Surface Macromolecules Research Articles

Molecular interactions of the Omicron, Kappa, and Delta SARS-CoV-2 spike proteins with quantum dots of graphene oxide.

The Omicron, Kappa, and Delta variants are different strains of the SARS-CoV-2 virus. Graphene oxide quantum dots (GOQDs) represent a burgeoning class of oxygen-enriched, zero-dimensional materials characterized by their sub-20-nm dimensions. Exhibiting pronounced quantum confinement and edge effects, GOQDs manifest exceptional physical-chemical attributes. This study delves into the potential of graphene oxide quantum dots, elucidating their inherent properties pertinent to the surface structures of SARS-CoV-2, employing an integrated computational approach for the repositioning of inhibitory agents. Following rigorous adjustment tests, a spectrum of divergent bonding conformations emerged, with particular emphasis placed on identifying the conformation exhibiting optimal adjustment scores and interactions. The investigation employed molecular docking simulations integrating affinity energy evaluations, electrostatic potential clouds, molecular dynamics encompassing average square root calculations, and the computation of Gibbs-free energy. These values quantify the strength of interaction between GOQDs and SARS-CoV-2 spike protein variants. The receptor structures were optimized using the CHARM-GUI server employing force field AMBERFF14SB. The algorithm embedded in CHARMM offers an efficient interpolation scheme and automatic step size selection, enhancing the efficiency of the optimization process. The 3D structures of the ligands are constructed and optimized with density functional theory (DFT) method based on the most stable conformer of each binder. Autodock Vina Software (ADV) was utilized, where essential parameters were specified. Electrostatic potential maps (MEPs) provide a visual depiction of molecules' charge distributions and related properties. After this, molecular dynamics simulations employing the CHARM36 force field in Gromacs 2022.2 were conducted to investigate GOs' interactions with surface macromolecules of SARS-CoV-2 in an explicit aqueous environment. Furthermore, our investigation suggests that lower values indicate stronger binding. Notably, GO-E consistently showed the most negative values across interactions with different variants, suggesting a higher affinity compared to other GOQDs (GO-A to GO-D).

E. coli cotransport with composite colloid in unsaturated porous media: Multi-risk on migration and biomolecular response

The diversity of colloidal types and the differences in the composite ratios in porous media are important factors governing the migration and biological risk of pathogenic microorganisms in the subsurface environment. In this study, E. coli O157:H7 was subjected to co-migration experiments with different compositions of the composite colloid montmorillonite (MMT)-Fe2O3, and the biomolecular response of E. coli under the action of colloids was analyzed by Raman spectroscopy to quantify the risk of E. coli under the action of composite colloids based on both. The results showed that Fe2O3 colloids inhibited E. coli migration mainly by electrostatic adsorption and reduced E. coli metabolism. MMT colloid inhibited E. coli migration mainly by blockage, and E. coli metabolism increased, and surface macromolecules decreased to reduce E. coli adhesion. MMT-Fe2O3 complex colloids inhibited migration through electrostatic attraction between the two and formation of cohesive colloids, with reduced E. coli metabolism and insignificant biomolecular response. It was briefly assessed that the composite colloids reduced E. coli risk less strongly than single colloids, stemming from the difference in the mechanism of influence and the actual need to consider colloid interactions. This conclusion can inform the management and control of pathogen risk in porous media environments.

Surface Nanomechanics of Bacteria under UV Radiation

AbstractIt is well established that UV radiation can inactivate bacteria by destroying DNA in the cell envelope, and maintaining the integrity of the cellular membrane. However, how UV radiation changes the surface properties and thus affects bacterial adhesion remain elusive. In this study, single‐cell force spectroscopy is employed to examine the surface nanomechanics of Pseudomonas aeruginosa under UV exposure. It shows that P. aeruginosa became stiffer after UV radiation, and its adhesion to silicon surface decreases with rupture length increasing. Nanospring signatures in the retraction force curve become less with lower spring constant but more plateau signatures with higher rupture length appear. These facts indicate the unfolding of the α‐helices of the pili. Besides, the worm‐like chain force curves with higher contour length indicate the structural degradation of transmembrane proteins or surface macromolecules obstruction. Accordingly, the bacterial adhesion decreases after UV radiation.

FliA-Dependent Surface Macromolecules Promote Initial Biofilm Development of Escherichia coli by Influencing the Bacterial Surface Properties

FliA is an important regulatory component for the synthesis of surface macromolecules which are involved in motility and biofilm development of Escherichia coli. In this study, the roles of FliA-dependent surface macromolecules in E. coli surface tension, surface heterogeneity and surface roughness, and initial biofilm development consisting of reversible and irreversible adhesion were investigated using E. coli MG1655 wild-type strain and fliA gene deleted mutant strain. Negative Gibbs free energy change values calculated using bacterial surface tensions obtained by a spectrophotometric method showed that both wild-type and mutant cells in water can reversibly adhere to the surface of the model solid, silicon nitride (Si3N4). The calculations further showed that bacterial reversible auto-adhesion and co-adhesion were also thermodynamically favorable. In comparison, the reversible adhesion and auto-adhesion capacities of wild-type cells were higher than the mutant cells. Direct measurements by atomic force microscopy (AFM) and thorough analysis of the recorded adhesion data showed that the irreversible adhesion strength of wild-type cells to Si3N4 in water was at least 2.0-fold greater than that of the mutants due to significantly higher surface heterogeneity resulting in higher surface roughness for the wild-type cells compared to those obtained for the mutants. These results suggest that strategies aimed at preventing E. coli biofilm development should also consider a combined method, such as modifying the surface of interest with a bacterial repellent layer and targeting the FliA and FliA-dependent surface macromolecules to reduce both reversible and irreversible bacterial adhesion and hence the initial biofilm development of E. coli.

Bacteria with a mouth: Discovery and new insights into cell surface structure and macromolecule transport.

A bacterium with a "mouth"-like pit structure isolated for the first time in the history of microbiology was a Gram-negative rod, containing glycosphingolipids in the cell envelope, and named Sphingomonas sp. strain A1. The pit was dynamic, with repetitive opening and closing during growth on alginate, and directly included alginate concentrated around the pit, particularly by flagellins, an alginate-binding protein localized on the cell surface. Alginate incorporated into the periplasm was subsequently transferred to the cytoplasm by cooperative interactions of periplasmic solute-binding proteins and an ATP-binding cassette transporter in the cytoplasmic membrane. The mechanisms of assembly, functions, and interactions between the above-mentioned molecules were clarified using structural biology. The pit was transplanted into other strains of sphingomonads, and the pitted recombinant cells were effectively applied to the production of bioethanol, bioremediation for dioxin removal, and other tasks. Studies of the function of the pit shed light on the biological significance of cell surface structures and macromolecule transport in bacteria.

A Journey on Extracellular Vesicles for Matrix Metalloproteinases: A Mechanistic Perspective.

Matrix metalloproteinases (MMPs) are key players in matrix remodeling and their function has been particularly investigated in cancer biology. Indeed, through extracellular matrix (ECM) degradation and shedding of diverse cell surface macromolecules, they are implicated in different steps of tumor development, from local expansion by growth to tissue invasion and metastasis. Interestingly, MMPs are also components of extracellular vesicles (EVs). EVs are membrane-limited organelles that cells release in their extracellular environment. These “secreted” vesicles are now well accepted players in cell-to-cell communication. EVs have received a lot of interest in recent years as they are also envisioned as sources of biomarkers and as potentially outperforming vehicles for the delivery of therapeutics. Molecular machineries governing EV biogenesis, cargo loading and delivery to recipient cells are complex and still under intense investigation. In this review, we will summarize the state of the art of our knowledge about the molecular mechanisms implicated in MMP trafficking and secretion. We focus on MT1-MMP, a major effector of invasive cell behavior. We will also discuss how this knowledge is of interest for a better understanding of EV-loading of MMPs. Such knowledge might be of use to engineer novel strategies for cancer treatment. A better understanding of these mechanisms could also be used to design more efficient EV-based therapies.

Towards Computationally Guided Design and Engineering of a Neisseria meningitidis Serogroup W Capsule Polymerase with Altered Substrate Specificity.

Heavy metal contamination of drinking water is a public health concern that requires the development of more efficient bioremediation techniques. Absorption technologies, including biosorption, provide opportunities for improvements to increase the diversity of target metal ions and overall binding capacity. Microorganisms are a key component in wastewater treatment plants, and they naturally bind metal ions through surface macromolecules but with limited capacity. The long-term goal of this work is to engineer capsule polymerases to synthesize molecules with novel functionalities. In previously published work, we showed that the Neisseria meningitidis serogroup W (NmW) galactose-sialic acid (Gal-NeuNAc) heteropolysaccharide binds lead ions effectively, thereby demonstrating the potential for its use in environmental decontamination applications. In this study, computational analysis of the NmW capsule polymerase galactosyltransferase (GT) domain was used to gain insight into how the enzyme could be modified to enable the synthesis of N-acetylgalactosamine-sialic acid (GalNAc-NeuNAc) heteropolysaccharide. Various computational approaches, including molecular modeling with I-TASSER and molecular dynamics (MD) simulations with NAMD, were utilized to identify key amino acid residues in the substrate binding pocket of the GT domain that may be key to conferring UDP-GalNAc specificity. Through these combined strategies and using BshA, a UDP-GlcNAc transferase, as a structural template, several NmW active site residues were identified as mutational targets to accommodate the proposed N-acetyl group in UDP-GalNAc. Thus, a rational approach for potentially conferring new properties to bacterial capsular polysaccharides is demonstrated.

Unique Dynamics of Hierarchical Constrained Macromolecular Ligands on Coordination Nanocage Surface Promotes Facile and Precise Assembly of Polymers.

With access to the solution structures of nanocomposites of coordination nanocages (CNCs) via scattering and chromatography techniques, their mysterious solution dynamics have been, for the first time, resolved, and interestingly, the surface macromolecules can be substituted by extra free macromolecules in solutions. Obvious exchange of macromolecules can be observed in the solution mixtures of CNC nanocomposites at high temperatures, revising the understanding of the dynamics of CNC nanocomposites. Being distinct from nanocomposites of a simple coordination complex, the quantified solution dynamics of CNC nanocomposites indicates a typical logarithmic time dependence with the dissociation of surface macromolecules as the thermodynamically limiting step, suggesting strongly coupled and hierarchically constrained dynamics among the surface macromolecules. Their dynamics can be activated only upon application of high temperature or selected solvents, and therefore, the rational design of polymer assemblies, for example, hybrid-arm star polymers with precisely controlled compositions and reprocessable, robust CNC-cross-linked supramolecular polymer networks, is facilitated.

Outer Membrane c-Type Cytochromes OmcA and MtrC Play Distinct Roles in Enhancing the Attachment of Shewanella oneidensis MR-1 Cells to Goethite.

The outer membrane c-type cytochromes (c-Cyts) OmcA and MtrC in Shewanella are key terminal reductases that bind and transfer electrons directly to iron (hydr)oxides. Although the amounts of OmcA and MtrC at the cell surface and their molecular structures are largely comparable, MtrC is known to play a more important role in dissimilatory iron reduction. To explore the roles of these outer membrane c-Cyts in the interaction of Shewanella oneidensis MR-1 with iron oxides, the processes of attachment of S. oneidensis MR-1 wild type and c-type cytochrome-deficient mutants (the ΔomcA, ΔmtrC, and ΔomcA ΔmtrC mutants) to goethite are compared via quartz crystal microbalance with dissipation monitoring (QCM-D). Strains with OmcA exhibit a rapid initial attachment. The quantitative model for QCM-D responses reveals that MtrC enhances the contact area and contact elasticity of cells with goethite by more than one and two times, respectively. In situ attenuated total reflectance Fourier transform infrared two-dimensional correlation spectroscopic (ATR-FTIR 2D-CoS) analysis shows that MtrC promotes the initial interfacial reaction via an inner-sphere coordination. Atomic force microscopy (AFM) analysis demonstrates that OmcA enhances the attractive force between cells and goethite by about 60%. As a result, OmcA contributes to a higher attractive force with goethite and induces a rapid short-term attachment, while MtrC is more important in the longer-term interaction through an enhanced contact area, which promotes interfacial reactions. These results reveal that c-Cyts OmcA and MtrC adopt different mechanisms for enhancing the attachment of S. oneidensis MR-1 cells to goethite. It improves our understanding of the function of outer membrane c-Cyts and the influence of cell surface macromolecules in cell-mineral interactions.IMPORTANCEShewanella species are one group of versatile and widespread dissimilatory iron-reducing bacteria, which are capable of respiring insoluble iron minerals via six multiheme c-type cytochromes. Outer membrane c-type cytochromes (c-Cyts) OmcA and MtrC are the terminal reductases in this pathway and have comparable protein structures. In this study, we elucidate the different roles of OmcA and MtrC in the interaction of S. oneidensis MR-1 with goethite at the whole-cell level. OmcA confers enhanced affinity toward goethite and results in rapid attachment. Meanwhile, MtrC significantly increases the contact area of bacterial cells with goethite and promotes the interfacial reaction, which may explain its central role in extracellular electron transfer. This study provides novel insights into the role of bacterial surface macromolecules in the interfacial interaction of bacteria with minerals, which is critical to the development of a comprehensive understanding of cell-mineral interactions.

VELCRO-INSPIRED SUPRAMOLECULAR SYSTEM FOR SILICA–RUBBER COUPLING

ABSTRACT The state-of-the-art silica–rubber coupling is based on forming chemical links between a silica surface and rubber macromolecules. However, the chemical links are relatively short and stiff, thus in case of a chemical breakage they are highly unlikely to recombine. This could result in a potential deterioration of the interphase properties over time. To overcome this drawback, a new approach to silica–rubber coupling was investigated in the current study. The new approach is inspired by the Velcro hook-and-loop system from nature that facilitates a re-connectability, thus re-formation of the interphase properties in case of a breakage. For this, various long oligomeric brushes were grafted onto silica surfaces considered to act as supramolecular hooks. Such modified silica were dispersed in rubber and vulcanized. The resulting cross-linked rubber matrix is considered to act as supramolecular loops. The prepared vulcanizates were compared with reference samples containing common coupling or covering agents. The reinforcing potential provided by the newly developed system is lower than the chemical coupling system but considerably higher than the covering system. The new system also provides better mechanical properties, recovery after cycling stretching, and heat treatment than the references. A new reinforcing mechanism is proposed for the silica grafted with oligomeric brushes that exhibits a good chemical compatibility to the rubber matrix.

Heparan sulfate proteoglycans regulate BMP signalling during neural crest induction

Bone morphogenetic protein (BMP) signalling is key to many developmental processes, including early regionalisation of the ectoderm. The neural crest is induced here by a combination of BMP and Wnt signals from nearby tissues with many secreted factors contributing to its initial specification at the neural plate border. Gremlin 1 (Grem1) is a secreted BMP antagonist expressed in the neural crest in Xenopus laevis but its function here is unknown. As well as binding BMPs, Grem1 has been shown to interact with heparan sulfate proteoglycans (HSPGs), a family of cell surface macromolecules that regulate a diverse array of signalling molecules by affecting their availability and mode of action. This study describes the impact of HSPGs on the function of Grem1 in neural crest induction. It shows for the first time that Grem1 is required for neural crest development in a two-step process comprising an early HSPG-independent, followed by a late HSPG-dependent phase.

Electromigration of cell surface macromolecules in DC electric fields during cell polarization and galvanotaxis

DC electric fields (EFs) can often induce cellular polarity, and direct migration of cells toward one of the electrical poles. The mechanism(s) by which cells sense weak EFs is not established. We present here a molecular flux model to describe electromigration of plasma membrane macromolecules and compare its predictions to electromigration of a lipid-anchored surface protein, tdTomato-GPI, under different experimental conditions. Gradients of tdTomato-GPI are assembled based on its electrophoretic and electro-osmotic mobilities and collapsed by its own diffusion. The flux model predicts greatest cathodal accumulation for tdTomato-GPI under slightly acidic conditions, and weak cathodal accumulation under alkaline conditions. Predictions by the flux model align closely with measurements of the electromigration of tdTomato-GPI except at pH 6, the only condition examined in which the protein exhibits a net positive surface charge. We use the model to predict the time course and relative steady state concentration difference for asymmetric accumulation of other surface macromolecules based on their physical properties. We also describe a method for identifying the physical properties of the plasma membrane proteins in zebrafish keratocytes, in order to predict likely candidates for the electric field receptor in this model migratory system that exhibits cathodal galvanotaxis, and to predict the asymmetric distribution of proteins in other cell types. We provide a physical basis for predicting the dynamics of electromigration for numerous cell surface macromolecules and provide evidence for supporting the role of electromigration in directing cell polarity, migration and growth in response to weak EFs.

Preparation of CdTe/Alginate Textile Fibres with Controllable Fluorescence Emission through a Wet-Spinning Process and Application in the Trace Detection of Hg2+ Ions.

Fluorescent textile fibres (FTFs) are widely used in many industrial fields. However, in addition to fibres with good fluorescence, fibres with excellent colour controllability, structural stability and appropriate mechanical strength still need to be developed. In this work, CdTe/alginate composite FTFs are prepared by taking advantage of the interactions between CdTe nanocrystals (NCs) and alginate macromolecules via a wet-spinning machine with a CaCl2 aqueous solution as the coagulation bath. CdTe NCs were chemically fixed in the fibre due to the interactions among surface ligands, macromolecules and coagulators (calcium ions), which ensured the excellent dispersity and good stability of the fibres. Förster resonance energy transfer (FRET) between NCs in the fibre was found to be restricted, which means that the emission colour of the fibres was totally controllable and could be predicted. Other properties of alginate fibres, such as flame retardance and mechanical strength, were also well preserved in the fluorescent fibres. Finally, FTFs showed good selectivity toward trace Hg2+ ions over other metallic ions, and the detection could be identified by the naked eye.

Electromigration of Cell Surface Macromolecules during Galvanotaxis

Weak, DC electric fields (EFs) direct cellular polarity, migration and outgrowth. They are used to induce polarity during tissue engineering and direct migration to promote epidermal wound repair. Fields as weak as 10 mV/mm, are sufficient to direct migration, although the mechanisms used by cells to sense such weak fields are still debated as weaknesses exist in the competing models. We hypothesize that cellular polarization is achieved by the redistribution of a cell surface, electric field receptor (EFR) in the presence of an applied EF. We are investigating the electromigration model that depends on electrically generated forces in the plane of the plasma membrane and parallel to the electric field vector, specifically, electrophoretic and electro-osmotic forces. Electrophoretic force drives net negatively charged macromolecules to the anode while electro-osmotic flow of water, in the boundary layer, drives macromolecules with large extracellular domains to the cathode. We have derived a model based on these opposing forces, to predict the relative concentration of surface proteins over space and time, allowing us to test the redistribution of known plasma membrane surface macromolecules in applied EFs and under controlled conditions. The model closely describes accumulation of a net negatively charged, GPI-anchored, fluorescent protein to the cathode under different field strengths, showing that redistribution reaches steady-state within minutes, significantly faster than cathodally migrating cells turn toward the cathode. The model is useful for determining the most likely candidates for the EFR on many different cell types.

Effects of hydrophilic surface macromolecule modifier loading on PES/O-g-C3N4 hybrid photocatalytic membrane for phenol removal

HydrophiLic surface modifying macromolecules (LSMM) modified polyethersulfone (PES) based photocatalytic membranes have been successfully prepared. This hybrid photocatalytic membrane applying oxygen-doped graphitic carbon nitride (g-C3N4) as a photocatalyst was successfully fabricated via phase inversion technique in flat sheet form at ambient temperature. The potential of LSMM as membrane modifier was explored in detail under various loadings (1–5 wt%). The results show that the LSMM addition successfully increased the membrane hydrophilicity which may consequently prevent the membrane from comprehensive fouling. More appearance of g-C3N4 on the membrane surface was observed by Scanning Electron Microscopy (SEM) and Atomic Force Microscope (AFM) analyses upon the LSMM addition. However, the trend tended to decline at the loading beyond 4 wt% of LSMM. At 4 wt% of LSMM, the PES/g-C3N4 membrane successfully decreased phenol concentration up to 35.78% and rejected 14.73% of phenol. From the water flux result, the application of LSMM in water treatment application was hindered by the flux deterioration but a considerably high flux for an ultrafiltration membrane. The results indicate that the introduction of LSMM in the PES/g-C3N4 hybrid photocatalytic membrane showed the great potential of LSMM as a membrane surface modifier for photocatalytic activities and membrane separation performance.

Physicochemical Factors That Favor Conjugation of an Antibiotic Resistant Plasmid in Non-growing Bacterial Cultures in the Absence and Presence of Antibiotics.

Horizontal gene transfer (HGT) of antibiotic resistance genes has received increased scrutiny from the scientific community in recent years owing to the public health threat associated with antibiotic resistant bacteria. Most studies have examined HGT in growing cultures. We examined conjugation in growing and non-growing cultures of E. coli using a conjugative multi antibiotic and metal resistant plasmid to determine physiochemical parameters that favor horizontal gene transfer. The conjugation frequency in growing and non-growing cultures was generally greater under shaken than non-shaken conditions, presumably due to increased frequency of cell collisions. Non-growing cultures in 9.1 mM NaCl had a similar conjugation frequency to that of growing cultures in Luria-Bertaini broth, whereas those in 1 mM or 90.1 mM NaCl were much lower. This salinity effect on conjugation was attributed to differences in cell-cell interactions and conformational changes in cell surface macromolecules. In the presence of antibiotics, the conjugation frequencies of growing cultures did not increase, but in non-growing cultures of 9.1 mM NaCl supplemented with Cefotaxime the conjugation frequency was as much as nine times greater than that of growing cultures. The mechanism responsible for the increased conjugation in non-growing bacteria was attributed to the likely lack of penicillin-binding protein 3 (the target of Cefotaxime), in non-growing cells that enabled Cefotaxime to interact with the plasmid and induce conjugation. Our results suggests that more attention may be owed to HGT in non-growing bacteria as most bacteria in the environment are likely not growing and the proposed mechanism for increased conjugation may not be unique to the bacteria/plasmid system we studied.

Inhibition of Herpes Simplex Virus-1 Entry into Human Cells by Nonsaccharide Glycosaminoglycan Mimetics.

Although heparan sulfate (HS) has been implicated in facilitating entry of enveloped viruses including herpes simplex virus (HSV), small molecules that effectively compete with this abundant, cell surface macromolecule remain unknown. We reasoned that entry of HSV-1 involving its glycoprotein D (gD) binding to HS could be competitively targeted through small, synthetic, nonsaccharide glycosaminoglycan mimetics (NSGMs). Screening a library of NSGMs identified a small, distinct group that bound gD with affinities of 8-120 nM. Studies on HSV-1 entry into HeLa, HFF-1, and VK2/E6E7 cells identified inhibitors with potencies in the range of 0.4-1.0 μM. These synthetic NSGMs are likely to offer promising chemical biology probes and/or antiviral drug discovery opportunities.

Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation.

To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

Proteoglycans in brain development and pathogenesis.

Proteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio-active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies.

Abstract 48: Role of Receptor for Advanced Glycation End Products (RAGE) in Regression of Diabetic Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder. Both progression and regression of atherosclerosis are adversely affected by diabetes. A key player in these processes is Receptor for Advanced Glycation End Products (RAGE). RAGE is a multiligand cell surface macromolecule, which binds ligands enriched in atherosclerotic plaques, such as advanced glycation endproducts (AGEs). RAGE is expressed on a wide array of cell types implicated in cardiovascular disease, such as endothelial cells, and inflammatory cells such as macrophages. The cytoplasmic domain of RAGE binds to the formin molecule DIAPH1 and DIAPH1 is required for RAGE ligands to activate cell signaling responses. RAGE acts as a key mediator of oxidative and inflammatory signaling pathways that are involved in atherosclerosis. We tested mechanisms of impaired regression of atherosclerosis in a murine model of aorta transplantation and found that deletion of Ager or Diaph1 in diabetic mice recipients of Ldlr null mice atherosclerotic aortas accelerates atherosclerosis regression and significantly reduces the lesional macrophage content when compared to diabetic wild-type recipient mice. The antiatherosclerotic effects in diabetic Ager null mice and diabetic Diaph1 null mice include reduced RAGE ligand AGEs in transplanted aortas, with reduced expression of a range of proatherogenic factors, including reactive oxygen species and inflammatory cytokines implicated in leukocyte recruitment and activation. We employed RNA sequencing to identify the key transcriptional events by which RAGE mediates its effects in donor or recipient macrophages in diabetic regressing plaques. Our results suggest that critical gene expression profiles, including those genes involved in inflammation, endothelial dysfunction, oxidative stress, monocyte/macrophage fate (recruitment, differentiation, proliferation), signal transduction and lipid metabolism, are beneficially modulated, at least in part, via Ager deletion in atherosclerosis regression. Taken together, these data increase our understanding of the role of RAGE in diabetic atherosclerosis, particularly in macrophages, and may provide avenues for therapeutic strategies to accelerate regression of atherosclerosis in diabetes.