Effect of Bilayer Thickness on Membrane Bending Rigidity

The bending rigidity $k_c$ of bilayer vesicles self-assembled from amphiphilic diblock copolymers has been measured using single and dual-micropipet techniques. These copolymers are nearly a factor of 5 greater in hydrophobic membrane thickness $d$ than their lipid counterparts, and an order of magnitude larger in molecular weight $\bar{M}_n$. The macromolecular structure of these amphiphiles lends insight into and extends relationships for traditional surfactant behavior. We find the scaling of $k_c$ with thickness to be nearly quadratic, in agreement with existing theories for bilayer membranes. The results here are key to understanding and designing soft interfaces such as biomembrane mimetics

Persistence-driven durotaxis: Generic, directed motility in rigidity gradients

Cells move differently on substrates with different elasticities. In particular, the persistence time of their motion is higher on stiffer substrates. We show that this behavior will result in a net transport of cells directed up a soft-to-stiff gradient. Using simple random walk models with controlled persistence and stochastic simulations, we characterize this propensity to move in terms of the durotactic index measured in experiments. A one-dimensional model captures the essential features of this motion and highlights the competition between diffusive spreading and linear, wavelike propagation. Since the directed motion is rooted in a non-directional change in the behavior of individual cells, the motility is a kinesis rather than a taxis. Persistence-driven durokinesis is generic and may be of use in the design of instructive environments for cells and other motile, mechanosensitive objects.Comment: 5 pages, 4 figure

Hysteresis in the cell response to time-dependent substrate stiffness

Mechanical cues like the rigidity of the substrate are main determinants for the decision making of adherent cells. Here we use a mechano-chemical model to predict the cellular response to varying substrate stiffness. The model equations combine the mechanics of contractile actin filament bundles with a model for the Rho-signaling pathway triggered by forces at cell-matrix contacts. A bifurcation analysis of cellular contractility as a function of substrate stiffness reveals a bistable response, thus defining a lower threshold of stiffness, below which cells are not able to build up contractile forces, and an upper threshold of stiffness, above which cells are always in a strongly contracted state. Using the full dynamical model, we predict that rate-dependent hysteresis will occur in the cellular traction forces when cells are exposed to substrates of time-dependent stiffness.Comment: Revtex, 4 PDF figure

The association of sleep and stress with psychological well-being and neuronal functional connectivity

Sufficient sleep and an adequate stress response are two important components when it comes to coping with adverse events. Previous studies have shown that both are related to the occurrence of psychological and physical disorders, emphasizing the necessity to explore both concepts within the scope of this PhD thesis individually as well as their association among each other. In Study 1, we investigated the association of sleep-related variables with psychological well-being based on an online survey. We found evidence that the association of psychological well-being towards chronotype follows a U-shaped function, which means that being an early or late chronotype is related to impaired well-being. Additionally, reduced sleep durations, especially when occurring on work days, was associated with depressive symptomatology and sleep quality. For Study 2 and 3 we deployed neuroimaging data, as both sleep deprivation and psychosocial stress have been proven to change neuronal activity and connectivity patterns in the aftermath of stress. Study 2 focused on replicating results concerning the previously reported increased connectivity of the amygdala with regions involved in the down-regulation of the physiological stress response, in emotion regulation, and in memory consolidation. Analyzing resting state connectivity after stress compared to the pre-stress condition, we found an increase in bilateral amygdala resting-state functional connectivity (RSFC) with the posterior cingulate cortex (PCC) and the adjacent precuneus only in male cortisol non-responders, but not in responders. We did not detect changes in amygdala RSFC between female cortisol responders and non-responders. This finding shows the influence of sex and cortisol reactivity, when exploring neural signatures of stress reactivity and recovery. In Study 3 we focused on male participants only, now expanding the results from Study 2 by exploring the impact of sleep loss on neural signatures of stress recovery. We found a negative association of sleep loss, as reported in a seven-day sleep diary, with the stress-induced change of left amygdala RSFC to several cortical brain regions, including the medial prefrontal cortex, dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, anterior insula, and PCC. That is, the higher the sleep loss, the more decrease in left amygdala RSFC was found with these regions after stress. Taken together, the results of this PhD thesis contribute to a better understanding of associations between sleep, stress, and psychological well-being on a behavioral as well as neuronal level.Ausreichend Schlaf und eine angemessene Stressantwort stellen zwei wichtige Faktoren im Umgang mit belastenden Ereignissen dar. Frühere Studien berichteten von einem Zusammenhang mit dem Auftreten von psychologischen und physischen Erkrankungen. Dies belegt die Notwendigkeit, deren Wirkung im Rahmen der vorliegenden Doktorarbeit sowohl als einzelne Konstrukte als auch in Verbindung zueinander zu explorieren. Im Rahmen der ersten Studie untersuchten wir den Zusammenhang von schlafbezogenen Variablen zu psychologischem Wohlbefinden mithilfe einer Online Umfrage. Die Ergebnisse zeigten, dass der Zusammenhang zwischen psychologischem Wohlbefinden und Chronotyp einer u-förmigen Funktion folgt. Damit haben vor allem sehr frühe und späte Chronotypen ein erhöhtes Risiko für vermindertes Wohlbefinden. Zusätzlich fanden wir, dass eine reduzierte Schlafdauer, vor allem an Arbeitstagen, mit vermehrten depressiven Symptomen und geringerer Schlafqualität assoziiert war. Für die anderen beiden Studien setzten wir bildgebende Verfahren (funktionelle Magnetresonanztomografie) ein, da sowohl Schlafmangel als auch psychosozialer Stress nachweislich einen Einfluss auf die neuronale Aktivität und funktionelle Konnektivität während der Erholung von Stress haben. In Studie 2 konzentrierten wir uns auf die Replikation von früheren Studienergebnissen, die eine stressbedingte Steigerung der Konnektivität zwischen der Amygdala und Gehirnregionen fanden, die in die Herabregulation der physiologischen Stressantwort, in die emotionale Antwort, und die Gedächtniskonsolidierung involviert sind. In der Phase nach einem Stressor fanden wir im Vergleich zu vor dem Stressor eine gesteigerte bilaterale Konnektivität der Amygdala zum posterioren cingulären Cortex (PCC) und dem angrenzenden Precuneus nur in männlichen Teilnehmern ohne Cortisolreaktion im Vergleich zu männlichen Teilnehmern mit einer Cortisolreaktion. Bei weiblichen Teilnehmerinnen fanden sich keine Unterschiede in funktioneller Konnektivität. Die Ergebnisse unterstreichen die Relevanz von Geschlecht und Cortisolraktion beim Betrachten der Erholungsphase nach Stress. Studie 3 erweitert die Ergebnisse aus Studie 2, indem nur bei männlichen Teilnehmern zusätzlich den Einfluss von Schlafmangel auf die neuronale Erholung von Stress untersuchten. Die Auswertung zeigte eine negative Assoziation zwischen Schlafmangel, der in einem siebentägigen Tagebuch festgehalten wurde, und der stressbedingten funktionelle Konnektivtät der linke Amygdala zu mehreren Gehirnregionen, u.a. dem medialen Präfrontalcortex, dem dorsolateralen Präfrontalcortex, dem dorsalen anterioren cingulären Cortex, der anterioren Insula, und dem PCC. Das bedeutet, je mehr Schlafmangel berichtet wurde, desto schwächer war die funktionelle Konnektivität der linken Amygdala zu den genannten Regionen. Zusammengefasst tragen die Ergebnisse der Doktorarbeit zu einem besseren Verständnis des Zusammenhangs von Schlaf, Stress und psychologischem Wohlbefinden auf sowohl Verhaltens. als auch neuronaler Ebene bei

Nano/Meso-scale principles and applications with flexibility: From delivery and self-recognition to differentiation

From viruses to tissue matrices, biology is filled with remarkable polymeric structures that motivate mimicry with goals of both clarifying and exploiting biological principles. Filamentous viruses inspired our development and computations of worm-like polymer micelles – ‘filomicelles’ – that persist in the circulation and deliver even better than spheres [1]. However, particles of any type interact with innate immune phagocytes while nearby ‘Self’ cells are spared due to a polypeptide that limits phagocytic clearance [2]. The phagocyte’s cytoskeleton forcibly drives the decision downstream of adhesion, proving analogous to how matrix elasticity directs stem cell fate [3, 4]. Key Words: block copolymer, self-assembly, shape, immunocompatability, differentiation References [1] Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko, and D.E. Discher. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnology (2007) 2: 249-255. [2] P.L. Rodriguez, T. Harada, D.A. Christian, D.A. Pantano, R.K. Tsai, and D.E. Discher. Minimal \u27Self\u27 peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science (2013) 339: 971-975. [3] A. Engler, S. Sen, H.L. Sweeey, and D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell (2006) 126: 677-689. [4] J. Swift, I.L. Ivanovska, … and D.E. Discher. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-directed Differentiation. Science (2013) 341: 1240104-1 to 15

Molecular Weight Dependence of Polymersome Membrane Elasticity and Stability

Vesicles prepared in water from a series of diblock copolymers and termed "polymersomes" are physically characterized. With increasing molecular weight $\bar{M}_n$, the hydrophobic core thickness $d$ for the self-assembled bilayers of polyethyleneoxide - polybutadiene (PEO-PBD) increases up to 20 $nm$ - considerably greater than any previously studied lipid system. The mechanical responses of these membranes, specifically, the area elastic modulus $K_a$ and maximal areal strain $\alpha_c$ are measured by micromanipulation. As expected for interface-dominated elasticity, $K_a$ ($\simeq$ 100 $pN/nm$) is found to be independent of $\bar{M}_n$. Related mean-field ideas also predict a limiting value for $\alpha_c$ which is universal and about 10-fold above that typical of lipids. Experiments indeed show $\alpha_c$ generally increases with $\bar{M}_n$, coming close to the theoretical limit before stress relaxation is opposed by what might be chain entanglements at the highest $\bar{M}_n$. The results highlight the interfacial limits of self-assemblies at the nano-scale.Comment: 16 pages, 5 figures, and 1 tabl

The RHMC Algorithm for 2 Flavours of Dynamical Staggered Fermions

We describe an implementation of the Rational Hybrid Monte Carlo (RHMC) algorithm for dynamical computations with two flavours of staggered quarks. We discuss several variants of the method, the performance and possible sources of error for each of them, and we compare the performance and results to the inexact R algorithm.Comment: Lattice2003(machine) 3 pages, 1 figure. Added referenc

Polymersomes

Polymersomes are self-assembled polymer shells composed of block copolymer amphiphiles. These synthetic amphiphiles have amphiphilicity similar to lipids, but they have much larger molecular weights, so for this reason — along with others reviewed here — comparisons of polymersomes with viral capsids composed of large polypeptide chains are highly appropriate. We summarize the wide range of polymers used to make polymersomes along with descriptions of physical properties such as stability and permeability. We also elaborate on emerging studies of in vivo stealthiness, programmed disassembly for controlled release, targeting in vitro, and tumor-shrinkage in vivo. Comparisons of polymersomes with viral capsids are shown to encompass and inspire many aspects of current designs