A colloid approach to self-assembling antibodies

Concentrated solutions of monoclonal antibodies have attracted considerable attention due to their importance in pharmaceutical formulations, yet their tendency to aggregate and the resulting high solution viscosity has posed considerable problems. It remains a very difficult task to understand and predict the phase behavior and stability of such solutions. Here we present a systematic study of the concentration dependence of the structural and dynamic properties of monoclonal antibodies using a combination of different scattering methods and microrheological experiments. To interpret these data, we use a colloid-inspired approach based on a simple patchy model, which explicitly takes into account the anisotropic shape and the charge distribution of the molecules. Combining theory, simulations and experiments, we are able to disentangle self-assembly and intermolecular interactions and to quantitatively describe the concentration dependence of structural and dynamic quantities such as the osmotic compressibility, the collective diffusion coefficient and the zero shear viscosity over the entire range of investigated concentrations. This simple patchy model not only allows us to consistently describe the thermodynamic and dynamic behavior of mAb solutions, but also provides a robust estimate of the attraction between their binding sites. It will thus be an ideal starting point for future work on antibody formulations, as it provides a quantitative assessment of the effects of additional excipients or chemical modifications on antibody interactions, and a prediction of their effect on solution viscosity

Suspensions of supracolloidal magnetic polymers: self-assembly properties from computer simulations

We study self-assembly in suspensions of supracolloidal polymer-like structures made of crosslinked magnetic particles. Inspired by self-assembly motifs observed for dipolar hard spheres, we focus on four different topologies of the polymer-like structures: linear chains, rings, Y-shaped and X-shaped polymers. We show how the presence of the crosslinkers, the number of beads in the polymer and the magnetic interparticle interaction affect the structure of the suspension. It turns out that for the same set of parameters, the rings are the least active in assembling larger structures, whereas the system of Y- and especially X-like magnetic polymers tend to form very large loose aggregates

Self-assembly of polymer-like structures of magnetic colloids: Langevin dynamics study of basic topologies

We study the self-assembly of colloidal magnetic particles permanently cross-linked into polymer-like structures with different topologies, that we call supracolloidal magnetic polymers (SMPs). In order to understand the influence of the interparticle permanent links, we investigate SMPs holding the main topologies observed in the self-assembly of non-cross-linked magnetic particles via grand canonical Monte Carlo simulations: chains, rings and simple branched structures. Here, using molecular dynamics simulations, we focus on systems of SMP pairs. Our results evidence that the presence of crosslinkers leads to the formation of new types of aggregates, not previously observed for individual magnetic colloids. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This research has been supported by the Russian Science Foundation [grant number 17-72-10145]. J.J.C. and T.S. acknowledge funding from a grant awarded by the Conselleria d’Innovació, Recerca i Turisme del Govern de les Illes Balears and the European Social Fund (ESF). T.S. also acknowledges financial support from the Spanish Ministerio de Economía y Competi-tividad and the European Regional Development Fund, [Project number FIS20015-63628-C2-2-R] (AEI/FEDER, UE). P.A.S and S.S.K acknowledge support from the Austrian Research Fund (FWF) [START-Projekt Y 627-N27]. S.S.K. also acknowledges support from the European Commission ETN-COLLDENSE [H2020-MSCA-ITN-2014], [grant number 642774]. The authors would like to thank F. Sciortino for his valuable contribution to the GCMC simulation results

Free energy calculations for rings and chains formed by dipolar hard spheres

We employ a method based on Monte Carlo grand-canonical simulations to precisely calculate partition functions of non-interacting chains and rings formed by dipolar hard spheres (DHS) at low temperature. The extended low temperature region offered by such cluster calculations, compared to what had been previously achieved with standard simulations, opens up the possibility of exploring a part of the DHS phase diagram which was inaccessible before. The reported results offer the unique opportunity of verifying well-established theoretical models based on the ideal gas of cluster approximation in order to clarify their range of validity. They also provide the basis for future studies in which cluster–cluster interactions will be included.info:eu-repo/semantics/publishedVersio

El tejido adiposo: algo más que un reservorio de energía

Adipose tissue is a reservoir of energy and also an organ that contributes to the aesthetics and health of human body working as an endocrine tissue. White adipose tissue, which is formed by unilocular adipose cells, can modify organic homeostasis by controlling energy expenditure and consumption and by producing adipokines that regulate food consumption, and carbohydrate and lipid metabolic utilization. Brown adipose tissue is structured by multilocular cells containing many small fat drops that can be easily hydrolyzed. This tissue is involved in adaptative or facultative thermogenesis because it contains the uncoupling-1 protein (UCP-1) which by inhibiting ATP synthesis releases heat. The size of brow adipose tissue is reduced with aging and the most recent future strategies to fight obesity may be by transforming white cells into brown adipose tissue. The present work reviews the main structural and functional characteristics of white and brown adipose tissue with emphasis in its endocrine and regulatory function.<br><br>El tejido adiposo es un reservorio de grasa y también un órgano que contribuye a la estética y a la salud de las personas, tarea que cumple funcionando como un tejido endocrino. El tejido adiposo blanco, formado por células adiposas uniloculares puede regular la homeostasis orgánica entre el gasto y el consumo de energía. Produce una serie de adipokinas que regulan el consumo de alimentos, la utilización de glucosa y de lípidos por parte del organismo. El tejido adiposo pardo o marrón, estructurado por células multiloculares, contiene numerosas gotas de grasa de pequeño tamaño, las que pueden ser hidrolizadas con mayor facilidad. El tejido participa en la termogénesis adaptativa o facultativa debido a la proteína desacoplante-1 (UCP-1) que inhibe la síntesis de ATP produciendo calor. Con la edad, este tejido se reduce y por ello actualmente se considera que una forma de combatir la obesidad es lograr que el tejido adiposo blanco adquiera característica de pardo. Este trabajo revisa las principales características estructurales y funcionales del tejido adiposo blanco y pardo, con énfasis en sus funciones reguladoras y endocrinas

Association of interleukin-6 polymorphisms with obesity or metabolic traits in young Mexican-Americans

Objective The objective of the study is to investigate the association of interleukin-6 (IL6) promoter single-nucleotide polymorphisms rs1800797 (-597 G/A) and rs1800796 (-572 G/C) with obesity or metabolic syndrome in Mexican-Americans. Methods The rs1800797 and rs1800796 single-nucleotide polymorphisms were genotyped in Mexican-Americans (n = 437) from South Texas, and results were correlated with measures of obesity and metabolic syndrome including body mass index, waist circumference, blood pressure, cholesterol, triglycerides, glucose, liver enzymes, plasma IL6 and high-sensitive C-reactive protein (hs-CRP). Results Significant associations were found for the rs1800796 variant with increased waist circumference, insulin resistance, lower IL6 levels and higher hs-CRP levels. The rs1800797 variant showed no associations with metabolic traits but was associated with higher IL6 levels and lower hs-CRP levels. Conclusions Findings in this study support the anti-inflammatory, anti-obesity and glucose homeostatic roles of IL6 in Mexican-American youth

Fat Mass–and Obesity-Associated (FTO) Gene Variant Is Associated With Obesity: Longitudinal Analyses in Two Cohort Studies and Functional Test

OBJECTIVE—To examine the longitudinal association of fat mass–and obesity-associated (FTO) variant with obesity, circulating adipokine levels, and FTO expression in various materials from human and mouse

Constitutive P2Y2 receptor activity regulates basal lipolysis in human adipocytes

White adipocytes are key regulators of metabolic homeostasis, which release stored energy as free fatty acids via lipolysis. Adipocytes possess both basal and stimulated lipolytic capacity, but limited information exists regarding the molecular mechanisms that regulate basal lipolysis. Here, we describe a mechanism whereby autocrine purinergic signaling and constitutive P2Y2 receptor activation suppresses basal lipolysis in primary human in vitro differentiated adipocytes. We found that human adipocytes possess cytoplasmic calcium tone due to ATP secretion and constitutive P2Y2 receptor activation. Pharmacological antagonism or knockdown of P2Y2 receptors increases intracellular cAMP levels and enhances basal lipolysis. P2Y2 receptor antagonism works synergistically with phosphodiesterase inhibitors in elevating basal lipolysis, but is dependent upon adenylate cyclase activity. Mechanistically, we suggest that the increased calcium tone exerts an anti-lipolytic effect by suppression of calcium-sensitive adenylate cyclase isoforms. We also observed that acute enhancement of basal lipolysis following P2Y2 receptor antagonism alters the profile of secreted adipokines leading to longer term adaptive decreases in basal lipolysis. Our findings reveal that basal lipolysis and adipokine secretion are controlled by autocrine purinergic signaling in human adipocytes

Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics

BACKGROUND: Recently, it has been shown that increasing body mass index (BMI) in asthma is associated with reduced exhaled NO. Our objective in this study was to determine if the BMI-related changes in exhaled NO differ across asthmatics and controls, and to determine if these changes are related to increased airway oxidative stress and systemic levels of leptin and adiponectin. METHODS: Observational study of the association of BMI, leptin, and adiponectin with exhaled nitric oxide (NO) and exhaled 8-isoprostanes in 67 non-smoking patients with moderate to severe persistent asthma during baseline conditions and 47 controls. Measurements included plasma levels of leptin, adiponectin, exhaled breath condensates for 8-isoprostanes, exhaled NO, pulmonary function tests, and questionnaires regarding asthma severity and control. RESULTS: In asthmatics, BMI and the ratio of leptin to adiponectin were respectively associated with reduced levels of exhaled NO (β = -0.04 [95% C.I. -0.07, -0.1], p < 0.003) and (β = -0.0018 [95% C.I. -0.003, -0.00034], p = 0.01) after adjusting for confounders. Also, BMI was associated with increased levels of exhaled 8-isoprostanes (β = 0.30 [95% C.I. 0.003, 0.6], p = 0.03) after adjusting for confounders. In contrast, we did not observe these associations in the control group of healthy non-asthmatics with a similar weight distribution. CONCLUSION: In adults with stable moderate to severe persistent asthma, but not in controls, BMI and the plasma ratio of leptin/adiponectin is associated with reduced exhaled NO. Also, BMI is associated with increased exhaled 8-isoprostanes. These results suggest that BMI in asthmatics may increase airway oxidative stress and could explain the BMI-related reductions in exhaled NO