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Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
Handheld, portable confocal laser endomicroscopy (CLE) is being explored in neurosurgery for its ability to image histopathological features of tissue at cellular resolution in real time during brain tumor surgery. Over the course of examination of the surgical tumor resection, hundreds to thousands of images may be collected. The high number of images requires significant time and storage load for subsequent reviewing, which motivated several research groups to employ deep convolutional neural networks (DCNNs) to improve its utility during surgery. DCNNs have proven to be useful in natural and medical image analysis tasks such as classification, object detection, and image segmentation.
This thesis proposes using DCNNs for analyzing CLE images of brain tumors. Particularly, it explores the practicality of DCNNs in three main tasks. First, off-the shelf DCNNs were used to classify images into diagnostic and non-diagnostic. Further experiments showed that both ensemble modeling and transfer learning improved the classifier’s accuracy in evaluating the diagnostic quality of new images at test stage. Second, a weakly-supervised learning pipeline was developed for localizing key features of diagnostic CLE images from gliomas. Third, image style transfer was used to improve the diagnostic quality of CLE images from glioma tumors by transforming the histology patterns in CLE images of fluorescein sodium-stained tissue into the ones in conventional hematoxylin and eosin-stained tissue slides.
These studies suggest that DCNNs are opted for analysis of CLE images. They may assist surgeons in sorting out the non-diagnostic images, highlighting the key regions and enhancing their appearance through pattern transformation in real time. With recent advances in deep learning such as generative adversarial networks and semi-supervised learning, new research directions need to be followed to discover more promises of DCNNs in CLE image analysis.
This thesis scrutinizes CLE technology for its ability to provide real-time intraoperative in vivo and ex vivo visualization of histopathological features of the normal and tumor brain tissues. First, the optimal settings for CLE imaging are studied in an animal model along with a generational comparison of CLE performance. Second, the ability of CLE to discriminate uninjured normal brain, injured normal brain and tumor tissues is demonstrated. Third, CLE was used to investigate cerebral microvasculature and blood flow in normal and pathological conditions. Fourth, the feasibility of CLE for providing optical biopsies of brain tumors was established during the fluorescence-guided neurosurgical procedures. This study established the optimal workflow and confirmed the high specificity of the CLE optical biopsies. Fifth, the feasibility of CLE was established for endoscopic endonasal approaches and interrogation of pituitary tumor tissue. Finally, improved and prolonged near wide-field fluorescent visualization of brain tumor margins was demonstrated with a scanning fiber endoscopy and 5-aminolevulinic acid.
These studies suggested a novel paradigm for neurosurgery-pathology workflow when the noninvasive intraoperative optical biopsies are used to interrogate the tissue and augment intraoperative decision making. Such optical biopsies could shorten the time for obtaining preliminary information on the histological composition of the tissue of interest and may lead to improved diagnostics and tumor resection. This work establishes a basis for future in vivo optical biopsy use in neurosurgery and planning of patient-related outcome studies. Future studies would lead to refinement and development of new confocal scanning technologies making noninvasive optical biopsy faster, convenient and more accurate.
Domestic dogs have assisted humans for millennia. However, the extent to which these helpful behaviors are prosocially motivated remains unclear. To assess the propensity of pet dogs to spontaneously and actively rescue distressed humans, this study tested whether sixty pet dogs would release their seemingly trapped owners from a large box. To examine the causal mechanisms that shaped this behavior, the readiness of each dog to open the box was tested in three conditions: 1) the owner sat in the box and called for help (“Distress” test), 2) an experimenter placed high-value food rewards in the box (“Food” test), and 3) the owner sat in the box and calmly read aloud (“Reading” test).
Dogs were as likely to release their distressed owner as to retrieve treats from inside the box, indicating that rescuing an owner may be a highly rewarding action for dogs. After accounting for ability, dogs released the owner more often when the owner called for help than when the owner read aloud calmly. In addition, opening latencies decreased with test number in the Distress test but not the Reading test. Thus, rescuing the owner could not be attributed solely to social facilitation, stimulus enhancement, or social contact-seeking behavior.
Dogs displayed more stress behaviors in the Distress test than in the Reading test, and stress scores decreased with test number in the Reading test but not in the Distress test. This evidence of emotional contagion supports the hypothesis that rescuing the distressed owner was an empathetically-motivated prosocial behavior. Success in the Food task and previous (in-home) experience opening objects were both strong predictors of releasing the owner. Thus, prosocial behavior tests for dogs should control for physical ability and previous experience.
The phenomenon of Fano resonance is ubiquitous in a large variety of wave scattering systems, where the resonance profile is typically asymmetric. Whether the parameter characterizing the asymmetry should be complex or real is an issue of great experimental interest. Using coherent quantum transport as a paradigm and taking into account of the collective contribution from all available scattering channels, we derive a universal formula for the Fano-resonance profile. We show that our formula bridges naturally the traditional Fano formulas with complex and real asymmetry parameters, indicating that the two types of formulas are fundamentally equivalent (except for an offset). The connection also reveals a clear footprint for the conductance resonance during a dephasing process. Therefore, the emergence of complex asymmetric parameter when fitting with experimental data needs to be properly interpreted. Furthermore, we have provided a theory for the width of the resonance, which relates explicitly the width to the degree of localization of the close-by eigenstates and the corresponding coupling matrices or the self-energies caused by the leads. Our work not only resolves the issue about the nature of the asymmetry parameter, but also provides deeper physical insights into the origin of Fano resonance. Since the only assumption in our treatment is that the transport can be described by the Green’s function formalism, our results are also valid for broad disciplines including scattering problems of electromagnetic waves, acoustics, and seismology.
Persistent currents (PCs), one of the most intriguing manifestations of the Aharonov-Bohm (AB) effect, are known to vanish for Schrödinger particles in the presence of random scatterings, e.g., due to classical chaos. But would this still be the case for Dirac fermions? Addressing this question is of significant value due to the tremendous recent interest in two-dimensional Dirac materials. We investigate relativistic quantum AB rings threaded by a magnetic flux and find that PCs are extremely robust. Even for highly asymmetric rings that host fully developed classical chaos, the amplitudes of PCs are of the same order of magnitude as those for integrable rings, henceforth the term superpersistent currents (SPCs). A striking finding is that the SPCs can be attributed to a robust type of relativistic quantum states, i.e., Dirac whispering gallery modes (WGMs) that carry large angular momenta and travel along the boundaries. We propose an experimental scheme using topological insulators to observe and characterize Dirac WGMs and SPCs, and speculate that these features can potentially be the base for a new class of relativistic qubit systems. Our discovery of WGMs in relativistic quantum systems is remarkable because, although WGMs are common in photonic systems, they are relatively rare in electronic systems.