Department of Bioscience & Bioengineering

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Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson's disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another. © Copyright: 2015 Chorell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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PLoS ONE

Bacterial chaperones CsgE and CsgC differentially modulate human α-Synuclein amyloid formation via transient contacts

We present here a detailed numerical study of the dynamical behavior of "soft" uncompressed grains in a granular chain where the grains interact via the intrinsically nonlinear Hertz force. It is well known that such a chain supports the formation of solitary waves (SWs). Here, however, the system response to the material properties of the grains and boundaries is explored further. In particular, we examine the details of the transition of the system from a SW phase to an equilibrium-like (or quasiequilibrium) phase, and for this reason we ignore the effects of dissipation in this study. We find that the soft walls slow the reflection of SWs at the boundaries of the system, which in turn slows the journey to quasiequilibrium. Moreover, the increased grain-wall compression as the boundaries are softened results in fewer average grain-grain contacts at any given time in the quasiequilibrium phase. These effects lead to increased kinetic energy fluctuations in the short term in softer systems. We conclude with a toy model that exploits the results of soft-wall systems. This toy model supports the formation of breather-like entities and may therefore be useful for localizing energy in desired places in the granular chain. © 2015 American Physical Society.

Physical Review E - Statistical, Nonlinear, and Soft Matter Physics

Granular chains with soft boundaries: Slowing the transition to quasiequilibrium

We present a method to induce electric fields and drive electrotaxis (galvanotaxis) without the need for electrodes to be in contact with the media containing the cell cultures. We report experimental results using a modification of the transmembrane assay, demonstrating the hindrance of migration of breast cancer cells (SCP2) when an induced a.c. electric field is present in the appropriate direction (i.e. in the direction of migration). Of significance is that migration of these cells is hindered at electric field strengths many orders of magnitude (5 to 6) below those previously reported for d.c. electrotaxis, and even in the presence of a chemokine (SDF-1α) or a growth factor (EGF). Induced a.c. electric fields applied in the direction of migration are also shown to hinder motility of non-transformed human mammary epithelial cells (MCF10A) in the presence of the growth factor EGF. In addition, we also show how our method can be applied to other cell migration assays (scratch assay), and by changing the coil design and holder, that it is also compatible with commercially available multi-well culture plates. © 2015, Nature Publishing Group. All rights reserved.

Scientific reports

Non-contact method for directing electrotaxis

RAGE is a multifunctional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the proinflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB, and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development. ©2015 AACR.

Cancer research

RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment

Inflammation is a double-edged sword. While short-lived, acute inflammation is essential for the repair and resolution of infection and damage, uncontrolled and unresolved chronic inflammation is central to several diseases, including cancer, autoimmune diseases, allergy, metabolic disease, and cardiovascular disease. This report aims to review the literature regarding several members of the nucleotide-binding domain, leucine-rich repeat-containing receptor (NLR) family of pattern recognition sensors/receptors that serve as checkpoints for inflammation. Understanding the negative regulation of inflammation is highly relevant to the development of therapeutics for inflammatory as well as infectious diseases. © 2015 Faculty of 1000 Ltd.

F1000Prime Reports

Holding the inflammatory system in check: NLRs keep it cool

Biomaterial induced activation of vascular endothelial growth factor (VEGF) pathway for angiogenesis is now gaining recognition as an effective option for tissue engineering. In this context, bivalent nickel (Ni2+) ion doped nano-hydroxyapatites (nHAp) were synthesized by wet chemical method, characterized and evaluated for their osteoconductive and proangiogenic properties. Electron microscopy (FESEM and TEM) along with ICP-OES analysis ensured formation of Ni2+ doped nanoparticles (average ferret diameter 15-17 nm). The 'apatite identity' of the nanoparticles was confirmed by XRD and FT-IR. Analysis revealed that Ni2+ doping caused no significant distortion in the crystal structure but decreased the crystallinity of nHAp considerably. Similarly, no major variation in the surface area (BET analysis), the zeta potential and the protein adsorption was observed among the samples. Biological characterization showed that Ni2+ doping influenced the cell viability, proliferation and differentiation of bone cells (MG-63) in a concentration dependent way. ELISA and RT-PCR study revealed that Ni2+ doped nHAp induced cellular VEGF expression many fold in comparison to control. Profiling of hypoxia inducible factor 1 alpha (HIF-1α) expression by immuno-cytochemistry and RT-PCR implied its involvement in cellular VEGF production. In conclusion, Ni2+ doped nHAp may serve as proangiogenic-osteogenic biomaterial for bone tissue engineering. © The Royal Society of Chemistry.

RSC Advances

Nickel doped nanohydroxyapatite: vascular endothelial growth factor inducing biomaterial for bone tissue engineering

Stearic acid and its derivatives have been used as gelators in food and pharmaceutical gel formulations. However, the mechanism pertaining to the stearic acid based gelation has not been deciphered yet. Keeping that in mind, we investigated the role of stearic acid on physic-chemical properties of oleogel. For this purpose, two different oil (sesame oil and soy bean oil) formulations/oleogels were prepared. In depth analysis of gel kinetics, gel microstructure, molecular interactions, thermal and mechanical behaviors of the oleogels were done. The properties of the oleogels were dependent on the type of the vegetable oil used and the concentration of the stearic acid. Avrami analysis of DSC thermograms indicated that heterogeneous nucleation was coupled with the one-dimensional growth of gelator fibers as the key phenomenon in the formation of oleogels. Viscoelastic and pseudoplastic nature of the oleogels was analyzed in-depth by fitting the stress relaxation data in modified Peleg's model and rheological studies, respectively. Textural studies have revealed that the coexistence of hydrogen bond dissipation and formation of new bonds is possible under stress conditions in the physical oleogels. © 2014 Elsevier B.V.

Materials Science and Engineering C

Stearic acid based oleogels: A study on the molecular, thermal and mechanical properties

The current study describes the synthesis and characterization of dual environment-responsive semi-interpenetrating hydrogels of polyhydroxyethyl methacrylate (pHEMA) and methyl cellulose (MC). HEMA was polymerized using free radical polymerization technique. Different proportions of MC were incorporated within the pHEMA matrix to induce environment-sensitive property. The microstructures of the hydrogels were studied under bright field microscopy. The hydrogels were thoroughly characterized using XRD, FTIR, swelling, mechanical and electrical studies. The micrographs of the hydrogels suggested formation of biphasic system. At lower proportions of MC, the hydrogels were oil-in-water type of formulations. An increase in the MC content resulted in the formation of bicontinuous biphasic formulations. Mechanical analysis suggested viscoelastic solid nature of the hydrogels. An increase in the MC content resulted in the increase in the viscous component. The electrical studies suggested resistive dominant behavior of the hydrogels. Thermal studies suggested better moisture retention capacity of the MC containing hydrogels. The hydrogels were found to be biocompatible in nature. © 2015 Taylor and Francis.

Designed Monomers and Polymers

Synthesis and characterization of novel dual environment-responsive hydrogels of Hydroxyethyl methacrylate and Methyl cellulose

The present study describes the preparation of extracellular matrix (ECM; from porcine omentum) based chitosan composite films for wound dressing applications. The films were prepared by varying the ECM content, whereas, the amount of chitosan was kept constant. The interactions amongst the components of the films were analyzed by FTIR and XRD studies. The films were thoroughly characterized for surface hydrophilicity, moisture retention capability, water vapor permeability, mechanical and biocompatibility. FTIR study indicated that both chitosan and ECM were present in their native form and did not lose their activity. XRD analysis suggested composition dependent change in the crystallinity of the films. The mechanical properties suggested that the composite films had sufficient properties to be used for wound dressing applications. An increase in the ECM content resulted in better hydrophilicity of the films and hence better the moisture retention capacity and retardant water vapor transmission rate property of the composite films. The films were found to be biocompatible to both blood and adipose tissue derived stem cells. In gist, the prepared films may be explored as wound dressing materials. © 2015, Springer Science+Business Media New York.

Journal of Materials Science: Materials in Medicine

Evaluation extracellular matrix–chitosan composite films for wound healing application

One of the important problems in functional genomics is how to select the disease genes. In this regard, the paper presents a new similarity measure to compute the functional similarity between two genes. It is based on the information of protein-protein interaction networks. A new gene selection algorithm is introduced to identify disease genes, integrating judiciously the information of gene expression profiles and protein-protein interaction networks. The proposed algorithm selects a set of genes from microarray data as disease genes by maximizing the relevance and functional similarity of the selected genes. The performance of the proposed algorithm, along with a comparison with other related methods, is demonstrated on colorectal cancer data set. © Springer International Publishing Switzerland 2015.