ResearchPad - mass-diffusivity https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Concept of an artificial muscle design on polypyrrole nanofiber scaffolds]]> https://www.researchpad.co/article/elastic_article_8464 Here we present the synthesis and characterization of two new conducting materials having a high electro-chemo-mechanical activity for possible applications as artificial muscles or soft smart actuators in biomimetic structures. Glucose-gelatin nanofiber scaffolds (CFS) were coated with polypyrrole (PPy) first by chemical polymerization followed by electrochemical polymerization doped with dodecylbenzensulfonate (DBS-) forming CFS-PPy/DBS films, or with trifluoromethanesulfonate (CF3SO3-, TF) giving CFS-PPy/TF films. The composition, electronic and ionic conductivity of the materials were determined using different techniques. The electro-chemo-mechanical characterization of the films was carried out by cyclic voltammetry and square wave potential steps in bis(trifluoromethane)sulfonimide lithium solutions of propylene carbonate (LiTFSI-PC). Linear actuation of the CFS-PPy/DBS material exhibited 20% of strain variation with a stress of 0.14 MPa, rather similar to skeletal muscles. After 1000 cycles, the creeping effect was as low as 0,2% having a good long-term stability showing a strain variation per cycle of -1.8% (after 1000 cycles). Those material properties are excellent for future technological applications as artificial muscles, batteries, smart membranes, and so on.

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<![CDATA[The tumor suppressor p53 can promote collective cellular migration]]> https://www.researchpad.co/article/5c5df35cd5eed0c4845811ac

Loss of function of the tumor suppressor p53 is known to increase the rate of migration of cells transiting the narrow pores of the traditional Boyden chamber assay. Here by contrast we investigate how p53 impacts the rate of cellular migration within a 2D confluent cell layer and a 3D collagen-embedded multicellular spheroid. We use two human carcinoma cell lines, the bladder carcinoma EJ and the colorectal carcinoma HCT116. In the confluent 2-D cell layer, for both EJ and HCT cells the migratory speeds and effective diffusion coefficients for the p53 null cells were significantly smaller than in p53-expressing cells. Compared to p53 expressers, p53-null cells exhibited more organized cortical actin rings together with reduced front-rear cell polarity. Furthermore, loss of p53 caused cells to exert smaller traction forces upon their substrates, and reduced formation of cryptic lamellipodia. In the 3D multicellular spheroid, loss of p53 consistently reduced collective cellular migration into surrounding collagen matrix. As regards the role of p53 in cellular migration, extrapolation from the Boyden chamber assay to other cellular microenvironments is seen to be fraught even in terms of the sign of the effect. Together, these paradoxical results show that the effects of p53 on cellular migration are context-dependent.

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<![CDATA[Optimal diameter reduction ratio of acinar airways in human lungs]]> https://www.researchpad.co/article/5c5ca2ead5eed0c48441ed50

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murray’s law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murray’s law over an entire human lung.

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<![CDATA[Paxillin phosphorylation at serine 273 and its effects on Rac, Rho and adhesion dynamics]]> https://www.researchpad.co/article/5b4a1919463d7e428027f887

Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signalling proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly. Paxillin is known to bind to a GIT1-βPIX-PAK1 complex, which increases the local activation of the small GTPase Rac. To understand quantitatively the behaviour of this system and how it relates to adhesion assembly/disassembly, we developed a mathematical model describing the dynamics of the small GTPases Rac and Rho as determined by paxillin S273 phosphorylation. Our model revealed that the system possesses bistability, where switching between uninduced (active Rho) and induced (active Rac) states can occur through a change in rate of paxillin phosphorylation or PAK1 activation. The bistable switch is characterized by the presence of memory, minimal change in the levels of active Rac and Rho within the induced and uninduced states, respectively, and the limited regime of monostability associated with the uninduced state. These results were validated experimentally by showing the presence of bimodality in adhesion assembly and disassembly rates, and demonstrating that Rac activity increases after treating Chinese Hamster Ovary cells with okadaic acid (a paxillin phosphatase inhibitor), followed by a modest recovery after 20 min washout. Spatial gradients of phosphorylated paxillin in a reaction-diffusion model gave rise to distinct regions of Rac and Rho activities, resembling polarization of a cell into front and rear. Perturbing several parameters of the model also revealed important insights into how signalling components upstream and downstream of paxillin phosphorylation affect dynamics.

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<![CDATA[Static and Dynamic Postural Changes after a Mountain Ultra-Marathon of 80 km and 5500 D+]]> https://www.researchpad.co/article/5989db07ab0ee8fa60bc89e8

The study aimed to investigate the effect of fatigue on static and dynamic postural stability after completing a mountain ultra-marathon. Twelve male athletes participated in the study. Postural stability was assessed before and immediately after the race. Static postural stability was evaluated on a dynamometric platform with eyes opened (OE) and closed (CE). Dynamic postural stability was assessed with OE on an instrumented plate which allowed medio-lateral oscillations. Stabilometric data were affected by fatigue in the OE condition, concerning sway path velocity (p = 0.0006), sway area velocity (p = 0.0006), area of the confidence ellipse (p = 0.0016), maximal anterior-posterior (AP) (p = 0.0017) and medio-lateral (ML) (p = 0.0039) oscillations. In the CE condition the sway path velocity (p = 0.0334), the maximal ML oscillations (p = 0.0161) and the area of the confident ellipse (p = 0.0180) were also negatively influenced. Stabilogram diffusion analysis showed in the OE condition an increase of short-term diffusion coefficients considering the anterior-posterior direction (Dfys; p = 0.0023) and the combination of the two (Dfr2s; p = 0.0032). Equally, long term diffusion coefficients increased considering the anterior-posterior direction (Dfyl; p = 0.0093) and the combination of the two (Dfr2l; p = 0.0086). In CE condition greater values were detected for medio-lateral direction (Dfxl; p = 0.033), anterior-posterior direction (Dfyl; p = 0.0459) and the combination of the two (Dfr2l; p = 0.0048). The dynamic postural stability test showed an increase of the time spent with the edges of the plate on the floor (p = 0.0152). Our results showed that mountain ultra-marathon altered static stability more than dynamic stability. An involvement of cognitive resources to monitor postural stability after fatiguing could be the explanation of the worsening in the automatic task (quiet standing) and of the positive compensation in the less automatic task (dynamic standing on the instrumented plate).

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<![CDATA[Evidences of Changes in Surface Electrostatic Charge Distribution during Stabilization of HPV16 Virus-Like Particles]]> https://www.researchpad.co/article/5989d9ddab0ee8fa60b685e9

The stabilization of human papillomavirus type 16 virus-like particles has been examined by means of different techniques including dynamic and static light scattering, transmission electron microscopy and electrophoretic mobility. All these techniques provide different and often complementary perspectives about the aggregation process and generation of stabilized virus-like particles after a period of time of 48 hours at a temperature of 298 K. Interestingly, static light scattering results point towards a clear colloidal instability in the initial systems, as suggested by a negative value of the second virial coefficient. This is likely related to small repulsive electrostatic interactions among the particles, and in agreement with relatively small absolute values of the electrophoretic mobility and, hence, of the net surface charges. At this initial stage the small repulsive interactions are not able to compensate binding interactions, which tend to aggregate the particles. As time proceeds, an increase of the size of the particles is accompanied by strong increases, in absolute values, of the electrophoretic mobility and net surface charge, suggesting enhanced repulsive electrostatic interactions and, consequently, a stabilized colloidal system. These results show that electrophoretic mobility is a useful methodology that can be applied to screen the stabilization factors for virus-like particles during vaccine development.

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<![CDATA[A mathematical model of aortic aneurysm formation]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdca9d

Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta, such that the diameter exceeds 3 cm. The natural history of AAA is progressive growth leading to rupture, an event that carries up to 90% risk of mortality. Hence there is a need to predict the growth of the diameter of the aorta based on the diameter of a patient’s aneurysm at initial screening and aided by non-invasive biomarkers. IL-6 is overexpressed in AAA and was suggested as a prognostic marker for the risk in AAA. The present paper develops a mathematical model which relates the growth of the abdominal aorta to the serum concentration of IL-6. Given the initial diameter of the aorta and the serum concentration of IL-6, the model predicts the growth of the diameter at subsequent times. Such a prediction can provide guidance to how closely the patient’s abdominal aorta should be monitored. The mathematical model is represented by a system of partial differential equations taking place in the aortic wall, where the media is assumed to have the constituency of an hyperelastic material.

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<![CDATA[Colony Expansion of Socially Motile Myxococcus xanthus Cells Is Driven by Growth, Motility, and Exopolysaccharide Production]]> https://www.researchpad.co/article/5989da30ab0ee8fa60b8448a

Myxococcus xanthus, a model organism for studies of multicellular behavior in bacteria, moves exclusively on solid surfaces using two distinct but coordinated motility mechanisms. One of these, social (S) motility is powered by the extension and retraction of type IV pili and requires the presence of exopolysaccharides (EPS) produced by neighboring cells. As a result, S motility requires close cell-to-cell proximity and isolated cells do not translocate. Previous studies measuring S motility by observing the colony expansion of cells deposited on agar have shown that the expansion rate increases with initial cell density, but the biophysical mechanisms involved remain largely unknown. To understand the dynamics of S motility-driven colony expansion, we developed a reaction-diffusion model describing the effects of cell density, EPS deposition and nutrient exposure on the expansion rate. Our results show that at steady state the population expands as a traveling wave with a speed determined by the interplay of cell motility and growth, a well-known characteristic of Fisher’s equation. The model explains the density-dependence of the colony expansion by demonstrating the presence of a lag phase–a transient period of very slow expansion with a duration dependent on the initial cell density. We propose that at a low initial density, more time is required for the cells to accumulate enough EPS to activate S-motility resulting in a longer lag period. Furthermore, our model makes the novel prediction that following the lag phase the population expands at a constant rate independent of the cell density. These predictions were confirmed by S motility experiments capturing long-term expansion dynamics.

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<![CDATA[The Neurite Outgrowth Inhibitory Nogo-A-Δ20 Region Is an Intrinsically Disordered Segment Harbouring Three Stretches with Helical Propensity]]> https://www.researchpad.co/article/5989db2cab0ee8fa60bd18bf

Functional recovery from central neurotrauma, such as spinal cord injury, is limited by myelin-associated inhibitory proteins. The most prominent example, Nogo-A, imposes an inhibitory cue for nerve fibre growth via two independent domains: Nogo-A-Δ20 (residues 544–725 of the rat Nogo-A sequence) and Nogo-66 (residues 1026–1091). Inhibitory signalling from these domains causes a collapse of the neuronal growth cone via individual receptor complexes, centred around sphingosine 1-phosphate receptor 2 (S1PR2) for Nogo-A-Δ20 and Nogo receptor 1 (NgR1) for Nogo-66. Whereas the helical conformation of Nogo-66 has been studied extensively, only little structural information is available for the Nogo-A-Δ20 region. We used nuclear magnetic resonance (NMR) spectroscopy to assess potential residual structural propensities of the intrinsically disordered Nogo-A-Δ20. Using triple resonance experiments, we were able to assign 94% of the non-proline backbone residues. While secondary structure analysis and relaxation measurements highlighted the intrinsically disordered character of Nogo-A-Δ20, three stretches comprising residues 561EAIQESL567, 639EAMNVALKALGT650, and 693SNYSEIAK700 form transient α-helical structures. Interestingly, 561EAIQESL567 is situated directly adjacent to one of the most conserved regions of Nogo-A-Δ20 that contains a binding motif for β1-integrin. Likewise, 639EAMNVALKALGT650 partially overlaps with the epitope recognized by 11C7, a Nogo-A-neutralizing antibody that promotes functional recovery from spinal cord injury. Diffusion measurements by pulse-field gradient NMR spectroscopy suggest concentration- and oxidation state-dependent dimerisation of Nogo-A-Δ20. Surprisingly, NMR and isothermal titration calorimetry (ITC) data could not validate previously shown binding of extracellular loops of S1PR2 to Nogo-A-Δ20.

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<![CDATA[Dynamic Nucleosome Movement Provides Structural Information of Topological Chromatin Domains in Living Human Cells]]> https://www.researchpad.co/article/5989da17ab0ee8fa60b7b89e

The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory. We analytically show that the mean-squared displacement (MSD) of nucleosome fluctuations within CDs is subdiffusive. The diffusion coefficient and the subdiffusive exponent depend on the structural information of CDs. This analytical result enabled us to extract information from the single-nucleosome imaging data for HeLa cells. Our observation that the MSD is lower at the nuclear periphery region than the interior region indicates that CDs in the heterochromatin-rich nuclear periphery region are more compact than those in the euchromatin-rich interior region with respect to the fractal dimensions as well as the size. Finally, we evaluated that the average size of CDs is in the range of 100–500 nm and that the relaxation time of nucleosome movement within CDs is a few seconds. Our results provide physical and dynamic insights into the genome architecture in living cells.

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<![CDATA[Diffusion and Binding of Mismatch Repair Protein, MSH2, in Breast Cancer Cells at Different Stages of Neoplastic Transformation]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdbba5

The interior of cells is a highly complex medium, containing numerous organelles, a matrix of different fibers and a viscous, aqueous fluid of proteins and small molecules. The interior of cells is also a highly dynamic medium, in which many components move, either by active transport or passive diffusion. The mobility and localization of proteins inside cells can provide important insights into protein function and also general cellular properties, such as viscosity. Neoplastic transformation affects numerous cellular properties, and our goal was to investigate the diffusional and binding behavior of the important mismatch repair (MMR) protein MSH2 in live human cells at various stages of neoplastic transformation. Toward this end, noncancerous, immortal, tumorigenic, and metastatic mammary epithelial cells were transfected with EGFP and EGFP-tagged MSH2. MSH2 forms two MMR proteins (MutSα and MutSβ) and we assume MSH2 is in the complex MutSα, though our results are similar in either case. Unlike the MutS complexes that bind to nuclear DNA, EGFP diffuses freely. EGFP and MutSα-EGFP diffusion coefficients were determined in the cytoplasm and nucleus of each cell type using fluorescence recovery after photobleaching. Diffusion coefficients were 14–24 μm2/s for EGFP and 3–7 μm2/s for MutSα-EGFP. EGFP diffusion increased in going from noncancerous to immortal cells, indicating a decrease in viscosity, with smaller changes in subsequent stages. MutSα produces an effective diffusion coefficient that, coupled with the free EGFP diffusion measurements, can be used to extract a pure diffusion coefficient and a pseudo-equilibrium constant K*. The MutSα nuclear K* increased sixfold in the first stage of cancer and then decreased in the more advanced stages. The ratio of nuclear to cytoplasmic K*for MutSα increased almost two orders of magnitude in going from noncancerous to immortal cells, suggesting that this quantity may be a sensitive metric for recognizing the onset of cancer.

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<![CDATA[Soret and Dufour Effects on MHD Peristaltic Flow of Jeffrey Fluid in a Rotating System with Porous Medium]]> https://www.researchpad.co/article/5989da6fab0ee8fa60b94646

The objective of present paper is to examine the peristaltic flow of magnetohydrodynamic (MHD) Jeffrey fluid saturating porous space in a channel through rotating frame. Unlike the previous attempts, the flow formulation is based upon modified Darcy's law porous medium effect in Jeffrey fluid situation. In addition the impacts due to Soret and Dufour effects in the radiative peristaltic flow are accounted. Rosseland’s approximation has been utilized for the thermal radiative heat flux. Lubrication approach is implemented for the simplification. Resulting problems are solved for the stream function, temperature and concentration. Graphical results are prepared and analyzed for different parameters of interest entering into the problems.

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<![CDATA[The Power of Heterogeneity: Parameter Relationships from Distributions]]> https://www.researchpad.co/article/5989da6cab0ee8fa60b93499

Complex scientific data is becoming the norm, many disciplines are growing immensely data-rich, and higher-dimensional measurements are performed to resolve complex relationships between parameters. Inherently multi-dimensional measurements can directly provide information on both the distributions of individual parameters and the relationships between them, such as in nuclear magnetic resonance and optical spectroscopy. However, when data originates from different measurements and comes in different forms, resolving parameter relationships is a matter of data analysis rather than experiment. We present a method for resolving relationships between parameters that are distributed individually and also correlated. In two case studies, we model the relationships between diameter and luminescence properties of quantum dots and the relationship between molecular weight and diffusion coefficient for polymers. Although it is expected that resolving complicated correlated relationships require inherently multi-dimensional measurements, our method constitutes a useful contribution to the modelling of quantitative relationships between correlated parameters and measurements. We emphasise the general applicability of the method in fields where heterogeneity and complex distributions of parameters are obstacles to scientific insight.

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<![CDATA[Classification and Segmentation of Nanoparticle Diffusion Trajectories in Cellular Micro Environments]]> https://www.researchpad.co/article/5989db54ab0ee8fa60bdcfb9

Darkfield and confocal laser scanning microscopy both allow for a simultaneous observation of live cells and single nanoparticles. Accordingly, a characterization of nanoparticle uptake and intracellular mobility appears possible within living cells. Single particle tracking allows to measure the size of a diffusing particle close to a cell. However, within the more complex system of a cell’s cytoplasm normal, confined or anomalous diffusion together with directed motion may occur. In this work we present a method to automatically classify and segment single trajectories into their respective motion types. Single trajectories were found to contain more than one motion type. We have trained a random forest with 9 different features. The average error over all motion types for synthetic trajectories was 7.2%. The software was successfully applied to trajectories of positive controls for normal- and constrained diffusion. Trajectories captured by nanoparticle tracking analysis served as positive control for normal diffusion. Nanoparticles inserted into a diblock copolymer membrane was used to generate constrained diffusion. Finally we segmented trajectories of diffusing (nano-)particles in V79 cells captured with both darkfield- and confocal laser scanning microscopy. The software called “TraJClassifier” is freely available as ImageJ/Fiji plugin via https://git.io/v6uz2.

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<![CDATA[Theory on the Mechanism of DNA Renaturation: Stochastic Nucleation and Zipping]]> https://www.researchpad.co/article/5989daefab0ee8fa60bc0acb

Renaturation of the complementary single strands of DNA is one of the important processes that requires better understanding in the view of molecular biology and biological physics. Here we develop a stochastic dynamical model on the DNA renaturation. According to our model there are at least three steps in the renaturation process viz. nonspecific-contact formation, correct-contact formation and nucleation, and zipping. Most of the earlier two-state models combined nucleation with nonspecific-contact formation step. In our model we suggest that it is considerably meaningful when we combine the nucleation with the zipping since nucleation is the initial step of zipping and nucleated and zipping molecules are indistinguishable. Nonspecific contact formation step is a pure three-dimensional diffusion controlled collision process. Whereas nucleation involves several rounds of one-dimensional slithering and internal displacement dynamics of one single strand of DNA on the other complementary strand in the process of searching for the correct-contact and then initiate nucleation. Upon nucleation, the stochastic zipping follows to generate a fully renatured double stranded DNA. It seems that the square-root dependency of the overall renaturation rate constant on the length of reacting single strands originates mainly from the geometric constraints in the diffusion controlled nonspecific-contact formation step. Further the inverse scaling of the renaturation rate on the viscosity of reaction medium also originates from nonspecific contact formation step. On the other hand the inverse scaling of the renaturation rate with the sequence complexity originates from the stochastic zipping which involves several rounds of crossing over the free-energy barrier at microscopic levels. When the sequence of renaturing single strands of DNA is repetitive with less complexity then the cooperative effects will not be noticeable since the parallel zipping will be a dominant enhancing factor. However for DNA strands with high sequence complexity and length one needs to consider the underlying cooperative effects both at microscopic and macroscopic levels to explain various scaling behaviours of the overall renaturation rate.

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<![CDATA[In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis]]> https://www.researchpad.co/article/5989db5fab0ee8fa60be1381

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.

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<![CDATA[Turing Patterning Using Gene Circuits with Gas-Induced Degradation of Quorum Sensing Molecules]]> https://www.researchpad.co/article/5989db27ab0ee8fa60bd08cb

The Turing instability was proposed more than six decades ago as a mechanism leading to spatial patterning, but it has yet to be exploited in a synthetic biology setting. Here we characterize the Turing instability in a specific gene circuit that can be implemented in vitro or in populations of clonal cells producing short-range activator N-Acyl homoserine lactone (AHL) and long-range inhibitor hydrogen peroxide (H2O2) gas. Slowing the production rate of the AHL-degrading enzyme, AiiA, generates stable fixed states, limit cycle oscillations and Turing patterns. Further tuning of signaling parameters determines local robustness and controls the range of unstable wavenumbers in the patterning regime. These findings provide a roadmap for optimizing spatial patterns of gene expression based on familiar quorum and gas sensitive E. coli promoters. The circuit design and predictions may be useful for (re)programming spatial dynamics in synthetic and natural gene expression systems.

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<![CDATA[Impact of Cattaneo-Christov Heat Flux in Jeffrey Fluid Flow with Homogeneous-Heterogeneous Reactions]]> https://www.researchpad.co/article/5989da77ab0ee8fa60b97240

Two-dimensional stretched flow of Jeffrey fluid in view of Cattaneo-Christov heat flux is addressed. Effects of homogeneous-heterogeneous reactions are also considered. Suitable transformations are used to form ordinary differential equations. Convergent series solutions are computed. Impact of significant parameters on the velocity, temperature, concentration and skin friction coefficient is addressed. Analysis of thermal relaxation is made. The obtained results show that ratio of relaxation to retardation times and Deborah number have inverse relation for velocity profile. Temperature distribution has decreasing behavior for Prandtl number and thermal relaxation time. Also concentration decreases for larger values of strength of homogeneous reaction parameter while it increases for strength of heterogeneous reaction parameter.

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<![CDATA[Single Molecule Studies of the Diffusion of Band 3 in Sickle Cell Erythrocytes]]> https://www.researchpad.co/article/5989da87ab0ee8fa60b9c898

Sickle cell disease (SCD) is caused by an inherited mutation in hemoglobin that leads to sickle hemoglobin (HbS) polymerization and premature HbS denaturation. Previous publications have shown that HbS denaturation is followed by binding of denatured HbS (a.k.a. hemichromes) to band 3, the consequent clustering of band 3 in the plane of the erythrocyte membrane that in turn promotes binding of autologous antibodies to the clustered band 3, and removal of the antibody-coated erythrocytes from circulation. Although each step of the above process has been individually demonstrated, the fraction of band 3 that is altered by association with denatured HbS has never been determined. For this purpose, we evaluated the lateral diffusion of band 3 in normal cells, reversibly sickled cells (RSC), irreversibly sickled cells (ISC), and hemoglobin SC erythrocytes (HbSC) in order to estimate the fraction of band 3 that was diffusing more slowly due to hemichrome-induced clustering. We labeled fewer than ten band 3 molecules per intact erythrocyte with a quantum dot to avoid perturbing membrane structure and we then monitored band 3 lateral diffusion by single particle tracking. We report here that the size of the slowly diffusing population of band 3 increases in the sequence: normal cells<HbSC<RSC<ISC. We also demonstrate that the size of the compartment in which band 3 is free to diffuse decreases roughly in the same order, with band 3 diffusing in two compartments of sizes 35 and 71 nm in normal cells, but only a single compartment in HbSC cells (58 nm), RSC (45 nm) and ISC (36 nm). These data suggest that the mobility of band 3 is increasingly constrained during SCD progression, suggesting a global impact of the mutated hemoglobin on erythrocyte membrane properties.

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<![CDATA[Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be0015

In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose.

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