Locally Learning Biomedical Data Using Diffusion Frames

Diffusion geometry techniques are useful to classify patterns and visualize high-dimensional datasets. Building upon ideas from diffusion geometry, we outline our mathematical foundations for learning a function on high-dimension biomedical data in a local fashion from training data. Our approach is based on a localized summation kernel, and we verify the computational performance by means of exact approximation rates. After these theoretical results, we apply our scheme to learn early disease stages in standard and new biomedical datasets

Effect of a contact lens on mouse retinal in vivo imaging: Effective focal length changes and monochromatic aberrations

For in vivo mouse retinal imaging, especially with Adaptive Optics instruments, application of a contact lens is desirable, as it allows maintenance of cornea hydration and helps to prevent cataract formation during lengthy imaging sessions. However, since the refractive elements of the eye (cornea and lens) serve as the objective for most in vivo retinal imaging systems, the use of a contact lens, even with 0 Dpt. refractive power, can alter the system's optical properties. In this investigation we examined the effective focal length change and the aberrations that arise from use of a contact lens. First, focal length changes were simulated with a Zemax mouse eye model. Then ocular aberrations with and without a 0 Dpt. contact lens were measured with a Shack-Hartmann wavefront sensor (SHWS) in a customized AO-SLO system. Total RMS wavefront errors were measured for two groups of mice (14-month, and 2.5-month-old), decomposed into 66 Zernike aberration terms, and compared. These data revealed that vertical coma and spherical aberrations were increased with use of a contact lens in our system. Based on the ocular wavefront data we evaluated the effect of the contact lens on the imaging system performance as a function of the pupil size. Both RMS error and Strehl ratios were quantified for the two groups of mice, with and without contact lenses, and for different input beam sizes. These results provide information for determining optimum pupil size for retinal imaging without adaptive optics, and raise critical issues for design of mouse optical imaging systems that incorporate contact lenses

Pattern Formation and Organization of Epithelial Tissues

Developmental biology is a study of how elaborate patterns, shapes, and functions emerge as an organism grows and develops its body plan. From the physics point of view this is very much a self-organization process. The genetic blueprint contained in the DNA does not explicitly encode shapes and patterns an animal ought to make as it develops from an embryo. Instead, the DNA encodes various proteins which, among other roles, specify how different cells function and interact with each other. Epithelial tissues, from which many organs are sculpted, serve as experimentally- and analytically-tractable systems to study patterning mechanisms in animal development. Despite extensive studies in the past decade, the mechanisms that shape epithelial tissues into functioning organs remain incompletely understood. This thesis summarizes various studies we have done on epithelial organization and patterning, both in abstract theory and in close contact with experiments. A novel mechanism to establish cellular left-right asymmetry based on planar polarity instabilities is discussed. Tissue chirality is often assumed to originate from handedness of biological molecules. Here we propose an alternative where it results from spontaneous symmetry breaking of planar polarity mechanisms. We show that planar cell polarity (PCP), a class of well-studied mechanisms that allows epithelia to spontaneously break rotational symmetry, is also generically capable of spontaneously breaking reflection symmetry. Our results provide a clear interpretation of many mutant phenotypes, especially those that result in incomplete inversion. To bridge theory and experiments, we develop quantitative methods to analyze fluorescence microscopy images. Included in this thesis are algorithms to selectively project intensities from a surface in z-stack images, analysis of cells forming short chain fragments, analysis of thick fluorescent bands using steerable ridge detector, and analysis of cell recoil in laser ablation experiments. These techniques, though developed in the context of zebrafish retina mosaic, are general and can be adapted to other systems. Finally we explore correlated noise in morphogenesis of fly pupa notum. Here we report unexpected correlation of noise in cell movements between left and right halves of developing notum, suggesting that feedback or other mechanisms might be present to counteract stochastic noise and maintain left-right symmetry.PHDPhysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/138800/1/hjeremy_1.pd

TOWARDS A COMPUTATIONAL MODEL OF RETINAL STRUCTURE AND BEHAVIOR

Human vision is our most important sensory system, allowing us to perceive our surroundings. It is an extremely complex process that starts with light entering the eye and ends inside of the brain, with most of its mechanisms still to be explained. When we observe a scene, the optics of the eye focus an image on the retina, where light signals are processed and sent all the way to the visual cortex of the brain, enabling our visual sensation. The progress of retinal research, especially on the topography of photoreceptors, is often tied to the progress of retinal imaging systems. The latest adaptive optics techniques have been essential for the study of the photoreceptors and their spatial characteristics, leading to discoveries that challenge the existing theories on color sensation. The organization of the retina is associated with various perceptive phenomena, some of them are straightforward and strictly related to visual performance like visual acuity or contrast sensitivity, but some of them are more difficult to analyze and test and can be related to the submosaics of the three classes of cone photoreceptors, like how the huge interpersonal differences between the ratio of different cone classes result in negligible differences in color sensation, suggesting the presence of compensation mechanisms in some stage of the visual system. In this dissertation will be discussed and addressed issues regarding the spatial organization of the photoreceptors in the human retina. A computational model has been developed, organized into a modular pipeline of extensible methods each simulating a different stage of visual processing. It does so by creating a model of spatial distribution of cones inside of a retina, then applying descriptive statistics for each photoreceptor to contribute to the creation of a graphical representation, based on a behavioral model that determines the absorption of photoreceptors. These apparent color stimuli are reconstructed in a representation of the observed scene. The model allows the testing of different parameters regulating the photoreceptor's topography, in order to formulate hypothesis on the perceptual differences arising from variations in spatial organization

Molecular Photochemistry

There have been various comprehensive and stand-alone text books on the introduction to Molecular Photochemistry which provide crystal clear concepts on fundamental issues. This book entitled "Molecular Photochemistry - Various Aspects" presents various advanced topics that inherently utilizes those core concepts/techniques to various advanced fields of photochemistry and are generally not available. The purpose of publication of this book is actually an effort to bring many such important topics clubbed together. The goal of this book is to familiarize both research scholars and post graduate students with recent advancement in various fields related to Photochemistry. The book is broadly divided in five parts: the photochemistry I) in solution, II) of metal oxides, III) in biology, IV) the computational aspects and V) applications. Each part provides unique aspect of photochemistry. These exciting chapters clearly indicate that the future of photochemistry like in any other burgeoning field is more exciting than the past

Complexity in Developmental Systems: Toward an Integrated Understanding of Organ Formation

During animal development, embryonic cells assemble into intricately structured organs by working together in organized groups capable of implementing tightly coordinated collective behaviors, including patterning, morphogenesis and migration. Although many of the molecular components and basic mechanisms underlying such collective phenomena are known, the complexity emerging from their interplay still represents a major challenge for developmental biology. Here, we first clarify the nature of this challenge and outline three key strategies for addressing it: precision perturbation, synthetic developmental biology, and data-driven inference. We then present the results of our effort to develop a set of tools rooted in two of these strategies and to apply them to uncover new mechanisms and principles underlying the coordination of collective cell behaviors during organogenesis, using the zebrafish posterior lateral line primordium as a model system. To enable precision perturbation of migration and morphogenesis, we sought to adapt optogenetic tools to control chemokine and actin signaling. This endeavor proved far from trivial and we were ultimately unable to derive functional optogenetic constructs. However, our work toward this goal led to a useful new way of perturbing cortical contractility, which in turn revealed a potential role for cell surface tension in lateral line organogenesis. Independently, we hypothesized that the lateral line primordium might employ plithotaxis to coordinate organ formation with collective migration. We tested this hypothesis using a novel optical tool that allows targeted arrest of cell migration, finding that contrary to previous assumptions plithotaxis does not substantially contribute to primordium guidance. Finally, we developed a computational framework for automated single-cell segmentation, latent feature extraction and quantitative analysis of cellular architecture. We identified the key factors defining shape heterogeneity across primordium cells and went on to use this shape space as a reference for mapping the results of multiple experiments into a quantitative atlas of primordium cell architecture. We also propose a number of data-driven approaches to help bridge the gap from big data to mechanistic models. Overall, this study presents several conceptual and methodological advances toward an integrated understanding of complex multi-cellular systems

A systems biology approach to axis formation during early zebrafish embryogenesis: from biophysical measurements to model inference

During early embryogenesis, secreted proteins dictate the body plan of developing individuals. The resulting patterns are thought to be imposed by a graded distribution of molecular signals. To this day, it is not fully understood how signaling gradients are formed, maintained and adjusted to body sizes of differently sized individuals. This dissertation aims to provide new insights into the biophysical underpinnings of signal molecule gradients of early embryonic patterning and propose novel mechanisms that allow for scale-invariant patterning. Two of the most important parameters controlling the range and shape of signaling gradients are the rate at which signaling molecules decay and diffuse. Despite their importance, such biophysical parameters have not been measured or have only been assessed under simplified assumptions or contexts for most developmental systems. In this dissertation I present two assays and specialized software packages that allow the assessment of these parameters in living zebrafish embryos. I then demonstrate how these tools can be used to answer long-standing questions in early embryogenesis, such as how the dorsal-ventral axis is formed. This thesis provides evidence suggesting, in contrast to current hypotheses, that the dorsal-ventral axis is formed by a simple source-sink mechanism. Moreover, I show how to use mathematical modeling equipped with parameters estimated from the biophysical measurements to describe scale-invariant patterning during germ layer patterning in zebrafish development. My model, together with a rigorous multidimensional parameter screen fitted in normal and articially size-reduced embryos, was able to identify a new mechanism that allows for scaling of the germ layers in differently-sized embryos with realistic parameter congurations. In summary, this dissertation outlines how a systems biology approach can play a crucial role to advance the understanding of classical open questions in developmental biology