Effective Interactions between Multilayered Ionic Microgels

Using a one-component reduction formalism, we calculate the effective interactions and the counterion density profiles for microgels that feature a multilayered shell structure. We follow a strategy that involves second order perturbation theory and obtain analytical expressions for the effective interactions by modeling the layers of the particles as linear superpostion of homogeneously charged spheres. The general method is applied to the important case of core–shell microgels and compared with the well-known results for a microgel that can be approximated by a macroscopic, and homogeneously charged, spherical macroion.     

Interactions between host and gut microbiota in domestic pigs: a review

ABSTRACT

It is well established that pig gut microbiota plays a critical role in maintaining metabolic homeostasis as well as in a myriad of physiological, neurological and immunological functions; including protection from pathogens and digestion of food materials – some of which would be otherwise indigestible by the pig. A rich and diverse gut microbial ecosystem (balanced microbiota) is the hallmark of good health; while qualitative and quantitative perturbations in the microbial composition can lead to development of various diseases. Alternatively, diseases caused by stressors or other factors have been shown to negatively impact the microbiota. This review focuses primarily on how commensal microorganisms in the gastrointestinal tract of pigs influence biochemical, physiological, immunological, and metabolic processes within the host animal.     

Interactions between epithelial and mesenchymal cells in intrahepatic peribiliary glands in normal and hepatolithiatic livers

The anatomy and pathology of the intrahepatic peribiliary glands were evaluated. In this study, we ultrastructuraly examined the peribiliary glands of normal and hepatolithiatic livers using common and serial ultrathin section observations. It is well known that these glands proliferate markedly in hepatolithiasis. These glands were composed of several acini surrounded by thickened and multilayered basement membranes, and there were mesenchymal cells (the majority were fibroblasts) in the periacinar fibrous connective tissue. Some cytoplasmic processes of acinar epithelial cells and mesenchymal cells in the periacinar connective tissue were in close contact with each other within the thickened and multilayered basement membranes. Such cell-to-cell interaction was most frequent in cases of hepatolithiasis, in which peribiliary glands proliferated markedly. In hepatolithiatic livers, some unmyelinated nerve fibers or axonal button profiles were in close contact with periacinar mesenchymal cells and also with cytoplasmic processes of glandular epithelial cells. Such contacts were rare in normal livers. These findings suggest that such epithelial and mesenchymal cell interactions and innervations play a part in the normal regulation of peribiliary glands and also in the proliferation of peribiliary galnds in hepatolithiasis.     

Modafinil and Cocaine Interactions

This Phase I trial evaluated the interaction between modafinil steady-state and cocaine. Twelve non-treatment seeking, cocaine dependent volunteers received four sets of randomized blinded infusions of saline, 20 mg IV cocaine, and 40 mg IV cocaine. Modafinil was given open label at 0 mg, 400 mg, or 800 mg. Modafinil combined with IV cocaine did not result in any significant hemodynamic interactions. Modafinil significantly dampened scores on Visual Analog Scale measures as compared to baseline cocaine conditions. No significant alterations in labs occurred. Further outpatient trials of modafinil appear to be warranted.     

Interactions between a rapid atrial stimulator and a multiprogrammable ventricular demand pacemaker

A patient with drug-resistant supraventricular tachycardia was well controlled for 8 years with a patient-activated rapid atrial pacemaker until she developed symptomatic bradycardic episodes. A multiprogrammable ventricular pacemaker was implanted. Assessment of the interactions between the two pacemakers demonstrated inhibition of VVI pacing by the atrial stimulator initially. Two months after implant no interaction was seen. At no time was VVT pacing affected by the atrial stimulator. Thus, interactions between these two units can occur and a multiprogrammable pacemaker should be used in this situation as it offers the flexibility to minimize any interaction that might be present.     

Interactions between the leukaemia-associated ETO homologues of nuclear repressor proteins

The eight-twenty-one (ETO) homologues, represented by ETO, myeloid transforming gene-related protein 1 (MTGR1) and myeloid transforming gene chromosome 16 (MTG16), are nuclear repressor proteins. ETO is part of the fusion protein acute myeloid leukaemia (AML)1-ETO, resulting from the translocation (8;21). Similarly, MTG16 is disrupted to become part of AML1/MTG16 in t(16;21). The aberrant expression of these chimeras could affect interplay between ETO homologues and contribute to the leukaemogenic process. We investigated possible interactions between the ETO homologues. Ectopic co-expression in COS-cells resulted in heterodimerisation of the various ETO homologues suggesting that they may co-operate. Similarly, the chimeric oncoprotein AML1-ETO interacted with both MTGR1 and MTG16. However, results from cell lines endogenously expressing more than one ETO homologue did not demonstrate co-precipitation. Results from IP-Western and size determination by gel filtration of deletion mutants expressed in COS-cells, indicated an important role of the HHR domain for oligomerisation. A role was also suggested for the Nervy domain in the homologue interactions. Our results suggest that ETO homologues can interact with each other as well as with AML1-ETO, although it is unclear as to what extent these interactions occur in vivo.     

Twins and the mystery of missing heritability: the contribution of gene–environment interactions

Since 2006, the advent of increasingly larger genome‐wide association studies and their meta‐analyses have led to numerous, replicated findings of genetic polymorphisms associated with many diseases and traits. Early studies suggested that the identified loci generally accounted for a small fraction of the genetic variance estimated from twin and family studies. This led to the concept of ‘missing heritability’. Here, the progress in accounting for a greater proportion of the variance is reviewed. In particular, gene–environment interactions can, for some traits and in certain circumstances, explain part of this missing heritability.     

Cell-to-Cell Electrical Interactions During Early and Late Repolarization

Cardiac electrical activity is significantly affected by variations in the conductance of gap junctions that connect myocytes to one another. To better understand how intrinsic (single cell) electrical activity is modulated by junctional conductance, we used a two-myocyte coupling system in which physically separate cells were electrically coupled via a variable resistance set by the investigator. This brief review summarizes our findings regarding: (1) the effect of the early phase of action potential repolarization (phase 1) and transient outward current ( I _to) on action potential conduction, and (2) the effect of coupling on the action potential plateau (late repolarization). We found that inhibition of I _to markedly increased the ability of action potentials to propagate from cell-to-cell when junctional conductance was low. Electrically coupling two myocytes together also suppressed their beat-to-beat variability in action potential duration and contraction. Similarly, early afterdepolarizations (EADS) were readily suppressed by connecting a normal myocyte to one generating EADs. This high sensitivity of the plateau to variations in junctional interactions arises from the large increase in membrane resistance that occurs during this phase of the action potential.     

Interactions between lymphocytes and hematopoietic progenitor cells in normal and leukemic human bone marrow (phase contrast observations)

Summary Single cell observations of normal and of leukemic human bone marrow cells demonstrated cell-cell interactions of lymphocytes with hematopoietic progenitor cells. In all cases lymphocytes and target cells were from the same individual. Lymphocyte-target cell interactions occurred more frequently with normal committed progenitor cells and leukemic blast cells from acute myeloid leukemia than with precursor cells of the proliferative cell pool, including granuloblasts, promonocytes, erythroblasts and megakaryocytes. Both induction of mitosis and degeneration of the progenitor cells occurred after cell-cell interaction with almost the same frequency. Acute myeloid leukemic blast cells degenerated after contact with lymphocytes with the same frequency as normal progenitor cells (i.e. in 16% of cell contacts), but especially during mitosis. In contrast, normal and regenerating bone marrow progenitor cells from myeloproliferative diseases demonstrated no degeneration after cell-cell interaction with lymphocytes during mitosis. Otherwise the induction of mitoses by lymphocyte-target cell interactions was more frequently observed in normal progenitor cells than in leukemic blasts.With technical assistance of Miss C. DomeyerSupported by Deutsche Forschungsgemeinschaft     

Interactions between zebrafish pigment cells responsible for the generation of Turing patterns

The reaction–diffusion system is one of the most studied nonlinear mechanisms that generate spatially periodic structures autonomous. On the basis of many mathematical studies using computer simulations, it is assumed that animal skin patterns are the most typical examples of the Turing pattern (stationary periodic pattern produced by the reaction–diffusion system). However, the mechanism underlying pattern formation remains unknown because the molecular or cellular basis of the phenomenon has yet to be identified. In this study, we identified the interaction network between the pigment cells of zebrafish, and showed that this interaction network possesses the properties necessary to form the Turing pattern. When the pigment cells in a restricted region were killed with laser treatment, new pigment cells developed to regenerate the striped pattern. We also found that the development and survival of the cells were influenced by the positioning of the surrounding cells. When melanophores and xanthophores were located at adjacent positions, these cells excluded one another. However, melanophores required a mass of xanthophores distributed in a more distant region for both differentiation and survival. Interestingly, the local effect of these cells is opposite to that of their effects long range. This relationship satisfies the necessary conditions required for stable pattern formation in the reaction–diffusion model. Simulation calculations for the deduced network generated wild-type pigment patterns as well as other mutant patterns. Our findings here allow further investigation of Turing pattern formation within the context of cell biology.     

Interactions between macrophages and helminths

Macrophages, the major population of tissue-resident mononuclear phagocytes, contribute significantly to the immune response during helminth infection. Alternatively activated macrophages (AAM) are induced early in the anti-helminth response following tissue insult and parasite recognition, amplifying the early type 2 immune cascade initiated by epithelial cells and ILC2s, and subsequently driving parasite expulsion. AAM also contribute to functional alterations in tissues infiltrated with helminth larvae, mediating both tissue repair and inflammation. Their activation is amplified and occurs more rapidly following reinfection, where they can play a dual role in trapping tissue migratory larvae and preventing or resolving the associated inflammation and damage. In this review, we will address both the known and emerging roles of tissue macrophages during helminth infection, in addition to considering both outstanding research questions and new therapeutic strategies.     

Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability

Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interactions between side chains—hydrophobic (Ala–Phe), polar (Ser–Asn) and charged (Lys–Glu)—are substantially altered in hydrophobic, water-filled nanopores, relative to bulk water. When the pore holds water at bulk density, the hydrophobic pair is strongly destabilized and is driven to large separations corresponding to the width and the length of the cylindrical pore. As the water density is reduced, the preference of Ala and Phe to be at the boundary decreases, and the contact pair is preferred. A model that accounts for the volume accessible to Phe and Ala in the solvent-depleted region near the pore boundary explains the simulation results. In the pore, the hydrogen-bonded interactions between Ser and Asn have an enhanced dependence on their relative orientations, as compared with bulk water. When the side chains of Lys and Glu are restrained to be side by side, parallel to each other, then salt bridge formation is promoted in the nanopore. Based on these results, we argue and demonstrate that for a generic amphiphilic sequence, cylindrical confinement is likely to enhance thermodynamic stability relative to the bulk.     

The Uncertainty Propagation for Carbon Atomic Interactions in Graphene under Resonant Vibration Based on Stochastic Finite Element Model

Graphene is one of the most promising two-dimensional nanomaterials with broad applications in many fields. However, the variations and fluctuations in the material and geometrical properties are challenging issues that require more concern. In order to quantify uncertainty and analyze the impacts of uncertainty, a stochastic finite element model (SFEM) is proposed to propagate uncertainty for carbon atomic interactions under resonant vibration. Compared with the conventional truss or beam finite element models, both carbon atoms and carbon covalent bonds are considered by introducing plane elements. In addition, the determined values of the material and geometrical parameters are expanded into the related interval ranges with uniform probability density distributions. Based on the SFEM, the uncertainty propagation is performed by the Monte Carlo stochastic sampling process, and the resonant frequencies of graphene are provided by finite element computation. Furthermore, the correlation coefficients of characteristic parameters are computed based on the database of SFEM. The vibration modes of graphene with the extreme geometrical values are also provided and analyzed. According to the computed results, the minimum and maximum values of the first resonant frequency are 0.2131 and 16.894 THz, respectively, and the variance is 2.5899 THz. The proposed SFEM is an effective method to propagate uncertainty and analyze the impacts of uncertainty in the carbon atomic interactions of graphene. The work in this paper provides an important supplement to the atomic interaction modeling in nanomaterials.     

Interactions between extracellular stimuli and excitation waves in an atrial reentrant loop

Introduction: The interactions between extracellular stimuli and excitation waves propagating in a reentrant loop are a complex function of stimulus parameters, structural properties, membrane state, and timing. Here the goal was a comprehensive understanding of the mechanisms and frequencies of the major interactions between the advancing excitation wave and a single extracellular stimulus, separated from issues of anatomic or geometric complexity. Methods and Results: A modernized computer model of a thin ring of uniform tissue that included a pair of extracellular stimulus electrodes (anode/cathode) was used to model one‐dimensional cardiac reentry. Questions and results included the following: (1) What are the major interactions between a stimulus and the reentrant propagation wave, and are they induced near the cathode or near the anode; and, for each interaction, what are the initiating amplitude range and timing interval? At the cathode, the well‐known mechanism of retrograde excitation terminated reentry; changes in timing or amplitude produced double‐wave reentry or phase reset. At the anode, termination occurred at different cells depending on stimulus amplitude. (2) Relatively how often did termination occur at the anode? For most stimulus amplitudes, termination occurred more often at the anode than at the cathode, although not always at the same cell. (3) With random timing, what is the probability of terminating reentry? Stimulation for 5 msec terminated reentry with a probability from 0% to approximately 10%, as a function of increasing stimulus amplitude. Conclusion: A single extracellular stimulus can initiate major changes in reentrant excitation via multiple mechanisms, even in a simple geometry. Termination of reentry, phase shifts, or double‐wave reentry each occurs over well‐defined ranges of stimulus amplitude and timing. (J Cardiovasc Electrophysiol, Vol. 14, pp. ***‐***, October 2003)     

Mutant libraries reveal negative design shielding proteins from supramolecular self-assembly and relocalization in cells

Understanding the molecular consequences of mutations in proteins is essential to map genotypes to phenotypes and interpret the increasing wealth of genomic data. While mutations are known to disrupt protein structure and function, their potential to create new structures and localization phenotypes has not yet been mapped to a sequence space. To map this relationship, we employed two homo-oligomeric protein complexes in which the internal symmetry exacerbates the impact of mutations. We mutagenized three surface residues of each complex and monitored the mutations’ effect on localization and assembly phenotypes in yeast cells. While surface mutations are classically viewed as benign, our analysis of several hundred mutants revealed they often trigger three main phenotypes in these proteins: nuclear localization, the formation of puncta, and fibers. Strikingly, more than 50% of random mutants induced one of these phenotypes in both complexes. Analyzing the mutant’s sequences showed that surface stickiness and net charge are two key physicochemical properties associated with these changes. In one complex, more than 60% of mutants self-assembled into fibers. Such a high frequency is explained by negative design: charged residues shield the complex from self-interacting with copies of itself, and the sole removal of the charges induces its supramolecular self-assembly. A subsequent analysis of several other complexes targeted with alanine mutations suggested that such negative design is common. These results highlight that minimal perturbations in protein surfaces’ physicochemical properties can frequently drive assembly and localization changes in a cellular context.

Understanding genotype to phenotype relationships is crucial to predict the molecular consequences of mutations (1). At the protein level, alanine scans have revealed how individual residues contribute to protein function, stability, and binding affinity (2–4). More recently, systematic mappings have been widely used to connect sequence variability to changes in protein structure (5, 6), stability (7–9), solubility (10), and functionality (2, 11–14). Similar efforts have been made to map the impact of mutations in protein–ligand (15, 16) and protein–protein interactions (17–21).However, mutations can impact proteins beyond their stability, function, or existing interactions with specific partners or ligands. Sequences can also encode how proteins distribute spatially in cells, either by addressing them to membrane-bound compartments (22) or by inducing their self-assembly into large polymeric structures (23–27) and membraneless compartments (28, 29). While changes in protein self-assembly and localization can serve a functional purpose in adaptation (30–36), they can also lead to disease (37). For example, the supramolecular self-assembly of hemoglobin and γD-crystallin cause sickle-cell disease and cataracts, respectively (38, 39). The mislocalization of nuclear proteins TDP-43 and FUS in the cytosol is associated with amyotrophic lateral sclerosis disease (40, 41), and the mislocalization of Ataxin-3 to the nucleus has been implicated in spinocerebellar ataxia type 3 disease (42). It is therefore critical to characterize principles by which mutations can trigger such supramolecular self-assembly and mislocalization.Symmetry is frequent in proteins (37, 43) and is a crucial property promoting their self-assembly into high-order structures (44–50). Indeed, a strong enrichment in symmetric homo-oligomers among natural filament-forming proteins has been reported (37). Previous work has also shown that point mutations to two hydrophobic amino acids—leucine and tyrosine—frequently led symmetric homo-oligomers to assemble into high-order assemblies. However, whether other types of amino acids would display a similar potential, whether they would do so often, and whether additional phenotypes of assembly and localization could emerge upon mutation remains unknown.Here, we assess the potential of mutations to trigger such changes in protein assembly and localization in vivo. We targeted two homo-oligomeric protein complexes and randomly mutated three neighboring residues at the surface of each complex. We expressed the mutants fused to a fluorescent protein to track their spatial distribution in yeast cells. We found that a vast sequence space led to changes in protein assembly and localization in both proteins with three predominant phenotypes: nuclear localization, the formation of filaments, and the formation of puncta. Sequencing of the mutants revealed that increasing surface stickiness frequently promoted nuclear localization in one of the two proteins. Surprisingly, in the other protein, a loss of negatively charged residues was sufficient to trigger protein self-assembly, with fibers frequently forming regardless of the type of mutation, including to alanine and glycine. We also observed that four out of eight additional complexes analyzed underwent supramolecular self-assembly or a change in cellular localization when surface charges were mutated to alanine, implying that negative design against supramolecular self-assembly and mislocalization is common among symmetric homo-oligomers.     

Viscosity Model for Nanoparticulate Suspensions Based on Surface Interactions

In this paper, a widely mechanistic model was developed to depict the rheological behaviour of nanoparticulate suspensions with solids contents up to 20 wt.%, based on the increase in shear stress caused by surface interaction forces among particles. The rheological behaviour is connected to drag forces arising from an altered particle movement with respect to the surrounding fluid. In order to represent this relationship and to model the viscosity, a hybrid modelling approach was followed, in which mechanistic relationships were paired with heuristic expressions. A genetic algorithm was utilized during model development, by enabling the algorithm to choose among several hard-to-assess model options. By the combination of the newly developed model with existing models for the various physical phenomena affecting viscosity, it can be applied to model the viscosity over a broad range of solids contents, shear rates, temperatures and particle sizes. Due to its mechanistic nature, the model even allows an extrapolation beyond the limits of the data points used for calibration, allowing a prediction of the viscosity in this area. Only two parameters are required for this purpose. Experimental data of an epoxy resin filled with boehmite nanoparticles were used for calibration and comparison with modelled values.     

Interactions between T cells and synovial fibroblasts

Abstract

T lymphocytes, synovial macrophages, and synovial fibroblasts are the three most abundant cell populations in rheumatoid arthritis synovial tissue, and each is believed to play an important role in the pathogenesis of joint inflammation and destruction. While interactions between T cells and macrophages and between macrophages and fibroblasts have been carefully studied, less attention has been paid to potential interactions between T lymphocytes and synovial fibroblasts. In this review we consider available data which suggests that cell–cell contact between T lymphocytes and synovial fibroblasts may lead to activation of each cell type. This interaction is likely to be significant in the pathophysiology of rheumatoid arthritis.