IST Austria Thesis

Transcription factors, by binding to specific sequences on the DNA, control the precise spatio-temporal expression of genes inside a cell. However, this specificity is limited, leading to frequent incorrect binding of transcription factors that might have deleterious consequences on the cell. By constructing a biophysical model of TF-DNA binding in the context of gene regulation, I will first explore how regulatory constraints can strongly shape the distribution of a population in sequence space. Then, by directly linking this to a picture of multiple types of transcription factors performing their functions simultaneously inside the cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions between transcription factors and binding sites that lead to erroneous regulatory states -- and understand the constraints this places on the design of regulatory systems. I will then develop a generic theoretical framework to investigate the coevolution of multiple transcription factors and multiple binding sites, in the context of a gene regulatory network that performs a certain function. As a particular tractable version of this problem, I will consider the evolution of two transcription factors when they transmit upstream signals to downstream target genes. Specifically, I will describe the evolutionary steady states and the evolutionary pathways involved, along with their timescales, of a system that initially undergoes a transcription factor duplication event. To connect this important theoretical model to the prominent biological event of transcription factor duplication giving rise to paralogous families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription factors, a major family in humans, and focus on the patterns of evolution that paralogs have undergone in their various protein domains in the recent past

Novel Mechanisms In The Sorting Of Proglucagon To The Secretory Granules Of The Regulated Secretory Pathway

The prohormone proglucagon encodes for multiple peptide hormones, including glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2, produced through tissue-specific processing by prohormone convertase (PC) 1/3 and PC2. In alpha cells, PC2 yields glucagon, the major counter-regulatory hormone to insulin, which together, control glucose homeostasis. In contrast, GLP-1 and GLP2 are mainly produced in intestinal L-cells by PC1/3. GLP-1 stimulates insulin secretion following a meal, and therefore has opposing function to glucagon regulating glucose homeostasis; in contrast, GLP-2 enhances gut nutrient absorption. Efficient sorting of proglucagon to secretory granules is required for nutrient-regulated secretion. The aim of this thesis is to discover the molecular mechanisms by which proglucagon is targeted to secretory granules, which ensures that proglucagon is correctly processed to mature hormones, and is necessary for prompt physiologic response to nutrient status. In this thesis, we identify several sorting signals within the hormone domains of proglucagon that encode targeting information. Using quantitative immunofluorescence microscopy and co-localization analyses, I was able to determine the molecular nature by which glucagon and GLP-1 enter granules. Despite these two hormones sharing a large degree of structural homology, it is their particular alpha-helix structures that enable the sorting of proglucagon. Further, I provide evidence that proglucagon is first sorted to granules prior to being processed to active hormones. Furthermore, I have identified carboxypeptidase E in the mechanism by which glucagon sorts within alpha cells. Together, each hormone carries with it a unique sorting “signature” to efficiently reach its destination, and allows alpha and L-cells to tightly regulate nutrient homeostasis

High-level visual object representation in juvenile and adult primates

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2018.Cataloged from PDF version of thesis.Includes bibliographical references (pages 109-130).Despite being reflexive, primate view invariant object recognition is a complex computational task. These computations are thought to reside in the ventral visual stream, specifically culminating in inferior temporal (IT) cortex. Recent research in machine learning has made great progress in modeling primate ventral visual stream computations. While the end result of current machine learning approaches produces models that are highly predictive of the adult state of the ventral stream, the learning approaches themselves are not biologically plausible, requiring tens of thousands to millions of human-labeled training points. Understanding primate visual development is therefore not only interesting from the perspective of neuroscience, but also has practical value in building more robust learning algorithms capable of functioning in domains where large amounts of human-labeled training information may be difficult or impossible to create. Better learning algorithms may also produce agents capable of adapting and behaving in the world not unlike humans. This thesis first describes work on predicting visual responses across the human ventral stream using convolutional neural networks (CNNs). We then describe a set of natural image statistics automatically incorporated into high-performing CNNs from supervised training-it is possible primate development incorporates these or similar natural image statistics into its synaptic strengths. Finally, we describe the first-large scale characterization of IT in 19-32 week old macaques. While we find longer response latencies in these younger animals, we do not find any differences in representation between adults and juveniles suggesting that, at 19-32 weeks of age, IT already supports robust object recognition consistent with adults. Our data provide an upper limit on the amount of training data needed to reach adult-level performance-approximately 2,800 hours of waking visual experience.by Darren Seibert.Ph. D

Designing multimodal interaction for the visually impaired

Although multimodal computer input is believed to have advantages over unimodal input, little has been done to understand how to design a multimodal input mechanism to facilitate visually impaired users\u27 information access. This research investigates sighted and visually impaired users\u27 multimodal interaction choices when given an interaction grammar that supports speech and touch input modalities. It investigates whether task type, working memory load, or prevalence of errors in a given modality impact a user\u27s choice. Theories in human memory and attention are used to explain the users\u27 speech and touch input coordination. Among the abundant findings from this research, the following are the most important in guiding system design: (1) Multimodal input is likely to be used when it is available. (2) Users select input modalities based on the type of task undertaken. Users prefer touch input for navigation operations, but speech input for non-navigation operations. (3) When errors occur, users prefer to stay in the failing modality, instead of switching to another modality for error correction. (4) Despite the common multimodal usage patterns, there is still a high degree of individual differences in modality choices. Additional findings include: (I) Modality switching becomes more prevalent when lower working memory and attentional resources are required for the performance of other concurrent tasks. (2) Higher error rates increases modality switching but only under duress. (3) Training order affects modality usage. Teaching a modality first versus second increases the use of this modality in users\u27 task performance. In addition to discovering multimodal interaction patterns above, this research contributes to the field of human computer interaction design by: (1) presenting a design of an eyes-free multimodal information browser, (2) presenting a Wizard of Oz method for working with visually impaired users in order to observe their multimodal interaction. The overall contribution of this work is that of one of the early investigations into how speech and touch might be combined into a non-visual multimodal system that can effectively be used for eyes-free tasks

Designing for mod development: user creativity as product development strategy on the firm-hosted 3D software platform

The thesis is designed to improve our understanding of user participation in Web-based development practices in the commercial setting of the 3D software industry. It aims to investigate whether the creative capacities of users and their contributions to the online firm-hosted 3D platform are indicative of a novel configuration of production that influences the processes of product development across firm boundaries. The thesis mobilizes the user participation literature developing in media research as its main theoretical framework. It builds on insights derived from work on user participation in media sites as seen through a cultural lens, in particular, as developed in Henry Jenkins' notions of 'participatory' and 'convergence culture'. The user participation literature is supported by a combination of insights drawn from work on communities of practice and user-centred innovation so as to offer a more robust approach to examine and appreciate the firm-hosted 3D platform as a site of user participation. More specifically, the conceptual framework for the study provides a basis for an examination of the ways a software developer finn encourages user participation in a market and of how this enables and facilitâtes particular modes of user creativity. These are shown to shape and maintain a firm-hosted platform that aids product development efforts that are expected to benefit the developer fimi. An empirical study of the platform, Second Life, provides the basis for the analysis of finn-user interactions which are shown to underpin a distinctive finn leaming process in the context of product development that occurs across permeable fimi boundaries. The thesis yields insight into the way a developer firm invites its user base to partner with it in product development, indicating how aspects of user participation associated with non-market dynamics are embedded in commercial activity and professionalism. The pivotal role of users is revealed in the design, development and sustainability of a firm-hosted 3D product. The findings point to interesting relationships between the distinctive creative capacities of users and the range of capabilities afforded by the firm-provided design space. Variations in user participation and contributions to product development suggest that particular patterns of learning opportunities occur. The analysis yields several new concepts including a 'modification effect market' which are used to extend existing conceptualizations of user participation in digitai development practices in the commercial setting of the 3D software industry