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Lamellar Membrane Perturbation by Surface-Active and Biological Molecules
Get PDFLike impressionist art, a multitude of subtle and complex interactions determine the behavior of biological systems but a generalized perception loses significant resolution. This is true within the discipline of soft matter, where the chemical multiplicity of the involved components and their resulting physical consequences within lamellar mesophase assemblies are commonly ignored. Therefore, it is imperative to investigate the minute thermodynamic considerations between varied lipidic lamellar mesophases and biologically relevant dopants (like surface-active agents and proteinaceous content) and their resulting physical behaviors. By using various microscopy techniques and x-ray diffraction measurements, lamellar mesophase behavior can be monitored upon the addition (in real-time or post-doping event) of these surface-active and biological substances, and the resulting analyses elucidate the microscopic information others have commonly missed. Such studies can not only enlighten scientists with a higher-level understanding of amphiphilic systems but also lead to the development of unique structural assemblies for various applications.In a larger perspective, this dissertation aims to assemble structurally-diverse lamellar mesophases and expose them to surface-active molecules (also written as surfactant or detergent) and proteinaceous content in varying methods to connect macroscopic and microscopic information. Employing various methodologies like directed aqueous hydration, water vapor hydration, and electroformation, both multilamellar and unilamellar mesophases populated by common lipids and fluorescently-tagged phospholipids were assembled. Such assemblies were then perturbed by symmetric (or internalized) or asymmetric (or external) doping of the focal substances. The consequential physical and structural properties of the mixed-component systems were then investigated to understand the impacts of chemical multiplicity. This dissertation only begins to expound the subtleties of chemistry within lamellar mesophases and question the value of generalized models of membrane behavior. Through these efforts, a new, adaptable, and inclusive intellectual framework of membranes can be developed and considered
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Giant Unilamellar Vesicles under Osmotic Stress: Insights into Protocellular Functionality and Synthetic Cell Engineering
No full textCells, the smallest structural and functional units of life, are constantly on the move. They engage in multitudes of activities ranging from nutrient procurement, communication, growth to replication and even migration. Cellular membrane, an encasement made of phospholipid bilayer not only compartmentalizes the cellular interior from the extracellular environment, playing a critical role in cell’s viability, but it is also the hub for all essential cellular communications with the surroundings. These often involve molecular level reorganization and morphological remodeling of the membrane interface - an energetically intensive cellular activity most commonly mediated by a host of protein machinery. This was not the case for early cells- a coagulated mass of informational macromolecules bound by lipid membrane- that lacked this advanced protein toolkit, however still survived to evolve into the modern cells that we know. How could the primitive cell-like systems make their ends meet?This dissertation investigates how protocells might have performed essential life functions through alternative mechanisms. Using giant unilamellar vesicles (GUVs) as models, my research explores the impact of osmotic stresses – those that arise merely by local gradients of concentration between inside and the outside of vesicular compartments – on membrane organization, dynamics, and function. My findings showcase how osmotic cycling of the GUVs can lead to the formation of multiple invaginations in vesicle, successfully engulfing and transferring solutes from the vesicle exteriors to the interiors. This simple physical process thus mimics the versatile biological mechanism of endocytosis for movement of macromolecules and materials across the living cell. Introducing compositional degrees of freedom in the make-up of these GUVs reveals how membrane molecules become selectively involved during these processes. During the formation of osmotically induced invaginations, different lipids sort differently into invaginations producing compositionally differentiated liquid-ordered and liquid-disordered domains. This compositional sorting eventually leads to materially asymmetric division of invaginations producing daughter compartments of distinctly different molecular signatures. In this same vein, creating phase separating vesicles with distinct lipid domains shows that disparity in domain water permeabilities can induce directional fluxes and eventual vectorial GUV propulsion under applied osmotic stress, mirroring motility mechanisms cells often adopt to migrate.
These results provide insights into how primitive cell-like structures may have achieved critical functions in absence of proteins. Not only does this study help in understanding plausible protocellular activity but it also paves way for creating synthetic cellular systems with life-like adaptive responses in fluctuating environments
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Biophysics of Synthetic Model Cells: The membrane transformative functions of essential proteins and molecules
Get PDFDespite being one of the smallest subunits of life, biological cells are immensely complex. Establishing clear causality requires significant effort and energy on the part of researchers, many of whom choose to synthesize models that include only the aspects relevant to a current research question–often referred to as synthetic cells. This thesis aims to present a perspective of the bottom-up approach to biology that utilizes synthetic cells to model biophysical interactions between molecules and membranes. Furthermore, my dissertation seeks to develop methods to reconstitute asymmetries of shapes, structures, molecular composition, and morphologies of minimal synthetic cells. In pursuit of this goal, we utilize and develop methods of giant unilamellar vesicle (GUV) synthesis, as well as image and model the membrane transformative effects of various molecules and proteins. Chapter 1 introduces the reader to the fundamentals of cell membranes, describing the properties of lipids and presenting methods of synthesizing these into GUVs, used as models in membrane biophysical research.In Chapter 2, we employ GUVs as a model to characterize the membrane transformative effects of a commonly used molecule for drug delivery - methyl-β-cyclodextrin (mβCD). We utilized fluorescence microscopy techniques to image the generation of membrane structures following GUV incubation with mβCD, whose leaflet-specific interactions led to a buildup of a differential stress within the membrane, responsible for the membrane deformations we observe.In Chapter 3 we examine the membrane remodeling effect of apolipoproteins (A class of protein that makes up a majority of what is commonly referred to as, “good cholesterol”) as they undergo complex, cooperative, and dynamic self-assembly with membrane lipids, producing nascent, discoidal high-density lipoproteins (nHDLs). We reveal the formation of nHDLs from GUVs is concomitant with significant morphological changes to the vesicle membrane, including transient poration, solute and solvent leakage, and phase separation, before ultimately lysing the cell into a collection of smaller, more stable, daughter cells.Finally, in Chapter 4, we will discuss the convergence of the previous two chapters, and the future direction of this experimental narrative. This includes the application of mβCD in the synthesis of artificial, tailor-made membrane asymmetry in synthetic cells, followed by the reconstitution of HDL particles that maintain this engineered asymmetry. We will discuss the preliminary experimental results and the practical applications of tailored compositional asymmetry in nanodiscs as a tool for studying integral membrane proteins in their native-like environment
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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