but not necessarily low order model. Furthermore the Volterra-Laguerre model is augmented with a delay parameter. Using this, the delay which would otherwise be expressed in the coefficients of the model, is made explicit. The methods proposed are studied both in simulated examples as well as using real eye tracking data from patients with Parkinson's disease and from healthy control subjects.

  • Time of Turmoil : Reading and Media Combination in the American Young Adult Novels Cathy’s Book, Skeleton Creek, and Endgame Author: Julie Blomberg Gudmundsson Link: Publication date: 2022-01-12 10:54

    In the beginning of the twenty-first century, Young Adult (YA) fiction experienced a renaissance, and YA novels began to appear on the best-seller lists in the US. Around the same time, many reports sounded alarms about rapidly declining rates of fiction reading among young adults. Often, such alarms identified an increased usage of the Internet in various forms as a possible culprit. In an attempt both to retain interest in YA fiction and to capitalize on the growing Internet usage among teens, many writers began to experiment with novel forms of storytelling that combined print fiction with other media. This study focuses on three such American YA novels to show a spectrum of experimental endeavors: Cathy’s Book: If Found Call (650) 266-8233 (2006), Skeleton Creek: Ryan’s Journal (2009), and Endgame: The Calling (2014). The novels are analyzed for their ways of combining media and forging specific “reading paths” through what I call nudges – the implicit and explicit instructions to the reader. In all three novels, reading is characterized by interruptions as the reader is asked to shift between media to access parts of the story and (re)construct the plot. This interrupted reading, I claim, has the function of drawing attention to the medium of storytelling. Therefore, media consciousness becomes a significant part of reading and this, I claim, supplements what Jonathan Culler has named “literary competence.” My study continues the revision of Culler’s understanding of literary competence that Maria Nikolajeva has undertaken for children’s literature. In particular, I draw on Nikolajeva’s set of interpretative codes and expand them for reading multimedia novels.

    In the introduction of the dissertation, I situate the three novels that I analyze within the context of YA fiction and teen reading and present the key frameworks for my analysis: media studies and theories of reading. In my first analytical chapter, focusing on Cathy’s Book, I explore how media combination promotes a reading based on ordering and detection. I further explore how media combination requires readers to critically assess each medium’s authenticity, concluding that source criticism and media consciousness are central competences promoted by the book. In the second analytical chapter, I explore how print and videos are “stitched” together in Skeleton Creek: Ryan’s Journal; this “stitching” of the media results in a “seamfull” reading process, the seams drawing attention to the semiotic significance of the medium of storytelling. Studying Endgame: The Calling in the last analytical chapter, I investigate what shape the reading process takes when the fictional work mimics games, and the print book itself contains a game. Endgame, I show, promotes “gamified reading” whose logic leads to the physical destruction of the print book. In the concluding chapter, I reflect on the significance of expanding Culler’s concept of literary competence in conjunction with how multimedia novels make use of metalepsis to raise concerns and queries about the distinction between ontological realms and the boundaries of the novel. Lastly, I consider some paths forward for research on reading and multimedia fiction.

  • Searching for Synergy : Radiosensitization of 177Lu-DOTATATE Author: Sara Lundsten Link: Publication date: 2022-01-10 09:20

    Cancers presents a major health challenge, and there is a pressing need to develop new therapeutic strategies. Surgery, chemotherapy and radiation are the most commonly used treatments for cancer today. Radiation can be given as targeted radionuclide therapy (TRT), i.e., systemic administration of a radiolabeled cancer-targeting molecule. This is especially suitable for inoperable and disseminated tumors.

    177Lu-DOTATATE, a TRT directed against the somatostatin receptors (SSTRs), was recently approved for therapy of a subset of neuroendocrine tumors (NETs). Although it has prolonged the life of NET patients, complete remission is seldom achieved. Consequently, to increase the efficacy of the treatment, this thesis aimed to assess potential radiosensitizing strategies for 177Lu-DOTATATE. The two radiosensitization targets in focus were HSP90, a chaperone protein with numerous oncogenic client proteins, and p53, a central regulator of DNA damage.

    In papers I and II, we investigated the HSP90-inhibitor Onalespib, as a treatment for NETs, and as a potential radiosensitizer. The drugs were assessed in vitro and in vivo. We concluded that Onalespib reduced NET cell growth and acted synergistically with 177Lu-DOTATATE. Inhibition of EGFR, a HSP90 client protein, was suggested as a mediator of the observed synergy. Furthermore, the combination had a favorable toxicity profile. 

    In paper III, we assessed the novel stapled peptide VIP116, which inhibits the p53 repressors MDM2 and MDM4, as a potentiator of 177Lu-DOTATATE in wildtype p53 neuroblastoma cells. Combination therapy exhibited growth-inhibitory effects, with resulting additive or synergistic effects. The treatment-mediated effects on p53 signaling were characterized, revealing a possible involvement of V-myc myelocytomatosis viral oncogene homolog, neuroblastoma derived (MYCN), a prognostic marker for poor survival in neuroblastoma.

    In paper IV, we aimed to improve targeted delivery of VIP116, with the use of lipid bilayer disks (lipodisks). VIP116 was successfully loaded onto epidermal growth factor receptor (EGFR)-targeting lipodisks, leading to specific delivery and reduction of viability of EGFR expressing tumor cells. The study provided a proof-of-concept for utilizing lipodisks as a drug delivery system for p53-stabilizing peptides.

    In conclusion, we have investigated, and found, suitable candidates for potentiating 177Lu-DOTATATE therapy. We have addressed the feasibility of the treatments, toxicity and targeted delivery. Moreover, the work has explored the biology of TRT. This is an area in need of more attention, as more and more radionuclide-based therapies are entering clinicals trials and reaching approval.