Characterization of Ligand-Induced Conformational Changes in the EGF Receptor

ABSTRACT OF DISSERTATION Characterization of ligand-induced conformational changes in the EGF receptor by Katherine S. Yang Doctor of Philosophy in Biochemistry Washington University in St. Louis, 2009 Professor Linda Pike, Chairperson The epidermal growth factor: EGF) receptor is a classical receptor tyrosine kinase that mediates cellular processes such as proliferation, migration, and differentiation in response to growth factor stimulation. Crystal structures of the EGF receptor suggest that its activation is associated with extensive conformational changes in both the extracellular and intracellular domains. However, evidence of these structural dynamics in intact cells has been lacking. This thesis describes the characterization of sequential ligand-induced conformational changes in the EGF receptor in live cells in real time using luciferase fragment complementation imaging. We find that these conformational changes are unique to the full-length activated EGF receptor. These studies identified a novel conformational change that was dependent on MAP kinase activation and desensitization of the EGF receptor. It has been unclear how MAP kinase desensitizes the EGF receptor following activation. Mutational analysis was done to identify residues involved in the MAP kinase-mediated EGF receptor desensitization. We use these analyses to provide a structural explanation for the MAP kinase-mediated desensitization of the EGF receptor. The luciferase complementation assay was further utilized to test the ability of different ligands for the EGF receptor family to induce dimer formation and intracellular domain conformational changes

Self-Assistant: Portable Progressive Muscle Relaxation Training Interface for Anxiety Reduction in Office Workers

Workload often triggers anxiety for office workers. While a variety of stress intervention and management techniques have been explored, there exist only a few of portable tangible interfaces for anxiety reduction. Contributing to the body of work, we introduce Self-Assistant, a portable anxiety intervention training interface. This is based on progressive muscle relaxation training which is an effective way for reducing stress and raise awareness of tension, and provide feelings of deep relaxation. This interface incorporates a stress ball with a pressure sensor and visual indicators which help track the user's anxiety level through squeeze actions. This is designed to help improve self-awareness of anxiety and stress, in turn self-regulating bodily functions, offering rapid and low-sensory stimulus training for anxiety relief. Finally, we discuss application scenarios and future work with Self-Assistant.Comment: Short Technical Report: Best student-led project in COMP0145: Research Methods and Making Skills (2022/23

Assessing risk to fresh water resources from long term CO2 injection- laboratory and field studies

In developing a site for geologic sequestration, one must assess potential consequences of failure to adequately contain injected carbon dioxide (CO2). Upward migration of CO2 or displacement of saline water because of increased pressure might impact protected water resources 100s to 1000s of meters above a sequestration interval. Questions posed are: (1) Can changes in chemistry of fresh water aquifers provide evidence of CO2 leakage from deep injection/sequestration reservoirs containing brine and or hydrocarbons? (2) What parameters can we use to assess potential impacts to water quality? (3) If CO2 leakage to freshwater aquifers occurs, will groundwater quality be degraded and if so, over what time period? Modeling and reaction experiments plus known occurrences of naturally CO2-charged potable water show that the common chemical reaction products from dissolution of CO2 into freshwater include rapid buffering of acidity by dissolution of calcite and slower equilibrium by reaction with clays and feldspars. Results from a series of laboratory batch reactions of CO2 with diverse aquifer rocks show geochemical response within hours to days after introduction of CO2. Results included decreased pH and increased concentrations of cations in CO2 experimental runs relative to control runs using argon (Ar). Some cation (Ba, Ca, Fe, Mg, Mn, and Sr) concentrations increased over and an order of magnitude during CO2 runs. Results are aquifer dependant in that experimental vessels containing different aquifer rocks showed different magnitudes of increase in cation concentrations. Field studies designed to improve understanding of risk to fresh water are underway in the vicinity of (1) SACROC oilfield in Scurry County, Texas, USA where CO2 has been injected for enhanced oil recovery (EOR) since 1972 and (2) the Cranfield unit in Adams County, Mississippi, USA where CO2 EOR is currently underway. Both field studies are funded by the U.S. Department of Energy (DOE) regional carbon sequestration partnership programs and industrial sponsors. Preliminary results of groundwater monitoring are currently available for the SACROC field study where researchers investigated 68 water wells and one spring during five field excursions between June 2006 and July 2008. Results to date show no trend of preferential degradation below drinking water standards in areas of CO2 injection (inside SACROC) as compared to areas outside of the SACROC oil field.Bureau of Economic Geolog

Bioorthogonal Small Molecule Imaging Agents Allow Single-Cell Imaging of MET

The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that has emerged as an important cancer target. Consequently, a number of different inhibitors varying in specificity are currently in clinical development. However, to date, it has been difficult to visualize MET expression, intracellular drug distribution and small molecule MET inhibition. Using a bioorthogonal approach, we have developed two companion imaging drugs based on both mono- and polypharmacological MET inhibitors. We show exquisite drug and target co-localization that can be visualized at single-cell resolution. The developed agents may be useful chemical biology tools to investigate single-cell pharmacokinetics and pharmacodynamics of MET inhibitors

Analysis Price List Update Process of Price List Management on Direct Material Procurement Department at PT. X

PT.X is one of the largest consumer goods manufacturing companies in Indonesia. As manufacturing companies PT. X has Direct Material (DIM) Procurement Department to control all direct material, which also controls the price list. The process of controlling price list update is still handled via email. The use of email as communication between internal PT. X and also with the vendor, cause email pilling up in the DIM Procurement staff’s inbox. This causes the process of updating material price list to become long and hard to control. There are approximately 4 500 direct materials and approximately 130 active vendors are handled by the DIM Procurement department annually. A large number of materials and vendor handled by DIM Procurement is one of the reasons why the process of controlling price list is important. Digitalization is one way to help the process of controlling and simplifying the price list update process. Improvements to the process of price list update will be done by designing the concept of a platform that helps improve the performance of DIM Procurement Department. The platform called price list catalog can be used to store and record all vendor price list changes. The suggestions for price list update process is to facilitate DIM Procurement department so they can easily control material price list, provide trusted price list, and always available on time. Keywords: price list catalog; price list control; price list data; pricing managemen

Phylogenomic analysis of natural selection pressure in Streptococcus genomes

<p>Abstract</p> <p>Background</p> <p>In comparative analyses of bacterial pathogens, it has been common practice to discriminate between two types of genes: (i) those shared by pathogens and their non-pathogenic relatives (core genes), and (ii) those found exclusively in pathogens (pathogen-specific accessory genes). Rather than attempting to <it>a priori </it>delineate genes into sets more or less relevant to pathogenicity, we took a broad approach to the analysis of <it>Streptococcus </it>species by investigating the strength of natural selection in all clusters of homologous genes. The genus <it>Streptococcus </it>is comprised of a wide variety of both pathogenic and commensal lineages, and we relate our findings to the pre-existing knowledge of <it>Streptococcus </it>virulence factors.</p> <p>Results</p> <p>Our analysis of 1730 gene clusters revealed 136 cases of positive Darwinian selection, which we suggest is most likely to result from an antagonistic interaction between the host and pathogen at the molecular level. A two-step validation procedure suggests that positive selection was robustly identified in our genomic survey. We found no evidence to support the notion that pathogen specific accessory genes are more likely to be subject to positive selection than core genes. Indeed, we even uncovered a few cases of essential gene evolution by positive selection. Among the gene clusters subject to positive selection, a large fraction (29%) can be connected to virulence. The most striking finding was that a considerable fraction of the positively selected genes are also known to have tissue specific patterns of expression during invasive disease. As current expression data is far from comprehensive, we suggest that this fraction was underestimated.</p> <p>Conclusion</p> <p>Our findings suggest that pathogen specific genes, although a popular focus of research, do not provide a complete picture of the evolutionary dynamics of virulence. The results of this study, and others, support the notion that the products of both core and accessory genes participate in complex networks that comprise the molecular basis of virulence. Future work should seek to understand the evolutionary dynamics of both core and accessory genes as a function of the networks in which they participate.</p

Cross-platform Analysis of Twitter and Parler during the 2020 U.S. Presidential Election

In the recent 2020 Presidential Election, President Trump and his campaign alleged that mail-in ballots were likely to be fraudulent and this claim stood against Twitter’s efforts to curb spreading of misinformation (Lima, 2020). This claim resulted in suspending those who participated in voter fraud misinformation (Twitter, 2021), including Trump himself. In response to Twitter’s action, Trump and those who supported Trump left Twitter, seeking an alternative social media. This migration was a strong collective action by users who felt more than simply constrained (Kiene, Monroy-Hernández & Hill, 2016) by a loss of belonging to the community when users faced increased censorship. Those who left Twitter found Parler as an alternative social networking service, which proclaims that they allow a user to “speak freely and express yourself openly, without fear of being deplatformed for your views” as an asylum. Parler has gained attention from conservatives who are looking for alternative social media, which supposedly accepts them for who they are. Based on this unique case, this study seeks to understand the impact of echo chambers on people’s expressed opinions on social media. Past research efforts on echo chambers, selective exposure, and network homogeneity (Stewart, Arif & Starbird, 2018; Jacobson, Myung & Johnson, 2016) mostly focused on a handful of popular social media, mostly either Facebook or Twitter, while neglecting the unique roles of other niche social media platforms in building online communities (Zannettou et al., 2018). We will address this critical gap by leveraging data from two social media platforms: Parler and Twitter as examples that represent distinctive user bases in terms of political ideology. We identify users who have the same account names on both platforms and examine the role of political homogeneity in the online opinion expression and sharing of information. We rely on the Social Identity Deindividuation Effects (SIDE) model to understand political behaviors of the users who used both Twitter and Parler. The SIDE model explains that deindividualization occurs when group norms are more salient and have a greater effect on individual behaviors than individual processes (Lea & Spears, 1992). The SIDE models focus on anonymity and explicit and implicit norms of online spaces, and supports that anonymity enhances the social influence processes and collective behavior (Spears, 2017). By applying this theoretical model, we are aiming to reveal how Parler’s homogeneous political climate – more conservative than Twitter – helped users to feel more anonymous than Twitter by providing a safe place for them to speak hatred. There are two research questions we wanted to answer. Our focus of interest is the people who used both Twitter and Parler and hereafter, they are called cross-platform users. RQ 1. Can we make use of the machine learning technique to identify the pattern of increasing or decreasing use of toxic language by cross-platform users in Twitter? RQ 2. Can we make use of the machine learning technique to identify the pattern of increasing or decreasing use of toxic language by cross-platform users in Parler?Ope

Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium.

Lung epithelial lineages have been difficult to maintain in pure form in&nbsp;vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the characterization of these cells. Here, we engineer mouse and human PSC lines carrying airway secretory lineage reporters that facilitate the tracking, purification, and profiling of this lung subtype. Through bulk and single-cell-based global transcriptomic profiling, we find PSC-derived airway secretory cells are susceptible to phenotypic plasticity exemplified by the tendency to co-express both a proximal airway secretory program as well as an alveolar type 2 cell program, which can be minimized by inhibiting endogenous Wnt signaling. Our results provide global profiles of engineered lung cell fates, a guide for improving their directed differentiation, and a human model of the developing airway