Structural characterization of interaction of K11 and K63 mixed-linkage polyubiquitin chains with the tUIMs of epsin1

Ubiquitylation or covalent attachment of ubiquitin (Ub) to a variety of substrate proteins in cells is a versatile post-translational modification involved in the regulation of numerous cellular processes. The distinct messages that polyubiquitylation encodes are attributed to the multitude of conformations possible through attachment of ubiquitin monomers within a polyubiquitin chain via a specific lysine residue. Thus the hypothesis is that linkage defines polyubiquitin conformation which in turn determines specific recognition by cellular receptors. Ubiquitylation of membrane surface receptor proteins plays a very important role in regulating receptor-mediated endocytosis as well as endosomal sorting for lysosomal degradation. Epsin1 is an endocytic adaptor protein with three tandem UIMs (Ubiquitin Interacting Motifs) which are responsible for the highly specific interaction between epsin and ubiquitylated receptors. Epsin1 is also an oncogenic protein and its expression is upregulated in some types of cancer. Recently it has been shown that novel K11 and K63 mixed-linkage polyubiquitin chains serve as internalization signal for MHC I (Major Histocompatibility Complex I) molecule through their association with the tUIMs of epsin1. However the molecular mode of action and structural details of the interaction between polyubiquitin chains on receptors and tUIMs of epsin1 is yet to be determined. This information is crucial for the development of anticancer therapeutics targeting epsin1. The molecular basis for the linkage-specific recognition of K11 and K63 mixed-linkage polyubiquitin chains by the tandem UIMs of the endocytic adaptor protein epsin1 is investigated using a combination of NMR methods.

Developmental Neural Correlates of Social Interaction

Children develop in a sea of reciprocal social interaction, but their brain development is predominately studied in non-interactive contexts (e.g., viewing photographs of faces). This dissertation investigated how the developing brain supports social interaction. Specifically, novel paradigms were used to target two facets of social experience—social communication and social motivation—across three studies in children and adults. In Study 1, adults listened to short vignettes—which contained no social information—that they believed to be either prerecorded or presented over an audio-feed by a live social partner. Simply believing that speech was from a live social partner increased activation in the brain’s mentalizing network—a network involved in thinking about others’ thoughts. Study 2 extended this paradigm to middle childhood, a time of increasing social competence and social network complexity, as well as structural and functional social brain development. Results showed that, as in adults, regions of the mentalizing network were engaged by live speech. Taken together, these findings indicate that the mentalizing network may support the processing of interactive communicative cues across development. Given this established importance of social-interactive context, Study 3 examined children’s social motivation when they believed they were engaged in a computer-based chat with a peer. Children initiated interaction via sharing information about their likes and hobbies and received responses from the peer. Compared to a non-social control, in which children chatted with a computer, peer interaction increased activation in mentalizing regions and reward circuitry. Further, within mentalizing regions, responsivity to the peer increased with age. Thus, across all three studies, social cognitive regions associated with mentalizing supported real-time social interaction. In contrast, the specific social context appeared to influence both reward circuitry involvement and age-related changes in neural activity. Future studies should continue to examine how the brain supports interaction across varied real-world social contexts. In addition to illuminating typical development, understanding the neural bases of interaction will offer insight into social disabilities such as autism, where social difficulties are often most acute in interactive situations. Ultimately, to best capture human experience, social neuroscience ought to be embedded in the social world.

The Promise of Access: Hope and Inequality in the Information Economy

In 2013, a series of posters began appearing in Washington, DC’s Metro system. Each declared “The internet: Your future depends on it” next to a photo of a middle-aged black Washingtonian, and an advertisement for the municipal government’s digital training resources. This hopeful discourse is familiar but where exactly does it come from? And how are our public institutions reorganized to approach the problem of poverty as a problem of technology? The Clinton administration’s ‘digital divide’ policy program popularized this hopeful discourse about personal computing powering social mobility, positioned internet startups as the ‘right’ side of the divide, and charged institutions of social reproduction such as schools and libraries with closing the gap and upgrading themselves in the image of internet startups. After introducing the development regime that builds this idea into the urban landscape through what I call the ‘political economy of hope’, and tracing the origin of the digital divide frame, this dissertation draws on three years of comparative ethnographic fieldwork in startups, schools, and libraries to explore how this hope is reproduced in daily life, becoming the common sense that drives our understanding of and interaction with economic inequality and reproduces that inequality in turn. I show that the hope in personal computing to power social mobility becomes a method of securing legitimacy and resources for both white émigré technologists and institutions of social reproduction struggling to understand and manage the persistent poverty of the information economy. I track the movement of this common sense between institutions, showing how the political economy of hope transforms them as part of a larger development project. This dissertation models a new, relational direction for digital divide research that grounds the politics of economic inequality with an empirical focus on technologies of poverty management. It demands a conceptual shift that sees the digital divide not as a bug within the information economy, but a feature of it.