2,416 research outputs found
Assembly and Trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator and Associated Proteins
Cystic Fibrosis (CF) is an autosomal recessive genetic disease that leads to severe malfunction in many organs, but particularly the lungs. The primary cause of this malfunction is the decrease of the airway surface liquid layer on the lung epithelium. The lack of hydration leads to mucus build up on the epithelial lining, leading to blockage of airways. The underlying cause of CF is the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), which results from mutations in the protein. Almost 90% of CF patients are caused by the deletion of the phenylalanine at position 508 of CFTR, which is believed to affect the folding and stability of CFTR. The misfolded ΔF508-CFTR undergoes ER associated degradation (ERAD), causing the failure of ΔF508-CFTR trafficking to the cell surface. Small molecule correctors yield moderate improvements in the trafficking of ΔF508-CFTR to the plasma membrane. It is currently not known if correctors increase trafficking through improved cargo loading of transport vesicles or through direct binding to CFTR. In this dissertation, real-time measurements of trafficking were utilized to identify the mechanistic details of chemical, biochemical, and thermal factors that impact CFTR correction, using the corrector molecule VX-809, a secondary mutation (I539T), and low temperature conditions. Each individually improved trafficking of ΔF508-CFTR to approximately 10% of wild-type levels. The combination of VX-809 with either low temperature or the I539T mutation increased the amount of CFTR on the plasma membrane to nearly 40%, indicating synergistic activity. The number of vesicles reaching the surface was significantly altered; however the amount of channel in each vesicle remained the same. Therefore, a 2 step therapeutic approach might be an ideal treatment for CF. The first step would be composed of a compound that mimics the mechanism of stabilization provided by low temperature or the I539T mutation, while the second step would be VX-809 or a similar corrector compound. These studies suggest that understanding how low temperature and second site suppressors alter ΔF508-CFTR could be key to the development of future therapeutics for the effective treatment of CF.
The precise pathophysiology of cystic fibrosis is not well studied. The involvement of another transport protein, epithelial sodium channel (ENaC), makes the situation more complicated. ENaC and CFTR are colocalized on the apical surface of epithelia cells. With our fluorescence microscopy techniques, we explored the effects of CFTR on the residence time of ENaC on the cell membrane. A reliable approach measuring the half-life of protein on the cell membrane is required for this study. We present a new approach to quantify the half-life of membrane proteins on the cell surface, through tagging the protein with the photoconvertible fluorescent protein, Dendra2. Total internal reflection fluorescence microscopy (TIRF) is applied to limit visualization of fluorescence to proteins located on the plasma membrane. Photoconversion of Dendra2 works as a pulse chase experiment by monitoring only the population of protein that has been photoconverted. As the protein is endocytosed the red emission decreases due to the protein leaving the TIRF field of view. The half-life of the protein on the plasma membrane was calculated upon imaging over time and quantifying the change in red fluorescence. Our method provides a unique opportunity to observe real-time protein turnover at the single cell level without addition of protein synthesis inhibitors. This technique will be valuable for the future protein half-life study
Goodbye Presentation
In this capstone presentation, visiting Chinese doctoral student Zhihui Zhang explains how she came to study at the University of Kentucky Libraries Special Collections Research Center; the archival projects she worked on, the individual people she met with, and the cultural heritage organization tours she went on; the differences and similarities between American and Chinese archival theory and practice; and how this experience will inform her Ph.D. program and her dissertation
Linking architecture and emotions: sensory dynamics and methodological innovations
Tesi en modalitat de compendi de publicacions(English) This study delves deeply into the complex relationship between the field of architecture and human emotions, aiming to fill a significant gap in existing research. It extensively explores the profound impact of architectural design elements, such as lighting, colour schemes, and the integration of natural landscapes, on emotional responses. This research goes beyond traditional focuses on aesthetics and sustainability, striving to innovate methods for assessing the emotional impact of architectural spaces.
In this study, we adopted a technological pathway from the laboratory to virtual reality, and finally to AI, combining theoretical analysis with practical experiments and case studies. The main research includes examining the effects of lighting and spatial dimension variations on people's emotions, as well as the application of facial emotion recognition technology in virtual reality architectural environments, exploring AI's perceptual capabilities as a tool in architectural design. These studies aim to narrow the gap between theoretical research and practical application, providing new perspectives and empirical data for the field of architectural design.
The study concludes with a reflection on the methodologies used and their broader implications for architectural design practice. It offers specific strategies for architects and designers, aimed at creating spaces that resonate emotionally and add substantial value to human experiences. By prioritizing emotional factors in the design process, this research seeks to enhance overall quality of life and promote well-being in thoughtfully designed architectural spaces.(Català ) Aquest estudi aprofundeix en la complexa relació entre el camp de l'arquitectura i les emocions humanes, amb l'objectiu de cobrir un buit significatiu en la investigació existent. Explora à mpliament l'impacte profund d'elements de disseny arquitectònic, com ara la il·luminació, els esquemes de colors i la integració de paisatges naturals, en les respostes emocionals. Aquesta recerca va més enllà dels enfocaments tradicionals en estètica i sostenibilitat, esforçant-se per innovar en mètodes per avaluar l'impacte emocional dels espais arquitectònics.
En aquest estudi, s'adopta una ruta tecnològica que va des del laboratori fins a la realitat virtual i, finalment, a la intel·ligència artificial, combinant anà lisi teòric amb experiments prà ctics i estudis de cas. La recerca principal inclou l'examen dels efectes de les variacions de la il·luminació i les dimensions espacials en les emocions de les persones, aixà com l'aplicació de la tecnologia de reconeixement facial d'emocions en entorns arquitectònics de realitat virtual, explorant les capacitats perceptives de la IA com a eina en el disseny arquitectònic. Aquests estudis busquen reduir la bretxa entre la recerca teòrica i l'aplicació prà ctica, proporcionant noves perspectives i dades empÃriques per al camp del disseny arquitectònic.
L'estudi conclou amb una reflexió sobre les metodologies utilitzades i les seves implicacions més à mplies per a la prà ctica del disseny arquitectònic. Ofereix estratègies especÃfiques per a arquitectes i dissenyadors, destinades a crear espais que ressonin emocionalment i afegeixin un valor substancial a les experiències humanes. En prioritzar els factors emocionals en el procés de disseny, aquesta recerca busca millorar la qualitat general de vida i promoure el benestar en espais arquitectònics dissenyats amb cura.(Español) Este estudio profundiza en la compleja relación entre el campo de la arquitectura y las emociones humanas, con el objetivo de llenar un vacÃo significativo en la investigación existente. Explora extensamente el profundo impacto de elementos de diseño arquitectónico, como la iluminación, los esquemas de colores y la integración de paisajes naturales, en las respuestas emocionales. Esta investigación va más allá de los enfoques tradicionales en estética y sostenibilidad, esforzándose por innovar en métodos para evaluar el impacto emocional de los espacios arquitectónicos.
En este estudio, se adopta una ruta tecnológica que va desde el laboratorio hasta la realidad virtual y, finalmente, a la inteligencia artificial, combinando análisis teórico con experimentos prácticos y estudios de caso. La investigación principal incluye el examen de los efectos de las variaciones de la iluminación y las dimensiones espaciales en las emociones de las personas, asà como la aplicación de la tecnologÃa de reconocimiento facial de emociones en entornos arquitectónicos de realidad virtual, explorando las capacidades perceptuales de la IA como herramienta en el diseño arquitectónico. Estos estudios buscan reducir la brecha entre la investigación teórica y la aplicación práctica, proporcionando nuevas perspectivas y datos empÃricos para el campo del diseño arquitectónico.
El estudio concluye con una reflexión sobre las metodologÃas utilizadas y sus implicaciones más amplias para la práctica del diseño arquitectónico. Ofrece estrategias especÃficas para arquitectos y diseñadores, destinadas a crear espacios que resuenen emocionalmente y añadan un valor sustancial a las experiencias humanas. Al priorizar los factores emocionales en el proceso de diseño, esta investigación busca mejorar la calidad general de vida y promover el bienestar en espacios arquitectónicos diseñados cuidadosamente.Postprint (published version
Uncovering emotional responses in architectural visits: a study on facial expression recognition using virtual reality
Simulating non-small cell lung cancer with a multiscale agent-based model
Background The epidermal growth factor receptor (EGFR) is frequently
overexpressed in many cancers, including non-small cell lung cancer (NSCLC). In
silcio modeling is considered to be an increasingly promising tool to add
useful insights into the dynamics of the EGFR signal transduction pathway.
However, most of the previous modeling work focused on the molecular or the
cellular level only, neglecting the crucial feedback between these scales as
well as the interaction with the heterogeneous biochemical microenvironment.
Results We developed a multiscale model for investigating expansion dynamics
of NSCLC within a two-dimensional in silico microenvironment. At the molecular
level, a specific EGFR-ERK intracellular signal transduction pathway was
implemented. Dynamical alterations of these molecules were used to trigger
phenotypic changes at the cellular level. Examining the relationship between
extrinsic ligand concentrations, intrinsic molecular profiles and microscopic
patterns, the results confirmed that increasing the amount of available growth
factor leads to a spatially more aggressive cancer system. Moreover, for the
cell closest to nutrient abundance, a phase-transition emerges where a minimal
increase in extrinsic ligand abolishes the proliferative phenotype altogether.
Conclusions Our in silico results indicate that, in NSCLC, in the presence of
a strong extrinsic chemotactic stimulus, and depending on the cell's location,
downstream EGFR-ERK signaling may be processed more efficiently, thereby
yielding a migration-dominant cell phenotype and overall, an accelerated
spatio-temporal expansion rate.Comment: 37 pages, 7 figure
RORS: Enhanced Rule-based OWL Reasoning on Spark
The rule-based OWL reasoning is to compute the deductive closure of an
ontology by applying RDF/RDFS and OWL entailment rules. The performance of the
rule-based OWL reasoning is often sensitive to the rule execution order. In
this paper, we present an approach to enhancing the performance of the
rule-based OWL reasoning on Spark based on a locally optimal executable
strategy. Firstly, we divide all rules (27 in total) into four main classes,
namely, SPO rules (5 rules), type rules (7 rules), sameAs rules (7 rules), and
schema rules (8 rules) since, as we investigated, those triples corresponding
to the first three classes of rules are overwhelming (e.g., over 99% in the
LUBM dataset) in our practical world. Secondly, based on the interdependence
among those entailment rules in each class, we pick out an optimal rule
executable order of each class and then combine them into a new rule execution
order of all rules. Finally, we implement the new rule execution order on Spark
in a prototype called RORS. The experimental results show that the running time
of RORS is improved by about 30% as compared to Kim & Park's algorithm (2015)
using the LUBM200 (27.6 million triples).Comment: 12 page
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