Materials for n-type organic electronics: synthesis and properties of fluoroarene-thiophene semiconductors

NASA Astrophysics Data System (ADS)

Facchetti, Antonio; Yoon, Myung-Han; Katz, Howard E.; Marks, Tobin J.

2003-11-01

Recent progress in the field of organic electronics is due to a fruitful combination of both innovative molecular design and promising low-cost material/device assembly. Targeting the first strategy, we present here the general synthesis of fluoroarene-containing thiophene-based semiconductors and the study of their properties with respect to the corresponding fluorine-free hole-transporting analogues. The new compounds have been characterized by elemental analysis, mass spectrometry, and 1H- and 19F NMR. The dramatic influence of fluorine substitution and molecular architecture has been investigated by solution/film optical absorption, fluorescence emission, and cyclic voltammetry. Single crystal data for all of the oligomers have been obtained and will be presented. Film microstructure and morphology of this new class of materials have been studied by XRD and SEM. Particular emphasis will be posed on the solution-processable oligomers and polymers.

Reactive Additives for Phenylethynyl-Containing Resins

NASA Technical Reports Server (NTRS)

Connell, John W.; Smith, Joseph G., Jr.; Hergenrother, Paul M.; Rommel, Monica L.

2005-01-01

Phenylethynyl-containing reactive additive (PERA) compounds and mixtures have been found to be useful for improving the processability of oligomers, polymers, co-oligomers, and copolymers that contain phenylethynyl groups. The additives can be incorporated in different forms: A solution of an amide acid or an imide of a PERA can be added to a solution of phenylethynyl-containing oligomer, polymer, co-oligomer, or copolymer; or An imide powder of a PERA can be mixed with a dry powder of a phenylethynyl-containing oligomer, polymer, co-oligomer, or copolymer. The effect of a given PERA on the processability and other properties of the resin system depends on whether the PERA is used in the amide acid or an imide form. With proper formulation, the PERA reduces the melt viscosity of the resin and thereby reduces the processing pressures needed to form the adhesive bonds, consolidate filled or unfilled moldings, or fabricate fiber-reinforced composite laminates. During thermal cure, a PERA reacts with itself as well as with the phenylethynyl-containing host resin and thereby becomes chemically incorporated into the resin system. The effects of the PERA on mechanical properties, relative to those of the host resin, depend on the amount of PERA used. Typically, the incorporation of the PERA results in (1) increases in the glass-transition temperature (Tg), modulus of elasticity, and parameters that characterize behavior under compression, and (2) greater retention of the aforementioned mechanical properties at elevated temperatures without (3) significant reduction of toughness or damage tolerance. Of the formulations tested thus far, the ones found to yield the best overall results were those for which the host resin was the amide acid form of a phenylethynyl-terminated imide (PETI) co-oligomer having a molecular weight of 5,000 g/mole [hence, designated PETI-5] and a PERA denoted as PERA-1. PETI-5 was made from 3,3',4'4'-biphenyltetracarboxylic dianhydride, 3,4'-oxydianiline (3,4'-ODA), 1,3-bis(3-aminophenoxy) benzene (1,3-APB), and 4-phenylethynylphthalic anhydride (PEPA). PERA-1 was made from 3,5-diamino- 4.-phenylethynylbenzophenon and equimolar amounts of phthalic anhydride and PEPA. To make PERA-1 in the imide form, the aforementioned ingredients were processed by refluxing in glacial acetic acid. To make the amide form of PERA-1, the ingredients were reacted in N-methyl-2-pyrrolidinone (NMP) under nitrogen at a temperature of 23 C (see figure). On the basis of the processability and other properties, a blend comprising 20 weight percent of PERA-1 and 80 weight percent PETI-5 was selected for further evaluation. Relative to neat PETI-5, the blend exhibited an increase in Tg; improved processability; and comparable values of shear strength in adhesion to titanium panels, open-hole compressive properties, compression properties after impact, and resistance to microcracking.

Acoustic activation of water-in-oil microemulsions for controlled salt dissolution.

PubMed

Baxamusa, Salmaan; Ehrmann, Paul; Ong, Jemi

2018-06-18

The dynamic nature of the oil-water interface allows for sequestration of material within the dispersed domains of a microemulsion. Microstructural changes should therefore change the dissolution rate of a solid surface in a microemulsion. We hypothesize that microstructural changes due to formulation and cavitation in an acoustic field will enable control over solid dissolution rates. Water-in-oil microemulsions were formulated using cyclohexane, water, Triton X-100, and hexanol. The microstructure and solvation properties of Winsor Type IV formulations were characterized. Dissolution rates of KH 2 PO 4 (KDP), were measured. A kinetic analysis isolated the effect of the microstructure, and rate enhancements due to cavitation effects on the microstructure were characterized by measuring dissolution rates in an ultrasonic field. Dispersed aqueous domains of 2-6 nm radius dissolve a solid block of KDP at 0-10 nm/min. Dissolution rate is governed not by the domain-surface collision frequency but rather by a dissolution probability per domain-surface encounter. Higher probabilities are correlated with larger domains. Rapid and reversible dissolution rate increases of up to 270× were observed under ultrasonic conditions, with <20% of the increase due to bulk heating effects. The rest is attributed to cavitation-induced changes to the domain microstructure, providing a simple method for remotely activating and de-activating dissolution. Copyright © 2018 Elsevier Inc. All rights reserved.

Microstructure of Tablet-Pharmaceutical Significance, Assessment, and Engineering.

PubMed

Sun, Changquan Calvin

2017-05-01

To summarize the microstructure - property relationship of pharmaceutical tablets and approaches to improve tablet properties through tablet microstructure engineering. The main topics reviewed here include: 1) influence of material properties and manufacturing process parameters on the evolution of tablet microstructure; 2) impact of tablet structure on tablet properties; 3) assessment of tablet microstructure; 4) development and engineering of tablet microstructure. Microstructure plays a decisive role on important pharmaceutical properties of a tablet, such as disintegration, drug release, and mechanical strength. Useful information on mechanical properties of a powder can be obtained from analyzing tablet porosity-pressure data. When helium pycnometry fails to accurately measure true density of a water-containing powder, non-linear regression of tablet density-pressure data is a useful alternative method. A component that is more uniformly distributed in a tablet generally exerts more influence on the overall tablet properties. During formulation development, it is highly recommended to examine the relationship between any property of interest and tablet porosity when possible. Tablet microstructure can be engineered by judicious selection of formulation composition, including the use of the optimum solid form of the drug and appropriate type and amount of excipients, and controlling manufacturing process.

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

NASA Astrophysics Data System (ADS)

Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

2015-03-01

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06556e

Preparation and characterization of dutasteride-loaded nanostructured lipid carriers coated with stearic acid-chitosan oligomer for topical delivery.

PubMed

Noor, Norhayati Mohamed; Sheikh, Khalid; Somavarapu, Satyanarayana; Taylor, Kevin M G

2017-08-01

Dutasteride, used for treating benign prostate hyperplasia (BPH), promotes hair growth. To enhance delivery to the hair follicles and reduce systemic effects, in this study dutasteride has been formulated for topical application, in a nanostructured lipid carrier (NLC) coated with chitosan oligomer-stearic acid (CSO-SA). CSO-SA has been successfully synthesized, as confirmed using 1 H NMR and FTIR. Formulation of dutasteride-loaded nanostructured lipid carriers (DST-NLCs) was optimized using a 2 3 full factorial design. This formulation was coated with different concentrations of stearic acid-chitosan solution. Coating DST-NLCs with 5% SA-CSO increased mean size from 187.6±7.0nm to 220.1±11.9nm, and modified surface charge, with zeta potentials being -18.3±0.9mV and +25.8±1.1mV for uncoated and coated DST-NLCs respectively. Transmission electron microscopy showed all formulations comprised approximately spherical particles. DST-NLCs, coated and uncoated with CSO-SA, exhibited particle size stability over 60days, when stored at 4-8°C. However, NLCs coated with CSO (without conjugation) showed aggregation when stored at 4-8°C after 30days. The measured particle size for all formulations stored at 25°C suggested aggregation, which was greatest for DST-NLCs coated with 10% CSO-SA and 5% CSO. All nanoparticle formulations exhibited rapid release in an in vitro release study, with uncoated NLCs exhibiting the fastest release rate. Using a Franz diffusion cell, no dutasteride permeated through pig ear skin after 48h, such that it was not detected in the receptor chamber for all samples. The amount of dutasteride in the skin was significantly different (p<0.05) for DST-NLCs (6.09±1.09μg/cm 2 ) without coating and those coated with 5% CSO-SA (2.82±0.40μg/cm 2 ), 10% CSO-SA (2.70±0.35μg/cm 2 ) and CSO (2.11±0.64μg/cm 2) . There was a significant difference (p<0.05) in the cytotoxicity (IC 50 ) between dutasteride alone and in the nanoparticles. DST-NLCs coated and uncoated with CSO-SA increased the maximum non-toxic concentration by 20-fold compared to dutasteride alone. These studies indicate that a stearic acid-chitosan conjugate was successfully prepared, and modified the surface charge of DST-NLCs from negative to positive. These stable, less cytotoxic, positively-charged dutasteride-loaded nanostructured lipid carriers, with stearic acid-chitosan oligomer conjugate, are appropriate for topical delivery and have potential for promotion of hair growth. Copyright © 2017. Published by Elsevier B.V.

Supplementation with xylanase and β-xylosidase to reduce xylo-oligomer and xylan inhibition of enzymatic hydrolysis of cellulose and pretreated corn stover

PubMed Central

2011-01-01

Background Hemicellulose is often credited with being one of the important physical barriers to enzymatic hydrolysis of cellulose, and acts by blocking enzyme access to the cellulose surface. In addition, our recent research has suggested that hemicelluloses, particularly in the form of xylan and its oligomers, can more strongly inhibit cellulase activity than do glucose and cellobiose. Removal of hemicelluloses or elimination of their negative effects can therefore become especially pivotal to achieving higher cellulose conversion with lower enzyme doses. Results In this study, cellulase was supplemented with xylanase and β-xylosidase to boost conversion of both cellulose and hemicellulose in pretreated biomass through conversion of xylan and xylo-oligomers to the less inhibitory xylose. Although addition of xylanase and β-xylosidase did not necessarily enhance Avicel hydrolysis, glucan conversions increased by 27% and 8% for corn stover pretreated with ammonia fiber expansion (AFEX) and dilute acid, respectively. In addition, adding hemicellulase several hours before adding cellulase was more beneficial than later addition, possibly as a result of a higher adsorption affinity of cellulase and xylanase to xylan than glucan. Conclusions This key finding elucidates a possible mechanism for cellulase inhibition by xylan and xylo-oligomers and emphasizes the need to optimize the enzyme formulation for each pretreated substrate. More research is needed to identify advanced enzyme systems designed to hydrolyze different substrates with maximum overall enzyme efficacy. PMID:21702938

Dual-Component Gelatinous Peptide/Reactive Oligomer Formulations as Conduit Material and Luminal Filler for Peripheral Nerve Regeneration

PubMed Central

Kohn-Polster, Caroline; Bhatnagar, Divya; Woloszyn, Derek J.; Richtmyer, Matthew; Starke, Annett; Springwald, Alexandra H.; Franz, Sandra; Schulz-Siegmund, Michaela; Kaplan, Hilton M.; Kohn, Joachim; Hacker, Michael C.

2017-01-01

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing oligomer, a dual-component hydrogel system (cGEL) was established. First, hollow cGEL tubes were fabricated by a continuous dosing and templating process. Conduits were characterized concerning their mechanical strength, in vitro and in vivo degradation and biocompatibility. Second, cGEL was reformulated as injectable shear thinning filler for established NGCs, here tyrosine-derived polycarbonate-based braided conduits. Thereby, the formulation contained the small molecule LM11A-31. The biofunctionalized cGEL filler was assessed regarding building block integration, mechanical properties, in vitro cytotoxicity, and growth permissive effects on human adipose tissue-derived stem cells. A positive in vitro evaluation motivated further application of the filler material in a sciatic nerve defect. Compared to the empty conduit and pristine cGEL, the functionalization performed superior, though the autologous nerve graft remains the gold standard. In conclusion, LM11A-31 functionalized cGEL filler with extracellular matrix (ECM)-like characteristics and specific biochemical cues holds great potential to support PNR. PMID:28531139

Dual-Component Gelatinous Peptide/Reactive Oligomer Formulations as Conduit Material and Luminal Filler for Peripheral Nerve Regeneration.

PubMed

Kohn-Polster, Caroline; Bhatnagar, Divya; Woloszyn, Derek J; Richtmyer, Matthew; Starke, Annett; Springwald, Alexandra H; Franz, Sandra; Schulz-Siegmund, Michaela; Kaplan, Hilton M; Kohn, Joachim; Hacker, Michael C

2017-05-21

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing oligomer, a dual-component hydrogel system (cGEL) was established. First, hollow cGEL tubes were fabricated by a continuous dosing and templating process. Conduits were characterized concerning their mechanical strength, in vitro and in vivo degradation and biocompatibility. Second, cGEL was reformulated as injectable shear thinning filler for established NGCs, here tyrosine-derived polycarbonate-based braided conduits. Thereby, the formulation contained the small molecule LM11A-31. The biofunctionalized cGEL filler was assessed regarding building block integration, mechanical properties, in vitro cytotoxicity, and growth permissive effects on human adipose tissue-derived stem cells. A positive in vitro evaluation motivated further application of the filler material in a sciatic nerve defect. Compared to the empty conduit and pristine cGEL, the functionalization performed superior, though the autologous nerve graft remains the gold standard. In conclusion, LM11A-31 functionalized cGEL filler with extracellular matrix (ECM)-like characteristics and specific biochemical cues holds great potential to support PNR.

Preparation and characterization of cyanocobalamin (vit B12) microemulsion properties and structure for topical and transdermal application.

PubMed

Salimi, Anayatollah; Sharif Makhmal Zadeh, Behzad; Moghimipour, Eskandar

2013-07-01

The objective of this study was to design a topical microemulsion of Vit B12 and to study the correlation between internal structure and physicochemical properties of the microemulsions. Microemulsions are thermodynamically stable mixtures of water, oil, surfactants and usually cosurfactants with several advantages for topical and transdermal drug delivery. The formulation of microemulsions for pharmaceutical use requires a clear understanding of the properties and microstructures of the microemulsions. In this study, phase behavior and microstructure of traditional and novel microemulsions of Vit B12 have been investigated by Small-angle X-ray (SAXS), differential scanning calorimetery (DSC) and measuring density, particle size, conductivity and surface tension. WO and bicontinuous microemulsion with different microstructures were found in novel and traditional formulations. In this study, amount of water, surfactant concentration, oil/ surfactant ratio and physicochemical properties of cosurfactants influenced the microstructures. In both formulations, water behavior was affected by the concentration of the surfactant. Water Solubilization capacity and enthalpy of exothermic peak of interfacial and free water of traditional formulations were more than novel ones. This means that the affinity of water to interfacial film is dependent on the surfactant properties.   This study showed that both microemulsions provided good solubility of Vit B12 with a wide range of internal structure. Low water solubilization capacity is a common property of microemulsions that can affect drug release and permeability through the skin.  Based on Vit B12 properties, specially, intermediate oil and water solubility, better drug partitioning into the skin may be obtained by traditional formulations with wide range of structure and high amount of free and bounded water.    

Statistical models and NMR analysis of polymer microstructure

USDA-ARS?s Scientific Manuscript database

Statistical models can be used in conjunction with NMR spectroscopy to study polymer microstructure and polymerization mechanisms. Thus, Bernoullian, Markovian, and enantiomorphic-site models are well known. Many additional models have been formulated over the years for additional situations. Typica...

Controlled Growth of Polypyrrole on Microelectrodes

NASA Astrophysics Data System (ADS)

Kannan, Bhuvaneswari; Williams, David E.; Travas-Sejdic, Jandranka

2009-07-01

Electrochemical growth of a conducting polymer generally leads to a microstructure which is an irregular assembly of irregular spheres, generally taken to be indicative of a diffusion-limited aggregation in which oligomers generated at or near the electrode aggregate into particles that in turn aggregate onto the electrode. We have explored the possibilities for controlling this growth mode by using short current pulses to form the polymer. We illustrate the alteration in growth morphology achievable by the use of different pulse sequences. In particular, we show the possibility to grow isolated dendrites (`nanowires') of conducting polymer on an electrode surface.

Liquid-Crystal Thermosets, a New Generation of High-Performance Liquid-Crystal Polymers

NASA Technical Reports Server (NTRS)

Dingemans, Theo; Weiser, Erik; Hou, Tan; Jensen, Brian; St. Clair, Terry

2004-01-01

One of the major challenges for NASA's next-generation reusable-launch-vehicle (RLV) program is the design of a cryogenic lightweight composite fuel tank. Potential matrix resin systems need to exhibit a low coefficient of thermal expansion (CTE), good mechanical strength, and excellent barrier properties at cryogenic temperatures under load. In addition, the resin system needs to be processable by a variety of non-autoclavable techniques, such as vacuum-bag curing, resin-transfer molding (RTM), vacuum-assisted resin-transfer molding (VaRTM), resin-film infusion (RFI), pultrusion, and advanced tow placement (ATP). To meet these requirements, the Advanced Materials and Processing Branch (AMPB) at NASA Langley Research Center developed a new family of wholly aromatic liquid-crystal oligomers that can be processed and thermally cross-linked while maintaining their liquid-crystal order. All the monomers were polymerized in the presence of a cross-linkable unit by use of an environmentally benign melt-condensation technique. This method does not require hazardous solvents, and the only side product is acetic acid. The final product can be obtained as a powder or granulate and has an infinite shelf life. The obtained oligomers melt into a nematic phase and do not exhibit isotropization temperatures greater than the temperatures of decomposition (Ti > T(sub dec)). Three aromatic formulations were designed and tested and included esters, ester-amides, and ester-imides. One of the major advantages of this invention, named LaRC-LCR or Langley Research Center-Liquid Crystal Resin, is the ability to control a variety of resin characteristics, such as melting temperature, viscosity, and the cross-link density of the final part. Depending on the formulation, oligomers can be prepared with melt viscosities in the range of 10-10,000 poise (100 rad/s), which can easily be melt-processed using a variety of composite-processing techniques. This capability provides NASA with custom-made matrix resins that meet the required processing conditions for the fabrication of textile composites. Once the resin is in place, the temperature is raised to 375 C and the oligomers are cross-linked into a high-glass-transition-temperature (Tg) nematic network without releasing volatiles. The mechanical properties of the fully crosslinked, composite articles are comparable to typical composites based on commercially available epoxy resins.

Dynamic light scattering for measuring microstructure and rheological properties of food

USDA-ARS?s Scientific Manuscript database

In recent years there has been significant interest in the determination of microstructural and rheological properties of viscoelastic food materials and their formulations. This is because the arrangement (architecture) of the micro­ and nano­components, size distribution, and rheological (mechanic...

Development of dental restorative materials based on visible light-cured multi-methacrylates

NASA Astrophysics Data System (ADS)

Tiba, Amer

The studies described in this dissertation focus on new visible light-curing (VLC) oligomers exhibiting low shrinkage, low water sorption, and improved mechanical properties. A family of multi-methacrylates, based on poly(isopropylidenediphenol) resin (BPA), was synthesized, characterized, and evaluated. The commercial BPA resin is prepared from enzymatic polymerization (oligomerization) of bisphenol A. The BPA resin, having an average of eight phenolic hydroxyl groups per molecule, was treated with propylene carbonate, and the resultant product, i.e., propoxylated BPA (PEBPA) oligomer, was confirmed by Fourier transform infrared spectroscopy (FT-IR) and sp{13}C nuclear magnetic resonance (NMR). The propoxylated BPA was subsequently treated with methacryloyl chloride to produce the multi-methacrylates, identified by FT-IR and NMR. The PEBPA oligomer multimethacrylate: triethylene glycol dimethacrylate (TEGDMA) (50:50/wt:wt) blends were combined with 0.5 wt. % camphoroquinone (CQ) and 1.0 wt. % N,N-dimethylaminoethyl methacrylate (DMAEMA). The control polymers were 2,2-bis(4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl) propane (BisGMA): TEGDMA(50:50/wt:wt) blends having the same levels of CQ/DMAEMA. Differential photocalorimetry (DPC) and differential scanning calorimetry (DSC) showed these multimethacrylate/TEGDMA (neat resin) blends have polymerization characteristics comparable to the BisGMA/TEGDMA controls. These new multifunctional oligomers have lower polymerization shrinkage and lower uptake of water and other liquids, compared to BisGMA based materials. In addition, two experimental oligomers, PEBPA #2 and #3, have higher compressive strength than the BisGMA control. A biocompatibility test of the polymerized multi-methacrylate resins was performed and compared with the conventional BisGMA/TEGDMA resin and blank controls, using cell culture techniques. Human gingival fibroblasts were used for biocompatibility evaluation of these resins. The results revealed that the BPA oligomer (multi-methacrylate) based resin significantly favored the cell growth of the human gingival fibroblasts, compared to the control. An experimental composite was made from EPBPA oligomers (multi-methacrylates). The compressive strength of the experimental EPBPA containing composite was not significantly different than the commercial composite Herculite HXR. SEM photomicrographs revealed more voids in the experimental composites than the commercial composite on both the external surfaces of the prepared specimens and the subsequent fractured surfaces. This is due to the molding technique for specimen preparation and lack of good mechanical mixing for filler incorporation prior to placement of the resin in the mold for subsequent photopolymerization. However, the water sorption for the experimental EPBPA-based composite was significantly lower than the commercial Herculite (HXR) composite. This is most likely related to the hydrophobic nature of the experimental resin. These results suggest that the new type of polyfunctional methacrylate oligomers (PEBPA) have potential application in formulating dental composites as direct esthetic restorative materials with improved properties.

Application of photocuring technique on wood surface and its prospects in Bangladesh

NASA Astrophysics Data System (ADS)

Bhattcacharia, S. K.; Khan, Mubarak A.

2005-07-01

Photocuring technique has unveiled a new horizon in polymer science. Application of photocuring technique on wood surface has enhanced the use of low grade wood. As Bangladesh is an overpopulated country, necessity of good quality wood is increasing day by day. So low grade wood, like Simul or Partex, locally produced particleboard, would come out with great use. As Partex board, produced from Jute sticks and various types of indigenous low grade wood and particle board are abundant in Bangladesh, so photocuring could play a major role to improve the quality of low grade wood and serve the nation. Already, a lot of research works were carried out by the local scientists to improve the wood surface using UV curing method. Different formulations were also developed by the local scientists using various oligomer, monomer and different types of additives. The used oligomers are epoxy, polyester, urethane, etc. and monomers of different functionalities and used additives are acrylic monomer, CaCO3, sand, MgSiO3, talc, etc. Thin films were prepared on glass plate with different formulations using UV radiation and different characteristics properties (pendulum hardness, abrasion, gloss (60° and 20°), microscratch hardness, weathering effect, adhesion strength, etc.) were studied. Now, a Pilot Plant has already been established with the financial assistance by the government of Bangladesh, worth US 3.5 million.

Analytical approaches to identify potential migrants in polyester-polyurethane can coatings.

PubMed

Louise Bradley, Emma; Driffield, Malcolm; Guthrie, James; Harmer, Nick; Thomas Oldring, Peter Kenneth; Castle, Laurence

2009-12-01

The safety of a polyester-polyurethane can coating has been assessed using a suite of complementary analytical methods to identify and estimate the concentrations of potential chemical migrants. The polyester was based on phthalic acids and aliphatic diols. The polyisocyanate cross-linking agent was 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethyl cyclohexane homopolymer (IPDI) blocked with methylethylketone oxime (MEKO) to make a one-part formulation. The overall migrate, obtained using solvent extraction of cured films, comprised almost completely of 12 cyclic and one linear polyester oligomer up to molecular weight 800 and containing up to six monomer units. These 13 oligomers covered a total of 28 isomeric forms. Other minor components detected were plasticisers and surfactants as well as impurities present in the starting materials. There was no detectable residue of either the blocked isocyanate (<0.01 microg/dm(2)) used as the starting substance or the unblocked isocyanate (<0.02 microg/dm(2)). The level of extractable IPDI was used as an indicator of the completeness of cure in experimental coatings. These studies revealed that there was an influence of time, temperature and catalyst content. Polymerisation was also influenced by the additives used and by the ageing of the wet coating formulation over several months. These studies allow parameters to be specified to ensure that commercial production coatings receive a full cure giving low migration characteristics.

Swelling, erosion and drug release characteristics of salbutamol sulfate from hydroxypropyl methylcellulose-based matrix tablets.

PubMed

Chaibva, Faith A; Khamanga, Sandile M M; Walker, Roderick B

2010-12-01

Hydrophilic matrix formulations are important and simple technologies that are used to manufacture sustained release dosage forms. Hydroxypropyl methylcellulose-based matrix tablets, with and without additives, were manufactured to investigate the rate of hydration, rate of erosion, and rate and mechanism of drug release. Scanning electron microscopy was used to assess changes in the microstructure of the tablets during drug release testing and whether these changes could be related to the rate of drug release from the formulations. The results revealed that the rate of hydration and erosion was dependent on the polymer combination(s) used, which in turn affected the rate and mechanism of drug release from these formulations. It was also apparent that changes in the microstructure of matrix tablets could be related to the different rates of drug release that were observed from the test formulations. The use of scanning electron microscopy provides useful information to further understand drug release mechanisms from matrix tablets.

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

PubMed Central

Burton, Scott A.; Ng, Chin-Yee; Simmers, Ryan; Moeckly, Craig; Brandwein, David; Gilbert, Tom; Johnson, Nathan; Brown, Ken; Alston, Tesha; Prochnow, Gayatri; Siebenaler, Kris

2010-01-01

ABSTRACT Purpose The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. Methods 3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. Results Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. Conclusions 3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery. PMID:20582455

Porous Cross-Linked Polyimide-Urea Networks

NASA Technical Reports Server (NTRS)

Meador, Mary Ann B. (Inventor); Nguyen, Baochau N. (Inventor)

2015-01-01

Porous cross-linked polyimide-urea networks are provided. The networks comprise a subunit comprising two anhydride end-capped polyamic acid oligomers in direct connection via a urea linkage. The oligomers (a) each comprise a repeating unit of a dianhydride and a diamine and a terminal anhydride group and (b) are formulated with 2 to 15 of the repeating units. The subunit was formed by reaction of the diamine and a diisocyanate to form a diamine-urea linkage-diamine group, followed by reaction of the diamine-urea linkage-diamine group with the dianhydride and the diamine to form the subunit. The subunit has been cross-linked via a cross-linking agent, comprising three or more amine groups, at a balanced stoichiometry of the amine groups to the terminal anhydride groups. The subunit has been chemically imidized to yield the porous cross-linked polyimide-urea network. Also provided are wet gels, aerogels, and thin films comprising the networks, and methods of making the networks.

Multiscale crystal defect dynamics: A coarse-grained lattice defect model based on crystal microstructure

NASA Astrophysics Data System (ADS)

Lyu, Dandan; Li, Shaofan

2017-10-01

Crystal defects have microstructure, and this microstructure should be related to the microstructure of the original crystal. Hence each type of crystals may have similar defects due to the same failure mechanism originated from the same microstructure, if they are under the same loading conditions. In this work, we propose a multiscale crystal defect dynamics (MCDD) model that models defects by considering its intrinsic microstructure derived from the microstructure or material genome of the original perfect crystal. The main novelties of present work are: (1) the discrete exterior calculus and algebraic topology theory are used to construct a scale-up (coarse-grained) dual lattice model for crystal defects, which may represent all possible defect modes inside a crystal; (2) a higher order Cauchy-Born rule (up to the fourth order) is adopted to construct atomistic-informed constitutive relations for various defect process zones, and (3) an hierarchical strain gradient theory based finite element formulation is developed to support an hierarchical multiscale cohesive (process) zone model for various defects in a unified formulation. The efficiency of MCDD computational algorithm allows us to simulate dynamic defect evolution at large scale while taking into account atomistic interaction. The MCDD model has been validated by comparing of the results of MCDD simulations with that of molecular dynamics (MD) in the cases of nanoindentation and uniaxial tension. Numerical simulations have shown that MCDD model can predict dislocation nucleation induced instability and inelastic deformation, and thus it may provide an alternative solution to study crystal plasticity.

Low-fat frankfurters formulated with a healthier lipid combination as functional ingredient: microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation.

PubMed

Delgado-Pando, Gonzalo; Cofrades, Susana; Ruiz-Capillas, Claudia; Solas, Maria Teresa; Triki, Mehdi; Jiménez-Colmenero, Francisco

2011-09-01

Oil (healthier lipid combination of olive, linseed and fish oils)-in-water emulsions stabilized with different protein systems (prepared with sodium caseinate (SC), soy protein isolate (SPI), and microbial transglutaminase (MTG)) were used as pork backfat replacers in low-fat frankfurters. Microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation of frankfurters were analyzed and found to be affected by the type of oil-in-water emulsion and by chilling storage (2° C, 41 days). Although the lipid oxidation levels attained were low, replacement of animal fat by healthier oil combinations in frankfurter formulation did promote a slight increase in lipid oxidation. Residual nitrite was affected (P < 0.05) by formulation and storage. Only 51-61% of the added nitrite was detectable in the product after processing and 17-46% at the end of storage. The microbial population was low in all formulations during chilling storage. Spermine was the most abundant amine (19-20 mg/kg), but similar in level to all samples. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characterisation and microstructure of reduced-fat chicken patties made with a novel polymer from Agrobacterium radiobacter k84.

PubMed

Calliari, Caroline Maria; de Souza, Evandro Leite; Castro-Goméz, Raúl Jorge Hernan; Honório, Vanessa Gonçalves; Magnani, Marciane

2015-04-15

Chicken patties elaborated with a novel polymer from Agrobacterium radiobacter k84 (ARB) were characterised during 60days of frozen storage. After cooking, formulations without ARB (F0), with ARB 5 g/100 g (F5) and ARB 10 g/100 g (F10) presented 4.23%, 2.83% and 0.11% fat, respectively. No differences were observed to water holding capacity, cooking yield and shear force among formulations. Microstructural analysis showed formation of meat emulsion for F5 and gel for F10. Colour and chicken flavour decreased with increase of ARB; no difference was found for tenderness among the formulations. Overall acceptance showed higher scores for F0 when compared to F5 and F10. Lipid oxidation was not a limiting factor for stability of patties; all formulations presented suitable microbiological quality over the assessed period. These results suggest ARB as a promising fat substitute, capable of maintain the quality aspects of chicken patties, although a negative impact in colour has been found. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tau Oligomers as Pathogenic Seeds: Preparation and Propagation In Vitro and In Vivo.

PubMed

Gerson, Julia E; Sengupta, Urmi; Kayed, Rakez

2017-01-01

Tau oligomers have been shown to be the main toxic tau species in a number of neurodegenerative disorders. In order to study tau oligomers both in vitro and in vivo, we have established methods for the reliable preparation, isolation, and detection of tau oligomers. Methods for the seeding of tau oligomers, isolation of tau oligomers from tissue, and detection of tau oligomers using tau oligomer-specific antibodies by biochemical and immunohistochemical methods are detailed below.

In Situ Imaging during Compression of Plastic Bonded Explosives for Damage Modeling

NASA Astrophysics Data System (ADS)

Yeager, John; Manner, Virginia; Patterson, Brian; Walters, David; Cordes, Nikolaus; Henderson, Kevin; Tappan, Bryce; Luscher, Darby

2017-06-01

The microstructure of plastic bonded explosives (PBXs) is known to influence behavior during insults such as deformation, heating or initiation to detonation. Obtaining three-dimensional microstructural data can be difficult due in part to fragility of the material and small feature size. X-ray computed tomography (CT) is an ideal characterization technique but the explosive crystals and binder in formulations such as PBX 9501 do not have sufficient x-ray contrast to differentiate between the components. Here, we have formulated several PBXs using octahydro-1,3,5,7-tetranitro-1,3,5,7- tetrazocine (HMX) crystals and low-density binder systems. The full three-dimensional microstructure of these samples has been characterized using microscale CT during uniaxial mechanical compression in an interrupted in situ modality. The rigidity of the binder was observed to significantly influence fracture, crystal-binder delamination, and material flow. Additionally, the segmented, 3D images were meshed for finite element simulation. Initial results of the mesoscale modeling exhibit qualitatively similar delamination. Los Alamos National Laboratory - LDRD.

Innovations in the development of healthier chicken sausages formulated with different lipid sources.

PubMed

Andrés, S C; Zaritzky, N E; Califano, A N

2009-08-01

Long-chain polyunsaturated n-3 fatty acids are critical nutrients for human health and the fortification of foods with these fatty acids is an important emerging area from the commercial and academic point of view. Development, characterization, and changes during refrigerated vacuum storage of low-fat chicken sausages formulated with preemulsified squid oil were examined and compared with those formulated with beef tallow. Physicochemical analysis and process yield after heat treatment were determined; the heat-treated sausages were evaluated by purge loss, color, texture, microstructure by SEM, microbial counts, fatty acid profile, lipid oxidation, and sensory analysis during refrigerated vacuum storage. Process yield of both formulations was higher than 97% and purge losses during storage were lower than 7%. Purge losses of oil-formulated sausages were lower than those with beef tallow. Sausages with squid oil resulted in higher lightness, lower redness and yellowness, and lower texture profile analysis parameters than the formulation prepared with beef tallow. Microstructure of both formulations was similar, except for the fat droplets that microscopic observations showed in the sausages made with beef tallow. Low lipid oxidation was detected in formulation with squid oil due to the the combination of ingredients and storage conditions. Microbial counts of both products were less than 5 log cfu/g at the end of 90 d of storage. The sausage formulated with squid oil presented more than 30 and 40 g/100 g of monounsaturated and polyunsaturated fatty acids, respectively. Docosahexaenoic acid was the predominant polyunsaturated fatty acid, followed by eicosapentaenoic acid and linoleic acid. Both products showed safe sanitary conditions, good sensory acceptability, and presented very good stability and quality attributes, but sausages formulated with squid oil showed a better fatty acid profile according to nutritional criteria.

Thermal aggregation of human immunoglobulin G in arginine solutions: Contrasting effects of stabilizers and destabilizers.

PubMed

Yoshizawa, Shunsuke; Arakawa, Tsutomu; Shiraki, Kentaro

2017-11-01

Arginine is widely used as aggregation suppressor of proteins in biotechnology and pharmaceutics. However, why the effect of arginine depends on the types of proteins and stresses, including monoclonal antibodies, is still unclear. Here we investigated the precise processes of the thermal aggregation of human immunoglobulin G (IgG) in the presence of additives. As expected, arginine was the best additive to suppress the formation of insoluble aggregates during heat treatment, though it was unable to preserve the monomer content. A systematic analysis of the additives showed that sugars and kosmotropic ion inhibit the formation of soluble oligomers. These behaviors indicate that the thermal aggregation of IgG occurs by (i) the formation of soluble oligomers, which is triggered by the unfolding process that can be stabilized by typical osmolytes, and (ii) the formation of insoluble aggregates through weak cluster-cluster interactions, which can be suppressed by arginine. Understanding the detailed mechanism of arginine will provide useful information for the rational formulation design of antibodies. Copyright © 2017 Elsevier B.V. All rights reserved.

Cellulosic fabrics printing with multifunctional encapsulated phthalocyanine pigment blue using phase separation method.

PubMed

Haroun, Ahmed A; Diab, H A; Hakeim, O A

2016-08-01

Aqueous dispersions of citric-acrylate (CAC) oligomer encapsulating C.I. Pigment Blue 15:3 (PB15:3) in the presence of glutaraldhyde were formulated using the phase separation method. FT-IR spectroscopy and centrifuge sedimentation are performed to confirm the encapsulation of pigment into CAC oligomer. The prepared capsules were characterized using thermal gravimetric analysis (TGA) and transmission electron microscope (TEM). The results revealed that the encapsulated pigment had a profound multifunctional impact and minimized the driving force of pigment printing on the cellulosic fabrics. Besides, the encapsulated pigment accelerated the pigment fixation on cellulosic fabrics without drying in one step and reduced the required amount of the binder, compared with the control sample. Furthermore, the printed fabrics exhibited good antibacterial performance against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The presence of the crosslinker could be stabilized the encapsulated pigment on the cellulosic fabrics. Moreover, the light and washing fastness for the printed fabrics using encapsulated pigment are higher than that in case of using control samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

Polyimide Aerogels Using Triisocyanate as Cross-linker.

PubMed

Nguyen, Baochau N; Meador, Mary Ann B; Scheiman, Daniel; McCorkle, Linda

2017-08-16

A family of polyimide (PI)-based aerogels is produced using Desmodur N3300A, an inexpensive triisocyanate, as the cross-linker. The aerogels are prepared by cross-linking amine end-capped polyimide oligomers with the triisocyanate. The polyimide oligomers are formulated using 2,2'-dimethylbenzidine, 4,4'-oxydianiline, or mixtures of both diamines, combined with 3,3',4,4'-biphenyltetracarboxylic dianhydride, and are chemically imidized at room temperature. Depending on the backbone chemistry, chain length, and polymer concentration, density of the aerogels ranged from 0.06 to 0.14 g/cm 3 and Brunauer-Emmett-Teller surface areas ranged from 350 to 600 m 2 /g. Compressive moduli of these aerogels were as high as 225 MPa, which are comparable to, or higher than, those previously reported prepared with similar backbone structures but with other cross-linkers. Because of their lower cost and commercial availability as cross-linker, the aerogels may have further potential as insulation for building and construction, clothing, sporting goods, and automotive applications, although lower-temperature stability may limit their use in some aerospace applications.

Angle-adjustable density field formulation for the modeling of crystalline microstructure

NASA Astrophysics Data System (ADS)

Wang, Zi-Le; Liu, Zhirong; Huang, Zhi-Feng

2018-05-01

A continuum density field formulation with particle-scale resolution is constructed to simultaneously incorporate the orientation dependence of interparticle interactions and the rotational invariance of the system, a fundamental but challenging issue in modeling the structure and dynamics of a broad range of material systems across variable scales. This generalized phase field crystal-type approach is based upon the complete expansion of particle direct correlation functions and the concept of isotropic tensors. Through applications to the modeling of various two- and three-dimensional crystalline structures, our study demonstrates the capability of bond-angle control in this continuum field theory and its effects on the emergence of ordered phases, and provides a systematic way of performing tunable angle analyses for crystalline microstructures.

Microphase separation in solid lipid dosage forms as the cause of drug release instability.

PubMed

Lopes, Diogo Gomes; Koutsamanis, Ioannis; Becker, Karin; Scheibelhofer, Otto; Laggner, Peter; Haack, Detlev; Stehr, Michael; Zimmer, Andreas; Salar-Behzadi, Sharareh

2017-01-30

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage. Copyright © 2016 Elsevier B.V. All rights reserved.

Functional Diversity of Isoamylase Oligomers: The ISA1 Homo-Oligomer Is Essential for Amylopectin Biosynthesis in Rice Endosperm1[W][OA

PubMed Central

Utsumi, Yoshinori; Utsumi, Chikako; Sawada, Takayuki; Fujita, Naoko; Nakamura, Yasunori

2011-01-01

Rice (Oryza sativa) endosperm has two isoamylase (ISA) oligomers, ISA1 homo-oligomer and ISA1-ISA2 hetero-oligomer. To examine their contribution to starch synthesis, expression of the ISA1 or ISA2 gene was differently regulated in various transgenic plants. Although suppression of ISA2 gene expression caused the endosperm to have only the homo-oligomer, no significant effects were detected on the starch phenotypes. In contrast, ISA2 overexpression led to endosperm having only the hetero-oligomer, and starch synthesis in the endosperm was drastically impaired, both quantitatively and qualitatively, because the starch was devoid of typical starch features, such as thermal and x-ray diffraction properties, and water-soluble highly branched maltodextrins were accumulated. In the ISA2 overexpressed line, about 60% to 70% of the ISA1-ISA2 hetero-oligomer was bound to starch, while the ISA homo- and hetero-oligomers from the wild type were mostly present in the soluble form at the early milking stage of the endosperm. Detailed analysis of the relative amounts of homo- and hetero-oligomers in various lines also led us to the conclusion that the ISA1 homo-oligomer is essential, but not the ISA1-ISA2 oligomer, for starch production in rice endosperm. The relative amounts of ISA1 and ISA2 proteins were shown to determine the ratio of both oligomers and the stoichiometry of both ISAs in the hetero-oligomer. It was noted when compared with the homo-oligomer that all the hetero-oligomers from rice endosperm and leaf and potato (Solanum tuberosum) tuber were much more stable at 40°C. This study provides substantial data on the structural and functional diversity of ISA oligomers between plant tissues and species. PMID:21436381

Microstructurally Based Prediction of High Strain Failure Modes in Crystalline Solids

DTIC Science & Technology

2016-07-05

SECURITY CLASSIFICATION OF: New three-dimensional dislocation-density based crystalline plasticity formulations was used with grain-boundary (GB...Army Research Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 High strain-rate; failure, crsytalline plasticity , dislocation-density...Solids Report Title New three-dimensional dislocation-density based crystalline plasticity formulations was used with grain-boundary (GB) kinematic

Stabilization, Characterization, and Selective Removal of Cystatin C Amyloid Oligomers*

PubMed Central

Östner, Gustav; Lindström, Veronica; Hjort Christensen, Per; Kozak, Maciej; Abrahamson, Magnus; Grubb, Anders

2013-01-01

The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers, and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry, shape by electron and atomic force microscopy, and, function by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers. PMID:23629649

Capping of Aβ42 Oligomers by Small Molecule Inhibitors

PubMed Central

2015-01-01

Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer’s disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric Aβ42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1–2 nm and high MW oligomers with heights of 3–5 nm. In both cases, the oligomers are disc-shaped with diameters of ∼10–15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5–20) of Aβ42 monomers and cap the height of the oligomers that are formed at 1–2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the Aβ42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation. PMID:25422864

Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

PubMed Central

Nors Perdersen, Martin; Foderà, Vito; Horvath, Istvan; van Maarschalkerweerd, Andreas; Nørgaard Toft, Katrine; Weise, Christoph; Almqvist, Fredrik; Wolf-Watz, Magnus; Wittung-Stafshede, Pernilla; Vestergaard, Bente

2015-01-01

Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an ‘oligomer stacking model’ for alpha-synuclein fibril elongation. PMID:26020724

Amyloid β oligomers induce interleukin-1β production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taneo, Jun; Adachi, Takumi; Yoshida, Aiko

2015-03-13

Amyloid β (Aβ) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1β (IL-1β) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of Aβ aggregates on IL-1β production in mouse primary microglia. We prepared Aβ oligomer and fibril from Aβ (1–42) peptide in vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, Aβ oligomers but not Aβ monomers or fibrils induced robust IL-1β production in themore » presence of lipopolysaccharide. Moreover, Aβ oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. Aβ oligomer-induced IL-1β production was inhibited not only by the cathepsin B inhibitor CA-074-Me but also by the reactive oxygen species (ROS) inhibitor N-acetylcysteine. Random chemical crosslinking abolished the ability of the oligomers to induce IL-1β. Thus, multimerization and fibrillization causes Aβ oligomers to lose the ability to induce IL-1β. These results indicate that Aβ oligomers, but not fibrils, induce IL-1β production in primary microglia in a cathepsin B- and ROS-dependent manner. - Highlights: • We prepared amyloid β (Aβ) fibrils with minimum contamination of Aβ oligomers. • Primary microglia (MG) produced IL-1β in response to Aβ oligomers, but not fibrils. • Only Aβ oligomers induced leakage of cathepsin B from endo/phagolysosomes. • IL-1β production in response to Aβ oligomers depended on both cathepsin B and ROS. • Crosslinking reduced the ability of the Aβ oligomers to induce IL-1β from MG.« less

Phenylethynyl terminated imide oligomers

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Bryant, Robert G. (Inventor); Jensen, Brian J. (Inventor); Havens, Stephen J. (Inventor)

1994-01-01

Four phenylethynyl amine compounds - 3 and 4-aminophenoxy-4'-phenylethynylbenzophenone, and 3 and 4-amino-4'-phenylethynylbenzophenone - were readily prepared and were used to endcap imide oligomers. Phenylethynyl-terminated amide acid oligomers and phenylethynyl-terminated imide oligomers with various molecular weights and compositions were prepared and characterized. These oligomers were cured at 300 to 400 C to provide crosslinked polyimides with excellent solvent resistance, high strength and modulus, and good high temperature properties. Adhesive panels, composites, films, and moldings from these phenylethynyl terminated imide oligomers gave excellent mechanical performance.

Phenylethynyl terminated imide oligomers

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Bryant, Robert G. (Inventor); Jensen, Brian J. (Inventor); Havens, Stephen J. (Inventor)

1995-01-01

Four phenylethynyl amine compounds - 3 and 4-aminophenoxy-4'-phenylethynylbenzophenone, and 3 and 4-amino-4'-phenylethynylbenzophenone - were readily prepared and were used to endcap imide oligomers. Phenylethynyl-terminated amide acid oligomers and phenylethynyl-terminated imide oligomers with various molecular weights and compositions were prepared and characterized. These oligomers were cured at 300 to 400 C to provide crosslinked polyimides with excellent solvent resistance, high strength and modulus, and good high temperature properties. Adhesive panels, composites, films, and moldings from these phenylethynyl terminated imide oligomers gave excellent mechanical performance.

Amyloid β-protein oligomers and Alzheimer’s disease

PubMed Central

2013-01-01

The oligomer cascade hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer’s disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer’s disease. We review here the results of in vivo, in vitro and in silico studies of amyloid β-protein oligomers, and discuss important caveats that should be considered in the evaluation of these results. This article is divided into four sections that mirror the main approaches used in the field to better understand oligomers: (1) attempts to locate and examine oligomers in vivo in situ; that is, without removing these species from their environment; (2) studies involving oligomers extracted from human or animal tissues and the subsequent characterization of their properties ex vivo; (3) studies of oligomers that have been produced synthetically and studied using a reductionist approach in relatively simple in vitro biophysical systems; and (4) computational studies of oligomers in silico. These multiple orthogonal approaches have revealed much about the molecular and cell biology of amyloid β-protein. However, as informative as these approaches have been, the amyloid β-protein oligomer system remains enigmatic. PMID:24289820

Effects of Emulsifier, Overrun and Dasher Speed on Ice Cream Microstructure and Melting Properties.

PubMed

Warren, Maya M; Hartel, Richard W

2018-03-01

Ice cream is a multiphase frozen food containing ice crystals, air cells, fat globules, and partially coalesced fat globule clusters dispersed in an unfrozen serum phase (sugars, proteins, and stabilizers). This microstructure is responsible for ice cream's melting characteristics. By varying both formulation (emulsifier content and overrun) and processing conditions (dasher speed), the effects of different microstructural elements, particularly air cells and fat globule clusters, on ice cream melt-down properties were studied. Factors that caused an increase in shear stress within the freezer, namely increasing dasher speed and overrun, caused a decrease in air cell size and an increase in extent of fat destabilization. Increasing emulsifier content, especially of polysorbate 80, caused an increase in extent of fat destabilization. Both overrun and fat destabilization influenced drip-through rates. Ice creams with a combination of low overrun and low fat destabilization had the highest drip-through rates. Further, the amount of remnant foam left on the screen increased with reduced drip-through rates. These results provide a better understanding of the effects of microstructure components and their interactions on drip-through rate. Manipulating operating and formulation parameters in ice cream manufacture influences the microstructure (air cells, ice crystals, and fat globule clusters). This work provides guidance on which parameters have most effect on air cell size and fat globule cluster formation. Further, the structural characteristics that reduce melt-down rate were determined. Ice cream manufacturers will use these results to tailor their products for the desired quality attributes. © 2018 Institute of Food Technologists®.

Clinical and laboratory evaluation of microstructural changes in the physical, mechanical and chemical properties of dental filling materials under the influence of an electromagnetic field.

PubMed

Moiseeva, Natalia S; Kunin, Anatoly A

2018-03-01

Restorative filling materials used for dental caries prevention and treatment consist of various components including monomers or oligomers, which play a significant role in forming the main structure of these materials, as well as in characterising their physical, mechanical and chemical properties. The necessity for the development and improvement of structural characteristics of polymeric dental filling materials intended for caries prevention and their life duration increase served as the initiating factor of our research. According to the research purpose and challenges, we studied the changes in the physical, mechanical and chemical properties of composite filling materials with and without electromagnetic field influence. The investigations in vivo include the study of microstructural features of polymeric filling materials by scanning electron microscopy (SEM) and the investigations in vitro include the study of sealed and extracted human teeth chips by using X-ray spectral analysis. We also evaluated the changes in the strength characteristics of dental filling materials with and without electromagnetic field influence. The analysis of the obtained data indicates the presence of structural changes in polymeric dental filling materials, including the material microstructure condensation confirmed by the SEM results, an increase in the strength and adhesion characteristics and certain regularities of the chemical elemental composition concentration change in the area of hard tooth tissue and dental filling material. These scientific data will provide tooth caries prevention and promote the increase of treatment quality.

Diamines Containing Pendent Phenylethynyl Groups

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Smith, Joseph G., Jr. (Inventor); Hergenrother, Paul M. (Inventor)

1997-01-01

Controlled molecular weight imide oligomers and co-oligomers containing pendent phenylethynyl groups (PEPIs) and endcapped with nonreactive or phenylethynyl groups have been prepared by the cyclodehydration of the precursor amide acid oligomers or co-oligomers containing pendent phenylethynyl groups and endcapped with nonreactive or phenylethynyl groups. The amine terminated amide acid oligomers or co-oligomers are prepared from the reaction of dianhydride(s) with an excess of diamine(s) and diamine containing pendent phenylethynyl groups and subsequently endcapped with a phenylethynyl phthalic anhydride or monofunctional anhydride. The anhydride terminated amide acid oligomers and co-oligomers are prepared from the reaction of diamine(s) and diamine containing pendent phenylethynyl group(s) with an excess of dianhydride(s) and subsequently endcapped with a phenylethynyl amine or monofunctional amine. The polymerizations are carried out in polar aprotic solvents such as and N,N-dimethylacetamide under nitrogen at room temperature. The amide acid oligomers or co-oligomers are subsequently cyclodehydrated either thermally or chemically to the corresponding imide oligomers. The polymers and copolymers prepared from these materials exhibit a unique and unexpected combination of properties that includes higher glass transition temperatures after curing and higher retention of neat resin, adhesive and carbon fiber reinforced mechanical properties at temperatures up to 204 C under wet conditions without sacrificing melt flow behavior and processability as compared to similar materials. These materials are useful as adhesives, coatings, films, moldings, and composite matrices.

Analysis of linear and cyclic oligomers in polyamide-6 without sample preparation by liquid chromatography using the sandwich injection method. II. Methods of detection and quantification and overall long-term performance.

PubMed

Mengerink, Y; Peters, R; Kerkhoff, M; Hellenbrand, J; Omloo, H; Andrien, J; Vestjens, M; van der Wal, S

2000-05-05

By separating the first six linear and cyclic oligomers of polyamide-6 on a reversed-phase high-performance liquid chromatographic system after sandwich injection, quantitative determination of these oligomers becomes feasible. Low-wavelength UV detection of the different oligomers and selective post-column reaction detection of the linear oligomers with o-phthalic dicarboxaldehyde (OPA) and 3-mercaptopropionic acid (3-MPA) are discussed. A general methodology for quantification of oligomers in polymers was developed. It is demonstrated that the empirically determined group-equivalent absorption coefficients and quench factors are a convenient way of quantifying linear and cyclic oligomers of nylon-6. The overall long-term performance of the method was studied by monitoring a reference sample and the calibration factors of the linear and cyclic oligomers.

The First Normal Stress Difference in Waterborne Paints Thickened by Hydrophobically Ethoxylated Urethane (HEUR) Rheology Modifier: A Simplified Phase Diagram

NASA Astrophysics Data System (ADS)

Chatterjee, Tirtha; van Dyk, Antony; Ginzburg, Valeriy; Nakatani, Alan

Since their invention in the 1970s, hydrophobically ethoxylated urethane (HEUR) associative thickeners are widely used to modify the rheology of waterborne paints. While their flow curves (viscosity vs. shear rate) and microstructure have been studied extensively in recent years, there is surprisingly little information on the paint normal stress under application conditions. However, understanding of normal stress behavior is critical for many applications such as brush drag and spatter. In this work we will demonstrate that in HEUR-based paints the first normal stress difference (N1) is controlled by two factors: (a) adsorption of HEUR molecules on latex particles and (b) ability of non-adsorbed HEUR to form transient bridges between particles with HEUR shells. By controlling these two effects, one can design a paint formulation with targeted N1 behavior (positive or negative N1 under high shear). Finally, a simplified phase diagram will be presented connecting formulation composition-microstructure- and N1 behavior. The results would serve as guidelines to formulate paints to meet the specific customer needs.

Physicochemical and microstructural properties of a novel edible film synthesized from Balangu seed mucilage.

PubMed

Sadeghi-Varkani, Atina; Emam-Djomeh, Zahra; Askari, Gholamreza

2018-03-01

This paper reports the synthesis of a novel edible film from Balangu seed mucilage (BSM) as a new carbohydrate source. Optimal formulation of the proposed edible film was found through fabricating several distinct films with different concentrations of BSM and glycerol. The effect of these formulation variables on the physical, mechanical, thermal, barrier, and microstructural properties of the manufactured films was then investigated. Optimal formulation of the BSM edible film was then determined based on the measured mechanical and barrier characteristics. These characteristics were found to deteriorate with an excessive use of glycerol which caused non-homogeneity of the films as observed through scanning electron micrographs. In-depth analysis of the optimal BSM film properties was performed through investigating its oxygen permeability, Fourier transform infrared spectroscopy, atomic force microscopy, X-ray diffraction, and water sorption isotherm. The superior mechanical and barrier characteristics of the obtained optimal BSM edible film make it a potential candidate for packaging that aim at an extended shelf-life. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion.

PubMed

Adler, Camille; Schönenberger, Monica; Teleki, Alexandra; Kuentz, Martin

2016-02-29

Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. β-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Compatibility study of a parenteral microdose polyethylene glycol formulation in medical devices and identification of degradation impurity by 2D-LC/MS.

PubMed

Dai, Lulu; Yeh, Geoffrey K; Ran, Yingqing; Yehl, Peter; Zhang, Kelly

2017-04-15

Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently used for drug delivery and administration. The compatibility of a parenteral drug microdose formulation in intravenous infusion (IV) devices was studied to support the clinical determination of absolute bioavailability by the microdosing method. The investigational microdose formulation containing PEG was found prone to significant loss of potency within hours of storage in the PVC IV tubing due to degradation. Degradation occurred only when both PEG and PVC tubing were present. The degradation product could not be detected by LC/MS due to the significant interference from the high concentration of PEG (4%) matrix and the extremely low level of drug (0.6ppm). To obtain structural information of the degradation impurity and understand the cause of the degradation, a simple heart-cutting 2D-LC/MS approach was utilized to effectively separate the impurity from the complex PEG oligomers and overcome the matrix interference, enabling mass spectrometric analysis of the impurity. An oxidation- dominated mechanism was proposed in which the combination of PEG auto-oxidation and dehydrochlorination of the PVC tubing yielded an oxidative environment that enhanced radical propagation and accelerated degradation of the investigational parent drug. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural Characteristics of the Alpha-Synuclein Oligomers Stabilized By the Flavonoid Baicalein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, D.-P.; Fink, A.L.; Uversky, V.N.

The flavonoid baicalein inhibits fibrillation of alpha-synuclein, which is a major component of Lewy bodies in Parkinson's disease. It has been known that baicalein induces the formation of alpha-synuclein oligomers and consequently prevents their fibrillation. In order to evaluate the structural properties of baicalein-stabilized oligomers, we purified oligomer species by HPLC and examined their stability and structure by CD, Fourier transform infrared spectroscopy, size exclusion chromatography HPLC, small-angle X-ray scattering, and atomic force microscopy. Baicalein-stabilized oligomers are beta-sheet-enriched according to CD and Fourier transform infrared spectroscopy analyses. They did not form fibrils even after very prolonged incubation. From small-angle X-raymore » scattering data and atomic force microscopy images, the oligomers were characterized as quite compact globular species. Oligomers were extremely stable, with a GdmCl C(m)=3.3 M. This high stability explains the previously observed inhibition properties of baicalein against alpha-synuclein fibrillation. These baicalein-stabilized oligomers, added to the solution of aggregating alpha-synuclein, were able to noticeably inhibit its fibrillation. After prolonged coincubation, short fibrils were formed, suggesting an effective interaction of oligomers with monomeric alpha-synuclein. Membrane permeability tests suggested that the baicalein-stabilized oligomers had a mild effect on the integrity of the membrane surface. This effect was rather similar to that of the monomeric protein, suggesting that targeted stabilization of certain alpha-synuclein oligomers might offer a potential strategy for the development of novel Parkinson's disease therapies.« less

Structural studies on HCN oligomers. [catalysts for prebiotic processes

NASA Technical Reports Server (NTRS)

Ferris, J. P.; Edelson, E. H.; Auyeung, J. M.; Joshi, P. C.

1981-01-01

NMR spectral studies on the HCN oligomers suggest the presence of carboxamide and urea groupings. The release of CO2, H2O, HCN, CH3CN, HCONH2 and pyridine on pyrolysis is consistent with the presence of these groupings as well as carboxylic acid groups. No basic primary amine groupings could be detected with fluorescamine. Hydrazinolysis of the HCN oligomers releases 10% of the amino acids normally released by acid hydrolysis. The oligomers give a positive biuret test but this is not due to the presence of peptide bonds. There is no conclusive evidence for the presence of peptide bonds in the HCN oligomers. No diglycine was detected on partial hydrolysis of the HCN oligomers at pH 8.5 suggesting that HCN oligomers were not a source of prebiotic peptides.

Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1*

PubMed Central

Rushworth, Jo V.; Griffiths, Heledd H.; Watt, Nicole T.; Hooper, Nigel M.

2013-01-01

Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction, and memory impairments that underlie Alzheimer disease (AD). The cellular prion protein (PrPC) was recently identified as a high affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognized by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrPC. The binding of Aβ oligomers to cell surface PrPC, as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. In SH-SY5Y cells, fluorescence microscopy and co-localization with subcellular markers revealed that the Aβ oligomers co-internalized with PrPC, accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, and downstream toxicity of Aβ oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aβ oligomers to cell surface PrPC impaired its ability to inhibit the activity of the β-secretase BACE1, which cleaves the amyloid precursor protein to produce Aβ. The green tea polyphenol (−)-epigallocatechin gallate and the red wine extract resveratrol both remodeled the fibrillar conformation of Aβ oligomers. The resulting nonfibrillar oligomers displayed significantly reduced binding to PrPC-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ oligomers bind to PrPC in a conformation-dependent manner and require the integrity of lipid rafts and the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets to alleviate the neurotoxic properties of Aβ oligomers in AD. PMID:23386614

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

PubMed Central

Izzo, Nicholas J.; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J.; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael A.; Arancio, Ottavio; Mach, Robert H.; Craven, Rolf; Head, Elizabeth; LeVine, Harry; Spires-Jones, Tara L.; Catalano, Susan M.

2014-01-01

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics. PMID:25390692

Purified high molecular weight synthetic Aβ(1-42) and biological Aβ oligomers are equipotent in rapidly inducing MTT formazan exocytosis.

PubMed

Weidner, Adam M; Housley, Molly; Murphy, M Paul; Levine, Harry

2011-06-15

Synthetic soluble Aβ oligomers are often used as a surrogate for biologic material in a number of model systems. We compared the activity of Aβ oligomers (synthetic and cell culture media derived) on the human SH-SY5Y neuroblastoma and C2C12 mouse myoblast cell lines in a novel, modified MTT assay. Separating oligomers from monomeric peptide by size exclusion chromatography produced effects at peptide concentrations approaching physiologic levels (10-100 nM). Purified oligomers, but not monomers or fibrils, elicited an increase of a detergent-insoluble form of MTT formazan within 2h as opposed to a control toxin (H(2)O(2)). This effect was comparable for biological and synthetic peptide in both cell types. Monomeric Aβ attenuated the effect of soluble oligomers. This study suggests that the activities of biological and synthetic oligomers are indistinguishable during early stages of Aβ oligomer-cell interaction. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pore-structure and microstructural investigation of organomodified/Inorganic nano-montmorillonite cementitious nanocomposites

NASA Astrophysics Data System (ADS)

Papatzani, Styliani; Grammatikos, Sotirios; Adl-Zarrabi, Bijan; Paine, Kevin

2018-04-01

In the present paper, the effect of three different types of nano-montmorillonite dispersions (nMt) on the (i) microstructure as witnessed by Scanning Electron Microscopy, (ii) long term density measurements and (iii) pore structure as determined via Mercury Intrusion Porosimetry of Portland - limestone cement formulations have been compared, in an effort to determine the upper and lower bound of nMt addition in cementitious nanocomposites. The reference formulation, contained 60% PC and 40% LS by mass of binder aiming at the minimization of clinker and maximization of other constituents. Two aqueous organomodified NMt dispersions (one dispersed with non-ionic fatty alcohol and the other with anionic alkyl aryl sulphonate) and one aqueous inorganic NMt dispersion (dispersed with sodium tripolyphosphate) were added at 0.5, 1, 2, 4 and 5.5% by mass of solids as replacement of Portland cement. The water to solids ratio was kept constant at 0.3. The inorganic nMt showed the greatest potentials for microstructural enhancement. The way in which the level of the nMt platelet separation affected the pastes was discussed. The research reported was part of a much broader project supported by the EU.

Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and brain tissue.

PubMed

Bruggink, Kim A; Jongbloed, Wesley; Biemans, Elisanne A L M; Veerhuis, Rob; Claassen, Jurgen A H R; Kuiperij, H Bea; Verbeek, Marcel M

2013-02-15

Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer's disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for Aβ oligomers by using the same capture and (labeled) detection antibody. The ELISA predominantly recognizes relatively small oligomers (10-25 kDa) and not monomers. In brain tissue of APP/PS1 transgenic mice, we found that Aβ oligomer levels increase with age. However, for measurements in human samples, pretreatment to remove human anti-mouse antibodies (HAMAs) was required. In HAMA-depleted human hippocampal extracts, the Aβ oligomer concentration was significantly increased in AD compared with nondemented controls. Aβ oligomer levels could also be quantified in pretreated cerebrospinal fluid (CSF) samples; however, no difference was detected between AD and control groups. Our data suggest that levels of small oligomers might not be suitable as biomarkers for AD. In addition, we demonstrate the importance of avoiding HAMA interference in assays to quantify Aβ oligomers in human body fluids. Copyright © 2012 Elsevier Inc. All rights reserved.

An oligodeoxyribonucleotide that supports catalytic activity in the hammerhead ribozyme domain.

PubMed Central

Chartrand, P; Harvey, S C; Ferbeyre, G; Usman, N; Cedergren, R

1995-01-01

A study of the activity of deoxyribonucleotide-substituted analogs of the hammerhead domain of RNA catalysis has led to the design of a 14mer oligomer composed entirely of deoxyribonucleotides that promotes the cleavage of an RNA substrate. Characterization of this reaction with sequence variants and mixed DNA/RNA oligomers shows that, although the all-deoxyribonucleotide oligomer is less efficient in catalysis, the DNA/substrate complex shares many of the properties of the all-RNA hammerhead domain such as multiple turnover kinetics and dependence on Mg2+ concentration. On the other hand, the values of kinetic parameters distinguish the DNA oligomer from the all-RNA oligomer. In addition, an analog of the oligomer having a single ribonucleotide in a strongly conserved position of the hammerhead domain is associated with more efficient catalysis than the all-RNA oligomer. Images PMID:7479070

Microstructural characterization of dental zinc phosphate cements using combined small angle neutron scattering and microfocus X-ray computed tomography.

PubMed

Viani, Alberto; Sotiriadis, Konstantinos; Kumpová, Ivana; Mancini, Lucia; Appavou, Marie-Sousai

2017-04-01

To characterize the microstructure of two zinc phosphate cement formulations in order to investigate the role of liquid/solid ratio and composition of powder component, on the developed porosity and, consequently, on compressive strength. X-ray powder diffraction with the Rietveld method was used to study the phase composition of zinc oxide powder and cements. Powder component and cement microstructure were investigated with scanning electron microscopy. Small angle neutron scattering (SANS) and microfocus X-ray computed tomography (XmCT) were together employed to characterize porosity and microstructure of dental cements. Compressive strength tests were performed to evaluate their mechanical performance. The beneficial effects obtained by the addition of Al, Mg and B to modulate powder reactivity were mitigated by the crystallization of a Zn aluminate phase not involved in the cement setting reaction. Both cements showed spherical pores with a bimodal distribution at the micro/nano-scale. Pores, containing a low density gel-like phase, developed through segregation of liquid during setting. Increasing liquid/solid ratio from 0.378 to 0.571, increased both SANS and XmCT-derived specific surface area (by 56% and 22%, respectively), porosity (XmCT-derived porosity increased from 3.8% to 5.2%), the relative fraction of large pores ≥50μm, decreased compressive strength from 50±3MPa to 39±3MPa, and favored microstructural and compositional inhomogeneities. Explain aspects of powder design affecting the setting reaction and, in turn, cement performance, to help in optimizing cement formulation. The mechanism behind development of porosity and specific surface area explains mechanical performance, and processes such as erosion and fluoride release/uptake. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phenylethynyl amine

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Bryant, Robert G. (Inventor); Jensen, Brian J. (Inventor); Havens, Stephen J. (Inventor)

1997-01-01

Four phenylethynyl amine compounds--3 and 4-aminophenoxy-4'-phenylethynylbenzophenone, and 3 and 4-amino-4'-phenylethynylbenzophenone--were readily prepared and were used to endcap imide oligomers. Phenylethynyl-terminated amide acid oligomers and phenylethynyl-terminated imide oligomers with various molecular weights and compositions were prepared and characterized. These oligomers were cured at 300.degree. C. to 400.degree. C. to provide crosslinked polyimides with excellent solvent resistance, high strength and modulus and good high temperature properties. Adhesive panels, composites, films and moldings from these phenylethynyl terminated imide oligomers gave excellent mechanical performance.

Preparation of Stable Amyloid-β Oligomers Without Perturbative Methods.

PubMed

Kotler, Samuel A; Ramamoorthy, Ayyalusamy

2018-01-01

Soluble amyloid-β (Aβ) oligomers have become a focal point in the study of Alzheimer's disease due to their ability to elicit cytotoxicity. A number of recent studies have concentrated on the structural characterization of soluble Aβ oligomers to gain insight into their mechanism of toxicity. Consequently, providing reproducible protocols for the preparation of such oligomers is of utmost importance. The method presented in this chapter details a protocol for preparing an Aβ oligomer, with a primarily disordered secondary structure, without the need for chemical modification or amino acid substitution. Due to the stability of these disordered Aβ oligomers and the reproducibility with which they form, they are amenable for biophysical and high-resolution structural characterization.

An X-ray transparent microfluidic platform for screening of the phase behavior of lipidic mesophases

PubMed Central

Khvostichenko, Daria S.; Kondrashkina, Elena; Perry, Sarah L.; Pawate, Ashtamurthy S.; Brister, Keith

2013-01-01

Lipidic mesophases are a class of highly ordered soft materials that form when certain lipids are mixed with water. Understanding the relationship between the composition and the microstructure of mesophases is necessary for fundamental studies of self-assembly in amphiphilic systems and for applications, such as crystallization of membrane proteins. However, the laborious formulation protocol for highly viscous mesophases and the large amounts of material required for sample formulation are significant obstacles in such studies. Here we report a microfluidic platform that facilitates investigations of the phase behavior of mesophases by reducing sample consumption, and automating and parallelizing sample formulation. The mesophases were formulated on-chip using less than 40 nL of material per sample and their microstructure was analyzed in situ using small-angle X-ray scattering (SAXS). The 220 μm-thick X-ray compatible platform was comprised of thin polydimethylsiloxane (PDMS) layers sandwiched between cyclic olefin copolymer (COC) sheets. Uniform mesophases were prepared using an active on-chip mixing strategy coupled with periodic cooling of the sample to reduce the viscosity. We validated the platform by preparing and analyzing mesophases of lipid monoolein (MO) mixed with aqueous solutions of different concentrations of β-octylglucoside (βOG), a detergent frequently used in membrane protein crystallization. Four samples were prepared in parallel on chip, by first metering and automatically diluting βOG to obtain detergent solutions of different concentration, then metering MO, and finally mixing by actuation of pneumatic valves. Integration of detergent dilution and subsequent mixing significantly reduced the number of manual steps needed for sample preparation. Three different types of mesophases typical for monoolein were successfully identified in SAXS data from on-chip samples. Microstructural parameters of identical samples formulated in different chips showed excellent agreement. Phase behavior observed on-chip corresponded well with that of samples prepared via the traditional coupled-syringe method (“off-chip”) using 300-fold larger amount of material, further validating the utility of the microfluidic platform for on-chip characterization of mesophase behavior. PMID:23882463

Electrografting of conductive oligomers and polymers using diazonium electroreduction

NASA Astrophysics Data System (ADS)

Lacroix, Jean Christophe; Trippe-Allard, Gaelle; Ghilane, Jalal; Martin, Pascal

2014-03-01

This paper describes the attachment of conjugated oligomers onto electrode surface through the reduction of diazonium compounds. In this connection some properties of conjugated oligomers and of layers grafted through diazonium electroreduction will first be briefly presented. The electrochemical behavior of conjugated oligomers grafted on a surface using diazonium electroreduction will then be discussed.

Structural and functional properties of prefibrillar α-synuclein oligomers.

PubMed

Pieri, Laura; Madiona, Karine; Melki, Ronald

2016-04-14

The deposition of fibrillar alpha-synuclein (α-syn) within inclusions (Lewy bodies and Lewy neurites) in neurons and glial cells is a hallmark of synucleinopathies. α-syn populates a variety of assemblies ranging from prefibrillar oligomeric species to fibrils whose specific contribution to neurodegeneration is still unclear. Here, we compare the specific structural and biological properties of distinct soluble prefibrillar α-syn oligomers formed either spontaneously or in the presence of dopamine and glutaraldehyde. We show that both on-fibrillar assembly pathway and distinct dopamine-mediated and glutaraldehyde-cross-linked α-syn oligomers are only slightly effective in perturbing cell membrane integrity and inducing cytotoxicity, while mature fibrils exhibit the highest toxicity. In contrast to low-molecular weight and unstable oligomers, large stable α-syn oligomers seed the aggregation of soluble α-syn within reporter cells although to a lesser extent than mature α-syn fibrils. These oligomers appear elongated in shape. Our findings suggest that α-syn oligomers represent a continuum of species ranging from unstable low molecular weight particles to mature fibrils via stable elongated oligomers composed of more than 15 α-syn monomers that possess seeding capacity.

Heat Resistant Characteristics of Major Royal Jelly Protein 1 (MRJP1) Oligomer

PubMed Central

Moriyama, Takanori; Ito, Aimi; Omote, Sumire; Miura, Yuri; Tsumoto, Hiroki

2015-01-01

Soluble royal jelly protein is a candidate factor responsible for mammiferous cell proliferation. Major royal jelly protein 1 (MRJP1), which consists of oligomeric and monomeric forms, is an abundant proliferative protein in royal jelly. We previously reported that MRJP1 oligomer has biochemical heat resistance. Therefore, in the present study, we investigated the effects of several heat treatments (56, 65 and 96°C) on the proliferative activity of MRJP1 oligomer. Heat resistance studies showed that the oligomer molecular forms were slightly maintained until 56℃, but the molecular forms were converted to macromolecular heat-aggregated MRJP1 oligomer at 65℃ and 96℃. But, the growth activity of MRJP1 oligomer treated with 96°C was slightly attenuated when compared to unheated MRJP1 oligomer. On the other hand, the cell proliferation activity was preserved until 96℃ by the cell culture analysis of Jurkat cells. In contrast, those of IEC-6 cells were not preserved even at 56°C. The present observations suggest that the bioactive heat-resistance properties were different by the origin of the cells. The cell proliferation analysis showed that MRJP1 oligomer, but not MRJP2 and MRJP3, significantly increased cell numbers, suggesting that MRJP1 oligomer is the predominant proliferation factor for mammiferous cells. PMID:26020775

Enzymatic production of defined chitosan oligomers with a specific pattern of acetylation using a combination of chitin oligosaccharide deacetylases

NASA Astrophysics Data System (ADS)

Hamer, Stefanie Nicole; Cord-Landwehr, Stefan; Biarnés, Xevi; Planas, Antoni; Waegeman, Hendrik; Moerschbacher, Bruno Maria; Kolkenbrock, Stephan

2015-03-01

Chitin and chitosan oligomers have diverse biological activities with potentially valuable applications in fields like medicine, cosmetics, or agriculture. These properties may depend not only on the degrees of polymerization and acetylation, but also on a specific pattern of acetylation (PA) that cannot be controlled when the oligomers are produced by chemical hydrolysis. To determine the influence of the PA on the biological activities, defined chitosan oligomers in sufficient amounts are needed. Chitosan oligomers with specific PA can be produced by enzymatic deacetylation of chitin oligomers, but the diversity is limited by the low number of chitin deacetylases available. We have produced specific chitosan oligomers which are deacetylated at the first two units starting from the non-reducing end by the combined use of two different chitin deacetylases, namely NodB from Rhizobium sp. GRH2 that deacetylates the first unit and COD from Vibrio cholerae that deacetylates the second unit starting from the non-reducing end. Both chitin deacetylases accept the product of each other resulting in production of chitosan oligomers with a novel and defined PA. When extended to further chitin deacetylases, this approach has the potential to yield a large range of novel chitosan oligomers with a fully defined architecture.

Heat Resistant Characteristics of Major Royal Jelly Protein 1 (MRJP1) Oligomer.

PubMed

Moriyama, Takanori; Ito, Aimi; Omote, Sumire; Miura, Yuri; Tsumoto, Hiroki

2015-01-01

Soluble royal jelly protein is a candidate factor responsible for mammiferous cell proliferation. Major royal jelly protein 1 (MRJP1), which consists of oligomeric and monomeric forms, is an abundant proliferative protein in royal jelly. We previously reported that MRJP1 oligomer has biochemical heat resistance. Therefore, in the present study, we investigated the effects of several heat treatments (56, 65 and 96°C) on the proliferative activity of MRJP1 oligomer. Heat resistance studies showed that the oligomer molecular forms were slightly maintained until 56℃, but the molecular forms were converted to macromolecular heat-aggregated MRJP1 oligomer at 65℃ and 96℃. But, the growth activity of MRJP1 oligomer treated with 96°C was slightly attenuated when compared to unheated MRJP1 oligomer. On the other hand, the cell proliferation activity was preserved until 96℃ by the cell culture analysis of Jurkat cells. In contrast, those of IEC-6 cells were not preserved even at 56°C. The present observations suggest that the bioactive heat-resistance properties were different by the origin of the cells. The cell proliferation analysis showed that MRJP1 oligomer, but not MRJP2 and MRJP3, significantly increased cell numbers, suggesting that MRJP1 oligomer is the predominant proliferation factor for mammiferous cells.

Glycyrrhiza and Uncaria Hook contribute to protective effect of traditional Japanese medicine yokukansan against amyloid β oligomer-induced neuronal death.

PubMed

Kanno, Hitomi; Kawakami, Zenji; Iizuka, Seiichi; Tabuchi, Masahiro; Mizoguchi, Kazushige; Ikarashi, Yasushi; Kase, Yoshio

2013-08-26

Yokukansan, a traditional Japanese (Kampo) medicine, composed of seven medicinal herbs has been traditionally used to treat neurosis, insomnia, and night crying and irritability in children. Recently, this medicine has been reported to improve the behavioral and psychological symptoms of dementia (BPSD) that often become problematic in patients with Alzheimer's disease (AD). Amyloid β (Aβ) oligomers, which are extremely toxic to neurons, are involved in neurodegeneration in AD. In animals, yokukansan has been proven to improve memory impairments and BPSD-like behavior in transgenic mice overexpressing amyloid precursor protein and mice intracerebroventricularly injected with Aβ oligomers. These results suggest that yokukansan is potentially able to reduce the neurotoxicity of Aβ oligomers. Therefore, the present study aimed to explore the improving effects brought by yokukansan that consists of seven herbs for Aβ oligomer-induced neurotoxicity in vitro and to identify the candidate herbs in yokukansan's action. Primary cultured rat cortical neurons were used. Neurotoxicity induced by Aβ oligomers (3µM) and improving effects of yokukansan (300-1000 µg/mL) and its constituent herbs were evaluated in MTT assay, DNA fragmentation analysis, and electron microscopic analysis at 48h after treatment with Aβ oligomers and drugs. Moreover, changes in expression of genes related to endoplasmic reticulum (ER) stress and in caspase-3 activity that is the enzyme closely related to apoptosis were analyzed to investigate the underlying mechanisms. Yokukansan ameliorated Aβ oligomer-induced neuronal damage in a dose-dependent manner in the MTT assay. This drug also suppressed DNA fragmentation caused by Aβ oligomers. Electron microscopic analysis suggested that yokukansan reduced karyopyknosis and the expansion of rough ER caused by Aβ oligomers. However, neither Aβ oligomers nor yokukansan affected the mRNA expression of any ER stress-related genes, including CHOP and GRP78. On the other hand, yokukansan dose-dependently suppressed Aβ oligomer-induced activation of caspase-3. Among the seven constituents of yokukansan, Glycyrrhiza and Uncaria Hook (60-200 µg/mL) suppressed Aβ oligomer-induced neuronal damage, DNA fragmentation, karyopyknosis, and caspase-3 activation to almost the same extent as yokukansan. The present results suggest that yokukansan possesses an ameliorative effect against Aβ oligomer-induced neuronal apoptosis through the suppression of caspase-3 activation. Glycyrrhiza and Uncaria Hook may, at least in part, contribute to the neuroprotective effect of yokukansan. These mechanisms may underlie the improving effects of yokukansan on memory impairment and BPSD-like behaviors induced by Aβ oligomers. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

3D Printed PEG-Based Hybrid Nanocomposites Obtained by Sol-Gel Technique.

PubMed

Chiappone, Annalisa; Fantino, Erika; Roppolo, Ignazio; Lorusso, Massimo; Manfredi, Diego; Fino, Paolo; Pirri, Candido Fabrizio; Calignano, Flaviana

2016-03-02

In this work, three-dimensional (3D) structured hybrid materials were fabricated combining 3D printing technology with in situ generation of inorganic nanoparticles by sol-gel technique. Those materials, consisting of silica nanodomains covalently interconnected with organic polymers, were 3D printed in complex multilayered architectures, incorporating liquid silica precursors into a photocurable oligomer in the presence of suitable photoinitiators and exposing them to a digital light system. A post sol-gel treatment in acidic vapors allowed the in situ generation of the inorganic phase in a dedicated step. This method allows to build hybrid structures operating with a full liquid formulation without meeting the drawbacks of incorporating inorganic powders into 3D printable formulations. The influence of the generated silica nanoparticle on the printed objects was deeply investigated at macro- and nanoscale; the resulting light hybrid structures show improved mechanical properties and, thus, have a huge potential for applications in a variety of advanced technologies.

Structural and functional properties of prefibrillar α-synuclein oligomers

PubMed Central

Pieri, Laura; Madiona, Karine; Melki, Ronald

2016-01-01

The deposition of fibrillar alpha-synuclein (α-syn) within inclusions (Lewy bodies and Lewy neurites) in neurons and glial cells is a hallmark of synucleinopathies. α-syn populates a variety of assemblies ranging from prefibrillar oligomeric species to fibrils whose specific contribution to neurodegeneration is still unclear. Here, we compare the specific structural and biological properties of distinct soluble prefibrillar α-syn oligomers formed either spontaneously or in the presence of dopamine and glutaraldehyde. We show that both on-fibrillar assembly pathway and distinct dopamine-mediated and glutaraldehyde-cross-linked α-syn oligomers are only slightly effective in perturbing cell membrane integrity and inducing cytotoxicity, while mature fibrils exhibit the highest toxicity. In contrast to low-molecular weight and unstable oligomers, large stable α-syn oligomers seed the aggregation of soluble α-syn within reporter cells although to a lesser extent than mature α-syn fibrils. These oligomers appear elongated in shape. Our findings suggest that α-syn oligomers represent a continuum of species ranging from unstable low molecular weight particles to mature fibrils via stable elongated oligomers composed of more than 15 α-syn monomers that possess seeding capacity. PMID:27075649

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers*

PubMed Central

Gu, Lei; Liu, Cong; Stroud, James C.; Ngo, Sam; Jiang, Lin; Guo, Zhefeng

2014-01-01

Aβ42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that Aβ42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar Aβ42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each Aβ42 protein forms a single β-sheet with three β-strands in an antiparallel arrangement. Each β-sheet consists of four Aβ42 molecules in a head-to-tail arrangement. Four β-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different β-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein β-strands undergo an ∼90° rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils. PMID:25118290

Polymerization on the rocks: theoretical introduction

NASA Technical Reports Server (NTRS)

Orgel, L. E.; Bada, J. L. (Principal Investigator)

1998-01-01

It is difficult if not impossible to synthesize long polymers of amino acids, nucleotides, etc., in homogeneous aqueous solution. We suggest that long polymers were synthesized on the surface of minerals in a prebiotic process analogous to solid-phase synthesis. Provided that the affinity of a mineral for an oligomer increases with the length of the oligomer, adsorption must become essentially irreversible for sufficiently long oligomers. Irreversibly adsorbed oligomers may be elongated indefinitely by repeated cycles in which the mineral with its adsorbed oligomers is first incubated with activated monomers and then washed free of deactivated monomer and side-products. We discuss in some detail the formation of oligomers of negatively-charged amino acids such as glutamic acid on anion-exchange minerals such as hydroxylapatite or illite. We show that the average length of adsorbed oligomers at steady state, n, depends on the balance between the rate of chain elongation and the rate of hydrolysis, and we derive a very approximate formula for n.

Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies

PubMed Central

Bram, Yaron; Frydman-Marom, Anat; Yanai, Inbal; Gilead, Sharon; Shaltiel-Karyo, Ronit; Amdursky, Nadav; Gazit, Ehud

2014-01-01

Soluble oligomeric assemblies of amyloidal proteins appear to act as major pathological agents in several degenerative disorders. Isolation and characterization of these oligomers is a pivotal step towards determination of their pathological relevance. Here we describe the isolation of Type 2 diabetes-associated islet amyloid polypeptide soluble cytotoxic oligomers; these oligomers induced apoptosis in cultured pancreatic cells, permeated model lipid vesicles and interacted with cell membranes following complete internalization. Moreover, antibodies which specifically recognized these assemblies, but not monomers or amyloid fibrils, were exclusively identified in diabetic patients and were shown to neutralize the apoptotic effect induced by these oligomers. Our findings support the notion that human IAPP peptide can form highly toxic oligomers. The presence of antibodies identified in the serum of diabetic patients confirms the pathological relevance of the oligomers. In addition, the newly identified structural epitopes may also provide new mechanistic insights and a molecular target for future therapy. PMID:24589570

A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1

PubMed Central

Lasagna-Reeves, Cristian A; Rousseaux, Maxime WC; Guerrero-Muñoz, Marcos J; Park, Jeehye; Jafar-Nejad, Paymaan; Richman, Ronald; Lu, Nan; Sengupta, Urmi; Litvinchuk, Alexandra; Orr, Harry T; Kayed, Rakez; Zoghbi, Huda Y

2015-01-01

Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies. DOI: http://dx.doi.org/10.7554/eLife.07558.001 PMID:25988806

In vivo assessment of parenteral formulations of oligo(3-hydroxybutyric Acid) conjugates with the model compound Ibuprofen.

PubMed

Stasiak, Pawel; Sznitowska, Malgorzata; Ehrhardt, Carsten; Luczyk-Juzwa, Maria; Grieb, Pawel

2010-12-01

Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid-phase extraction and using indometacin as internal standard (detection limit, 0.05 microg/ml). No significant differences in the pharmacokinetic parameters (C (max), T (max), AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives.

Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent

PubMed Central

Ibrahim, Khalid A.; El-Eswed, Bassam I.; Abu-Sbeih, Khaleel A.; Arafat, Tawfeeq A.; Al Omari, Mahmoud M. H.; Darras, Fouad H.; Badwan, Adnan A.

2016-01-01

An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers) in medicine and food fields because they are not only water-soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC/MS), and ninhydrin test. PMID:27455287

Polymerization on the rocks: negatively-charged alpha-amino acids

NASA Technical Reports Server (NTRS)

Hill, A. R. Jr; Bohler, C.; Orgel, L. E.; Bada, J. L. (Principal Investigator)

1998-01-01

Oligomers of the negatively-charged amino acids, glutamic acid, aspartic acid, and O-phospho-L-serine are adsorbed by hydroxylapatite and illite with affinities that increase with oligomer length. In the case of oligo-glutamic acids adsorbed on hydroxylapatite, addition of an extra residue results in an approximately four-fold increase in the strength of adsorption. Oligomers much longer than the 7-mer are retained tenaciously by the mineral. Repeated incubation of short oligo-glutamic acids adsorbed on hydroxylapatite or illite with activated monomer leads to the accumulation of oligomers at least 45 units long. The corresponding reactions of aspartic acid and O-phospho-L-serine on hydroxylapatite are less effective in generating long oligomers, while illite fails to accumulate substantial amounts of long oligomers of aspartic acid or of O-phospho-L-serine.

DNA sequence similarity recognition by hybridization to short oligomers

DOEpatents

Milosavljevic, Aleksandar

1999-01-01

Methods are disclosed for the comparison of nucleic acid sequences. Data is generated by hybridizing sets of oligomers with target nucleic acids. The data thus generated is manipulated simultaneously with respect to both (i) matching between oligomers and (ii) matching between oligomers and putative reference sequences available in databases. Using data compression methods to manipulate this mutual information, sequences for the target can be constructed.

Controlling Microstructure of Yttria-Stabilized Zirconia Prepared from Suspensions and Solutions by Plasma Spraying with High Feed Rates

NASA Astrophysics Data System (ADS)

Musalek, Radek; Medricky, Jan; Tesar, Tomas; Kotlan, Jiri; Pala, Zdenek; Lukac, Frantisek; Illkova, Ksenia; Hlina, Michal; Chraska, Tomas; Sokolowski, Pawel; Curry, Nicholas

2017-12-01

Introduction of suspension and solution plasma spraying led to a breakthrough in the deposition of yttria-stabilized zirconia (YSZ) coatings and enabled preparation of new types of layers. However, their deposition with high feed rates needed, for example, for the deposition of thermal barrier coatings (TBCs) on large-scale components, is still challenging. In this study, possibility of high-throughput plasma spraying of YSZ coatings is demonstrated for the latest generation of high-enthalpy hybrid water-stabilized plasma (WSP-H) torch technology. The results show that microstructure of the coatings prepared by WSP-H may be tailored for specific applications by the choice of deposition conditions, in particular formulation of the liquid feedstock. Porous and columnar coatings with low thermal conductivity (0.5-0.6 W/mK) were prepared from commercial ethanol-based suspension. Dense vertically cracked coatings with higher thermal conductivity but also higher internal cohesion were deposited from suspension containing ethanol/water mixture and coarser YSZ particles. Spraying of solution formulated from diluted zirconium acetate and yttrium nitrate hexahydrate led also to the successful deposition of YSZ coating combining regions of porous and denser microstructure and providing both low thermal conductivity and improved cohesion of the coating. Enthalpy content, liquid-plasma interaction and coating buildup mechanisms are also discussed.

Synthesis and characterization of oligobenzimidazoles: Electrochemical, electrical, optical, thermal and rectification properties

NASA Astrophysics Data System (ADS)

Anand, Siddeswaran; Muthusamy, Athianna

2018-03-01

A series of benzimidazole monomers, (2-(2, 4-dihydroxyphenyl)-1H-benzimidazol-5-yl)(phenyl) methanone (BIKH), 2-(3-ethoxy-2-hydroxyphenyl)-1H-benzo [d]imidazole-5-yl) (phenyl) methanone (BIKE) and 2-(5-bromo-2-hydroxyphenyl)-1H-benzo [d]imidazole-5-yl) (phenyl) methanone (BIKB) were prepared by condensing three substituted aromatic aldehydes with 3, 4-diaminobenzophenone. In aqueous alkaline medium the benzimidazoles were converted in to oligomers by oxidative polycondensation using NaOCl as oxidant. The formation of monomers and oligomers were confirmed with 1H, 13C NMR, FT-IR, and UV-visible spectroscopic techniques. The oligomers were investigated for their optical, electrical, electrochemical and thermal properties. The electrochemical and optical band gaps of monomers and oligomers were calculated using both UV-visible spectroscopy and cyclic voltametry respectively. The band gap values of monomers are compared with band gap values obtained from quantum theoretical calculations with DFT. The electrical conductivity studies of iodine doped and undoped oligomers were done using two point probe technique. It is found that these values are showing good correlation with the charge densities on imidazole nitrogen obtained from Huckel method. The conductivity of oligomers increases with increase in iodine vapour contact time. The dielectric properties of oligomers have been investigated at different temperature and frequency. The dielectric measurement data were used to calculate the AC conductivity and activation energy of oligomers. Oligomer OBIKH is having greater thermal stability due to its number of chain propagation sites than other oligomers and is shown by its high carbines residue of around 60% at 600 °C in thermogravimetric analysis. I-V characteristics of oligobenzimidazole p-n diodes have shown good rectifying nature in the range -4 to 4 V.

Determination of oligomers in virgin and recycled polyethylene terephthalate (PET) samples by UPLC-MS-QTOF.

PubMed

Ubeda, Sara; Aznar, Margarita; Nerín, Cristina

2018-03-01

An oligomer is a molecule that consists of a few monomer units. It can be formed during polymer manufacturing and also due to polymer degradation processes or even during use conditions. Since oligomers are not included in chemical databases, their identification is a complex process. In this work, the oligomers present in 20 different PET pellet samples have been determined. Two different sample treatment procedures, solvent extraction and total dissolution, were applied in order to select the most efficient one. The analyses were carried out by UPLC-MS-QTOF. The use of high resolution mass spectrometry allowed the structural elucidation of these compounds and their correct identification. The main oligomers identified were cyclic as well as lineal from the first, second, and third series. All of them were composed of terephthalic acid (TPA), diethylene glycol (DEG), and ethylene glycol (EG). Quantitative values were very different in both procedures. In total dissolution of PET samples, the concentration of oligomers was always, at least, 10 times higher than in solvent extraction; some of the compounds were only detected when total dissolution was used. Results showed that the oligomers with the highest concentration values were dimers and trimers, cyclic, as well as lineal, from the first and second series. The oligomer with the maximum concentration value was TPA 2 -EG-DEG that was found in all the samples in a concentration range from 2493 to 19,290 ng/g PET. No differences between virgin and recycled PET were found. Migration experiments were performed in two PET bottles, and results showed the transference of most of these oligomers to a fat food simulant (ethanol 95%). Graphical abstract Graphical abstract of the two procedures developd and optimized for identifying oligomers in PET pellets and in migration form PET bottles.

Alzheimer's amyloid-β oligomers rescue cellular prion protein induced tau reduction via the Fyn pathway.

PubMed

Chen, Rong-Jie; Chang, Wei-Wei; Lin, Yu-Chun; Cheng, Pei-Lin; Chen, Yun-Ru

2013-09-18

Amyloid-β (Aβ) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). Aβ oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, Aβ oligomers have been shown to specifically interact with cellular prion protein (PrP(C)) where the role of PrP(C) in AD is still not fully understood. To investigate the downstream mechanism of PrP(C) and Aβ oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP(C) and studied the effect under Aβ oligomer treatment. By Western blotting, we found that PrP(C) overexpression down-regulated tau protein and Aβ oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP(C), the high AD risk polymorphic allele in human prion gene. PrP(C) lacking the Aβ oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP(C) effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP(C)-induced tau reduction and Aβ oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated Aβ-PrP(C)-tau signaling. Overall, our results demonstrated that PrP(C) down-regulated tau via the Fyn pathway and the effect can be regulated by Aβ oligomers. Our study facilitated the understanding of molecular mechanisms among PrP(C), tau, and Aβ oligomers.

Mathematical modeling of microstructural development in hypoeutectic cast iron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maijer, D.; Cockcroft, S.L.; Patt, W.

A mathematical heat-transfer/microstructural model has been developed to predict the evolution of proeutectic austenite, white iron eutectic, and gray iron eutectic during solidification of hypoeutectic cast iron, based on the commercial finite-element code ABAQUS. Specialized routines which employ relationships describing nucleation and growth of equiaxed primary austenite, gray iron eutectic, and white iron eutectic have been formulated and incorporated into ABAQUS through user-specified subroutines. The relationships used in the model to describe microstructural evolution have been adapted from relationships describing equiaxed growth in the literature. The model has been validated/fine tuned against temperature data collected from a QuiK-Cup sample, whichmore » contained a thermocouple embedded approximately in the center of the casting. The phase distribution predicted with the model has been compared to the measured phase distribution inferred from the variation in hardness within the QuiK-Cup sample and from image analysis of photomicrographs of the polished and etched microstructure. Overall, the model results were found to agree well with the measured distribution of the microstructure.« less

Laccase-Catalyzed Synthesis of Low-Molecular-Weight Lignin-Like Oligomers and their Application as UV-Blocking Materials.

PubMed

Lim, Jieyan; Sana, Barindra; Krishnan, Ranganathan; Seayad, Jayasree; Ghadessy, Farid J; Jana, Satyasankar; Ramalingam, Balamurugan

2018-02-02

The laccase-catalyzed oxidative polymerization of monomeric and dimeric lignin model compounds was carried out with oxygen as the oxidant in aqueous medium. The oligomers were characterized by using gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS) analysis. Oxidative polymerization led to the formation of oligomeric species with a number-average molecular weight (M n ) that ranged from 700 to 2300 Da with a low polydispersity index. Spectroscopic analysis provided insight into the possible modes of linkages present in the oligomers, and the oligomerization is likely to proceed through the formation of C-C linkages between phenolic aromatic rings. The oligomers were found to show good UV light absorption characteristics with high molar extinction coefficient (5000-38 000 m -1  cm -1 ) in the UV spectral region. The oligomers were blended independently with polyvinyl chloride (PVC) by using solution blending to evaluate the compatibility and UV protection ability of the oligomers. The UV/Vis transmittance spectra of the oligomer-embedded PVC films indicated that these lignin-like oligomers possessed a notable ability to block UV light. In particular, oligomers obtained from vanillyl alcohol and the dimeric lignin model were found to show good photostability in accelerated UV weathering experiments. The UV-blocking characteristics and photostability were finally compared with the commercial low-molecular-weight UV stabilizer 2,4-dihydroxybenzophenone. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A quantification method for heat-decomposable methylglyoxal oligomers and its application on 1,3,5-trimethylbenzene SOA

NASA Astrophysics Data System (ADS)

Rodigast, Maria; Mutzel, Anke; Herrmann, Hartmut

2017-03-01

Methylglyoxal forms oligomeric compounds in the atmospheric aqueous particle phase, which could establish a significant contribution to the formation of aqueous secondary organic aerosol (aqSOA). Thus far, no suitable method for the quantification of methylglyoxal oligomers is available despite the great effort spent for structure elucidation. In the present study a simplified method was developed to quantify heat-decomposable methylglyoxal oligomers as a sum parameter. The method is based on the thermal decomposition of oligomers into methylglyoxal monomers. Formed methylglyoxal monomers were detected using PFBHA (o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride) derivatisation and gas chromatography-mass spectrometry (GC/MS) analysis. The method development was focused on the heating time (varied between 15 and 48 h), pH during the heating process (pH = 1-7), and heating temperature (50, 100 °C). The optimised values of these method parameters are presented. The developed method was applied to quantify heat-decomposable methylglyoxal oligomers formed during the OH-radical oxidation of 1,3,5-trimethylbenzene (TMB) in the Leipzig aerosol chamber (LEipziger AerosolKammer, LEAK). Oligomer formation was investigated as a function of seed particle acidity and relative humidity. A fraction of heat-decomposable methylglyoxal oligomers of up to 8 % in the produced organic particle mass was found, highlighting the importance of those oligomers formed solely by methylglyoxal for SOA formation. Overall, the present study provides a new and suitable method for quantification of heat-decomposable methylglyoxal oligomers in the aqueous particle phase.

Fluorene- and benzofluorene-cored oligomers as low threshold and high gain amplifying media

NASA Astrophysics Data System (ADS)

Kazlauskas, Karolis; Kreiza, Gediminas; Bobrovas, Olegas; AdomÄ--nienÄ--, Ona; AdomÄ--nas, Povilas; Jankauskas, Vygintas; JuršÄ--nas, Saulius

2015-07-01

Deliberate control of intermolecular interactions in fluorene- and benzofluorene-cored oligomers was attempted via introduction of different-length alkyl moieties to attain high emission amplification and low amplified spontaneous emission (ASE) threshold at high oligomer concentrations. Containing fluorenyl peripheral groups decorated with different-length alkyl moieties, the oligomers were found to express weak concentration quenching of emission, yet excellent carrier drift mobilities (close to 10-2 cm2/V/s) in the amorphous films. Owing to the larger radiative decay rates (>1.0 × 109 s-1) and smaller concentration quenching, fluorene-cored oligomers exhibited down to one order of magnitude lower ASE thresholds at higher concentrations as compared to those of benzofluorene counterparts. The lowest threshold (300 W/cm2) obtained for the fluorene-cored oligomers at the concentration of 50 wt % in polymer matrix is among the lowest reported for solution-processed amorphous films in ambient conditions, what makes the oligomers promising for lasing application. Great potential in emission amplification was confirmed by high maximum net gain (77 cm-1) revealed for these compounds. Although the photostability of the oligomers was affected by photo-oxidation, it was found to be comparable to that of various organic lasing materials including some commercial laser dyes evaluated under similar excitation conditions.

Amyloid Oligomers and Protofibrils, but Not Filaments, Self-Replicate from Native Lysozyme

PubMed Central

2015-01-01

Self-assembly of amyloid fibrils is the molecular mechanism best known for its connection with debilitating human disorders such as Alzheimer’s disease but is also associated with various functional cellular responses. There is increasing evidence that amyloid formation proceeds along two distinct assembly pathways involving either globular oligomers and protofibrils or rigid monomeric filaments. Oligomers, in particular, have been implicated as the dominant molecular species responsible for pathogenesis. Yet the molecular mechanisms regulating their self-assembly have remained elusive. Here we show that oligomers/protofibrils and monomeric filaments, formed along distinct assembly pathways, display critical differences in their ability to template amyloid growth at physiological vs denaturing temperatures. At physiological temperatures, amyloid filaments remained stable but could not seed growth of native monomers. In contrast, oligomers and protofibrils not only remained intact but were capable of self-replication using native monomers as the substrate. Kinetic data further suggested that this prion-like growth mode of oligomers/protofibrils involved two distinct activities operating orthogonal from each other: autocatalytic self-replication of oligomers from native monomers and nucleated polymerization of oligomers into protofibrils. The environmental changes to stability and templating competence of these different amyloid species in different environments are likely to be important for understanding the molecular mechanisms underlying both pathogenic and functional amyloid self-assembly. PMID:24884889

Amyloid oligomers and protofibrils, but not filaments, self-replicate from native lysozyme.

PubMed

Mulaj, Mentor; Foley, Joseph; Muschol, Martin

2014-06-25

Self-assembly of amyloid fibrils is the molecular mechanism best known for its connection with debilitating human disorders such as Alzheimer's disease but is also associated with various functional cellular responses. There is increasing evidence that amyloid formation proceeds along two distinct assembly pathways involving either globular oligomers and protofibrils or rigid monomeric filaments. Oligomers, in particular, have been implicated as the dominant molecular species responsible for pathogenesis. Yet the molecular mechanisms regulating their self-assembly have remained elusive. Here we show that oligomers/protofibrils and monomeric filaments, formed along distinct assembly pathways, display critical differences in their ability to template amyloid growth at physiological vs denaturing temperatures. At physiological temperatures, amyloid filaments remained stable but could not seed growth of native monomers. In contrast, oligomers and protofibrils not only remained intact but were capable of self-replication using native monomers as the substrate. Kinetic data further suggested that this prion-like growth mode of oligomers/protofibrils involved two distinct activities operating orthogonal from each other: autocatalytic self-replication of oligomers from native monomers and nucleated polymerization of oligomers into protofibrils. The environmental changes to stability and templating competence of these different amyloid species in different environments are likely to be important for understanding the molecular mechanisms underlying both pathogenic and functional amyloid self-assembly.

Hypoglycemic activities of A- and B-type procyanidin oligomer-rich extracts from different Cinnamon barks.

PubMed

Lu, Zhaolian; Jia, Qi; Wang, Rui; Wu, Ximin; Wu, Yingchun; Huang, Caiguo; Li, Yiming

2011-02-15

Procyanidin oligomers in Cinnamon are thought to be responsible for the biological activity in the treatment of diabetes mellitus (DM). To clarify types of procyanidin oligomers in different Cinnamon species and investigate their different effects, the present study investigated procyanidin oligomers in polyphenolic oligomer-rich extracts of three Cinnamon samples by LC-MS methods, and their hypoglycemic activities were detected in vivo and in vitro. The results showed that two of the three samples from Cinnamomum cassia were rich in B-type procyanidin oligomers, and the other sample was rich in A-type procyanidin oligomers. The Cinnamon extracts were administered at doses of 200 and 300 mg/kg body wt. in high-fat diet-fed and low-dose streptozotocin (STZ)-induced diabetic mice for 14 days. The results showed that blood glucose concentrations were significantly decreased in all Cinnamon extract groups compared with the control group (p<0.05). Administration of the Cinnamon extracts significantly increased the consumption of extracellular glucose in insulin-resistant HepG2 cells and normal HepG2 cells compared with the control group. These results suggest that both A- and B-type procyanidin oligomers in different Cinnamon species have hypoglycemic activities and may improve insulin sensitivity in type 2 DM. Copyright © 2010 Elsevier GmbH. All rights reserved.

A Combined Photochemical and Multicomponent Reaction Approach to Precision Oligomers.

PubMed

Konrad, Waldemar; Bloesser, Fabian R; Wetzel, Katharina S; Boukis, Andreas C; Meier, Michael A R; Barner-Kowollik, Christopher

2018-03-07

We introduce the convergent synthesis of linear monodisperse sequence-defined oligomers through a unique approach, combining the Passerini three-component reaction (P-3CR) and a Diels-Alder (DA) reaction based on photocaged dienes. A set of oligomers is prepared resting on a Passerini linker unit carrying an isocyano group for chain extension by P-3CR and a maleimide moiety for photoenol conjugation enabling a modular approach for chain growth. Monodisperse oligomers are accessible in a stepwise fashion by switching between both reaction types. Employing sebacic acid as a core unit allows the synthesis of a library of symmetric sequence-defined oligomers. The oligomers consist of alternating P-3CR and photoblocks with molecular weights up to 3532.16 g mol -1 , demonstrating the successful switching from P-3CR to photoenol conjugation. In-depth characterization was carried out including size-exclusion chromatography (SEC), high-resolution electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy, evidencing the monodisperse nature of the precision oligomers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

NASA Astrophysics Data System (ADS)

Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M.; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

2015-10-01

The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.

SDS-PAGE analysis of Aβ oligomers is disserving research into Alzheimer´s disease: appealing for ESI-IM-MS

NASA Astrophysics Data System (ADS)

Pujol-Pina, Rosa; Vilaprinyó-Pascual, Sílvia; Mazzucato, Roberta; Arcella, Annalisa; Vilaseca, Marta; Orozco, Modesto; Carulla, Natàlia

2015-10-01

The characterization of amyloid-beta peptide (Aβ) oligomer forms and structures is crucial to the advancement in the field of Alzheimer´s disease (AD). Here we report a critical evaluation of two methods used for this purpose, namely sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), extensively used in the field, and ion mobility coupled to electrospray ionization mass spectrometry (ESI-IM-MS), an emerging technique with great potential for oligomer characterization. To evaluate their performance, we first obtained pure cross-linked Aβ40 and Aβ42 oligomers of well-defined order. Analysis of these samples by SDS-PAGE revealed that SDS affects the oligomerization state of Aβ42 oligomers, thus providing flawed information on their order and distribution. In contrast, ESI-IM-MS provided accurate information, while also reported on the chemical nature and on the structure of the oligomers. Our findings have important implications as they challenge scientific paradigms in the AD field built upon SDS-PAGE characterization of Aβ oligomer samples.

Liquid Phase Miscibility Gap Materials

NASA Technical Reports Server (NTRS)

Gelles, S. H.; Markworth, A. J.

1985-01-01

The manner in which the microstructural features of liquid-phase miscibility gap alloys develop was determined. This will allow control of the microstructures and the resultant properties of these alloys. The long-duration low gravity afforded by the shuttle will allow experiments supporting this research to be conducted with minimal interference from buoyancy effects and gravitationally driven convection currents. Ground base studies were conducted on Al-In, Cu-Pb, and Te-Tl alloys to determine the effect of cooling rate, composition, and interfacial energies on the phase separation and solidification processes that influence the development of microstructure in these alloys. Isothermal and directional cooling experiments and simulations are conducted. The ground based activities are used as a technological base from which flight experiments formulated and to which these flight experiments are compared.

Preparation of Imide Oligomers via Concurrent Reactive Extrusion

NASA Technical Reports Server (NTRS)

Avakian, Roger W. (Inventor); Hu, Ling (Inventor)

2018-01-01

Reactive extrusion can be used in a continuous, solvent-less preparation of imide oligomers involving two competing reactions among three ingredients, the first reaction between a dianhydride and a diamine and the second reaction between an endcap and the same diamine. The imide oligomer can form a composite via conventional production methods or via formation of a film from imide oligomer re-melted in an extruder before being impregnated into tape or fabric.

Imide Oligomers Endcapped with Phenylethynl Phthalic Anhydrides and Polymers Therefrom

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

1998-01-01

Controlled molecular weight phenylethynyl terminated imide oligomers (PETIs) have been prepared by the cyclodehydration of precursor phenylethynyl terminated amic acid oligomers. Amino terminated amic acid oligomers are prepared from the reaction of dianhydride(s) with an excess of diamine(s) and subsequently endcapped with phenylethynyl phthalic anhydride(s) (PEPA). The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N.N-dimethylacetamide under nitrogen at room temperature. The amic acid oligomers are subsequently cyclodehydrated either thermally or cheznicauy to the corresponding imide oligomers. Direct preparation of PETIs from the reaction of dianhydxide(s) with an excess of diamine(s) and endcapped with phenylethynyl phthalic anhydride(s) has been performed in m-cresol. Phenylethynyl phthalic anhydrides are synthesized by the palladium catalyzed reaction of phenylacetylene with bromo substituted phthalic anhydrides in triethylamine. These new materials exhibit excellent properties and are potentially useful as adhesives, coatings, films, moldings and composite matrices.

Imide oligomers endcapped with phenylethynyl phthalic anhydrides and polymers therefrom

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Smith, Jr., Joseph G. (Inventor)

1996-01-01

Controlled molecular weight phenylethynyl terminated imide oligomers (PETIs) have been prepared by the cyclodehydration of precursor phenylethynyl terminated amic acid oligomers. Amino terminated amic acid oligomers are prepared from the reaction of dianhydride(s) with an excess of diamine(s) and subsequently endcapped with phenylethynyl phthalic anhydride(s) (PEPA). The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide under nitrogen at room temperature. The amic acid oligomers are subsequently cyclodehydrated either thermally or chemically to the corresponding imide oligomers. Direct preparation of PETIs from the reaction of dianhydride(s) with an excess of diamine(s) and endcapped with phenylethynyl phthalic anhydride(s) has been performed in m-cresol. Phenylethynyl phthalic anhydrides are synthesized by the palladium catalyzed reaction of phenylacetylene with bromo substituted phthalic anhydrides in triethylamine. These new materials exhibit excellent properties and are potentially useful as adhesives, coatings, films, moldings and composite matrices.

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

PubMed Central

Choi, Bong-Kyu; Choi, Mal-Gi; Kim, Jae-Yeol; Yang, Yoosoo; Lai, Ying; Kweon, Dae-Hyuk; Lee, Nam Ki; Shin, Yeon-Kyun

2013-01-01

Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of α-synuclein (α-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of α-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large α-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large α-Syn oligomers preferentially bind to the N-terminal domain of a vesicular SNARE protein, synaptobrevin-2, which blocks SNARE-mediated lipid mixing by preventing SNARE complex formation. In sharp contrast, the α-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large α-Syn oligomers. Thus, the results suggest that large α-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity. PMID:23431141

Diverse mechanisms of antidiabetic effects of the different procyanidin oligomer types of two different cinnamon species on db/db mice.

PubMed

Chen, Liang; Sun, Peng; Wang, Ting; Chen, Kaixian; Jia, Qi; Wang, Heyao; Li, Yiming

2012-09-12

The procyanidin oligomers are thought to be responsible for the antidiabetic activity of cinnamon. To investigate the hypoglycemic effects of different procyanidin oligomer types, the procyanidin oligomer-rich extracts were prepared from two different cinnamon species. Using high-performance liquid chromatography with purified procyanidin oligomers as reference compounds, we found that the Cinnamomum cassia extract (CC-E) and Cinnamomum tamala extract (CT-E) were rich in B- and A-type procyanidin oligomers, respectively. In the experiment, 8-week-old diabetic (db/db) mice were gavaged with CC-E and CT-E (both 200 mg/kg per day) for 4 weeks. Both CC-E and CT-E exhibited antidiabetic effects. Moreover, histopathological studies of the pancreas, liver, and adipose tissue showed that CC-E promoted lipid accumulation in the adipose tissue and liver, whereas CT-E mainly improved the insulin concentration in the blood and pancreas.

The rheology, microstructure and sensory characteristics of a gluten-free bread formulation enhanced with orange pomace.

PubMed

O'Shea, Norah; Doran, Linda; Auty, Mark; Arendt, Elke; Gallagher, Eimear

2013-12-01

The present manuscript studied a previously optimised gluten-free bread formulation containing 5.5% orange pomace (OP) in relation to the batter characteristics (i.e. pre-baking), microstructure (of the flours, batter and bread) and sensory characteristics of the bread. Rheology, RVA and mixolab results illustrated that orange pomace improved the robustness of the gluten-free batter and decreased the occurrence of starch gelatinisation. This was confirmed from the confocal laser scanning microscopy (CLSM) images, which showed potato starch granules to be more expanded in the control batter when compared to the sample containing orange pomace. Starch granules were also observed to be more enlarged and swollen in the CLSM bread images, suggesting a higher level of gelatinisation occurred in the control sample. Sensory analysis was carried out on the optimised and control bread; panellists scored the flavour, crumb appearance and overall acceptability of the OP-containing breads comparable to the control.

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization.

PubMed

Teng, Edmond; Taylor, Karen; Bilousova, Tina; Weiland, David; Pham, Thaidan; Zuo, Xiaohong; Yang, Fusheng; Chen, Ping-Ping; Glabe, Charles G; Takacs, Alison; Hoffman, Dennis R; Frautschy, Sally A; Cole, Gregory M

2015-10-01

Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer's disease (AD). These effects have been postulated to arise from DHA's pleiotropic effects on AD pathophysiology, including its effects on β-amyloid (Aβ) production, aggregation, and toxicity. While in vitro studies suggest that DHA may inhibit and reverse the formation of toxic Aβ oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on Aβ indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal Aβ plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble Aβ oligomer levels in the hippocampus. Further quantification of specific conformational populations of Aβ oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) Aβ oligomers and decreased prefibrillar (i.e. putatively more toxic) Aβ oligomers. These results provide in vivo evidence suggesting that DHA can modulate Aβ aggregation by stabilizing soluble fibrillar Aβ oligomers and thus reduce the formation of both Aβ plaques and prefibrillar Aβ oligomers. However, since fibrillar Aβ oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar Aβ oligomer levels for more effective prevention of AD in clinical settings. Published by Elsevier Inc.

Computer simulations and theoretical aspects of the depletion interaction in protein-oligomer mixtures.

PubMed

Boncina, M; Rescic, J; Kalyuzhnyi, Yu V; Vlachy, V

2007-07-21

The depletion interaction between proteins caused by addition of either uncharged or partially charged oligomers was studied using the canonical Monte Carlo simulation technique and the integral equation theory. A protein molecule was modeled in two different ways: either as (i) a hard sphere of diameter 30.0 A with net charge 0, or +5, or (ii) as a hard sphere with discrete charges (depending on the pH of solution) of diameter 45.4 A. The oligomers were pictured as tangentially jointed, uncharged, or partially charged, hard spheres. The ions of a simple electrolyte present in solution were represented by charged hard spheres distributed in the dielectric continuum. In this study we were particularly interested in changes of the protein-protein pair-distribution function, caused by addition of the oligomer component. In agreement with previous studies we found that addition of a nonadsorbing oligomer reduces the phase stability of solution, which is reflected in the shape of the protein-protein pair-distribution function. The value of this function in protein-protein contact increases with increasing oligomer concentration, and is larger for charged oligomers. The range of the depletion interaction and its strength also depend on the length (number of monomer units) of the oligomer chain. The integral equation theory, based on the Wertheim Ornstein-Zernike approach applied in this study, was found to be in fair agreement with Monte Carlo results only for very short oligomers. The computer simulations for a model mimicking the lysozyme molecule (ii) are in qualitative agreement with small-angle neutron experiments for lysozyme-dextran mixtures.

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

PubMed Central

Nilson, Ashley N.; English, Kelsey C.; Gerson, Julia E.; Barton Whittle, T.; Nicolas Crain, C.; Xue, Judy; Sengupta, Urmi; Castillo-Carranza, Diana L.; Zhang, Wenbo; Gupta, Praveena; Kayed, Rakez

2016-01-01

It is well-established that inflammation plays an important role in Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies. PMID:27716675

Association Thermodynamics and Conformational Stability of β-Sheet Amyloid β(17-42) Oligomers: Effects of E22Q (Dutch) Mutation and Charge Neutralization

PubMed Central

Blinov, Nikolay; Dorosh, Lyudmyla; Wishart, David; Kovalenko, Andriy

2010-01-01

Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type Aβ17–42 oligomers with different protonation states of Glu22, as well the E22Q (Dutch) mutants. The association free energy of small β-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the β-sheet oligomers. The charge reduction of the wild-type Aβ17–42 oligomers upon protonation of the solvent-exposed Glu22 at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type Aβ17–42 oligomers at neutral pH and the Dutch mutants, on the one hand, and the Aβ17–42 oligomers with protonated Glu22, on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp23 and Lys28. Peculiarities in the conformational stability and the association thermodynamics for the different models of the Aβ17–42 oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure. PMID:20338850

Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau.

PubMed

Lasagna-Reeves, Cristian A; Castillo-Carranza, Diana L; Sengupta, Urmi; Guerrero-Munoz, Marcos J; Kiritoshi, Takaki; Neugebauer, Volker; Jackson, George R; Kayed, Rakez

2012-01-01

Intracerebral injection of brain extracts containing amyloid or tau aggregates in transgenic animals can induce cerebral amyloidosis and tau pathology. We extracted pure populations of tau oligomers directly from the cerebral cortex of Alzheimer disease (AD) brain. These oligomers are potent inhibitors of long term potentiation (LTP) in hippocampal brain slices and disrupt memory in wild type mice. We observed for the first time that these authentic brain-derived tau oligomers propagate abnormal tau conformation of endogenous murine tau after prolonged incubation. The conformation and hydrophobicity of tau oligomers play a critical role in the initiation and spread of tau pathology in the naïve host in a manner reminiscent of sporadic AD.

DFT Modeling of Cross-Linked Polyethylene: Role of Gold Atoms and Dispersion Interactions.

PubMed

Blaško, Martin; Mach, Pavel; Antušek, Andrej; Urban, Miroslav

2018-02-08

Using DFT modeling, we analyze the concerted action of gold atoms and dispersion interactions in cross-linked polyethylene. Our model consists of two oligomer chains (PEn) with 7, 11, 15, 19, or 23 carbon atoms in each oligomer cross-linked with one to three Au atoms through C-Au-C bonds. In structures with a single gold atom the C-Au-C bond is located in the central position of the oligomer. Binding energies (BEs) with respect to two oligomer radical fragments and Au are as high as 362-489 kJ/mol depending on the length of the oligomer chain. When the dispersion contribution in PEn-Au-PEn oligomers is omitted, BE is almost independent of the number of carbon atoms, lying between 293 and 296 kJ/mol. The dispersion energy contributions to BEs in PEn-Au-PEn rise nearly linearly with the number of carbon atoms in the PEn chain. The carbon-carbon distance in the C-Au-C moiety is around 4.1 Å, similar to the bond distance between saturated closed shell chains in the polyethylene crystal. BEs of pure saturated closed shell PEn-PEn oligomers are 51-187 kJ/mol. Both Au atoms and dispersion interactions contribute considerably to the creation of nearly parallel chains of oligomers with reasonably high binding energies.

Single-molecule FRET studies on alpha-synuclein oligomerization of Parkinson’s disease genetically related mutants

NASA Astrophysics Data System (ADS)

Tosatto, Laura; Horrocks, Mathew H.; Dear, Alexander J.; Knowles, Tuomas P. J.; Dalla Serra, Mauro; Cremades, Nunilo; Dobson, Christopher M.; Klenerman, David

2015-11-01

Oligomers of alpha-synuclein are toxic to cells and have been proposed to play a key role in the etiopathogenesis of Parkinson’s disease. As certain missense mutations in the gene encoding for alpha-synuclein induce early-onset forms of the disease, it has been suggested that these variants might have an inherent tendency to produce high concentrations of oligomers during aggregation, although a direct experimental evidence for this is still missing. We used single-molecule Förster Resonance Energy Transfer to visualize directly the protein self-assembly process by wild-type alpha-synuclein and A53T, A30P and E46K mutants and to compare the structural properties of the ensemble of oligomers generated. We found that the kinetics of oligomer formation correlates with the natural tendency of each variant to acquire beta-sheet structure. Moreover, A53T and A30P showed significant differences in the averaged FRET efficiency of one of the two types of oligomers formed compared to the wild-type oligomers, indicating possible structural variety among the ensemble of species generated. Importantly, we found similar concentrations of oligomers during the lag-phase of the aggregation of wild-type and mutated alpha-synuclein, suggesting that the properties of the ensemble of oligomers generated during self-assembly might be more relevant than their absolute concentration for triggering neurodegeneration.

Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin

PubMed Central

Chang, Lan; Cui, Wei; Yang, Yong; Xu, Shujun; Zhou, Wenhua; Fu, Hongjun; Hu, Shengquan; Mak, Shinghung; Hu, Juwei; Wang, Qin; Pui-Yan Ma, Victor; Chung-lit Choi, Tony; Dik-lung Ma, Edmond; Tao, Liang; Pang, Yuanping; Rowan, Michael J.; Anwyl, Roger; Han, Yifan; Wang, Qinwen

2015-01-01

β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer’s disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD. PMID:26194093

Microstructural comparison of the kinematics of discrete and continuum dislocations models

NASA Astrophysics Data System (ADS)

Sandfeld, Stefan; Po, Giacomo

2015-12-01

The Continuum Dislocation Dynamics (CDD) theory and the Discrete Dislocation Dynamics (DDD) method are compared based on concise mathematical formulations of the coarse graining of discrete data. A numerical tool for converting from a discrete to a continuum representation of a given dislocation configuration is developed, which allows to directly compare both simulation approaches based on continuum quantities (e.g. scalar density, geometrically necessary densities, mean curvature). Investigating the evolution of selected dislocation configurations within analytically given velocity fields for both DDD and CDD reveals that CDD contains a surprising number of important microstructural details.

[Production technology and use of composite materials in the aeronautics industry, risks and pathology in the manufacturing workers].

PubMed

Franco, G; Candura, F

1985-01-01

The type and applications of composite materials have increased greatly during the last forty years, particularly in the aircraft and aerospace industries. The foreseeable increase of the employment of composite materials in future needs an adequate engagement in finding out health risks involved with technological processes. Composite materials - considered as a close union between a continuous glass, aramid or carbon reinforcing fibre and a epoxy matrix - present several advantages over traditional materials. Structural epoxy adhesives are defined as complex formulated systems. By mixing a large number of ingredients a formulated resin is obtained, which represents the start of the production process for adhesive manufacture. The most important ingredients such as catalysts, accelerators, the groups of epoxy monomers and oligomers, additives most used and their role into the epoxy matrices are illustrated. Of the various technologies existing for the fabrication of aircraft structures the one so called "vacuum bag" is described. The knowledge of the chemical composition of the substances used in the production of composite materials and epoxy adhesives allows to verify the possible existence of hazard for workers health. Among the potentially dangerous chemicals, epoxy monomers and oligomers, catalysts, accelerators are to be considered. The metabolism and the mechanisms of toxicity of epoxides are summarized. However the toxic effects of most epoxides are far from being wholly investigated. In man epoxides ingestion, inhalation or absorption through the skin can lead to several toxic effects: irritation and sensitisation, alterations of liver and nervous function. Finally some epoxides are considered to be carcinogenic in animals and in man; however for many compounds, the results are not yet conclusive. From what it is said above come out the necessity of a careful sanitary control of the workers exposed to these hazards, control that is made difficult by the lack of adequate biological indices for the risks found.

A non-classical Mindlin plate model incorporating microstructure, surface energy and foundation effects.

PubMed

Gao, X-L; Zhang, G Y

2016-07-01

A non-classical model for a Mindlin plate resting on an elastic foundation is developed in a general form using a modified couple stress theory, a surface elasticity theory and a two-parameter Winkler-Pasternak foundation model. It includes all five kinematic variables possible for a Mindlin plate. The equations of motion and the complete boundary conditions are obtained simultaneously through a variational formulation based on Hamilton's principle, and the microstructure, surface energy and foundation effects are treated in a unified manner. The newly developed model contains one material length-scale parameter to describe the microstructure effect, three surface elastic constants to account for the surface energy effect, and two foundation parameters to capture the foundation effect. The current non-classical plate model reduces to its classical elasticity-based counterpart when the microstructure, surface energy and foundation effects are all suppressed. In addition, the new model includes the Mindlin plate models considering the microstructure dependence or the surface energy effect or the foundation influence alone as special cases, recovers the Kirchhoff plate model incorporating the microstructure, surface energy and foundation effects, and degenerates to the Timoshenko beam model including the microstructure effect. To illustrate the new Mindlin plate model, the static bending and free vibration problems of a simply supported rectangular plate are analytically solved by directly applying the general formulae derived.

A non-classical Mindlin plate model incorporating microstructure, surface energy and foundation effects

PubMed Central

Zhang, G. Y.

2016-01-01

A non-classical model for a Mindlin plate resting on an elastic foundation is developed in a general form using a modified couple stress theory, a surface elasticity theory and a two-parameter Winkler–Pasternak foundation model. It includes all five kinematic variables possible for a Mindlin plate. The equations of motion and the complete boundary conditions are obtained simultaneously through a variational formulation based on Hamilton's principle, and the microstructure, surface energy and foundation effects are treated in a unified manner. The newly developed model contains one material length-scale parameter to describe the microstructure effect, three surface elastic constants to account for the surface energy effect, and two foundation parameters to capture the foundation effect. The current non-classical plate model reduces to its classical elasticity-based counterpart when the microstructure, surface energy and foundation effects are all suppressed. In addition, the new model includes the Mindlin plate models considering the microstructure dependence or the surface energy effect or the foundation influence alone as special cases, recovers the Kirchhoff plate model incorporating the microstructure, surface energy and foundation effects, and degenerates to the Timoshenko beam model including the microstructure effect. To illustrate the new Mindlin plate model, the static bending and free vibration problems of a simply supported rectangular plate are analytically solved by directly applying the general formulae derived. PMID:27493578

Characterization of 3-Aminopropyl Oligosilsesquioxane.

PubMed

Dimzon, Ian Ken D; Frömel, Tobias; Knepper, Thomas P

2016-05-03

The synthesis routes in the production of polysilsesquioxanes have largely relied upon in situ formations. This perspective often leads to polymers in which their basic structures including molecular weight and functionality are unknown [ Lichtenhan , J. D. ; et al. Silsesquioxane-siloxane copolymers from polyhedral silsesquioxanes Macromolecules , 1993 , 26 , 2141 - 2142 , http://dx.doi.org/10.1021/ma0060a053 ]. For a better understanding of the polysilsesquioxane properties and applications, there is a need to develop more techniques to enable their chemical characterization. An innovative method was developed to determine the molecular weight distribution (MWD) of an oligosilsesquioxane synthesized in-house from (3-aminopropyl)triethoxysilane. This method, which can be applied to other silsesquioxanes, siloxanes, and similar oligomers and polymers, involved separation using high performance liquid chromatography (HPLC) and detection using mass spectrometry (MS) with electrospray ionization (ESI). The novelty of the method lies on the unique determination of the absolute concentrations of the individual homologues present in the sample formulation. The use of absolute concentrations is necessary in estimating the MWD of the formulation when relative percentage, which is based solely on mass spectral ion intensities, becomes irrelevant due to the disproportionate response factors of the homologues. Determination of absolute concentration requires the use of single-homologue calibration standards. Because of commercial unavailability, these standards were prepared by efficient fractionation of the original formulation.

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

PubMed Central

Izzo, Nicholas J.; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F.; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M.

2014-01-01

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics. PMID:25390368

Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

PubMed

Izzo, Nicholas J; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M

2014-01-01

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

Donor-acceptor-donor thienyl/bithienyl-benzothiadiazole/quinoxaline model oligomers: experimental and theoretical studies.

PubMed

Pina, João; de Melo, J Seixas; Breusov, D; Scherf, Ullrich

2013-09-28

A comprehensive spectral and photophysical investigation of four donor-acceptor-donor (DAD) oligomers consisting of electron-deficient 2,1,3-benzothiadiazole or quinoxaline moieties linked to electron-rich thienyl or bithienyl units has been undertaken. Additionally, a bis(dithienyl) substituted naphthalene was also investigated. The D-A-D nature of these oligomers resulted in the presence of an intramolecular charge transfer (ICT) state, which was further substantiated by solvatochromism studies (analysis with the Lippert-Mataga formalism). Hereby, significant differences have been obtained for the fluorescence quantum yields of the oligomers in the non-polar solvent methylcyclohexane vs. the polar ethanol. The study was further complemented with the determination of the optimized ground-state molecular geometries for the oligomers together with the prediction of the lowest vertical one-electron excitation energy and the relevant molecular orbital contours using DFT calculations. The electronic transitions show a clear HOMO to LUMO charge-transfer character. In contrast to the thiophene oligomers (the oligothiophenes with n = 1-7), where the intersystem crossing (ISC) yield decreases with n, the studied DAD oligomers were found to show an increase in the ISC efficiency with the number of (donor) thienyl units.

Combined HILIC-ELSD/ESI-MS(n) enables the separation, identification and quantification of sugar beet pectin derived oligomers.

PubMed

Remoroza, C; Cord-Landwehr, S; Leijdekkers, A G M; Moerschbacher, B M; Schols, H A; Gruppen, H

2012-09-01

The combined action of endo-polygalacturonase (endo-PGII), pectin lyase (PL), pectin methyl esterase (fungal PME) and RG-I degrading enzymes enabled the extended degradation of methylesterified and acetylated sugar beet pectins (SBPs). The released oligomers were separated, identified and quantified using hydrophilic interaction liquid chromatography (HILIC) with online electrospray ionization ion trap mass spectrometry (ESI-IT-MS(n)) and evaporative light scattering detection (ELSD). By MS(n), the structures of galacturonic acid (GalA) oligomers having an acetyl group in the O-2 and/or O-3 positions eluting from the HILIC column were elucidated. The presence of methylesterified and/or acetylated galacturonic acid units within an oligomer reduced the interaction with the HILIC column significantly compared to the unsubstituted GalA oligomers. The HILIC column enables a good separation of most oligomers present in the digest. The use of ELSD to quantify oligogalacturonides was validated using pure GalA standards and the signal was found to be independent of the chemical structure of the oligomer being detected. The combination of chromatographic and enzymatic strategies enables to distinguish SBPs having different methylesters and acetyl group distribution. Copyright © 2012 Elsevier Ltd. All rights reserved.

Power of Ultra Performance Liquid Chromatography/Electrospray Ionization-MS Reconstructed Ion Chromatograms in the Characterization of Small Differences in Polymer Microstructure.

PubMed

Epping, Ruben; Panne, Ulrich; Falkenhagen, Jana

2018-03-06

From simple homopolymers to functionalized, 3-dimensional structured copolymers, the complexity of polymeric materials has become more and more sophisticated. With new applications, for instance, in the semiconductor or pharmaceutical industry, the requirements for the characterization have risen with the complexity of the used polymers. For each additional distribution, an additional dimension in analysis is needed. Small, often isomeric heterogeneities in topology or microstructure can usually not be simply separated chromatographically or distinguished by any common detector but affect the properties of materials significantly. For a drug delivery system, for example, the degree of branching and branching distribution is crucial for the formation of micelles. Instead of a complicated, time-consuming, and/or expensive 2D-chromatography or ion mobility spectrometry (IMS) method, that also has its limitations, in this work, a simple approach using size exclusion chromatography (SEC) coupled with electrospray ionization (ESI) mass spectrometry is proposed. The online coupling allows the analysis of reconstructed ion chromatograms (RICs) of each degree of polymerization. While a complete separation often cannot be achieved, the derived retention times and peak widths lead to information on the existence and dispersity of heterogeneities. Although some microstructural heterogeneities like short chain branching can for large polymers be characterized with methods such as light scattering, for oligomers where the heterogeneities just start to form and their influence is at the maximum, they are inaccessible with these methods. It is also shown that with a proper calibration even quantitative information can be obtained. This method is suitable to detect small differences in, e.g., branching, 3D-structure, monomer sequence, or tacticity and could potentially be used in routine analysis to quickly determine deviations.

Elucidation of amyloid beta-protein oligomerization mechanisms: discrete molecular dynamics study.

PubMed

Urbanc, B; Betnel, M; Cruz, L; Bitan, G; Teplow, D B

2010-03-31

Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(1-40) and Abeta(1-42) and their Arctic mutants, [E22G]Abeta(1-40) and [E22G]Abeta(1-42). We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were in agreement with prior experimental findings. Unlike Abeta(1-40), Abeta(1-42) had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higher-order oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]Abeta(1-40) formed paranuclei with a similar propensity to that of Abeta(1-42). Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in Abeta(1-42) oligomer formation whereas Abeta(1-40) oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in Abeta(1-40) oligomerization but did not contribute to the oligomerization of Abeta(1-42) or the Arctic mutants. The oligomer structure of both Arctic peptides resembled Abeta(1-42) more than Abeta(1-40), consistent with their potentially more toxic nature.

Montmorillonite catalysis of RNA oligomer formation in aqueous solution. A model for the prebiotic formation of RNA

NASA Technical Reports Server (NTRS)

Ferris, J. P.; Ertem, G.

1993-01-01

Oligomers of adenylic acid of up to the 11-mer in length are formed by the reaction of the phosphorimidazolide of adenosine (ImpA) in pH 8 aqueous solution at room temperature in the presence of Na(+)-montmorillonite. These oligomers are joined by phosphodiester bonds in which the 3',5'-linkage predominates over the 2',5'-linkage by a 2:1 ratio. Reaction of a 9:1 mixture of ImpA, A5'ppA results in the formation of oligomers with a 3:1 ratio of 3',5'- to 2',5'-linked phosphodiester bonds. A high proportion of these oligomers contain the A5'ppA grouping. A5'ppA reacts much more rapidly with ImpA than does 5'-ADP (ppA) or 5'-ATP (pppA). The exchangeable cation associated with the montmorillonite effects the observed catalysis with Li+, Na+, NH4+, and Ca2+ being the more effective while Mg2+ and Al3+ are almost ineffective catalysts. 2',5'-Linked oligomers, up to the tetramer in length, are formed using UO2(2+)-montmorillonite. The structure analysis of individual oligomer fractions was performed by selective enzymatic and KOH hydrolytic studies followed by HPLC analysis of the reaction products. It is concluded from the composition of the oligomers that the rate of addition ImpA to a 3'-terminus containing a 2',5'-linkage is slower than the addition to a nucleoside joined by a 3',5'-linked phosphodiester bond. The potential importance of mineral catalysis of the formation of RNA and other oligomers on primitive Earth is discussed.

Detergent-dispersant additives based on high-molecular-weight alkylphenols

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulieva, K.N.; Namazova, I.I.; Ismailova, N.D.

1988-09-01

This article describes the synthesis and investigation of Mannich bases produced for alkylphenols, obtained in turn from ethylene oligomers. These oligomers are the still bottoms from distillation products of high-temperature oligomerization of ethylene in the presence of triethylaluminum. Two narrow cuts obtained from the distillation of oligomer fraction were used to study the influence of ethylene oligomer molecular weight on the properties of the additives. The additives were blended in DS-11 oil to evaluate their detergency-dispersancy and other properties. Comparison blends were made with succinimide additives based on the same ethylene oligomers. The Mannich bases give improvements in the oxidationmore » resistance, anticorrosion properties, and detergency-dispersancy of the DS-11 diesel oil.« less

Degradation of a Sodium Acrylate Oligomer by an Arthrobacter sp

PubMed Central

Hayashi, Takaya; Mukouyama, Masaharu; Sakano, Kouichi; Tani, Yoshiki

1993-01-01

Arthrobacter sp. strain NO-18 was first isolated from soil as a bacterium which could degrade the sodium acrylate oligomer and utilize it as the sole source of carbon. When 0.2% (wt/wt) oligomer was added to the culture medium, the acrylate oligomer was found to be degraded by 70 to 80% in 2 weeks, using gel permeation chromatography. To determine the maximum molecular weight for biodegradation, the degradation test was done with the hexamer, heptamer, and octamer, which were separated from the oligomer mixture by fractional gel permeation chromatography. The hexamer and heptamer were consumed to the extents of 58 and 36%, respectively, in 2 weeks, but the octamer was not degraded. Oligomers with three different terminal groups were synthesized to examine the effect of the different terminal groups on biodegradation, but few differences were found. Arthrobacter sp. NO-18 assimilated acrylic acid, propionic acid, glutaric acid, 2-methylglutaric acid, and 1,3,5-pentanetricarboxylic acid. Degradation of the acrylic unit structure by this strain is discussed. PMID:8517751

Effects of adding methacrylate monomers on viscosity and mechanical properties of experimental light-curing soft lining materials based on urethane (meth)acrylate oligomers.

PubMed

Kanie, Takahito; Kadokawa, Akihiko; Arikawa, Hiroyuki; Fujii, Koichi; Ban, Seiji

2008-11-01

We investigated the viscosity and mechanical properties of experimental light-curing soft lining materials based on six commercially available urethane (meth)acrylate oligomers. The viscosities of the six oligomers were 1.9, 20.6, 26.8, 144.0, 185.3, and 8803.4 Pa*s at 25 degrees C. Two monomers (ethyl- and butyl-methacrylate) were added at 20 wt% to these oligomers to decrease the viscosity, resulting in viscosity reductions of 0.2 to 13.6 Pa*s for the six oligomers. The mechanical properties (compressive modulus, Shore A hardness, and tensile strength) were measured after two times light-polymerization for 3 min. The addition of the monomers to the oligomers only slightly changed the mechanical properties, in contrast to the large viscosity changes. Based on these results, it appears that the addition of ethyl- or butyl-methacrylate monomers is useful for decreasing the viscosity of experimental light-curing soft lining materials without changing their mechanical properties.

Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease

NASA Astrophysics Data System (ADS)

Viola, Kirsten L.; Sbarboro, James; Sureka, Ruchi; de, Mrinmoy; Bicca, Maíra A.; Wang, Jane; Vasavada, Shaleen; Satpathy, Sreyesh; Wu, Summer; Joshi, Hrushikesh; Velasco, Pauline T.; Macrenaris, Keith; Waters, E. Alex; Lu, Chang; Phan, Joseph; Lacor, Pascale; Prasad, Pottumarthi; Dravid, Vinayak P.; Klein, William L.

2015-01-01

One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

Violation of the isolated square rule for group 13-15 oligomers: theoretical prediction of a new class of inorganic polymers.

PubMed

Timoshkin, Alexey Y; Schaefer, Henry F

2005-02-21

It is widely thought that the oligomer compounds [RMYR]n (M-group 13, Y-group 15 element) should obey the isolated square rule found for the boron-nitrogen cages. In contrast to these expectations, the needle-shaped oligomers, which violate this rule, are more stable compared to the cage (fullerene-like) oligomers for all MY pairs (M = B, Al, Ga, In; Y = N, P, As). The stability of the needle-shaped clusters improves with increasing oligomerization degree. Thus, the isolated square rule, which is analogous to the isolated pentagon rule widely applied for fullerenes, should not serve as the basis for searches for the most stable structures of the inorganic oligomers. Generation of the needle-shaped oligomers from the group 13 and 15 hydrides is thermodynamically favorable. A synthesis of novel inorganic polymers, formed by fusion of trimeric M3Y3 rings, is expected to be viable.

Transesterification of PHA to oligomers covalently bonded with (bio)active compounds containing either carboxyl or hydroxyl functionalities.

PubMed

Kwiecień, Iwona; Radecka, Iza; Kowalczuk, Marek; Adamus, Grażyna

2015-01-01

This manuscript presents the synthesis and structural characterisation of novel biodegradable polymeric controlled-release systems of pesticides with potentially higher resistance to weather conditions in comparison to conventional forms of pesticides. Two methods for the preparation of pesticide-oligomer conjugates using the transesterification reaction were developed. The first method of obtaining conjugates, which consist of bioactive compounds with the carboxyl group and polyhydroxyalkanoates (PHAs) oligomers, is "one-pot" transesterification. In the second method, conjugates of bioactive compounds with hydroxyl group and polyhydroxyalkanoates oligomers were obtained in two-step method, through cyclic poly(3-hydroxybutyrate) oligomers. The obtained pesticide-PHA conjugates were comprehensively characterised using GPC, 1H NMR and mass spectrometry techniques. The structural characterisation of the obtained products at the molecular level with the aid of mass spectrometry confirmed that both of the synthetic strategies employed led to the formation of conjugates in which selected pesticides were covalently bonded to PHA oligomers via a hydrolysable ester bond.

General Analytical Schemes for the Characterization of Pectin-Based Edible Gelled Systems

PubMed Central

Haghighi, Maryam; Rezaei, Karamatollah

2012-01-01

Pectin-based gelled systems have gained increasing attention for the design of newly developed food products. For this reason, the characterization of such formulas is a necessity in order to present scientific data and to introduce an appropriate finished product to the industry. Various analytical techniques are available for the evaluation of the systems formulated on the basis of pectin and the designed gel. In this paper, general analytical approaches for the characterization of pectin-based gelled systems were categorized into several subsections including physicochemical analysis, visual observation, textural/rheological measurement, microstructural image characterization, and psychorheological evaluation. Three-dimensional trials to assess correlations among microstructure, texture, and taste were also discussed. Practical examples of advanced objective techniques including experimental setups for small and large deformation rheological measurements and microstructural image analysis were presented in more details. PMID:22645484

Characterisation of pore structures of pharmaceutical tablets: A review.

PubMed

Markl, Daniel; Strobel, Alexa; Schlossnikl, Rüdiger; Bøtker, Johan; Bawuah, Prince; Ridgway, Cathy; Rantanen, Jukka; Rades, Thomas; Gane, Patrick; Peiponen, Kai-Erik; Zeitler, J Axel

2018-03-01

Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process. In future, additive manufacturing is a potential game changer to design the inner structures and realise a tailor-made pore structure. In pharmaceutical development the pore structure is most commonly only described by the total porosity of the tablet matrix. Yet it is of great importance to consider other parameters to fully resolve the interplay between microstructure and dosage form performance. Specifically, tortuosity, connectivity, as well as pore shape, size and orientation all impact the flow paths and play an important role in describing the fluid flow in a pharmaceutical tablet. This review presents the key properties of the pore structures in solid dosage forms and it discusses how to measure these properties. In particular, the principles, advantages and limitations of helium pycnometry, mercury porosimetry, terahertz time-domain spectroscopy, nuclear magnetic resonance and X-ray computed microtomography are discussed. Copyright © 2018 Elsevier B.V. All rights reserved.

Separation and determination of secoisolariciresinol diglucoside oligomers and their hydrolysates in the flaxseed extract by high-performance liquid chromatography.

PubMed

Li, Xin; Yuan, Jian-Ping; Xu, Shi-Ping; Wang, Jiang-Hai; Liu, Xin

2008-03-28

Flaxseed contains the largest amount of lignan secoisolariciresinol diglucoside (SDG) oligomers and is the richest dietary source of SDG. SDG oligomers in the flaxseed extract are often hydrolyzed to break the ester linkages for the release of SDG and the glycosidic bonds for the release of secoisolariciresinol (SECO). The hydrolysates of SDG oligomers are complicated because of the production of esters in an alcohol-containing medium. In this study, a new gradient reversed-phase high-performance liquid chromatography (HPLC) method has been developed to be suitable for the separation and determination of: (1) SDG oligomers extracted from the defatted flaxseed powder by a 70% aqueous methanol solution; (2) SDG oligomers and their alkaline hydrolysates, including SDG, p-coumaric acid glucoside and its methyl ester, ferulic acid glucoside and its methyl ester in an alkaline hydrolytic solution; and (3) the succedent acid hydrolysates, including secoisolariciresinol monoglucoside (SMG), SECO, anhydrosecoisolariciresinol (anhydro-SECO), p-coumaric acid and its methyl ester, ferulic acid and its methyl ester, 5-hydroxymethyl-2-furfural (HMF) and its degradation product in an acid hydrolytic solution. The content of SDG oligomers in a defatted flaxseed powder was found to be 38.5 mg/g on a dry matter basis, corresponding to a SDG content of 15.4 mg/g, which was determined after alkaline hydrolysis. Furthermore, this study presented a major reaction pathway for the hydrolysis of SDG oligomers.

Esters of oligo-(glycerol carbonate-glycerol): New biobased oligomeric surfactants.

PubMed

Holmiere, Sébastien; Valentin, Romain; Maréchal, Philippe; Mouloungui, Zéphirin

2017-02-01

Glycerol carbonate is one of the most potentially multifunction glycerol-derived compounds. Glycerol is an important by-product of the oleochemical industry. The oligomerization of glycerol carbonate, assisted by the glycerol, results in the production of polyhydroxylated oligomers rich in linear carbonate groups. The polar moieties of these oligomers (M w <1000Da) were supplied by glycerol and glycerol carbonate rather than ethylene oxide as in most commercial surfactants. The insertion of linear carbonate groups into the glycerol-based skeleton rendered the oligomers amphiphilic, resulting in a decrease in air/water surface tension to 57mN/m. We improved the physical and chemical properties of the oligomers, by altering the type of acylation reaction and the nature of the acyl donor. The polar head is constituted of homo-oligomers and hetero-oligomers. Homo-oligomers are oligoglycerol and/or oligocarbonate, hetero-oligomers are oligo(glycerol-glycerol carbonate). Coprah oligoesters had the best surfactant properties (CMC<1mg/mL, π cmc <30mN/m), outperforming molecules of fossil origin, such as ethylene glycol monododecyl ether, glycol ethers and fatty acid esters of sorbitan polyethoxylates. The self-assembling properties of oligocarbonate esters were highlighted by their ability to stabilize inverse and multiple emulsions. The oligo-(glycerol carbonate-glycerol ether) with relatively low molecular weights showed properties of relatively high-molecular weight molecules, and constitute a viable "green" alternative to ethoxylated surfactants. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of Processible Electroactive Oligomers and Polymers

DTIC Science & Technology

1991-10-01

of structure and electroactive properties. Electroactive molecules including fused ring (ladder oligomers) dyes , squarylium -heterocyclic moieties...Electroactive molecules including fused ring (ladder oligomers) dyes , squarylium -heterocyclic moieties, phenylpolyenes, thienylpolyenes, carbocyanine dyes ...phenylpolyenes, thienylpolyenes, carbocyanine dyes , and tetraazaannulenes have also been synthetically incorporated into a variety of traditional

Efficient Reformulation of the Thermoelastic Higher-order Theory for Fgms

NASA Technical Reports Server (NTRS)

Bansal, Yogesh; Pindera, Marek-Jerzy; Arnold, Steven M. (Technical Monitor)

2002-01-01

Functionally graded materials (FGMs) are characterized by spatially variable microstructures which are introduced to satisfy given performance requirements. The microstructural gradation gives rise to continuously or discretely changing material properties which complicate FGM analysis. Various techniques have been developed during the past several decades for analyzing traditional composites and many of these have been adapted for the analysis of FGMs. Most of the available techniques use the so-called uncoupled approach in order to analyze graded structures. These techniques ignore the effect of microstructural gradation by employing specific spatial material property variations that are either assumed or obtained by local homogenization. The higher-order theory for functionally graded materials (HOTFGM) is a coupled approach developed by Aboudi et al. (1999) which takes the effect of microstructural gradation into consideration and does not ignore the local-global interaction of the spatially variable inclusion phase(s). Despite its demonstrated utility, however, the original formulation of the higher-order theory is computationally intensive. Herein, an efficient reformulation of the original higher-order theory for two-dimensional elastic problems is developed and validated. The use of the local-global conductivity and local-global stiffness matrix approach is made in order to reduce the number of equations involved. In this approach, surface-averaged quantities are the primary variables which replace volume-averaged quantities employed in the original formulation. The reformulation decreases the size of the global conductivity and stiffness matrices by approximately sixty percent. Various thermal, mechanical, and combined thermomechanical problems are analyzed in order to validate the accuracy of the reformulated theory through comparison with analytical and finite-element solutions. The presented results illustrate the efficiency of the reformulation and its advantages in analyzing functionally graded materials.

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

PubMed

De Haan, David O; Tapavicza, Enrico; Riva, Matthieu; Cui, Tianqu; Surratt, Jason D; Smith, Adam C; Jordan, Mary-Caitlin; Nilakantan, Shiva; Almodovar, Marisol; Stewart, Tiffany N; de Loera, Alexia; De Haan, Audrey C; Cazaunau, Mathieu; Gratien, Aline; Pangui, Edouard; Doussin, Jean-François

2018-04-03

Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS 2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light-absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ∼80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CH 3 CO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events.

Liquid Crystalline Thermosets from Ester, Ester-Imide, and Ester-Amide Oligomers

NASA Technical Reports Server (NTRS)

Dingemans, Theodornus J. (Inventor); Weiser, Erik S. (Inventor); SaintClair, Terry L. (Inventor)

2005-01-01

Main chain thermotropic liquid crystal esters, ester-imides, and ester-amides were prepared from AA, BB, and AB type monomeric materials and were end-capped with phenylacetylene, phenylmaleimide, or nadimide reactive end-groups. The resulting reactive end-capped liquid crystal oligomers exhibit a variety of improved and preferred physical properties. The end-capped liquid crystal oligomers are thermotropic and have, preferably, molecular weights in the range of approximately 1000-15,OOO grams per mole. The end-capped liquid crystal oligomers have broad liquid crystalline melting ranges and exhibit high melt stability and very low melt viscosities at accessible temperatures. The end-capped liquid crystal oligomers are stable for up to an hour in the melt phase. These properties make the end-capped liquid crystal oligomers highly processable by a variety of melt process shape forming and blending techniques including film extrusion, fiber spinning, reactive injection molding (RIM), resin transfer molding (RTM), resin film injection (RFI), powder molding, pultrusion, injection molding, blow molding, plasma spraying and thermo-forming. Once processed and shaped, the end- capped liquid crystal oligomers were heated to further polymerize and form liquid crystalline thermosets (LCT). The fully cured products are rubbers above their glass transition temperatures. The resulting thermosets display many properties that are superior to their non-end-capped high molecular weight analogs.

Template-based modeling and ab initio refinement of protein oligomer structures using GALAXY in CAPRI round 30.

PubMed

Lee, Hasup; Baek, Minkyung; Lee, Gyu Rie; Park, Sangwoo; Seok, Chaok

2017-03-01

Many proteins function as homo- or hetero-oligomers; therefore, attempts to understand and regulate protein functions require knowledge of protein oligomer structures. The number of available experimental protein structures is increasing, and oligomer structures can be predicted using the experimental structures of related proteins as templates. However, template-based models may have errors due to sequence differences between the target and template proteins, which can lead to functional differences. Such structural differences may be predicted by loop modeling of local regions or refinement of the overall structure. In CAPRI (Critical Assessment of PRotein Interactions) round 30, we used recently developed features of the GALAXY protein modeling package, including template-based structure prediction, loop modeling, model refinement, and protein-protein docking to predict protein complex structures from amino acid sequences. Out of the 25 CAPRI targets, medium and acceptable quality models were obtained for 14 and 1 target(s), respectively, for which proper oligomer or monomer templates could be detected. Symmetric interface loop modeling on oligomer model structures successfully improved model quality, while loop modeling on monomer model structures failed. Overall refinement of the predicted oligomer structures consistently improved the model quality, in particular in interface contacts. Proteins 2017; 85:399-407. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Early and Selective Impairments in Axonal Transport Kinetics of Synaptic Cargoes Induced by Soluble Amyloid β-Protein Oligomers

PubMed Central

Tang, Yong; Scott, David A.; Das, Utpal; Edland, Steven D.; Radomski, Kryslaine; Koo, Edward H.; Roy, Subhojit

2013-01-01

The downstream targets of amyloid β (Aβ)-oligomers remain elusive. One hypothesis is that Aβ-oligomers interrupt axonal transport. Although previous studies have demonstrated Aβ-induced transport blockade, early effects of low-n soluble Aβ-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aβ on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar (pm) levels of cell-derived soluble Aβ-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity – analyzing all data in a blinded fashion. Aβ-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl d-aspartate receptor/glycogen synthase kinase-3β dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for Aβ-induced axonal transport deficits. PMID:22309053

Liquid crystalline thermosets from ester, ester-imide, and ester-amide oligomers

NASA Technical Reports Server (NTRS)

Dingemans, Theodorous J. (Inventor); Weiser, Erik S. (Inventor); St. Clair, Terry L. (Inventor)

2005-01-01

Main chain thermotropic liquid crystal esters, ester-imides, and ester-amides were prepared from AA, BB, and AB type monomeric materials and were end-capped with phenylacetylene, phenylmaleimide, or nadimide reactive end-groups. The resulting reactive end-capped liquid crystal oligomers exhibit a variety of improved and preferred physical properties. The end-capped liquid crystal oligomers are thermotropic and have, preferably, molecular weights in the range of approximately 1000-15,000 grams per mole. The end-capped liquid crystal oligomers have broad liquid crystalline melting ranges and exhibit high melt stability and very low melt viscosities at accessible temperatures. The end-capped liquid crystal oligomers are stable for up to an hour in the melt phase. These properties make the end-capped liquid crystal oligomers highly processable by a variety of melt process shape forming and blending techniques including film extrusion, fiber spinning, reactive injection molding (RIM), resin transfer molding (RTM), resin film injection (RFI), powder molding, pultrusion, injection molding, blow molding, plasma spraying and thermo-forming. Once processed and shaped, the end-capped liquid crystal oligomers were heated to further polymerize and form liquid crystalline thermosets (LCT). The fully cured products are rubbers above their glass transition temperatures. The resulting thermosets display many properties that are superior to their non-end-capped high molecular weight analogs.

Adhesive Properties of Cured Phenylethynyl Containing Imides

NASA Technical Reports Server (NTRS)

Jensen, Brian J.; Chang, Alice C.

1997-01-01

Considerable attention has been directed towards acetylene terminated oligomers over the last 20 years' and recent work has focused on phenylethynyl terminated imide (PETI) oligomers. These reactive oligomers possess several features which make them attractive candidates for use as composite matrices and adhesives. The phenylethynyl group can be readily incorporated into many different functionalized oligomers. The reactive oligomers possess relatively low melt viscosities and thermally cure without the evolution of volatile by-products. Once cured, they typically display high glass transition temperatures (Tgs), excellent solvent resistance and high mechanical properties. new modified phenylethynyl-terminated imide (LaRC MPEI) oligomers were synthesized at various molecular weights utilizing a small amount of trifunctional amine. As long as the amount of triamine is relatively small, this approach produces a mixture of linear, star-shaped and branched polymer chains that has lower melt and solution viscosity than an equivalent molecular weight linear phenylethynyl terminated imide oligomers. The work reported herein involves the synthesis and characterization of a copolymer using this approach and the preparation of blends utilizing a phenylethynyl containing reactive plasticizer of lower molecular weight called LaRC LV-121. The chemistry and properties of this new MPEI as well as some blends of MPEI with LV-121, are presented and compared to the linear version, LARC-PETI-5.

Intracellular soluble α‐synuclein oligomers reduce pyramidal cell excitability

PubMed Central

Kaufmann, Timothy J.; Harrison, Paul M.; Richardson, Magnus J. E.; Pinheiro, Teresa J. T.

2016-01-01

Key points The presynaptic protein α‐synuclein forms aggregates during Parkinson's disease.Accumulating evidence suggests that the small soluble oligomers of α‐synuclein are more toxic than the larger aggregates appearing later in the disease.The link between oligomer toxicity and structure still remains unclear.In the present study, we have produced two structurally‐defined oligomers that have a similar morphology but differ in secondary structure.These oligomers were introduced into neocortical pyramidal cells during whole‐cell recording and, using a combination of experimentation and modelling, electrophysiological parameters were extracted.Both oligomeric species had similar effects on neuronal properties reducing input resistance, time constant and increasing capacitance. The net effect was a marked reduction in neuronal excitability that could impact on network activity. Abstract The presynaptic protein α‐synuclein (αSyn) aggregates during Parkinson's disease (PD) to form large proteinaceous amyloid plaques, the spread of which throughout the brain clinically defines the severity of the disease. During early stages of aggregation, αSyn forms soluble annular oligomers that show greater toxicity than much larger fibrils. These oligomers produce toxicity via a number of possible mechanisms, including the production of pore‐forming complexes that permeabilize membranes. In the present study, two well‐defined species of soluble αSyn oligomers were produced by different protocols: by polymerization of monomer and by sonication of fibrils. The two oligomeric species produced were morphologically similar, with both having an annular structure and consisting of approximately the same number of monomer subunits, although they differed in their secondary structure. Oligomeric and monomeric αSyn were injected directly into the soma of pyramidal neurons in mouse neocortical brain slices during whole‐cell patch clamp recording. Using a combined experimental and modelling approach, neuronal parameters were extracted to measure, for the first time in the neocortex, specific changes in neuronal electrophysiology. Both species of oligomer had similar effects: (i) a significant reduction in input resistance and the membrane time constant and (ii) an increase in the current required to trigger an action potential with a resultant reduction in the firing rate. Differences in oligomer secondary structure appeared to produce only subtle differences in the activity of the oligomers. Monomeric αSyn had no effect on neuronal parameters, even at high concentrations. The oligomer‐induced fall in neuronal excitability has the potential to impact both network activity and cognitive processing. PMID:26915902

The effect of polar end of long-chain fluorocarbon oligomers in promoting the superamphiphobic property over multi-scale rough Al alloy surfaces

NASA Astrophysics Data System (ADS)

Saifaldeen, Zubayda S.; Khedir, Khedir R.; Camci, Merve T.; Ucar, Ahmet; Suzer, Sefik; Karabacak, Tansel

2016-08-01

Rough structures with re-entrant property and their subsequent surface energy reduction with long-chain fluorocarbon oligomers are both critical in developing superamphiphobic (SAP, i.e. both super hydrophobic and superoleophobic) surfaces. However, morphology of the low-surface energy layer on a rough re-entrant substrate can strongly depend on the fluorocarbon oligomers used. In this study, the effect of polar end of different kinds of long-chain fluorocarbon oligomers in promoting a self-assembled monolayer with close packed molecules and robust adhesion on multi-scale rough Al alloy surfaces was investigated. Hierarchical Al alloy surfaces with microgrooves and nanograss structures were developed by a simple combination of one-directional mechanical sanding and post treatment in boiling de-ionized water (DIW). Three types of long-chain fluorocarbon oligomers of 1H, 1H, 2H, 2H-perfluorodecyltriethoxysilane (PFDTS), 1H, 1H, 2H, 2H-perfluorodecyltrichlorosilane (PFDCS), and perfluorooctanoic acid (PFOA) were chemically vaporized onto these rough Al alloy surfaces. The PFDCS exhibited the lowest surface free energy of less than 10 mN/m. The contact angle and sliding angle measurements for water, ethylene glycol, and peanut oil verified the SAP property of hierarchical rough Al alloy surfaces treated with alkylsilane oligomers (PFDTS, PFDCS). However, the hierarchical surfaces treated with fluorocarbon oligomer with polar acidic tail (PFOA) showed highly amphiphobic properties but could not reach the threshold for SAP. Chemical stability of the hierarchical Al alloy surfaces treated with the fluorocarbon oligomers was tested under the harsh conditions of ultra-sonication in acetone and annealing at high temperature after different treatment times. Contact angle measurements revealed the robustness of the alkylsilane oligomers and deterioration of the PFOA coating particularly for low surface tension liquids. The robust adhesion and close-packing of the alkylsilane molecules as well as their vertical orientation with exposure of more CF3 groups instead of CF2 groups due to the polar silane-based tail are believed to be the main reasons behind their improved chemical stability. The selection of fluorocarbon oligomer with proper polar tail which can promote a self-assembled monolayer with close-packed molecules could make it possible for utilizing shorter fluorocarbon oligomers, which is environmentally favorable, to develop high surface energy materials with SAP properties.

Analysis and characterization of aluminum chlorohydrate oligocations by capillary electrophoresis.

PubMed

Ouadah, Nesrine; Moire, Claudine; Kuntz, Jean-François; Brothier, Fabien; Cottet, Hervé

2017-04-07

Aluminum chlorohydrates (ACH) are the active ingredients used in most antiperspirant products. ACH is a water soluble aluminum complex which contains several oligomeric polycations of aluminum with degrees of polymerization up to Al 13 or Al 30 . The characterization and quantification of ACH oligo-cations remain a challenging issue of primary interest for developing structure/antiperspirant activity correlations, and for controlling the ACH ingredients. In this work, highly repeatable capillary electrophoresis (CE) separation of A l3 + , Al 13 and Al 30 oligomers contained in ACH samples was obtained at pH 4.8, owing to a careful choice of the background electrolyte counter-ion and chromophore, capillary I.D. and capillary coating. This is the first reported separation of Al 13 and Al 30 oligomers in conditions that are compatible with the aluminum speciation in ACH solution or in conditions of antiperspirant application/formulation. Al 13 and Al 30 effective charge numbers were also determined from the sensitivity of detection in indirect UV detection mode. The relative mass proportion of Al 13 compared to Al 13 +Al 30 could be determined in different aluminum chlorohydrate samples. Due to its simplicity, repeatability/reproducibility, minimal sample preparation and mild analytical conditions, CE appears to be a promising analytical separation technique for the characterization of ACH materials and for the study of structure/antiperspirant activity correlations. Copyright © 2017. Published by Elsevier B.V.

Micromechanical modelling of polyethylene

NASA Astrophysics Data System (ADS)

Alvarado Contreras, Jose Andres

2008-10-01

The increasing use of polyethylene in diverse applications motivates the need for understanding how its molecular properties relate to the overall behaviour of the material. Although microstructure and mechanical properties of polymers have been the subject of several studies, the irreversible microstructural rearrangements occurring at large deformations are not completely understood. The purpose of this thesis is to describe how the concepts of Continuum Damage Mechanics can be applied to modelling of polyethylene materials under different loading conditions. The first part of the thesis consists of the theoretical formulation and numerical implementation of a three-dimensional micromechanical model for crystalline polyethylene. Based on the theory of shear slip on crystallographic planes, the proposed model is expressed in the framework of viscoplasticity coupled with degradation at large deformations. Earlier models aid in the interpretation of the mechanical behaviour of crystalline polyethylene under different loading conditions; however, they cannot predict the microstructural damage caused by deformation. The model, originally due to Parks and Ahzi (199o), was further developed in the light of the concept of Continuum Damage Mechanics to consider the original microstructure, the particular irreversible rearrangements, and the deformation mechanisms. Damage mechanics has been a matter of intensive research by many authors, yet it has not been introduced to the micromodelling of semicrystalline polymeric materials such as polyethylene. Regarding the material representation, the microstructure is simplified as an aggregate of randomly oriented and perfectly bonded crystals. To simulate large deformations, the new constitutive model attempts to take into account existence of intracrystalline microcracks. The second part of the work presents the theoretical formulation and numerical implementation of a three-dimensional constitutive model for the mechanical behaviour of semicrystalline polyethylene. The model proposed herein attempts to describe the deformation and degradation process in semicrystalline polyethylene following the approach of damage mechanics. Structural degradation, an important phenomenon at large deformations, has not received sufficient attention in the literature. The modifications to the constitutive equations consist essentially of introducing the concept of Continuum Damage Mechanics to describe the rupture of the intermolecular (van der Waals) bonds that hold crystals as coherent structures. In order to model the mechanical behaviour, the material morphology is simplified as a collection of inclusions comprising the crystalline and amorphous phases with their characteristic average volume fractions. In the spatial arrangement, each inclusion consists of crystalline material lying in a thin lamella attached to an amorphous layer. To consider microstructural damage, two different approaches are analyzed. The first approach assumes damage occurs only in the crystalline phase, i.e., degradation of the amorphous phase is ignored. The second approach considers the effect of damage on the mechanical behaviour of both the amorphous and crystalline phases. To illustrate the proposed constitutive formulations, the models were used to predict the responses of crystalline and semicrystalline polyethylene under uniaxial tension and simple shear. The numerical simulations were compared with experimental data previously obtained by Bartczak et al. (1994), G'Sell and Jonas (1981), G'Sell et al. (1983), Hillmansen et al. (2000), and Li et al. (2001). Our model's predictions show a consistently good agreement with the experimental results and a significant improvement with respect to the ones obtained by Parks and Ahzi (1990), Schoenfeld et al. (1995), Yang and Chen (2001), Lee et al. (i993b), Lee et al. (1993a), and Nikolov et al. (2006). The newly proposed formulations demonstrate that these types of constitutive models based on Continuum Damage Mechanics are appropriate for predicting large deformations and failure in polyethylene materials.

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

PubMed Central

Sandberg, Anders; Luheshi, Leila M.; Söllvander, Sofia; Pereira de Barros, Teresa; Macao, Bertil; Knowles, Tuomas P. J.; Biverstål, Henrik; Lendel, Christofer; Ekholm-Petterson, Frida; Dubnovitsky, Anatoly; Lannfelt, Lars; Dobson, Christopher M.; Härd, Torleif

2010-01-01

Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a double-cysteine mutant (called Aβcc) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ40cc and Aβ42cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Aβcc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ42cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ42, in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ42 is more toxic than the shorter Aβ40, and why certain inherited mutations are linked to protofibril formation and early-onset AD. PMID:20713699

Transport efficiency in transdermal drug delivery: What is the role of fluid microstructure?

PubMed

Liuzzi, Roberta; Carciati, Antonio; Guido, Stefano; Caserta, Sergio

2016-03-01

Interaction of microstructured fluids with skin is ubiquitous in everyday life, from the use of cosmetics, lotions, and drugs, to personal care with detergents or soaps. The formulation of microstructured fluids is crucial for the control of the transdermal transport. In biomedical applications transdermal delivery is an efficient approach, alternative to traditional routes like oral and parenteral administration, for local release of drugs. Poor skin permeability, mainly due to its outer layer, which acts as the first barrier against the entry of external compounds, greatly limits the applicability of transdermal delivery. In this review, we focus on recent studies on the improvement of skin transport efficiency by using microemulsions (ME). Quantitative techniques, which are able to investigate both skin morphology and penetration processes, are also reviewed. ME are increasingly used as transdermal systems due to their low preparation cost, stability and high bioavailability. ME may act as penetration enhancers for many active principles, but ME microstructure should be chosen appropriately considering several factors such as ratio and type of ingredients and physic-chemical properties of the active components. ME microstructure is strongly affected by the flow conditions applied during processing, or during spreading and rubbing onto skin. Although the role played by ME microstructure has been generally recognized, the skin transport mechanisms associated with different ME microstructures are still to be elucidated and further investigations are required to fully exploit the potential of ME in transdermal delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Esculin and its oligomer fractions inhibit adhesion and migration of U87 glioblastoma cells and in vitro angiogenesis.

PubMed

Mokdad-Bzeouich, Imen; Kovacic, Hervé; Ghedira, Kamel; Chebil, Latifa; Ghoul, Mohamed; Chekir-Ghedira, Leila; Luis, José

2016-03-01

Cancer metastasis is the major cause of cancer-related death. Chemoprevention is defined as the use of natural or synthetic substances to prevent cancer formation or cancer progress. In the present study, we investigate the antitumor activity of esculin and its oligomer fractions in U87 glioblastoma cells. We showed that esculin and its oligomers reduced U87 cell growth in a dose dependent manner. They also inhibited cell adhesion to collagen IV and vitronectin by interfering with the function of their respective receptors α2β1 and αvβ5 integrins. Furthermore, the tested samples were able to reduce migration of U87 cells towards another extracellular matrix fibronectin. Moreover, esculin and its oligomer fractions inhibited in vitro angiogenesis of endothelial cells (HMEC-1). In summary, our data provide the first evidence that esculin and its oligomer fractions are able to reduce adhesion, migration of glioblastoma cells and in vitro angiogenesis. Esculin and its oligomers may thus exert multi-target functions against cancer cells.

Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

PubMed

Sanz-Blasco, Sara; Valero, Ruth A; Rodríguez-Crespo, Ignacio; Villalobos, Carlos; Núñez, Lucía

2008-07-23

Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

Binding of ATP by pertussis toxin and isolated toxin subunits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hausman, S.Z.; Manclark, C.R.; Burns, D.L.

1990-07-03

The binding of ATP to pertussis toxin and its components, the A subunit and B oligomer, was investigated. Whereas, radiolabeled ATP bound to the B oligomer and pertussis toxin, no binding to the A subunit was observed. The binding of ({sup 3}H)ATP to pertussis toxin and the B oligomer was inhibited by nucleotides. The relative effectiveness of the nucleotides was shown to be ATP > GTP > CTP > TTP for pertussis toxin and ATP > GTP > TTP > CTP for the B oligomer. Phosphate ions inhibited the binding of ({sup 3}H)ATP to pertussis toxin in a competitive manner;more » however, the presence of phosphate ions was essential for binding of ATP to the B oligomer. The toxin substrate, NAD, did not affect the binding of ({sup 3}H)ATP to pertussis toxin, although the glycoprotein fetuin significantly decreased binding. These results suggest that the binding site for ATP is located on the B oligomer and is distinct from the enzymatically active site but may be located near the eukaryotic receptor binding site.« less

[Differences in oligomerization of nucleocapsid protein of epidemic human influenza A(H1N1), A(H1N2) and B viruses].

PubMed

Prokudina, E N; Semenova, N P; Chumakov, V M; Burtseva, E I; Slepushkin, A N

2003-01-01

A comparative analysis of involving the nucleocapsid protein (NP) into shaping-up of SDS-resistant oligomers was carried out presently in circulating epidemic strains of human influenza, viruses A and B. The study results of viral isolates obtained from clinical samples and recent standard strains revealed that the involvement of NP in the SDS-resistant oligomers, which are different in various subtypes of influenza A viruses. According to this sign, the human viruses A(9H3N2) are close to the avian ones, in which, as proved by us previously, virtually the entire NP transforms itself into the oligomers resistant to SDS. About 10-20% of NP are involved in shaping-up the virus influenza A(H1N1) of SDS-resistant oligomers. No SDS-resistant NP-oligomers were detected in influenza of type B. It is suggested that the prevalence of human viruses A(H3N2) in NP-oligomers are the peculiarities of NP structure and of the presence of the PB1 protein from avian influenza virus.

Pore and grain boundary migration under a temperature gradient: A phase-field model study

DOE PAGES

Biner, S. B.

2016-03-16

In this study, the collective migration behavior of pores and grain boundaries under a temperature gradient is studied for simple single crystal, bi-crystal and polycrystal configurations with a phase-field model formulism. For simulation of the microstructure of solids, composed of pores and grain boundaries, the results indicate that not only the volume fraction of pores, but also its spatial partitioning between the grain boundary junctions and the grain boundary segments appears to be important. In addition to various physical properties, the evolution kinetics, under given temperature gradients, will be strongly influenced with the initial morphology of a poly-crystalline microstructure.

Aqueous phase oligomerization of α,β-unsaturated carbonyls and acids investigated using ion mobility spectrometry coupled to mass spectrometry (IMS-MS)

NASA Astrophysics Data System (ADS)

Renard, Pascal; Tlili, Sabrine; Ravier, Sylvain; Quivet, Etienne; Monod, Anne

2016-04-01

One of the current essential issues to unravel our ability to forecast future climate change and air quality, implies a better understanding of natural processes leading to secondary organic aerosol (SOA) formation, and in particular the formation and fate of oligomers. The difficulty in characterizing macromolecules is to discern between large oxygenated molecules from series of oligomers containing repeated small monomers of diverse structures. In the present study, taking advantage from previously established radical vinyl oligomerization of methyl vinylketone (MVK) in the aqueous phase, where relatively simple oligomers containing up to 14 monomers were observed, we have investigated the same reactivity on several other unsaturated water soluble organic compounds (UWSOCs) and on a few mixtures of these precursor compounds. The technique used to characterize the formed oligomers was a traveling wave ion mobility spectrometry coupled to a hybrid quadrupole - time of flight mass spectrometer (IMS-MS) fitted with an electrospray source and ultra-high performance liquid chromatography (UPLC). The technique allows for an additional separation, especially for large ions, containing long carbon chains. We have shown the efficiency of the IMS-mass spectrometry technique to detect oligomers derived from MVK photooxidation in the aqueous phase. The results were then compared to other oligomers, derived from ten other individual biogenic UWSOCs. The technique allowed distinguishing between different oligomers arising from different precursors. It also clearly showed that compounds bearing a non-conjugated unsaturation did not provide oligomerization. Finally, it was shown that the IMS-mass spectrometry technique, applied to mixtures of unsaturated conjugated precursors, exhibited the ability of these precursors to co-oligomerize, i.e. forming only one complex oligomer system bearing monomers of different structures. The results are discussed in terms of atmospheric implications for the detection of oligomers in complex chamber and/or field samples.

Structure-Property Relationships of Architectural Coatings by Neutron Methods

NASA Astrophysics Data System (ADS)

Nakatani, Alan

2015-03-01

Architectural coatings formulations are multi-component mixtures containing latex polymer binder, pigment, rheology modifiers, surfactants, and colorants. In order to achieve the desired flow properties for these formulations, measures of the underlying structure of the components as a function of shear rate and the impact of formulation variables on the structure is necessary. We have conducted detailed measurements to understand the evolution under shear of local microstructure and larger scale mesostructure in model architectural coatings formulations by small angle neutron scattering (SANS) and ultra small angle neutron scattering (USANS), respectively. The SANS results show an adsorbed layer of rheology modifier molecules exist on the surface of the latex particles. However, the additional hydrodynamic volume occupied by the adsorbed surface layer is insufficient to account for the observed viscosity by standard hard sphere suspension models (Krieger-Dougherty). The USANS results show the presence of latex aggregates, which are fractal in nature. These fractal aggregates are the primary structures responsible for coatings formulation viscosity. Based on these results, a new model for the viscosity of coatings formulations has been developed, which is capable of reproducing the observed viscosity behavior.

Protection against peroxynitrite by cocoa polyphenol oligomers.

PubMed

Arteel, G E; Sies, H

1999-11-26

Flavonoids, natural plant constituents, protect against peroxynitrite and can thereby play a role in defense against this mediator of inflammation. Procyanidin oligomers of different size (monomer through nonamer), isolated from the seeds of Theobroma cacao, were examined for their ability to protect against peroxynitrite-dependent oxidation of dihydrorhodamine 123 and nitration of tyrosine. By molarity, oligomers were more effective than the monomeric epicatechin; the tetramer was particularly efficient at protecting against oxidation and nitration reactions. These results suggest that epicatechin oligomers found in cocoa powder and chocolate may be a potent dietary source for defense against peroxynitrite.

Oligomerization of mononucleotides on montmorillonite: A potential approach to the prebiotic synthesis of RNA. [Abstract only

NASA Technical Reports Server (NTRS)

Ferris, James P.; Ertem, Goezen; Ding, Zi Ping; Prabahar, Joseph

1994-01-01

The condensation of the 5'-phosphorimidazolide of adenosine (ImpA) on montmorillonite in a pH 8 aqueous solution yields oligomers containing up to 10 monomer units. The regiospecificity of 3',5'-phosphodiester bond formation is enhanced by addition of 10% diadenosine pyrophosphate (AppA) to the reaction mixture. A series of activated derivatives of 5'-AMP was prepared to investigate the effect of the leaving group on oligomer formation. The benzimidazole and p-dimethylamino-pyridine derivatives gave the best yields of oligomers. Factors important for oligomer formation is discussed.

Application of guar-xanthan gum mixture as a partial fat replacer in meat emulsions.

PubMed

Rather, Sajad A; Masoodi, F A; Akhter, Rehana; Rather, Jahangir A; Gani, Adil; Wani, S M; Malik, A H

2016-06-01

The physicochemical, oxidative, texture and microstructure properties were evaluated for low fat meat emulsions containing varying levels of guar/xanthan gum mixture (1:1 ratio) as a fat substitute. Partial replacement of fat with guar/xanthan gum resulted in higher emulsion stability and cooking yield but lower penetration force. Proximate composition revealed that high fat control had significantly higher fat and lower moisture content due to the difference in basic formulation. Colour evaluation revealed that low fat formulations containing gum mixture had significantly lower lightness and higher yellowness values than high fat control formulation. However non-significant difference was observed in redness values between low fat formulations and the high fat control. The pH values of the low fat formulations containing gum mixture were lower than the control formulations (T0 and TC). The MetMb% of the high fat emulsion formulation was higher than low fat formulations. The significant increase of TBARS value, protein carbonyl groups and loss of protein sulphydryl groups in high fat formulation reflect the more oxidative degradation of lipids and muscle proteins during the preparation of meat emulsion than low fat formulations. The SEM showed a porous matrix in the treatments containing gum mixture. Thus, the guar/xanthan gum mixture improved the physicochemical and oxidative quality of low fat meat emulsions than the control formulations.

Laser-Induced Population Inversion in Rhodamine 6G for Lysozyme Oligomer Detection.

PubMed

Hanczyc, Piotr; Sznitko, Lech

2017-06-06

Fluorescence spectroscopy is a common method for detecting amyloid fibrils in which organic fluorophores are used as markers that exhibit an increase in quantum yield upon binding. However, most of the dyes exhibit enhanced emission only when bound to mature fibrils, and significantly weaker signals are obtained in the presence of amyloid oligomers. In the concept of population inversion, a laser is used as an excitation source to keep the major fraction of molecules in the excited state to create the pathways for the occurrence of stimulated emission. In the case of the proteins, the conformational changes lead to the self-ordering and thus different light scattering conditions that can influence the optical signatures of the generated light. Using this methodology, we show it is possible to optically detect amyloid oligomers using commonly available staining dyes in which population inversion can be induced. The results indicate that rhodamine 6G molecules are complexed with oligomers, and using a laser-assisted methodology, weakly emissive states can be detected. Significant spectral red-shifting of rhodamine 6G dispersed with amyloid oligomers and a notable difference determined by comparison of spectra of the fibrils suggest the existence of specific dye aggregates around the oligomer binding sites. This approach can provide new insights into intermediate oligomer states that are believed to be responsible for toxic seeding in neurodegeneration diseases.

Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers.

PubMed

McHale-Owen, Harriet; Bate, Clive

2018-03-01

The production of amyloid-β (Aβ) is the key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of Aβ within the brain cause synapse degeneration and the dementia that is characteristic of AD. Here the factors that affect the release of disease-relevant forms Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released soluble Aβ oligomers that caused synapse damage in cultured neurons. Supernatants from 7PA2 cells treated with the cholesterol synthesis inhibitor squalestatin contained similar concentrations of Aβ 42 to control cells but did not cause synapse damage in neuronal cultures. These supernatants contained reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers. Treatment of 7PA2 cells with platelet-activating factor (PAF) antagonists had similar effects; it reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. PAF activated cholesterol ester hydrolases (CEH), enzymes that released cholesterol from stores of cholesterol esters. Inhibition of CEH also reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. The Aβ monomers produced by treated cells protected neurons against Aβ oligomer-induced synapse damage. These studies indicate that pharmacological manipulation of cells can alter the ratio of Aβ monomer:oligomer released and consequently their effects on synapses. Copyright © 2017 Elsevier B.V. All rights reserved.

Properties of Poly- and Oligopentacenes Synthesized from Modular Building Blocks

DOE PAGES

Kumarasamy, Elango; Sanders, Samuel N.; Pun, Andrew B.; ...

2016-02-09

Here, we describe a facile route to well-defined, solution-processable pentacene oligomers (2 to 7) and homopolymer using Suzuki–Miyaura cross-coupling reactions. This synthetic strategy leads to regioisomers, regiopure syn- and anti-trimers were also synthesized, revealing minimal changes in solution properties but significant changes in the solid state arising from differing levels of crystallinity. The materials were characterized by steady state absorption spectroscopy and cyclic voltammetry to study their electronic structure. The steady state absorption spectra exhibit a new high-energy transition in the oligomers, which intensifies as a function of oligomer length, thus increasing the range of absorption to include the entiremore » visible spectrum. Density functional theory calculations indicate that the new peak results directly from the oligomerization. Solid state UV–vis suggests that while the monomer is amorphous, bricklayer packing in the higher oligomers significantly alters the solid state absorption relative to solution. The effect of oligomerization on packing was corroborated by GIWAXS analysis, which revealed crystalline domains in the oligomers. These domains, which are most evident in anti-trimer, become more pronounced upon thermal annealing. Photodegradation studies revealed considerable stability enhancement of oligomers toward oxygen and cycloaddition reactions relative to monomer. The synthesis and characterization of the first higher oligomers and homopolymer of pentacene should pave the way to applications in singlet fission, organic field-effect transistors, and organic photovoltaics.« less

Molecular dynamics simulations of low-ordered alzheimer β-amyloid oligomers from dimer to hexamer on self-assembled monolayers.

PubMed

Zhao, Jun; Wang, Qiuming; Liang, Guizhao; Zheng, Jie

2011-12-20

Accumulation of small soluble oligomers of amyloid-β (Aβ) in the human brain is thought to play an important pathological role in Alzheimer's disease. The interaction of these Aβ oligomers with cell membrane and other artificial surfaces is important for the understanding of Aβ aggregation and toxicity mechanisms. Here, we present a series of exploratory molecular dynamics (MD) simulations to study the early adsorption and conformational change of Aβ oligomers from dimer to hexamer on three different self-assembled monolayers (SAMs) terminated with CH(3), OH, and COOH groups. Within the time scale of MD simulations, the conformation, orientation, and adsorption of Aβ oligomers on the SAMs is determined by complex interplay among the size of Aβ oligomers, the surface chemistry of the SAMs, and the structure and dynamics of interfacial waters. Energetic analysis of Aβ adsorption on the SAMs reveals that Aβ adsorption on the SAMs is a net outcome of different competitions between dominant hydrophobic Aβ-CH(3)-SAM interactions and weak CH(3)-SAM-water interactions, between dominant electrostatic Aβ-COOH-SAM interactions and strong COOH-SAM-water interactions, and between comparable hydrophobic and electrostatic Aβ-OH-SAM interactions and strong OH-SAM-water interactions. Atomic force microscopy images also confirm that all of three SAMs can induce the adsorption and polymerization of Aβ oligomers. Structural analysis of Aβ oligomers on the SAMs shows a dramatic increase in structural stability and β-sheet content from dimer to trimer, suggesting that Aβ trimer could act as seeds for Aβ polymerization on the SAMs. This work provides atomic-level understanding of Aβ peptides at interface. © 2011 American Chemical Society

Effect of the electrostatic surface potential on the oligomerization of full-length human recombinant prion protein at single-molecule level

NASA Astrophysics Data System (ADS)

Wang, Bin; Lou, Zhichao; Zhang, Haiqian; Xu, Bingqian

2016-03-01

The electrostatic surface potential (ESP) of prion oligomers has critical influences on the aggregating processes of the prion molecules. The atomic force microscopy (AFM) and structural simulation were combined to investigate the molecular basis of the full-length human recombinant prion oligomerization on mica surfaces. The high resolution non-intrusive AFM images showed that the prion oligomers formed different patterns on mica surfaces at different buffer pH values. The basic binding units for the large oligomers were determined to be prion momoners (Ms), dimers (Ds), and trimers (Ts). The forming of the D and T units happened through the binding of hydrophobic β-sheets of the M units. In contrast, the α-helices of these M, D, and T units were the binding areas for the formation of large oligomers. At pH 4.5, the binding units M, D, and T showed clear polarized ESP distributions on the surface domains, while at pH 7.0, they showed more evenly distributed ESPs. Based on the conformations of oligomers observed from AFM images, the D and T units were more abundantly on mica surface at pH 4.5 because the ESP re-distribution of M units helped to stabilize these larger oligomers. The amino acid side chains involved in the binding interfaces were stabilized by hydrogen bonds and electrostatic interactions. The detailed analysis of the charged side chains at pH 4.5 indicated that the polarized ESPs induced the aggregations among M, D, and T to form larger oligomers. Therefore, the hydrogen bonds and electrostatic interactions worked together to form the stabilized prion oligomers.

Aging Enables Ca2+ Overload and Apoptosis Induced by Amyloid-β Oligomers in Rat Hippocampal Neurons: Neuroprotection by Non-Steroidal Anti-Inflammatory Drugs and R-Flurbiprofen in Aging Neurons.

PubMed

Calvo-Rodríguez, María; García-Durillo, Mónica; Villalobos, Carlos; Núñez, Lucía

2016-07-22

The most important risk factor for Alzheimer's disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload.

Structural requirements of cholesterol for binding to Vibrio cholerae hemolysin.

PubMed

Ikigai, Hajime; Otsuru, Hiroshi; Yamamoto, Koichiro; Shimamura, Tadakatsu

2006-01-01

Cholesterol is necessary for the conversion of Vibrio cholerae hemolysin (VCH) monomers into oligomers in liposome membranes. Using different sterols, we determined the stereochemical structures of the VCH-binding active groups present in cholesterol. The VCH monomers are bound to cholesterol, diosgenin, campesterol, and ergosterol, which have a hydroxyl group at position C-3 (3betaOH) in the A ring and a C-C double bond between positions C-5 and C-6 (C-C Delta(5)) in the B ring. They are not bound to epicholesterol and dihydrocholesterol, which form a covalent link with a 3alphaOH group and a C-C single bond between positions C-5 and C-6, respectively. This result suggests that the 3betaOH group and the C-CDelta(5) bond in cholesterol are required for VCH monomer binding. We further examined VCH oligomer binding to cholesterol. However, this oligomer did not bind to cholesterol, suggesting that the disappearance of the cholesterol-binding potential of the VCH oligomer might be a result of the conformational change caused by the conversion of the monomer into the oligomer. VCH oligomer formation was observed in liposomes containing sterols with the 3betaOH group and the C-C Delta(5) bond, and it correlated with the binding affinity of the monomer to each sterol. Therefore, it seems likely that monomer binding to membrane sterol leads to the assembly of the monomer. However, since oligomer formation was induced by liposomes containing either epicholesterol or dihydrocholesterol, the 3betaOH group and the C-C Delta(5) bond were not essential for conversion into the oligomer.

Effect of the electrostatic surface potential on the oligomerization of full-length human recombinant prion protein at single-molecule level

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Bin; Xu, Bingqian, E-mail: bxu@engr.uga.edu; Lou, Zhichao

2016-03-21

The electrostatic surface potential (ESP) of prion oligomers has critical influences on the aggregating processes of the prion molecules. The atomic force microscopy (AFM) and structural simulation were combined to investigate the molecular basis of the full-length human recombinant prion oligomerization on mica surfaces. The high resolution non-intrusive AFM images showed that the prion oligomers formed different patterns on mica surfaces at different buffer pH values. The basic binding units for the large oligomers were determined to be prion momoners (Ms), dimers (Ds), and trimers (Ts). The forming of the D and T units happened through the binding of hydrophobicmore » β-sheets of the M units. In contrast, the α-helices of these M, D, and T units were the binding areas for the formation of large oligomers. At pH 4.5, the binding units M, D, and T showed clear polarized ESP distributions on the surface domains, while at pH 7.0, they showed more evenly distributed ESPs. Based on the conformations of oligomers observed from AFM images, the D and T units were more abundantly on mica surface at pH 4.5 because the ESP re-distribution of M units helped to stabilize these larger oligomers. The amino acid side chains involved in the binding interfaces were stabilized by hydrogen bonds and electrostatic interactions. The detailed analysis of the charged side chains at pH 4.5 indicated that the polarized ESPs induced the aggregations among M, D, and T to form larger oligomers. Therefore, the hydrogen bonds and electrostatic interactions worked together to form the stabilized prion oligomers.« less

Montmorillonite-catalysed formation of RNA oligomers: the possible role of catalysis in the origins of life

PubMed Central

Ferris, James P

2006-01-01

Large deposits of montmorillonite are present on the Earth today and it is believed to have been present at the time of the origin of life and has recently been detected on Mars. It is formed by aqueous weathering of volcanic ash. It catalyses the formation of oligomers of RNA that contain monomer units from 2 to 30–50. Oligomers of this length are formed because this catalyst controls the structure of the oligomers formed and does not generate all possible isomers. Evidence of sequence-, regio- and homochiral selectivity in these oligomers has been obtained. Postulates on the role of selective versus specific catalysts on the origins of life are discussed. An introduction to the origin of life is given with an emphasis on reaction conditions based on the recent data obtained from zircons 4.0–4.5 Ga. PMID:17008218

Genotoxic and anti-genotoxic effects of esculin and its oligomer fractions against mitomycin C-induced DNA damages in mice.

PubMed

Mokdad Bzeouich, Imen; Mustapha, Nadia; Maatouk, Mouna; Ghedira, Kamel; Ghoul, Mohamed; Chekir-Ghedira, Leila

2016-12-01

Mitomycin C is one of the most effective chemotherapeutic drugs against various solid tumors. However, despite its wide spectrum of clinical benefits, this agent is capable of inducing various types of genotoxicity. In this study, we investigated the effect of esculin and its oligomer fractions (E1, E2 and E3) against mitomycin C induced genotoxicity in liver and kidney cells isolated from Balb/C mice using the comet assay. Esculin and its oligomer fractions were not genotoxic at the tested doses (20 mg/kg and 40 mg/kg b.w). A significant decrease in DNA damages was observed, suggesting a protective role of esculin and its oligomer fractions against the genotoxicity induced by mitomycin C on liver and kidney cells. Moreover, esculin and its oligomer fractions did not induce an increase of malondialdehyde levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Phenylethynyl Phthalic Anhydride

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

1997-01-01

Controlled molecular weight PhenylEthynyl Terminated Imide oligomers (PETIs) have been prepared by the cyclodehydration of precursor phenylethynyl terminated amic acid oligomers. Amino terminated amic acid oligomers are prepared from the reaction of dianhydride(s) with an excess of diamine(s) and subsequently endcapped with PhenylEthynyl Phthalic Anhydride(s) (PEPA). The polymerizations are carried out in polar aprotic solvents such as N-methyl-2pyrrolidinone or N N-dimethylacetamide under nitrogen at room temperature. The amic acid oligomers are subsequently cyclodehydrated either thermally or chemically to the corresponding imide oligomers. Direct preparation of PETIs from the reaction of dianhydride(s) with an excess of diamine(s) and endcapped with phenylethynyl phthalic anhydride(s) has been performed in m-cresol. Phenylethynyl phthalic anhydrides are synthesized by the palladium catalyzed reaction of phenylacetylene with bromo substituted phthalic anhydrides in triethylamine. These new materials exhibit excellent properties and are potentially useful as adhesives, coatings, films, moldings and composite matrices.

Enhanced Circular Dichroism via Symmetry Breaking in a Chiral Plasmonic Nanoparticle Oligomer

NASA Astrophysics Data System (ADS)

Le, Khai Q.

2018-02-01

A chiral plasmonic nanoparticle oligomer, consisting of four symmetrically arranged nanodisks of different heights and having different optical absorption responses to left and right-handed circularly polarized light illumination, has been experimentally reported in the literature. The resulting circular dichroism (CD) signal was detectable with state of the art CD spectrometers but was much weaker than those of existing chiral nanostructures, i.e., three-dimensional (3-D) chiral metamaterials. In this letter, via symmetry breaking in such an oligomer, the author demonstrates that the CD can be enhanced up to six times compared to that of a symmetric oligomer, and is in the range of a relevant 3-D chiral metamolecule. Through investigation of geometrical parameters including particle size, asymmetric and symmetric gaps, the CD evolution was reported, which provides a useful guideline for design of two-dimensional chiral oligomers adopted as efficient probes for CD spectroscopic applications.

Effect of phosphate activating group on oligonucleotide formation on montmorillonite: the regioselective formation of 3',5'-linked oligoadenylates

NASA Technical Reports Server (NTRS)

Prabahar, K. J.; Cole, T. D.; Ferris, J. P.

1994-01-01

The effects of amine structure on the montmorillonite-catalyzed oligomerization of the 5'-phosphoramidates of adenosine are investigated. 4-Aminopyridine derivatives yielded oligoadenylates as long as dodecamers with a regioselectivity for 3',5'-phosphodiester bond formation averaging 88%. Linear and cyclic oligomers are obtained and no A5'ppA-containing products are detected. Oligomers as long as the hexanucleotide are obtained using 2-aminobenzimidazole as the activating group. A predominance of pA2'pA is detected in the dimer fraction along with cyclic 3',5'-trimer; no A5'ppA-containing oligomers were detected. Little or no oligomer formation was observed when morpholine, piperidine, pyrazole, 1,2,4-triazole, and 2-pyridone are used as phosphate-activating groups. The effects of the structure of the phosphate activating group on the oligomer structure and chain lengths are discussed.

Abiotic ligation of DNA oligomers templated by their liquid crystal ordering

NASA Astrophysics Data System (ADS)

Fraccia, Tommaso P.; Smith, Gregory P.; Zanchetta, Giuliano; Paraboschi, Elvezia; Yi, Yougwooo; Walba, David M.; Dieci, Giorgio; Clark, Noel A.; Bellini, Tommaso

2015-03-01

It has been observed that concentrated solutions of short DNA oligomers develop liquid crystal ordering as the result of a hierarchically structured supramolecular self-assembly. In mixtures of oligomers with various degree of complementarity, liquid crystal microdomains are formed via the selective aggregation of those oligomers that have a sufficient degree of duplexing and propensity for physical polymerization. Here we show that such domains act as fluid and permeable microreactors in which the order-stabilized molecular contacts between duplex terminals serve as physical templates for their chemical ligation. In the presence of abiotic condensing agents, liquid crystal ordering markedly enhances ligation efficacy, thereby enhancing its own phase stability. The coupling between order-templated ligation and selectivity provided by supramolecular ordering enables an autocatalytic cycle favouring the growth of DNA chains, up to biologically relevant lengths, from few-base long oligomers. This finding suggests a novel scenario for the abiotic origin of nucleic acids.

Role of small oligomers on the amyloidogenic aggregation free-energy landscape.

PubMed

He, Xianglan; Giurleo, Jason T; Talaga, David S

2010-01-08

We combine atomic-force-microscopy particle-size-distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T, and dynamic light scattering to develop a quantitative kinetic model for the aggregation of beta-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type for comparison with fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free-energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location in the aggregation free-energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.

Efficient Reformulation of HOTFGM: Heat Conduction with Variable Thermal Conductivity

NASA Technical Reports Server (NTRS)

Zhong, Yi; Pindera, Marek-Jerzy; Arnold, Steven M. (Technical Monitor)

2002-01-01

Functionally graded materials (FGMs) have become one of the major research topics in the mechanics of materials community during the past fifteen years. FGMs are heterogeneous materials, characterized by spatially variable microstructure, and thus spatially variable macroscopic properties, introduced to enhance material or structural performance. The spatially variable material properties make FGMs challenging to analyze. The review of the various techniques employed to analyze the thermodynamical response of FGMs reveals two distinct and fundamentally different computational strategies, called uncoupled macromechanical and coupled micromechanical approaches by some investigators. The uncoupled macromechanical approaches ignore the effect of microstructural gradation by employing specific spatial variations of material properties, which are either assumed or obtained by local homogenization, thereby resulting in erroneous results under certain circumstances. In contrast, the coupled approaches explicitly account for the micro-macrostructural interaction, albeit at a significantly higher computational cost. The higher-order theory for functionally graded materials (HOTFGM) developed by Aboudi et al. is representative of the coupled approach. However, despite its demonstrated utility in applications where micro-macrostructural coupling effects are important, the theory's full potential is yet to be realized because the original formulation of HOTFGM is computationally intensive. This, in turn, limits the size of problems that can be solved due to the large number of equations required to mimic realistic material microstructures. Therefore, a basis for an efficient reformulation of HOTFGM, referred to as user-friendly formulation, is developed herein, and subsequently employed in the construction of the efficient reformulation using the local/global conductivity matrix approach. In order to extend HOTFGM's range of applicability, spatially variable thermal conductivity capability at the local level is incorporated into the efficient reformulation. Analytical solutions to validate both the user-friendly and efficient reformulations am also developed. Volume discretization sensitivity and validation studies, as well as a practical application of the developed efficient reformulation are subsequently carried out. The presented results illustrate the accuracy and implementability of both the user-friendly formulation and the efficient reformulation of HOTFGM.

Oligomers and Polymers Based on Pentacene Building Blocks

PubMed Central

Lehnherr, Dan; Tykwinski, Rik R.

2010-01-01

Functionalized pentacene derivatives continue to provide unique materials for organic semiconductor applications. Although oligomers and polymers based on pentacene building blocks remain quite rare, recent synthetic achievements have provided a number of examples with varied structural motifs. This review highlights recent work in this area and, when possible, contrasts the properties of defined-length pentacene oligomers to those of mono- and polymeric systems.

Programmable Oligomers Targeting 5′-GGGG-3′ in the Minor Groove of DNA and NF-κB Binding Inhibition

PubMed Central

Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B.

2009-01-01

A series of hairpin oligomers containing benzimidazole (Bi) and imidazopyridine (Ip) rings were synthesized and screened to target 5′-WGGGGW-3′, a core sequence in the DNA binding site of NF-κB, a prolific transcription factor important in biology and disease. Five Bi and Ip containing oligomers bound to the 5′-WGGGGW-3′ site with high affinity. One of the oligomers (Im-Im-Im-Im-γ-PyBi-PyBi-β-Dp) was able to inhibit DNA binding by the transcription factor NF-κB. PMID:17095230

Nonenzymatic synthesis of RNA and DNA oligomers on hexitol nucleic acid templates: the importance of the A structure

NASA Technical Reports Server (NTRS)

Kozlov, I. A.; Politis, P. K.; Van Aerschot, A.; Busson, R.; Herdewijn, P.; Orgel, L. E.; Bada, J. L. (Principal Investigator); Dolan, M. (Principal Investigator)

1999-01-01

Hexitol nucleic acid (HNA) is an analogue of DNA containing the standard nucleoside bases, but with a phosphorylated 1,5-anhydrohexitol backbone. HNA oligomers form duplexes having the nucleic acid A structure with complementary DNA or RNA oligomers. The HNA decacytidylate oligomer is an efficient template for the oligomerization of the 5'-phosphoroimidazolides of guanosine or deoxyguanosine. Comparison of the oligomerization efficiencies on HNA, RNA, and DNA decacytidylate templates under various conditions suggests strongly that only nucleic acid double helices with the A structure support efficient template-directed synthesis when 5'-phosphoroimidazolides of nucleosides are used as substrates.

A chitin deacetylase from the endophytic fungus Pestalotiopsis sp. efficiently inactivates the elicitor activity of chitin oligomers in rice cells.

PubMed

Cord-Landwehr, Stefan; Melcher, Rebecca L J; Kolkenbrock, Stephan; Moerschbacher, Bruno M

2016-11-30

To successfully survive in plants, endophytes need strategies to avoid being detected by the plant immune system, as the cell walls of endophytes contain easily detectible chitin. It is possible that endophytes "hide" this chitin from the plant immune system by modifying it, or oligomers derived from it, using chitin deacetylases (CDA). To explore this hypothesis, we identified and expressed a CDA from Pestalotiopsis sp. (PesCDA), an endophytic fungus, in E. coli and characterized this enzyme and its chitosan oligomer products. We found that when PesCDA modifies chitin oligomers, the products are partially deacetylated chitosan oligomers with a specific acetylation pattern: GlcNAc-GlcNAc-(GlcN) n -GlcNAc (n ≥ 1). Then, in a bioactivity assay where suspension-cultured rice cells were incubated with the PesCDA products (processed chitin hexamers), we found that, unlike the substrate hexamers, chitosan oligomer products no longer elicited the plant immune system. Thus, this endophytic enzyme can prevent the endophyte from being recognized by the plant immune system; this might represent a more general hypothesis for how certain fungi are able to live in or on their hosts.

A chitin deacetylase from the endophytic fungus Pestalotiopsis sp. efficiently inactivates the elicitor activity of chitin oligomers in rice cells

PubMed Central

Cord-Landwehr, Stefan; Melcher, Rebecca L. J.; Kolkenbrock, Stephan; Moerschbacher, Bruno M.

2016-01-01

To successfully survive in plants, endophytes need strategies to avoid being detected by the plant immune system, as the cell walls of endophytes contain easily detectible chitin. It is possible that endophytes “hide” this chitin from the plant immune system by modifying it, or oligomers derived from it, using chitin deacetylases (CDA). To explore this hypothesis, we identified and expressed a CDA from Pestalotiopsis sp. (PesCDA), an endophytic fungus, in E. coli and characterized this enzyme and its chitosan oligomer products. We found that when PesCDA modifies chitin oligomers, the products are partially deacetylated chitosan oligomers with a specific acetylation pattern: GlcNAc-GlcNAc-(GlcN)n-GlcNAc (n ≥ 1). Then, in a bioactivity assay where suspension-cultured rice cells were incubated with the PesCDA products (processed chitin hexamers), we found that, unlike the substrate hexamers, chitosan oligomer products no longer elicited the plant immune system. Thus, this endophytic enzyme can prevent the endophyte from being recognized by the plant immune system; this might represent a more general hypothesis for how certain fungi are able to live in or on their hosts. PMID:27901067

The newly identified K+ channel blocker talatisamine attenuates beta-amyloid oligomers induced neurotoxicity in cultured cortical neurons.

PubMed

Wang, Yanxia; Song, Mingke; Hou, Lina; Yu, Zhihua; Chen, Hongzhuan

2012-06-19

Loss of cytosolic K(+) through up-regulated delayed rectifier K(+) channels play an important role in beta-amyloid (Aβ) induced neurotoxicity. Potent K(+) channel blocker, particular specific for I(K) channels has been suggested as an attractive candidate for the treatment of Alzheimer's disease (AD). Talatisamine is a novel I(K) channel blocker discovered by virtual screening and electrophysiological characterization. In the present study, we examined the neuroprotective effect of talatisamine against Aβ oligomers induced cytotoxicity in primarily cultured cortical neurons. The neurotoxicity related to K(+) loss caused by Aβ40 oligomers included enhanced I(K) density, increased cell membrane permeability, reduced cell viability, and impaired mitochondrial transmembrane potential. Decreased Bcl-2 and increased Bax level, activation of Caspase-3 and Caspase-9 were also observed after Aβ40 oligomers incubation. Talatisamine (120 μM) and TEA (5mM) inhibited the enhanced I(K) caused by Aβ40 oligomers, attenuated cytotoxicity of Aβ oligomers by restoring cell viability and suppressing K(+) loss related apoptotic response. Our results suggested that talatisamine may become a leading compound as I(K) channel blocker for neuroprotection. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Nitrogen Containing Organic Compounds and Oligomers in Secondary Organic Aerosol Formed by Photooxidation of Isoprene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Tran B.; Laskin, Julia; Laskin, Alexander

2011-07-06

Electrospray ionization high-resolution mass spectrometry (ESI HR-MS) was used to probe molecular structures of oligomers in secondary organic aerosol (SOA) generated in laboratory experiments on isoprene photooxidation at low- and high-NOx conditions. Up to 80-90% of the observed products are oligomers and up to 33% are nitrogen-containing organic compounds (NOC). We observe oligomers with up to 8 monomer units in length. Tandem mass spectrometry (MSn) confirms NOC compounds are organic nitrates and elucidates plausible chemical building blocks contributing to oligomer formation. Most organic nitrates are comprised of methylglyceric acid units. Other important multifunctional C2-C5 monomer units are identified including methylglyoxal,more » hydroxyacetone, hydroxyacetic acid, glycolaldehyde, and 2-methyltetrols. The majority of the NOC oligomers contain only one nitrate moiety resulting in a low average N:C ratio of 0.019. Average O:C ratios of the detected SOA compounds are 0.54 under the low-NOx conditions and 0.83 under the high-NOx conditions. Our results underscore the importance of isoprene photooxidation as a source of NOC in organic particulate matter.« less

Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate

PubMed Central

Yang, Ting; Li, Shaomin; Xu, Huixin

2017-01-01

Soluble oligomers of amyloid β-protein (oAβ) isolated from the brains of Alzheimer's disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble Aβ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These species have little or no cytotoxic activity in several bioassays. However, incubation of HMW oAβ in mildly alkaline buffer led to their quantitative dissociation into low molecular weight oligomers (∼8–70 kDa), and these were now far more bioactive: they impaired hippocampal LTP, decreased neuronal levels of β2-adrenergic receptors, and activated microglia in wt mice in vivo. Thus, most soluble Aβ assemblies in AD cortex are large and inactive but under certain circumstances can dissociate into smaller, highly bioactive species. Insoluble amyloid plaques likely sequester soluble HMW oligomers, limiting their potential to dissociate. We conclude that conditions that destabilize HMW oligomers or retard the sequestration of their smaller, more bioactive components are important drivers of Aβ toxicity. Selectively targeting these small, cytotoxic forms should be therapeutically beneficial. SIGNIFICANCE STATEMENT Oligomers of amyloid β-protein (oAβ) are tought to play an important role in Alzheimer's disease (AD), but there is confusion and controversy about what types and sizes of oligomers have disease-relevant activity. Using size-exclusion chromatography and three distinct measures of bioactivity, we show that the predominant forms of Aβ in aqueous extracts of AD brain are high molecular weight (HMW) and relatively inactive. Importantly, under certain conditions, the abundant HMW oAβ can dissociate into low molecular weight species, and these low molecular weight oligomers are significantly more bioactive on synapses and microglia than the HMW species from which they are derived. We conclude that conditions that destabilize HMW oAβ or retard the sequestration of smaller, more bioactive components are important drivers of Aβ toxicity. PMID:28053038

Thiol-Ene functionalized siloxanes for use as elastomeric dental impression materials

PubMed Central

Cole, Megan A.; Jankousky, Katherine C.; Bowman, Christopher N.

2014-01-01

Objectives Thiol- and allyl-functionalized siloxane oligomers are synthesized and evaluated for use as a radical-mediated, rapid set elastomeric dental impression material. Thiol-ene siloxane formulations are crosslinked using a redox-initiated polymerization scheme, and the mechanical properties of the thiol-ene network are manipulated through the incorporation of varying degrees of plasticizer and kaolin filler. Formulations with medium and light body consistencies are further evaluated for their ability to accurately replicate features on both the gross and microscopic levels. We hypothesize that thiol-ene functionalized siloxane systems will exhibit faster setting times and greater detail reproduction than commercially available polyvinylsiloxane (PVS) materials of comparable consistencies. Methods Thiol-ene functionalized siloxane mixtures formulated with varying levels of redox initiators, plasticizer, and kaolin filler are made and evaluated for their polymerization speed (FTIR), consistency (ISO4823.9.2), and surface energy (goniometer). Feature replication is evaluated quantitatively by SEM. The Tg, storage modulus, and creep behavior are determined by DMA. Results Increasing redox initiation rate increases the polymerization rate but at high levels also limits working time. Combining 0.86 wt% oxidizing agent with up to 5 wt% plasticizer gave a working time of 3 min and a setting time of 2 min. The selected medium and light body thiol-ene formulations also achieved greater qualitative detail reproduction than the commercial material and reproduced micrometer patterns with 98% accuracy. Significance Improving detail reproduction and setting speed is a primary focus of dental impression material design and synthesis. Radical-mediated polymerizations, particularly thiol-ene reactions, are recognized for their speed, reduced shrinkage, and ‘click’ nature. PMID:24553250

Accelerated Microstructure Imaging via Convex Optimization (AMICO) from diffusion MRI data.

PubMed

Daducci, Alessandro; Canales-Rodríguez, Erick J; Zhang, Hui; Dyrby, Tim B; Alexander, Daniel C; Thiran, Jean-Philippe

2015-01-15

Microstructure imaging from diffusion magnetic resonance (MR) data represents an invaluable tool to study non-invasively the morphology of tissues and to provide a biological insight into their microstructural organization. In recent years, a variety of biophysical models have been proposed to associate particular patterns observed in the measured signal with specific microstructural properties of the neuronal tissue, such as axon diameter and fiber density. Despite very appealing results showing that the estimated microstructure indices agree very well with histological examinations, existing techniques require computationally very expensive non-linear procedures to fit the models to the data which, in practice, demand the use of powerful computer clusters for large-scale applications. In this work, we present a general framework for Accelerated Microstructure Imaging via Convex Optimization (AMICO) and show how to re-formulate this class of techniques as convenient linear systems which, then, can be efficiently solved using very fast algorithms. We demonstrate this linearization of the fitting problem for two specific models, i.e. ActiveAx and NODDI, providing a very attractive alternative for parameter estimation in those techniques; however, the AMICO framework is general and flexible enough to work also for the wider space of microstructure imaging methods. Results demonstrate that AMICO represents an effective means to accelerate the fit of existing techniques drastically (up to four orders of magnitude faster) while preserving accuracy and precision in the estimated model parameters (correlation above 0.9). We believe that the availability of such ultrafast algorithms will help to accelerate the spread of microstructure imaging to larger cohorts of patients and to study a wider spectrum of neurological disorders. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Distinct Annular Oligomers Captured along the Assembly and Disassembly Pathways of Transthyretin Amyloid Protofibrils

PubMed Central

Pires, Ricardo H.; Karsai, Árpád; Saraiva, Maria J.; Damas, Ana M.; Kellermayer, Miklós S. Z.

2012-01-01

Background Defects in protein folding may lead to severe degenerative diseases characterized by the appearance of amyloid fibril deposits. Cytotoxicity in amyloidoses has been linked to poration of the cell membrane that may involve interactions with amyloid intermediates of annular shape. Although annular oligomers have been detected in many amyloidogenic systems, their universality, function and molecular mechanisms of appearance are debated. Methodology/Principal Findings We investigated with high-resolution in situ atomic force microscopy the assembly and disassembly of transthyretin (TTR) amyloid protofibrils formed of the native protein by pH shift. Annular oligomers were the first morphologically distinct intermediates observed in the TTR aggregation pathway. Morphological analysis suggests that they can assemble into a double-stack of octameric rings with a 16±2 nm diameter, and displaying the tendency to form linear structures. According to light scattering data coupled to AFM imaging, annular oligomers appeared to undergo a collapse type of structural transition into spheroid oligomers containing 8–16 monomers. Disassembly of TTR amyloid protofibrils also resulted in the rapid appearance of annular oligomers but with a morphology quite distinct from that observed in the assembly pathway. Conclusions/Significance Our observations indicate that annular oligomers are key dynamic intermediates not only in the assembly but also in the disassembly of TTR protofibrils. The balance between annular and more compact forms of aggregation could be relevant for cytotoxicity in amyloidogenic disorders. PMID:22984597

Detection of TDP-43 Oligomers in Frontotemporal Lobar Degeneration–TDP

PubMed Central

Kao, Patricia F.; Chen, Yun-Ru; Liu, Xiao-Bo; DeCarli, Charles; Seeley, William W.; Jin, Lee-Way

2016-01-01

Objective The proteinaceous inclusions in TDP-43 proteinopathies such as frontotemporal lobar degeneration (FTLD)-TDP are made of high–molecular-weight aggregates of TDP-43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP-43 amyloid oligomer antibody called TDP-O to determine the presence and abundance of TDP-43 oligomers among different subtypes of FTLD-TDP as well as in hippocampal sclerosis (HS), which represents a non-FTLD pathology with TDP-43 inclusions. Methods Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP-O. Electron microscopy was used to assess the subcellular locations of TDP-O–decorated structures. Results TDP-43 inclusions staining with TDP-O were present in FTLD-TDP and were most conspicuous for FTLD-TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP-O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP-43 inclusions. Ultrastructurally, TDP-43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes. Interpretation TDP-43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP-43 aggregates and mark the different properties of TDP-43 inclusions between FTLD-TDP and HS. PMID:25921485

Elucidation of the internal physical and chemical microstructure of pharmaceutical granules using X-ray micro-computed tomography, Raman microscopy and infrared spectroscopy.

PubMed

Crean, Barry; Parker, Andrew; Roux, Delphine Le; Perkins, Mark; Luk, Shen Y; Banks, Simon R; Melia, Colin D; Roberts, Clive J

2010-11-01

X-ray micro-computed tomography (XMCT) was used in conjunction with confocal Raman mapping to measure the intra-granular pore size, binder volumes and to provide spatial and chemical maps of internal granular components in α-lactose monohydrate granules formulated with different molecular weights of polyvinyl pyrrolidone (PVP). Infrared spectroscopy was used to understand the molecular association of binder domains. Granules were prepared by high-shear aqueous granulation from α-lactose monohydrate and PVP K29/32 or K90. XMCT was used to visualise the granule microstructure, intra-granular binder distribution and measure intra-granular porosity, which was subsequently related to intrusion porosimetry measurements. Confocal Raman microscopy and infrared microscopy were employed to investigate the distribution of components within the granule and explore the nature of binder substrate interactions. XMCT data sets of internal granule microstructure provided values of residual porosity in the lactose:PVP K29/32 and lactose:PVP K90 granules of 32.41 ± 4.60% and 22.40 ± 0.03%, respectively. The binder volumes of the lactose:PVP K29/32 and lactose:PVP K90 granules were 2.98 ± 0.10% and 3.38 ± 0.07%, respectively, and were attributed to PVP-rich binder domains within the granule. Confocal Raman microscopy revealed anisotropic domains of PVP between 2 μm and 20 μm in size surrounded by larger particles of lactose, in both granule types. Raman data showed that PVP domains contained various amounts of lactose, whilst IR microscopy determined that the PVP was molecularly associated with lactose, rather than residual water. The work shows that XMCT can be applied to investigate granular microstructure and resolve the porosity and the excipient and binder volumes. Combining this technique with vibrational techniques provides further structural information and aids the interpretations of the XMCT images. When used complementarily, these techniques highlighted that porosity and binder volume were the most significant microstructural differences between the α-lactose monohydrate granules formulated with the different grades of PVP. Copyright © 2010 Elsevier B.V. All rights reserved.

Ultrasound scatter in heterogeneous 3D microstructures: Parameters affecting multiple scattering

NASA Astrophysics Data System (ADS)

Engle, B. J.; Roberts, R. A.; Grandin, R. J.

2018-04-01

This paper reports on a computational study of ultrasound propagation in heterogeneous metal microstructures. Random spatial fluctuations in elastic properties over a range of length scales relative to ultrasound wavelength can give rise to scatter-induced attenuation, backscatter noise, and phase front aberration. It is of interest to quantify the dependence of these phenomena on the microstructure parameters, for the purpose of quantifying deleterious consequences on flaw detectability, and for the purpose of material characterization. Valuable tools for estimation of microstructure parameters (e.g. grain size) through analysis of ultrasound backscatter have been developed based on approximate weak-scattering models. While useful, it is understood that these tools display inherent inaccuracy when multiple scattering phenomena significantly contribute to the measurement. It is the goal of this work to supplement weak scattering model predictions with corrections derived through application of an exact computational scattering model to explicitly prescribed microstructures. The scattering problem is formulated as a volume integral equation (VIE) displaying a convolutional Green-function-derived kernel. The VIE is solved iteratively employing FFT-based con-volution. Realizations of random microstructures are specified on the micron scale using statistical property descriptions (e.g. grain size and orientation distributions), which are then spatially filtered to provide rigorously equivalent scattering media on a length scale relevant to ultrasound propagation. Scattering responses from ensembles of media representations are averaged to obtain mean and variance of quantities such as attenuation and backscatter noise levels, as a function of microstructure descriptors. The computational approach will be summarized, and examples of application will be presented.

Flows of Wet Foamsand Concentrated Emulsions

NASA Technical Reports Server (NTRS)

Nemer, Martin B.

2005-01-01

The aim of this project was is to advance a microstructural understanding of foam and emulsion flows. The dynamics of individual surfactant-covered drops and well as the collective behavior of dilute and concentrated was explored using numerical simulations. The long-range goal of this work is the formulation of reliable microphysically-based statistical models of emulsion flows.

The Thermal and Microstructural Effect of Plasticizing HMX-Nitrocellulose Composites

DOE PAGES

Yeager, John David; Watkins, Erik Benjamin; Duque, Amanda Lynn; ...

2017-03-15

Thermal ignition via self-heating (cook-off) of cyclotetramethylene-tetranitramine (HMX)-containing plastic-bonded explosives (PBXs) is driven by the β → δ phase transition in the HMX, which is affected if not dominated by microstructure. Here, we studied the HMX-binder interface and phase transition for several variations of PBX 9404 (HMX with plasticized nitrocellulose [NC] binder). Neutron reflectometry was used to examine the interface under several conditions—pristine, after aging, and after thermal treatment. The initial interfacial structure depended on the plasticizer, but the interface homogenized over time. Thermal and optical analyses showed that all formulated materials had higher transition temperatures than neat HMX. Thismore » effect increased with NC content.« less

The Thermal and Microstructural Effect of Plasticizing HMX-Nitrocellulose Composites

NASA Astrophysics Data System (ADS)

Yeager, John D.; Watkins, Erik B.; Higginbotham Duque, Amanda L.; Majewski, Jaroslaw

2018-01-01

Thermal ignition via self-heating (cook-off) of cyclotetramethylene-tetranitramine (HMX)-containing plastic-bonded explosives (PBXs) is driven by the β → δ phase transition in the HMX, which is affected if not dominated by microstructure. Here, the HMX-binder interface and phase transition were studied for several variations of PBX 9404 (HMX with plasticized nitrocellulose [NC] binder). Neutron reflectometry was used to examine the interface under several conditions-pristine, after aging, and after thermal treatment. The initial interfacial structure depended on the plasticizer, but the interface homogenized over time. Thermal and optical analyses showed that all formulated materials had higher transition temperatures than neat HMX. This effect increased with NC content.

FaptaSyme: A Strategy for Converting a Monomer/Oligomer-Nonselective Aptameric Sensor into an Oligomer-Selective One.

PubMed

Evangelista, Baggio A; Kim, Yoon-Seong; Kolpashchikov, Dmitry M

2018-04-26

Aptameric sensors can bind molecular targets and produce output signals, a phenomenon that is used in bioassays. In some cases, it is important to distinguish between monomeric and oligomeric forms of a target. Here, we propose a strategy to convert a monomer/oligomer-nonselective sensor into an oligomer-selective sensor. We designed an aptazyme that produced a high fluorescent output in the presence of oligomeric α-synuclein (a molecular marker of Parkinson's disease) but not its monomeric form. The strategy is potentially useful in the design of point-of-care tests for the diagnosis of neurodegenerative diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Emerging structural details of transient amyloid-β oligomers suggest designs for effective small molecule modulators

NASA Astrophysics Data System (ADS)

Chandra, Bappaditya; Halder, Swagata; Adler, Juliane; Korn, Alexander; Huster, Daniel; Maiti, Sudipta

2017-05-01

Small oligomers are the major toxic species in many amyloid related diseases, but they are difficult to characterize and target. Here we construct tetra-peptides FXFX (X = F/K), designed to exploit cation-π, π-π and hydrophobic interactions to disrupt the critical F19-L34 contact recently found in Aβ40 oligomers. FRFR accelerates Aβ40 aggregation, and strongly inhibits its binding to lipid membranes, which is important in the context of toxicity. FKFK lacks both of these effects, which correlates with the weaker interaction of K with aromatic residues. Thus it appears possible to tune specific contacts in the oligomer and effectively change its properties.

Effects of electronics, aromaticity, and solvent polarity on the rate of azaquinone-methide-mediated depolymerization of aromatic carbamate oligomers.

PubMed

Robbins, Jessica S; Schmid, Kyle M; Phillips, Scott T

2013-04-05

This paper uses physical-organic studies on well-defined oligomers to establish design principles for creating aromatic poly(carbamates) that depolymerize from head-to-tail in low dielectric constant environments when exposed to specific applied signals. We show that either increasing electron density or decreasing the aromaticity of aromatic repeating units in poly(carbamates) increase the overall depolymerization rate. For example, a methoxybenzene-based repeating unit provides depolymerization rates that are 143× faster than oligomers that contain a benzene-based repeating unit. Furthermore, the rate of depolymerization in the methoxybenzene-based system is tolerant to low dielectric environments, whereas the benzene-based oligomers are not.

The Effect of Molecular Weight on the Composite Properties of Cured Phenylethynyl Terminated Imide Oligomers

NASA Technical Reports Server (NTRS)

Smith, J. G., Jr.; Connell, J. W.; Hergenrother, P. M.

1997-01-01

As part of a program to develop high temperature/high performance structural resins for aeronautical applications, imide oligomers containing terminal phenylethynyl groups with calculated number average molecular weights of 1250, 2500 and 5000 g/mol were prepared, characterized, and evaluated as adhesives and composite matrix resins. The goal of this work was to develop resin systems that are processable using conventional processing equipment into void free composites that exhibit high mechanical properties with long term high temperature durability, and are not affected by exposure to common aircraft fluids. The imide oligomers containing terminal phenylethynyl groups were fabricated into titanium adhesive specimens and IM-7 carbon fiber laminates under 0.1 - 1.4 MPa for 1 hr at 350-371 C. The lower molecular weight oligomers exhibited higher cured Tg, better processability, and better retention of mechanical properties at elevated temperature without significantly sacrificing toughness or damage tolerance than the higher molecular weight oligomer. The neat resin, adhesive and composite properties of the cured polymers will be presented.

A simple procedure for preparing chitin oligomers through acetone precipitation after hydrolysis in concentrated hydrochloric acid.

PubMed

Kazami, Nao; Sakaguchi, Masayoshi; Mizutani, Daisuke; Masuda, Tatsuhiko; Wakita, Satoshi; Oyama, Fumitaka; Kawakita, Masao; Sugahara, Yasusato

2015-11-05

Chitin oligomers are of interest because of their numerous biologically relevant properties. To prepare chitin oligomers containing 4-6 GlcNAc units [(GlcNAc)4-6], α- and β-chitin were hydrolyzed with concentrated hydrochloric acid at 40 °C. The reactant was mixed with acetone to recover the acetone-insoluble material, and (GlcNAc)4-6 was efficiently recovered after subsequent water extraction. Composition analysis using gel permeation chromatography and MALDI-TOF mass spectrometry indicated that (GlcNAc)4-6 could be isolated from the acetone-insoluble material with recoveries of approximately 17% and 21% from the starting α-chitin and β-chitin, respectively. The acetone precipitation method is highly useful for recovering chitin oligomers from the acid hydrolysate of chitin. The changes in the molecular size and higher-order structure of chitin during the course of hydrolysis were also analyzed, and a model that explains the process of oligomer accumulation is proposed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Single-Molecule Imaging Reveals that Small Amyloid-β1–42 Oligomers Interact with the Cellular Prion Protein (PrPC)

PubMed Central

Ganzinger, Kristina A; Narayan, Priyanka; Qamar, Seema S; Weimann, Laura; Ranasinghe, Rohan T; Aguzzi, Adriano; Dobson, Christopher M; McColl, James; St George-Hyslop, Peter; Klenerman, David

2014-01-01

Oligomers of the amyloid-β peptide (Aβ) play a central role in the pathogenesis of Alzheimer’s disease and have been suggested to induce neurotoxicity by binding to a plethora of cell-surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrPC) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrPC and that the species bound to PrPC are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oAβ-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways. PMID:25294384

Cytotoxic Helix-Rich Oligomer Formation by Melittin and Pancreatic Polypeptide

PubMed Central

Singh, Pradeep K.; Ghosh, Dhiman; Tewari, Debanjan; Mohite, Ganesh M.; Carvalho, Edmund; Jha, Narendra Nath; Jacob, Reeba S.; Sahay, Shruti; Banerjee, Rinti; Bera, Amal K.; Maji, Samir K.

2015-01-01

Conversion of amyloid fibrils by many peptides/proteins involves cytotoxic helix-rich oligomers. However, their toxicity and biophysical studies remain largely unknown due to their highly dynamic nature. To address this, we chose two helical peptides (melittin, Mel and pancreatic polypeptide, PP) and studied their aggregation and toxicity. Mel converted its random coil structure to oligomeric helical structure upon binding to heparin; however, PP remained as helix after oligomerization. Interestingly, similar to Parkinson’s associated α-synuclein (AS) oligomers, Mel and PP also showed tinctorial properties, higher hydrophobic surface exposure, cellular toxicity and membrane pore formation after oligomerization in the presence of heparin. We suggest that helix-rich oligomers with exposed hydrophobic surface are highly cytotoxic to cells irrespective of their disease association. Moreover as Mel and PP (in the presence of heparin) instantly self-assemble into stable helix-rich amyloidogenic oligomers; they could be represented as models for understanding the biophysical and cytotoxic properties of helix-rich intermediates in detail. PMID:25803428

Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein

PubMed Central

Roberts, Hazel L.; Brown, David R.

2015-01-01

In a number of neurological diseases including Parkinson’s disease (PD), α‑synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of “toxic oligomers”: a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described. PMID:25816357

Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

PubMed Central

Chen, Serene W.; Drakulic, Srdja; Deas, Emma; Ouberai, Myriam; Aprile, Francesco A.; Arranz, Rocío; Ness, Samuel; Roodveldt, Cintia; Guilliams, Tim; De-Genst, Erwin J.; Klenerman, David; Wood, Nicholas W.; Knowles, Tuomas P.J.; Alfonso, Carlos; Rivas, Germán; Abramov, Andrey Y.; Valpuesta, José María; Dobson, Christopher M.; Cremades, Nunilo

2015-01-01

We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species. PMID:25855634

Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition

NASA Astrophysics Data System (ADS)

Nedumpully-Govindan, Praveen; Kakinen, Aleksandr; Pilkington, Emily H.; Davis, Thomas P.; Chun Ke, Pu; Ding, Feng

2016-01-01

Experimental studies have shown that many naturally occurring polyphenols have inhibitory effect on the aggregation of several proteins. Here, we use discrete molecular dynamics (DMD) simulations and high-throughput dynamic light scattering (DLS) experiments to study the anti-aggregation effects of two polyphenols, curcumin and resveratrol, on the aggregation of islet amyloid polypeptide (IAPP or amylin). Our DMD simulations suggest that the aggregation inhibition is caused by stabilization of small molecular weight IAPP off-pathway oligomers by the polyphenols. Our analysis indicates that IAPP-polyphenol hydrogen bonds and π-π stacking combined with hydrophobic interactions are responsible for the stabilization of oligomers. The presence of small oligomers is confirmed with DLS measurements in which nanometer-sized oligomers are found to be stable for up to 7.5 hours, the time frame within which IAPP aggregates in the absence of polyphenols. Our study offers a general anti-aggregation mechanism for polyphenols, and further provides a computational framework for the future design of anti-amyloid aggregation therapeutics.

Analysis of PEG oligomers in black gel inks: Discrimination and ink dating.

PubMed

Sun, Qiran; Luo, Yiwen; Xiang, Ping; Yang, Xu; Shen, Min

2017-08-01

Carbon-based black gel inks are common samples in forensic practice of questioned document examination in China, but there are few analytical methods for this type of ink. In this study, a liquid chromatography-.high resolution mass spectrometry (LC-HRMS) method was established for the analysis of PEG oligomers in carbon-based black gel ink entries. The coupled instruments achieve both the identification and quantification of PEG oligomers in ink entries with reproducible results. Twenty carbon-based black gel inks, whose Raman spectra appeared identical, were analyzed using the LC-HRMS method. As a result, the twenty gel inks were classified into four groups according to the distribution of PEG oligomers. Artificially aging of PEG 400 and a gel ink showed that as PEG degraded, the relative amounts of low molecular weight PEG oligomers increased, while those of high molecular weight decreased. The degradation of PEG oligomers in a naturally aged gel ink was consistent with those in the artificially aged samples, but occurred more slowly. This study not only provided a new method for discriminating carbon-based black gel ink entries, but also offered a new approach for studying the relative ink dating of carbon-based black gel ink entries. Copyright © 2017 Elsevier B.V. All rights reserved.

Selective amyloid β oligomer assay based on abasic site-containing molecular beacon and enzyme-free amplification.

PubMed

Zhu, Linling; Zhang, Junying; Wang, Fengyang; Wang, Ya; Lu, Linlin; Feng, Chongchong; Xu, Zhiai; Zhang, Wen

2016-04-15

Amyloid-beta (Aβ) oligomers are highly toxic species in the process of Aβ aggregation and are regarded as potent therapeutic targets and diagnostic markers for Alzheimer's disease (AD). Herein, a label-free molecular beacon (MB) system integrated with enzyme-free amplification strategy was developed for simple and highly selective assay of Aβ oligomers. The MB system was constructed with abasic site (AP site)-containing stem-loop DNA and a fluorescent ligand 2-amino-5,6,7-trimethyl-1,8-naphyridine (ATMND), of which the fluorescence was quenched upon binding to the AP site in DNA stem. Enzyme-free amplification was realized by target-triggered continuous opening of two delicately designed MBs (MB1 and MB2). Target DNA hybridization with MB1 and then MB2 resulted in the release of two ATMND molecules in one binding event. Subsequent target recycling could greatly amplify the detection sensitivity due to the greatly enhanced turn-on emission of ATMND fluorescence. Combining with Aβ oligomers aptamers, the strategy was applied to analyze Aβ oligomers and the results showed that it could quantify Aβ oligomers with high selectivity and monitor the Aβ aggregation process. This novel method may be conducive to improve the diagnosis and pathogenic study of Alzheimer's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Active Immunization Against hIAPP Oligomers Ameliorates the Diabetes- Associated Phenotype in a Transgenic Mice Model.

PubMed

Bram, Yaron; Peled, Sivan; Brahmachari, Sayanti; Harlev, Michael; Gazit, Ehud

2017-10-25

Type 2 diabetes is characterized by insulin tolerance in target cells followed by a reduction of pancreatic β-cell mass. Islet amyloid polypeptide oligomeric assemblies were shown to contribute to β-cell apoptosis by forming discrete pores that destabilize the cellular membrane. We previously characterized α-helical cytotoxic islet amyloid polypeptide oligomers which interact with cell membranes, following a complete internalization that leads to cellular apoptosis. Moreover, antibodies which bind the oligomers and neutralize the cytotoxicity were exclusively identified in the serum of type 2 diabetes patients. Here, we examined the usage of the newly characterized oligomers as an active immunization agent targeting amyloid self- assembly in a diabetes-associated phenotype transgenic mice model. Immunized transgenic mice showed an increase in hIAPP-antibody serum titer as well as improvement in diabetes-associated parameters. Lower fasting blood glucose levels, higher insulin, and lower islet amyloid polypeptide accumulation were observed. Furthermore, antibodies derived from the immunized mice reduced hIAPP oligomers cytotoxicity towards β-cells in a dose-dependent manner. This study highlights the significance of targeting the early amyloid self-assembly events for potential disease management. Furthermore, it demonstrates that α-helical oligomers conformers are valid epitope for the development of future immunization therapy.

Single molecule imaging of green fluorescent proteins in living cells: E-cadherin forms oligomers on the free cell surface.

PubMed Central

Iino, R; Koyama, I; Kusumi, A

2001-01-01

Single green fluorescent protein (GFP) molecules were successfully imaged for the first time in living cells. GFP linked to the cytoplasmic carboxyl terminus of E-cadherin (E-cad-GFP) was expressed in mouse fibroblast L cells, and observed using an objective-type total internal reflection fluorescence microscope. Based on the fluorescence intensity of individual fluorescent spots, the majority of E-cad-GFP molecules on the free cell surface were found to be oligomers of various sizes, many of them greater than dimers, suggesting that oligomerization of E-cadherin takes place before its assembly at cell-cell adhesion sites. The translational diffusion coefficient of E-cad-GFP is reduced by a factor of 10 to 40 upon oligomerization. Because such large decreases in translational mobility cannot be explained solely by increases in radius upon oligomerization, an oligomerization-induced trapping model is proposed in which, when oligomers are formed, they are trapped in place due to greatly enhanced tethering and corralling effects of the membrane skeleton on oligomers (compared with monomers). The presence of many oligomers greater than dimers on the free surface suggests that these greater oligomers are the basic building blocks for the two-dimensional cell adhesion structures (adherens junctions). PMID:11371443

Microstructural study of a nitroxide-mediated poly(ethylene oxide)/polystyrene block copolymer (PEO-b-PS) by electrospray tandem mass spectrometry.

PubMed

Girod, Marion; Phan, Trang N T; Charles, Laurence

2008-08-01

Electrospray ionization tandem mass spectrometry has been used to characterize the microstructure of a nitroxide-mediated poly(ethylene oxide)/polystyrene block copolymer, called SG1-capped PEO-b-PS. The main dissociation route of co-oligomers adducted with lithium or silver cation was observed to proceed via the homolytic cleavage of a C-ON bond, aimed at undergoing reversible homolysis during nitroxide mediated polymerization. This cleavage results in the elimination of the terminal SG1 end-group as a radical, inducing a complete depolymerization process of the PS block from the so-formed radical cation. These successive eliminations of styrene molecules allowed a straightforward determination of the PS block size. An alternative fragmentation pathway of the radical cation was shown to provide structural information on the junction group between the two blocks. Proposed dissociation mechanisms were supported by accurate mass measurements. Structural information on the SG1 end-group could be reached from weak abundance fragment ions detected in the low m/z range of the MS/MS spectrum. Amongst fragments typically expected from PS dissociation, only beta ions were produced. Moreover, specific dissociation of the PEO block was not observed to occur in MS/MS, suggesting that these rearrangement reactions do not compete effectively with dissociations of the odd-electron fragment ions. Information about the PEO block length and the initiated end-group were obtained in MS(3) experiments.

Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-β Oligomers in Membrane Binding and Membrane Permeability

PubMed Central

2015-01-01

Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer’s disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1–40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3–42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3–42 and Aβ1–42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3–42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3–42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3–42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability. PMID:24950761

Self-assembly of conjugated oligomers and polymers at the interface: structure and properties.

PubMed

Xu, Lirong; Yang, Liu; Lei, Shengbin

2012-08-07

In this review, we give a brief account on the recent scanning tunneling microscopy investigation of interfacial structures and properties of π-conjugated semiconducting oligomers and polymers, either at the solid-air (including solid-vacuum) or at the solid-liquid interface. The structural aspects of the self-assembly of both oligomers and polymers are highlighted. Conjugated oligomers can form well ordered supramolecular assemblies either at the air-solid or liquid-solid interface, thanks to the relatively high mobility and structural uniformity in comparison with polymers. The backbone structure, substitution of side chains and functional groups can affect the assembling behavior significantly, which offers the opportunity to tune the supramolecular structure of these conjugated oligomers at the interface. For conjugated polymers, the large molecular weight limits the mobility on the surface and the distribution in size also prevents the formation of long range ordered supramolecular assembly. The submolecular resolution obtained on the assembling monolayers enables a detailed investigation of the chain folding at the interface, both the structural details and the effect on electronic properties. Besides the ability in studying the assembling structures at the interfaces, STM also provides a reasonable way to evaluate the distribution of the molecular weight of conjugated polymers by statistic of the contour length of the adsorbed polymer chains. Both conjugated oligomers and polymers can form composite assemblies with other materials. The ordered assembly of oligomers can act as a template to controllably disperse other molecules such as coronene or fullerene. These investigations open a new avenue to fine tune the assembling structure at the interface and in turn the properties of the composite materials. To summarize scanning tunneling microscopy has demonstrated its surprising ability in the investigation of the assembling structures and properties of conjugated oligomers and polymers. The information obtained could benefit the understanding of the elements affecting the film morphology and helps the optimization of device performance.

The molecular biology of environmental aromatic hydrocarbons: Progress report for the period September 1, 1986 through July 31, 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiss, S.B.

Our laboratory has explored the use of short DNA oligomers as targets for activated polycyclic aromatic hydrocarbons, such as benzo(a)pyrene diol epoxide (BPDE), in order to detect alterations in DNA sequence arrangement. In this model system, oligomers alkylated with (+)-BPDE are ligated into M13 viral DNA and used to transfect Escherichia coli. These cells are plated on agar, incubated at 37/sup 0/C, progeny viral clones are selected, amplified, and the viral DNAs isolated are sequenced at the site of oligomer insertion. We have devised a procedure for the preparation of unique duplex DNA oligomers such that the site of oligomermore » alkylation is specific for a single deoxynucleotide species in the two DNA strands. The procedure for oligomer assembly also allows us to vary the position of the alkylated residue in each of the two strands. Using our model system, the results obtained over the past year can be summarized as follows. When nonalkylated oligomer constructs are ligated into M13 viral DNA and used to transfect E. coli, no modifications in DNA sequence arrangement are detected in progeny viral DNAs. On the other hand, with oligomer constructs containing BP-adducts two major types of modifications in DNA sequence arrangement were observed: (1) large deletions, and (2) nonhomologous (illegitimate) recombinants. Both of these DNA modifications result in the complete removal of the oligomer insert. Transfection of E. coli that are recA/sup -/ does not alter these DNA modifications, therefore, it appears that the deletions and recombinants induced by the alkylated inserts are not under control of the RecA gene. As the distance between the alkylated residues in the duplex strands is increased, the number of recombinant events detected is reduced. In addition to the above types of DNA modifications, restoration of the original nucleotide sequence in the alkylated construct was also observed in progeny viral DNAs. 7 refs., 6 figs., 2 tabs.« less

Effects of magnesium ions on the stabilization of RNA oligomers of defined structures.

PubMed Central

Serra, Martin J; Baird, John D; Dale, Taraka; Fey, Bridget L; Retatagos, Kimberly; Westhof, Eric

2002-01-01

Optical melting was used to determine the stabilities of 11 small RNA oligomers of defined secondary structure as a function of magnesium ion concentration. The oligomers included helices composed of Watson-Crick base pairs, GA tandem base pairs, GU tandem base pairs, and loop E motifs (both eubacterial and eukaryotic). The effect of magnesium ion concentration on stability was interpreted in terms of two simple models. The first assumes an uptake of metal ion upon duplex formation. The second assumes nonspecific electrostatic attraction of metal ions to the RNA oligomer. For all oligomers, except the eubacterial loop E, the data could best be interpreted as nonspecific binding of metal ions to the RNAs. The effect of magnesium ions on the stability of the eubacterial loop E was distinct from that seen with the other oligomers in two ways. First, the extent of stabilization by magnesium ions (as measured by either change in melting temperature or free energy) was three times greater than that observed for the other helical oligomers. Second, the presence of magnesium ions produces a doubling of the enthalpy for the melting transition. These results indicate that magnesium ion stabilizes the eubacterial loop E sequence by chelating the RNA specifically. Further, these results on a rather small system shed light on the large enthalpy changes observed upon thermal unfolding of large RNAs like group I introns. It is suggested that parts of those large enthalpy changes observed in the folding of RNAs may be assigned to variations in the hydration states and types of coordinating atoms in some specifically bound magnesium ions and to an increase in the observed cooperativity of the folding transition due to the binding of those magnesium ions coupling the two stems together. Brownian dynamic simulations, carried out to visualize the metal ion binding sites, reveal rather delocalized ionic densities in all oligomers, except for the eubacterial loop E, in which precisely located ion densities were previously calculated. PMID:12003491

Physical and chemical microstructural damage in pressed CL-20 explosives

NASA Astrophysics Data System (ADS)

Demol, Gauthier; Sandusky, Harold W.

2000-04-01

The ultimate utility of CL-20 as an ingredient in explosive and propellant formulations will depend upon the ability to understand the factors that are responsible for batch-to-batch variability with respect to sensitivity, and also to control the sensitivity in formulations within acceptable limits. We used light microscopy of cold-mounted, polished samples to characterize CL-20 at various stages in its life cycle. The evolution of damage from the initial neat crystals of CL-20 to the ready-to-use pressed pellets shows that processing seriously damages the crystals. These crystals are very brittle, and several explanations are proposed.

Mesoscale Thermodynamically motivated Statistical Mechanics based Kinetic Model for Sintering monoliths

NASA Astrophysics Data System (ADS)

Mohan, Nisha

Modeling the evolution of microstructure during sintering is a persistent challenge in ceramics science, although needed as the microstructure impacts properties of an engineered material. Bridging the gap between microscopic and continuum models, kinetic Monte Carlo (kMC) methods provide a stochastic approach towards sintering and microstructure evolution. These kMC models work at the mesoscale, with length and time-scales between those of atomistic and continuum approaches. We develop a sintering/compacting model for the two-phase sintering of boron nitride ceramics and allotropes alike. Our formulation includes mechanisms for phase transformation between h-BN and c-BN and takes into account thermodynamics of pressure and temperature on interaction energies and mechanism rates. In addition to replicating the micro-structure evolution observed in experiments, it also captures the phase diagram of Boron Nitride materials. Results have been analyzed in terms of phase diagrams and crystal growth. It also serves with insights to guide the choice of additives and conditions for the sintering process.While detailed time and spatial resolutions are lost in any MC, the progression of stochastic events still captures plausible local energy minima and long-time temporal developments. DARPA.

A diffusion model-free framework with echo time dependence for free-water elimination and brain tissue microstructure characterization.

PubMed

Molina-Romero, Miguel; Gómez, Pedro A; Sperl, Jonathan I; Czisch, Michael; Sämann, Philipp G; Jones, Derek K; Menzel, Marion I; Menze, Bjoern H

2018-03-23

The compartmental nature of brain tissue microstructure is typically studied by diffusion MRI, MR relaxometry or their correlation. Diffusion MRI relies on signal representations or biophysical models, while MR relaxometry and correlation studies are based on regularized inverse Laplace transforms (ILTs). Here we introduce a general framework for characterizing microstructure that does not depend on diffusion modeling and replaces ill-posed ILTs with blind source separation (BSS). This framework yields proton density, relaxation times, volume fractions, and signal disentanglement, allowing for separation of the free-water component. Diffusion experiments repeated for several different echo times, contain entangled diffusion and relaxation compartmental information. These can be disentangled by BSS using a physically constrained nonnegative matrix factorization. Computer simulations, phantom studies, together with repeatability and reproducibility experiments demonstrated that BSS is capable of estimating proton density, compartmental volume fractions and transversal relaxations. In vivo results proved its potential to correct for free-water contamination and to estimate tissue parameters. Formulation of the diffusion-relaxation dependence as a BSS problem introduces a new framework for studying microstructure compartmentalization, and a novel tool for free-water elimination. © 2018 International Society for Magnetic Resonance in Medicine.

Styrene-terminated polysulfone oligomers as matrix material for graphite reinforced composites: An initial study

NASA Technical Reports Server (NTRS)

Garcia, Dana; Bowles, Kenneth J.; Vannucci, Raymond D.

1987-01-01

Styrene terminated polysulfone oligomers are part of an oligomeric class of compounds with end groups capable of thermal polymerization. These materials can be used as matrices for graphite reinforced composites. The initial evaluation of styrene terminated polysulfone oligomer based composites are summarized in terms of fabrication methods, and mechanical and environmental properties. In addition, a description and evaluation is provided of the NASA/Industry Fellowship Program for Technology Transfer.

Method to produce water-soluble sugars from biomass using solvents containing lactones

DOEpatents

Dumesic, James A.; Luterbacher, Jeremy S.

2015-06-02

A process to produce an aqueous solution of carbohydrates that contains C6-sugar-containing oligomers, C6 sugar monomers, C5-sugar-containing oligomers, C5 sugar monomers, or any combination thereof is presented. The process includes the steps of reacting biomass or a biomass-derived reactant with a solvent system including a lactone and water, and an acid catalyst. The reaction yields a product mixture containing water-soluble C6-sugar-containing oligomers, C6-sugar monomers, C5-sugar-containing oligomers, C5-sugar monomers, or any combination thereof. A solute is added to the product mixture to cause partitioning of the product mixture into an aqueous layer containing the carbohydrates and a substantially immiscible organic layer containing the lactone.

Method to produce water-soluble sugars from biomass using solvents containing lactones

DOEpatents

Dumesic, James A.; Luterbacher, Jeremy S.

2017-08-08

A process to produce an aqueous solution of carbohydrates that contains C6-sugar-containing oligomers, C6 sugar monomers, C5-sugar-containing oligomers, C5 sugar monomers, or any combination thereof is presented. The process includes the steps of reacting biomass or a biomass-derived reactant with a solvent system including a lactone and water, and an acid catalyst. The reaction yields a product mixture containing water-soluble C6-sugar-containing oligomers, C6-sugar monomers, C5-sugar-containing oligomers, C5-sugar monomers, or any combination thereof. A solute is added to the product mixture to cause partitioning of the product mixture into an aqueous layer containing the carbohydrates and a substantially immiscible organic layer containing the lactone.

Effect of Amphiphiles on the Rheology of Triglyceride Networks

NASA Astrophysics Data System (ADS)

Seth, Jyoti

2014-11-01

Networks of aggregated crystallites form the structural backbone of many products from the food, cosmetic and pharmaceutical industries. Such materials are generally formulated by cooling a saturated solution to yield the desired solid fraction. Crystal nucleation and growth followed by aggregation leads to formation of a space percolating fractal-network. It is understood that microstructural hierarchy and particle-particle interactions determine material behavior during processing, storage and use. In this talk, rheology of suspensions of triglycerides (TAG, like tristearin) will be explored. TAGs exhibit a rich assortment of polymorphs and form suspensions that are evidently sensitive to surface modifying additives like surfactants and polymers. Here, a theoretical framework will be presented for suspensions containing TAG crystals interacting via pairwise potentials. The work builds on existing models of fractal aggregates to understand microstructure and its correlation with material rheology. Effect of amphiphilic additives is derived through variation of particle-particle interactions. Theoretical predictions for storage modulus will be compared against experimental observations and data from the literature and micro structural predictions against microscopy. Such a theory may serve as a step towards predicting short and long-term behavior of aggregated suspensions formulated via crystallization.

The Influence of Inspection Angle, Wave Type and Beam Shape on Signal-to-Noise Ratios in Ultrasonic Pitch-Catch Inspections

NASA Astrophysics Data System (ADS)

Margetan, F. J.; Li, Anxiang; Thompson, R. B.

2007-03-01

Grain noise, which arises from the scattering of sound waves by microstructure, can limit the detection of small internal defects in metal components. Signal-to-noise (S/N) ratios for ultrasonic pitch/catch inspections are primarily determined by three factors: the scattering ability of the defect; the inherent noisiness of the microstructure (per unit volume); and finite-beam effects. An approximate single-scattering model has been formulated which contains terms representing each of these factors. In this paper the model is applied to a representative pitch/catch inspection problem, namely, the detection of a circular crack in a nickel cylinder. The object is to estimate S/N ratios for various choices of the inspection angle and sonic wave types, and to demonstrate how S/N is determined by the interplay of the defect, microstructure, and finite-beam factors. We also explore how S/N is influenced by the sizes, shapes, and orientations of the transmitter and receiver sound beams.

Investigation of the effect of aggregates' morphology on concrete creep properties by numerical simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lavergne, F.; Sab, K., E-mail: karam.sab@enpc.fr; Sanahuja, J.

2015-05-15

Prestress losses due to creep of concrete is a matter of interest for long-term operations of nuclear power plants containment buildings. Experimental studies by Granger (1995) have shown that concretes with similar formulations have different creep behaviors. The aim of this paper is to numerically investigate the effect of size distribution and shape of elastic inclusions on the long-term creep of concrete. Several microstructures with prescribed size distribution and spherical or polyhedral shape of inclusions are generated. By using the 3D numerical homogenization procedure for viscoelastic microstructures proposed by Šmilauer and Bažant (2010), it is shown that the size distributionmore » and shape of inclusions have no measurable influence on the overall creep behavior. Moreover, a mean-field estimate provides close predictions. An Interfacial Transition Zone was introduced according to the model of Nadeau (2003). It is shown that this feature of concrete's microstructure can explain differences between creep behaviors.« less

Miscibility Gap Closure, Interface Morphology, and Phase Microstructure of 3D Li xFePO 4 Nanoparticles from Surface Wetting and Coherency Strain

DOE PAGES

Welland, Michael J.; Karpeyev, Dmitry; O’Connor, Devin T.; ...

2015-09-10

We study the mesoscopic effects which suppress phase-segregation in Li xFePO 4 nanoparticles using a multiphysics phase-field model implement on a high performance cluster. We simulate 3D spherical particles of radii from 3nm to 40nm and examine the equilibrium microstructure and voltage profiles as a they depend on size and overall lithiation. The model includes anisotropic, concentration-dependent elastic moduli, misfit strain, and facet dependent surface wetting within a Cahn-Hilliard formulation. Here, we find that the miscibility gap vanishes for particles of radius ~ 5 nm, and the solubility limits change with overall particle lithiation. The corresponding voltage plateau, indicative ofmore » phase-segregation, changes in extent and also vanishes. Surface wetting is found to have a strong effect on stabilizing a variety of microstructures, exaggerating the shifting of solubility limits, and shortening the voltage plateau.« less

Effect of freezing on microstructure and degree of syneresis in differently formulated fruit fillings.

PubMed

Cropotova, Janna; Tylewicz, Urszula; Dellarosa, Nicolò; Laghi, Luca; Romani, Santina; Dalla Rosa, Marco

2016-03-15

This study describes the syneresis and its effect on microstructure in fruit fillings within a wide range of the total soluble solids content and with or without hydrocolloids upon freezing. Linear models showed the relevance of the addition of pectin and gellan gum to fillings to prevent syneresis, increasing the water-holding capacity especially after freezing. Microstructural experiments by means of NMR spin-spin relaxometry combined with fluorescence microscopy allowed to observe that the continuous hydrocolloid gel, containing the dispersed solution of native fruit parts with the addition of inulin and sugars, changed its structure/distribution according to the amount of each ingredient and due to the freezing process. Relaxometry results confirmed that hydrocolloids strength was correlated (R(2)>0.92) with water-holding capacity, due to a relationship between the signal given by the water chemically exchanging with biopolymers, and the changes in the degree of syneresis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of caprylocaproyl macrogolglycerides based microemulsion drug delivery vehicles for an amphiphilic drug.

PubMed

Djordjevic, Ljiljana; Primorac, Marija; Stupar, Mirjana; Krajisnik, Danina

2004-03-01

Microemulsion systems composed of water, isopropyl myristate, PEG-8 caprylic/capric glycerides (Labrasol), and polyglyceryl-6 dioleate (Plurol Oleique), were investigated as potential drug delivery vehicles for an amphiphilic model drug (diclofenac diethylamine). Pseudo-ternary phase diagram of the investigated system, at constant surfactant/cosurfactant mass ratio (Km 4:1) was constructed at room temperature by titration, and the oil-to-surfactant/cosurfactant mass ratios (O/SC) that exhibit the maximum in the solubilization of water were found. This allowed the investigation of the continuous structural inversion from water-in-oil to oil-in-water microemulsions on dilution with water phase. Furthermore, electrical conductivity (sigma) of the system at Km 1:4, and O/SC 0.250 was studied, and the percolation phenomenon was observed. Conductivity and apparent viscosity (eta') measurement results well described colloidal microstructure of the selected formulations, including gradual changes during their formation. Moreover, sigma, eta', and pH values of six selected microemulsion vehicles which differ in water phase volume fraction (phi(w)) at the selected Km and O/SC values, were measured. In order to investigate the influence of the amphiphilic drug on the vehicle microstructures, each system was formulated with 1.16% (w/w) diclofenac diethylamine. Electrical conductivity, and eta' of the investigated systems were strongly affected by drug incorporation. The obtained results suggest that diclofenac diethylamine interacts with the specific microstructure of the investigated vehicles, and that the different drug release kinetics from these microemulsions may be expected. The investigated microemulsions should be very interesting as new drug carrier systems for dermal application of diclofenac diethylamine.

Preparation of hydroxyapatite-titania hybrid coatings on titanium alloy.

PubMed

Un, Serhat; Durucan, Caner

2009-08-01

Hydroxypapatite-titania hybrid films on Ti6Al4V alloys were prepared by sol-gel technique by incorporating presynthesized hydroxypapatite (Ca(10)(PO(4))(6)(OH)(2) or HAp) powders into a titanium-alkoxide dip coating solution. Titania network was formed by the hydrolysis and condensation of Ti-isopropoxide Ti[OCH(CH(3))(2)](4)-based sols. The effect of titania sol formulation, specifically the effect of organic solvents on the microstructure of the dip coated films calcined at 500 degrees C has been investigated. The coatings exhibit higher tendency for cracking when a high vapor pressure solvent, such as ethanol (C(2)H(5)OH) is used causing development of higher macroscopic stresses during evaporation of the sol. Titania sol formulations replacing the solvent with n-proponal (CH(3)(CH(2))(2)OH) and acetly-acetone (C(5)H(8)O) combinations enhanced the microstructural integrity of the coating during evaporation and calcination treatments. Sol-gel processing parameters, such as multilayer coating application and withdrawal rate, can be employed to change the titania thickness in the range of 0.120-1.1 microm and to control the microstructure of HAp-titania hybrid coatings. A high-calcination temperature in the range of 400-600 degrees C does not cause a distinct change in crystals nature of the titania matrix or HAp, but results in more cracking due to the combined effect of densification originated stresses and thermal stresses upon cooling. Slower withdraw rates and multilayer dip coating lead to coatings more vulnerable to microcracking.

Rock-Fluid Interactions Under Stress: How Rock Microstructure Controls The Evolution of Porosity and Permeability

NASA Astrophysics Data System (ADS)

Vanorio, T.

2016-12-01

Monitoring chemo-mechanical processes geophysically — e.g., fluid disposal or storage, thermal and chemical stimulation of reservoirs, or natural fluids simply entering a new system in the subsurface— raises numerous concerns because of the likelihood of fluid-rock chemical interactions and our limited ability to decipher the geophysical signature of coupled processes. One of the missing links is coupling the evolution of porosity, permeability, and velocity of rocks together with reactive transport, since rocks deform and their microstructure evolves, as a result of chemical reactions under stress. This study describes recent advances in rock-physics experiments to understand the effects of dissolution-induced compaction on acoustic velocity, porosity, and permeability. Data observation includes time-lapse experiments and imaging tracking transport and elastic properties, the rock microstructure, and the pH and chemical composition of the fluid permeating the rock. Results show that the removal of high surface area, mineral phases such as microcrystalline calcite and clay appears to be mostly responsible for dissolution-induced compaction. Nevertheless, it is the original rock microstructure and its response to stress that ultimately defines how solution-transfer and rock compaction feed back upon each other. This work has a dual aim: understanding the mechanisms underlying permanent modifications to the rock microstructure and providing a richer set of experimental information to inform the formulation of new simulations and rock modeling.

A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP.

PubMed

Serrano, Arnaldo L; Lomont, Justin P; Tu, Ling-Hsien; Raleigh, Daniel P; Zanni, Martin T

2017-11-22

Transiently populated oligomers formed en route to amyloid fibrils may constitute the most toxic aggregates associated with many amyloid-associated diseases. Most nucleation theories used to describe amyloid aggregation predict low oligomer concentrations and do not take into account free energy costs that may be associated with structural rearrangements between the oligomer and fiber states. We have used isotope labeling and two-dimensional infrared spectroscopy to spectrally resolve an oligomeric intermediate during the aggregation of the human islet amyloid protein (hIAPP or amylin), the protein associated with type II diabetes. A structural rearrangement includes the F 23 G 24 A 25 I 26 L 27 region of hIAPP, which starts from a random coil structure, evolves into ordered β-sheet oligomers containing at least 5 strands, and then partially disorders in the fibril structure. The supercritical concentration is measured to be between 150 and 250 μM, which is the thermodynamic parameter that sets the free energy of the oligomers. A 3-state kinetic model fits the experimental data, but only if it includes a concentration independent free energy barrier >3 kcal/mol that represents the free energy cost of refolding the oligomeric intermediate into the structure of the amyloid fibril; i.e., "oligomer activation" is required. The barrier creates a transition state in the free energy landscape that slows fibril formation and creates a stable population of oligomers during the lag phase, even at concentrations below the supercritical concentration. Largely missing in current kinetic models is a link between structure and kinetics. Our experiments and modeling provide evidence that protein structural rearrangements during aggregation impact the populations and kinetics of toxic oligomeric species.

Crystal Structure of an Activated Variant of Small Heat Shock Protein Hsp16.5

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mchaourab, Hassane S.; Lin, Yi-Lun; Spiller, Benjamin W.

How does the sequence of a single small heat shock protein (sHSP) assemble into oligomers of different sizes? To gain insight into the underlying structural mechanism, we determined the crystal structure of an engineered variant of Methanocaldococcus jannaschii Hsp16.5 wherein a 14 amino acid peptide from human heat shock protein 27 (Hsp27) was inserted at the junction of the N-terminal region and the {alpha}-crystallin domain. In response to this insertion, the oligomer shell expands from 24 to 48 subunits while maintaining octahedral symmetry. Oligomer rearrangement does not alter the fold of the conserved {alpha}-crystallin domain nor does it disturb themore » interface holding the dimeric building block together. Rather, the flexible C-terminal tail of Hsp16.5 changes its orientation relative to the {alpha}-crystallin domain which enables alternative packing of dimers. This change in orientation preserves a peptide-in-groove interaction of the C-terminal tail with an adjacent {beta}-sandwich, thereby holding the assembly together. The interior of the expanded oligomer, where substrates presumably bind, retains its predominantly nonpolar character relative to the outside surface. New large windows in the outer shell provide increased access to these substrate-binding regions, thus accounting for the higher affinity of this variant to substrates. Oligomer polydispersity regulates sHSPs chaperone activity in vitro and has been implicated in their physiological roles. The structural mechanism of Hsp16.5 oligomer flexibility revealed here, which is likely to be highly conserved across the sHSP superfamily, explains the relationship between oligomer expansion observed in disease-linked mutants and changes in chaperone activity.« less

Induction of Covalently Crosslinked p62 Oligomers with Reduced Binding to Polyubiquitinated Proteins by the Autophagy Inhibitor Verteporfin.

PubMed

Donohue, Elizabeth; Balgi, Aruna D; Komatsu, Masaaki; Roberge, Michel

2014-01-01

Autophagy is a cellular catabolic process responsible for the degradation of cytoplasmic constituents, including organelles and long-lived proteins, that helps maintain cellular homeostasis and protect against various cellular stresses. Verteporfin is a benzoporphyrin derivative used clinically in photodynamic therapy to treat macular degeneration. Verteporfin was recently found to inhibit autophagosome formation by an unknown mechanism that does not require exposure to light. We report that verteporfin directly targets and modifies p62, a scaffold and adaptor protein that binds both polyubiquitinated proteins destined for degradation and LC3 on autophagosomal membranes. Western blotting experiments revealed that exposure of cells or purified p62 to verteporfin causes the formation of covalently crosslinked p62 oligomers by a mechanism involving low-level singlet oxygen production. Rose bengal, a singlet oxygen producer structurally unrelated to verteporfin, also produced crosslinked p62 oligomers and inhibited autophagosome formation. Co-immunoprecipitation experiments demonstrated that crosslinked p62 oligomers retain their ability to bind to LC3 but show defective binding to polyubiquitinated proteins. Mutations in the p62 PB1 domain that abolish self-oligomerization also abolished crosslinked oligomer formation. Interestingly, small amounts of crosslinked p62 oligomers were detected in untreated cells, and other groups noted the accumulation of p62 forms with reduced SDS-PAGE mobility in cellular and animal models of oxidative stress and aging. These data indicate that p62 is particularly susceptible to oxidative crosslinking and lead us to propose a model whereby oxidized crosslinked p62 oligomers generated rapidly by drugs like verteporfin or over time during the aging process interfere with autophagy.

Induction of Covalently Crosslinked p62 Oligomers with Reduced Binding to Polyubiquitinated Proteins by the Autophagy Inhibitor Verteporfin

PubMed Central

Donohue, Elizabeth; Balgi, Aruna D.; Komatsu, Masaaki; Roberge, Michel

2014-01-01

Autophagy is a cellular catabolic process responsible for the degradation of cytoplasmic constituents, including organelles and long-lived proteins, that helps maintain cellular homeostasis and protect against various cellular stresses. Verteporfin is a benzoporphyrin derivative used clinically in photodynamic therapy to treat macular degeneration. Verteporfin was recently found to inhibit autophagosome formation by an unknown mechanism that does not require exposure to light. We report that verteporfin directly targets and modifies p62, a scaffold and adaptor protein that binds both polyubiquitinated proteins destined for degradation and LC3 on autophagosomal membranes. Western blotting experiments revealed that exposure of cells or purified p62 to verteporfin causes the formation of covalently crosslinked p62 oligomers by a mechanism involving low-level singlet oxygen production. Rose bengal, a singlet oxygen producer structurally unrelated to verteporfin, also produced crosslinked p62 oligomers and inhibited autophagosome formation. Co-immunoprecipitation experiments demonstrated that crosslinked p62 oligomers retain their ability to bind to LC3 but show defective binding to polyubiquitinated proteins. Mutations in the p62 PB1 domain that abolish self-oligomerization also abolished crosslinked oligomer formation. Interestingly, small amounts of crosslinked p62 oligomers were detected in untreated cells, and other groups noted the accumulation of p62 forms with reduced SDS-PAGE mobility in cellular and animal models of oxidative stress and aging. These data indicate that p62 is particularly susceptible to oxidative crosslinking and lead us to propose a model whereby oxidized crosslinked p62 oligomers generated rapidly by drugs like verteporfin or over time during the aging process interfere with autophagy. PMID:25494214

Crystal structure of an activated variant of small heat shock protein Hsp16.5.

PubMed

McHaourab, Hassane S; Lin, Yi-Lun; Spiller, Benjamin W

2012-06-26

How does the sequence of a single small heat shock protein (sHSP) assemble into oligomers of different sizes? To gain insight into the underlying structural mechanism, we determined the crystal structure of an engineered variant of Methanocaldococcus jannaschii Hsp16.5 wherein a 14 amino acid peptide from human heat shock protein 27 (Hsp27) was inserted at the junction of the N-terminal region and the α-crystallin domain. In response to this insertion, the oligomer shell expands from 24 to 48 subunits while maintaining octahedral symmetry. Oligomer rearrangement does not alter the fold of the conserved α-crystallin domain nor does it disturb the interface holding the dimeric building block together. Rather, the flexible C-terminal tail of Hsp16.5 changes its orientation relative to the α-crystallin domain which enables alternative packing of dimers. This change in orientation preserves a peptide-in-groove interaction of the C-terminal tail with an adjacent β-sandwich, thereby holding the assembly together. The interior of the expanded oligomer, where substrates presumably bind, retains its predominantly nonpolar character relative to the outside surface. New large windows in the outer shell provide increased access to these substrate-binding regions, thus accounting for the higher affinity of this variant to substrates. Oligomer polydispersity regulates sHSPs chaperone activity in vitro and has been implicated in their physiological roles. The structural mechanism of Hsp16.5 oligomer flexibility revealed here, which is likely to be highly conserved across the sHSP superfamily, explains the relationship between oligomer expansion observed in disease-linked mutants and changes in chaperone activity.

Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ(42) oligomers via a metalloproteinase-dependent mechanism.

PubMed

Sandoval, Karin E; Farr, Susan A; Banks, William A; Crider, Albert M; Morley, John E; Witt, Ken A

2013-07-03

Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble Aβ42 oligomer brain content with and without co-administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 µg i.c.v. in 2 µL) improved learning, which was blocked by phosphoramidon (1 and 10mM, respectively). NNC 26-9100 decreased total soluble Aβ42, an effect which was blocked by phosphoramidon (10mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Aβ42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Aβ42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Aβ42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Aβ42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism. Copyright © 2013 Elsevier B.V. All rights reserved.

Biomimetic peptoid polymers

DOEpatents

Zuckermann, Ronald N.; Chu, Tammy K.; Nam, Ki Tae

2015-07-07

The present invention provides for novel peptoid oligomers that are capable of self-assembling into two-dimensional sheet structures. The peptoid oligomers can have alternately hydrophilic or polar side-chains and hydrophobic or apolar side-chains. The peptoid oligomers, and the two-dimensional sheet structures, can be applied to biological applications where the peptoid plays a role as a biological scaffold or building block. Also, the two-dimensional sheet structures of the present invention can be used as two-dimensional nanostructures in device applications.

Transient increase in sAPPα secretion in response to Aβ1-42 oligomers: an attempt of neuronal self-defense?

PubMed

Rose, Christiane; Dorard, Emilie; Audrain, Mickael; Gorisse-Hussonnois, Lucie; Cartier, Nathalie; Braudeau, Jérome; Allinquant, Bernadette

2018-01-01

Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1-42. Whether extracellular Aβ1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1-42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6-9 hours later. Preventing the generation of sAPPα by using small interfering RNAs (siRNAs) for the α-secretases ADAM10 and ADAM17 or for APP led to increased Aβ1-42 oligomer-induced cell death after 24 hours. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7 hours later. Finally, acute injection of Aβ1-42 oligomers into wild-type mouse hippocampi induced transient secretion of sAPPα 48-72 hours later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

PETIs as High-Temperature Resin-Transfer-Molding Materials

NASA Technical Reports Server (NTRS)

Connell, John N.; Smith, Joseph G., Jr.; Hergenrother, Paul M.

2005-01-01

Compositions of, and processes for fabricating, high-temperature composite materials from phenylethynyl-terminated imide (PETI) oligomers by resin-transfer molding (RTM) and resin infusion have been developed. Composites having a combination of excellent mechanical properties and long-term high-temperature stability have been readily fabricated. These materials are particularly useful for the fabrication of high-temperature structures for jet-engine components, structural components on highspeed aircraft, spacecraft, and missiles. Phenylethynyl-terminated amide acid oligomers that are precursors of PETI oligomers are easily made through the reaction of a mixture of aromatic diamines with aromatic dianhydrides at high stoichiometric offsets and 4-phenylethynylphthalic anhydride (PEPA) as an end-capper in a polar solvent such as N-methylpyrrolidinone (NMP). These oligomers are subsequently cyclodehydrated -- for example, by heating the solution in the presence of toluene to remove the water by azeotropic distillation to form low-molecular-weight imide oligomers. More precisely, what is obtained is a mixture of PETI oligomeric species, spanning a range of molecular weights, that exhibits a stable melt viscosity of less than approximately 60 poise (and generally less than 10 poise) at a temperature below 300 deg C. After curing of the oligomers at a temperature of 371 deg C, the resulting polymer can have a glass-transition temperature (Tg) as high as 375 C, the exact value depending on the compositions.

Targeting Cancer with Antisense Oligomers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hnatowich, DJ

With financial assistance from the Department of Energy, we have shown definitively that radiolabeled antisense DNAs and other oligomers will accumulate in target cancer cells in vitro and in vivo by an antisense mechanism. We have also shown that the number of mRNA targets for our antisense oligomers in the cancer cell types that we have investigated so far is sufficient to provide and antisense image and/or radiotherapy of cancer in mice. These studies have been reported in about 10 publications. However our observation over the past several years has shown that radiolabeled antisense oligomers administered intravenously in their nativemore » and naked form will accumulate and be retained in target xenografts by an antisense mechanism but will also accumulate at high levels in normal organs such as liver, spleen and kidneys. We have investigated unsuccessfully several commercially available vectors. Thus the use of radiolabeled antisense oligomers for the imaging of cancer must await novel approaches to delivery. This laboratory has therefore pursued two new paths, optical imaging of tumor and Auger radiotherapy. We are developing a novel method of optical imaging tumor using antisense oligomers with a fluorophore is administered while hybridized with a shorter complementary oligomer with an inhibitor. In culture and in tumored mice that the duplex remains intact and thus nonfluorescent until it encounters its target mRNA at which time it dissociates and the antisense oligomer binds along with its fluorophore to the target. Simultaneous with the above, we have also observed, as have others, that antisense oligomers migrate rapidly and quantitatively to the nucleus upon crossing cell membranes. The Auger electron radiotherapy path results from this observation since the nuclear migration properties could be used effectively to bring and to retain in the nucleus an Auger emitting radionuclide such as 111In or 125I bound to the antisense oligomer. Since the object becomes radiotherapy rather than imaging, the delivery problem may be obviated by attaching the antisense oligomer to an antitumor antibody to improve delivery following intravenous administration. Since many antibodies are trapped in endosomes following internalization, a cell penetrating peptide such as tat will also be included to ensure transport of the complex without entrapment. Rather than covalent conjugation of the three entities, we are using streptavidin as linker after biotinylated each component. Our recent efforts have concentrated on establishing the influence of the streptavidin linker on the properties of each component within the delivery nanoparticle. Thus, we have shown that the Herceptin antibody, when linked to a labeled oligomer via streptavidin, remains capable of directing the label oligomer to Her2+ tumor cells in vitro and Her2+ tumor xenografts in mice. In addition, we have demonstrated that a labeled antisense oligomer within the nanoparticle remains capable of migrating to the nucleus and binding to its target mRNA in vitro and in vivo. We have shown that the tat peptide also preserves its properties of cell transport when incubated as one component of the nanoparticle. Most recently, we have addressed another of our concerns, namely whether the streptavidin would adversely effect the biodistribution of the antisense oligomer. We were pleased to find that the 99mTc-labeled antisense MORF within the Herceptin three component and two component nanoparticles accumulated and was retained in tumor in a manner suggestive of radiolabeled Herceptin itself. Thus the preserved properties within the streptavidin delivery nanoparticle of the Herceptin antibody, the tat peptide and the 111In labeled antisense MORF oligomer will explain why we have successfully demonstrated an Auger electron-mediated, antisense-mediated radiotherapy in cells in culture. One remaining concern is that the delivery nanoparticle may deliver the Auger electron emitting radionuclide to the nucleus of normal cells as well as tumor cells. We have now performed tumored mice studies of the three component delivery nanoparticle with the antisense MORF labeled with Cy3 so that tissue slices could be examined by immunohistology for evidence of MORF accumulations in the nuclei of both tumor and normal tissues. Microscopic examination shows nuclear staining in approximately 20% of the tumor cells in animals injected with the antisense nanoparticle and 10% of the tumor cells in animals receiving the sense nanoparticle, whereas no nuclear staining is seen in the tumor cells of mice given the PBS injection as another control. No nuclear staining was observed in all sections from all normal organs. Finally, my colleagues and I wish to express our gratitude to the DOE for their generous support of our research at a time when the NIH was unwilling to fund what they believed to be a risky« less

Transient dichroism in photoreceptor membranes indicates that stable oligomers of rhodopsin do not form during excitation.

PubMed Central

Downer, N W; Cone, R A

1985-01-01

If a photoexcited rhodopsin molecule initiates the formation of rhodopsin oligomers during the process of visual excitation, the rate of rotational diffusion of the rhodopsin molecules involved should change markedly. Using microsecond-flash photometry, we have observed the rotational diffusion of rhodopsin throughout the time period of visual excitation and found that no detectable change occurs in its rotational diffusion rate. Partial chemical cross-linking of the retina yields oligomers of rhodopsin and causes a significant decrease in the rotational diffusion rate of rhodopsin even when as little as 20% of rhodopsin is dimeric. Moreover, the pattern of oligomers formed by cross-linking, taken together with the magnitude of decreases in rotational diffusion rate accompanying the cross-linking reaction, suggests that rhodopsin is a monomer in the dark-adapted state. The experiments reported here show that photoexcited rhodopsin molecules do not irreversibly associate with unbleached neighbors during the time course of the receptor response. Hence, it is not likely that stable oligomers of rhodopsin trigger the excitation of the photoreceptor cell. Images FIGURE 1 PMID:3919778

Protecting and Leaving Functions of Trimethylsilyl Groups in Trimethylsilylated Silicates for the Synthesis of Alkoxysiloxane Oligomers.

PubMed

Yoshikawa, Masashi; Tamura, Yasuhiro; Wakabayashi, Ryutaro; Tamai, Misa; Shimojima, Atsushi; Kuroda, Kazuyuki

2017-11-06

The concept of protecting groups and leaving groups in organic synthesis was applied to the synthesis of siloxane-based molecules. Alkoxy-functionalized siloxane oligomers composed of SiO 4 , RSiO 3 , or R 2 SiO 2 units were chosen as targets (R: functional groups, such as Me and Ph). Herein we describe a novel synthesis of alkoxysiloxane oligomers based on the substitution reaction of trimethylsilyl (TMS) groups with alkoxysilyl groups. Oligosiloxanes possessing TMS groups were reacted with alkoxychlorosilane in the presence of BiCl 3 as a catalyst. TMS groups were substituted with alkoxysilyl groups, leading to the synthesis of alkoxysiloxane oligomers. Siloxane oligomers composed of RSiO 3 and R 2 SiO 2 units were synthesized more efficiently than those composed of SiO 4 units, suggesting that the steric hindrance around the TMS groups of the oligosiloxanes makes a difference in the degree of substitution. This reaction uses TMS groups as both protecting and leaving groups for SiOH/SiO - groups. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

New oligomers containing pendant 4-aryl-7-phenylfluorene units as efficient charge transporting materials for OLEDs

NASA Astrophysics Data System (ADS)

Krucaite, G.; Baranauskyte, U.; Tavgeniene, D.; Andruleviciute, V.; Sutkuviene, S.; Yao, B.; Xie, Z.; Zhang, B.; Grigalevicius, S.

2017-10-01

Monomers and oligomers containing electronically isolated 4-aryl-7-phenylfluorene fragments have been synthesized by the multi-step synthetic route. The materials were characterized by thermo-gravimetric analysis, differential scanning calorimetry and electron photoemission technique. The oligomers represent materials of very high thermal stability having initial thermal degradation temperatures in the range of 402-412 °C. The glass transition temperatures of the amorphous oligomers were in the rage of 97-129 °C. The electron photoemission spectra of thin layers of the oligomeric materials showed ionization potentials in the range of 5.7-6.1 eV. Hole injecting/transporting properties of the electroactive oligomers were tested in the structures of organic light emitting diodes with tris(quinolin-8-olato)aluminium as a green emitter. The device containing hole-transporting material with 4-biphenyl-7-phenylfluorene electrophores exhibited the best overall performance with low turn on voltage of 4.4 V, high current efficiency exceeding 3.6 cd/A and maximum brightness exceeding 3200 cd/m2.

WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.

PubMed

Vargas, Jessica Y; Ahumada, Juan; Arrázola, Macarena S; Fuenzalida, Marco; Inestrosa, Nibaldo C

2015-02-01

Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Low molecular weight oligomers of amyloid peptides display β-barrel conformations: A replica exchange molecular dynamics study in explicit solvent

NASA Astrophysics Data System (ADS)

De Simone, Alfonso; Derreumaux, Philippe

2010-04-01

The self-assembly of proteins and peptides into amyloid fibrils is connected to over 40 pathological conditions including neurodegenerative diseases and systemic amyloidosis. Diffusible, low molecular weight protein and peptide oligomers that form in the early steps of aggregation appear to be the harmful cytotoxic species in the molecular etiology of these diseases. So far, the structural characterization of these oligomers has remained elusive owing to their transient and dynamic features. We here address, by means of full atomistic replica exchange molecular dynamics simulations, the energy landscape of heptamers of the amyloidogenic peptide NHVTLSQ from the beta-2 microglobulin protein. The simulations totaling 5 μs show that low molecular weight oligomers in explicit solvent consist of β-barrels in equilibrium with amorphous states and fibril-like assemblies. The results, also accounting for the influence of the pH on the conformational properties, provide a strong evidence of the formation of transient β-barrel assemblies in the early aggregation steps of amyloid-forming systems. Our findings are discussed in terms of oligomers cytotoxicity.

Two forms of Vibrio cholerae O1 El Tor hemolysin derived from identical precursor protein.

PubMed

Ikigai, H; Ono, T; Nakae, T; Otsuru, H; Shimamura, T

1999-01-08

Vibrio cholerae O1 grown in heart infusion broth produces two forms of El Tor hemolysin (ETH) monomers of 65 and 50 kDa. These monomers form several different sizes of mixed oligomers ranging from 180 to 280 kDa in the liposomal membranes. We found that the N-terminal amino acid sequences, NH2-Trp-Pro-Ala-Pro-Ala-Asn-Ser-Glu, of both the 65- and 50-kDa toxins were identical. We assumed, therefore, that the 65- and 50-kDa toxins were derivatives of the identical precursor protein and the 50-kDa protein was a truncated derivative of 65-kDa ETH. To substantiate this assumption, we treated the 260-kDa oligomer with trypsin and obtained a 190-kDa oligomer. This 190-kDa oligomer consisted of only the 50-kDa subunits. Both 260- and 190-kDa oligomers formed ion channels indistinguishable from each other in planar lipid bilayers. These results suggest that the essential part of the ETH in forming the membrane-damaging aggregate is a 50-kDa protein.

Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases

PubMed Central

Evangelisti, Elisa; Cascella, Roberta; Becatti, Matteo; Marrazza, Giovanna; Dobson, Christopher M.; Chiti, Fabrizio; Stefani, Massimo; Cecchi, Cristina

2016-01-01

The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ42 peptide associated with Alzheimer’s disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca2+ across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane. PMID:27619987

Selectivity in subunit composition of Ena/VASP tetramers

PubMed Central

Riquelme, Daisy N.; Meyer, Aaron S.; Barzik, Melanie; Keating, Amy; Gertler, Frank B.

2015-01-01

The members of the actin regulatory family of Ena/VASP proteins form stable tetramers. The vertebrate members of the Ena/VASP family, VASP, Mena and EVL, have many overlapping properties and expression patterns, but functional and regulatory differences between paralogues have been observed. The formation of mixed oligomers may serve a regulatory role to refine Ena/VASP activity. While it has been assumed that family members can form mixed oligomers, this possibility has not been investigated systematically. Using cells expressing controlled combinations of VASP, Mena and EVL, we evaluated the composition of Ena/VASP oligomers and found that VASP forms oligomers without apparent bias with itself, Mena or EVL. However, Mena and EVL showed only weak hetero-oligomerization, suggesting specificity in the association of Ena/VASP family members. Co-expression of VASP increased the ability of Mena and EVL to form mixed oligomers. Additionally, we found that the tetramerization domain (TD) at the C-termini of Ena/VASP proteins conferred the observed selectivity. Finally, we demonstrate that replacement of the TD with a synthetic tetramerizing coiled coil sequence supports homo-oligomerization and normal VASP subcellular localization. PMID:26221026

Synthesis of a new π-conjugated redox oligomer: Electrochemical and optical investigation

NASA Astrophysics Data System (ADS)

Blili, Saber; Zaâboub, Zouhour; Maaref, Hassen; Haj Said, Ayoub

2017-01-01

A new π-conjugated redox oligomer was prepared according a two-Step Synthesis. Firstly, an oligophenylene (OMPA) was obtained from the anodic oxidation of the (4-methoxyphenyl)acetonitrile. Then, the resulting material was chemically modified by the Knoevenagel condensation with the ferrocenecarboxaldehyde. This reaction led to a redox-conjugated oligomer the Fc-OMPA. The synthesized material was characterized using different spectroscopic techniques: NMR, FTIR, UV-vis and photoluminescence (PL) spectroscopy. The Fc-OMPA was used to modify a platinum electrode surface and the electrochemical response of the ferrocene redox-center was investigated by cyclic voltammetry. Moreover, the room temperature PL spectra of Fc-OMPA revealed that the ferrocene moiety, which acts as an electron donor, can effectively quench the oligomer luminescence. However, when ferrocene was oxidized to ferrocenium ion, the intramolecular charge transfer process was prevented which consequently enhanced the light emission. Thus, the oligomer light-emission can be, chemically or electrochemically tuned. The obtained results showed that the prepared material is a good candidate for the elaboration of electrochemical sensors and for the development of luminescent Redox-switchable devices.

"Sizing" the oligomers of Azami Green fluorescent protein with FCS and antibunching

NASA Astrophysics Data System (ADS)

Temirov, Jamshid; Werner, James H.; Goodwin, Peter M.; Bradbury, Andrew R. M.

2012-02-01

Fluorescent proteins are invaluable molecules in fluorescence microscopy and spectroscopy. The size and brightness of fluorescent proteins often dictates the application they may be used for. While a monomeric protein may be the least perturbative structure for labeling a protein in a cell, often oligomers (dimers and tetramers) of fluorescent proteins can be more stable. However, from a quantitative microscopy standpoint, it is important to realize the photophysical properties of monomers do not necessarily multiply by their number when they form oligomers. In this work we studied oligomerization states of the Azami Green (AG) protein with fluorescence correlation spectroscopy (FCS) and photon antibunching or photon pair correlation spectroscopy (PPCS). FCS was used to measure the hydrodynamic size of the oligomers, whereas antibunching was used to count the number of fluorescent emitters in the oligomers. The results exhibited that the dimers of AG were single emitters and the tetramers were dual-emitters, indicative of dipole-dipole interactions and energy transfer between the monomeric units. We also used these methods to estimate the number of fluorescent proteins displayed on T7 phage molecules.

Poly(ester amine) Composed of Polyethylenimine and Pluronic Enhance Delivery of Antisense Oligonucleotides In Vitro and in Dystrophic mdx Mice

PubMed Central

Wang, Mingxing; Wu, Bo; Tucker, Jason D; Bollinger, Lauren E; Lu, Peijuan; Lu, Qilong

2016-01-01

A series of poly(esteramine)s (PEAs) constructed from low molecular weight polyethyleneimine (LPEI) and Pluronic were evaluated for the delivery of antisense oligonuclotides (AOs), 2′-O-methyl phosphorothioate RNA (2′-OMePS) and phosphorodiamidate morpholino oligomer (PMO) in cell culture and dystrophic mdx mice. Improved exon-skipping efficiency of both 2′-OMePS and PMO was observed in the C2C12E50 cell line with all PEA polymers compared with PEI 25k or LF-2k. The degree of efficiency was found in the order of PEA 01, PEA 04 > PEA 05 > others. The in vivo study in mdx mice demonstrated enhanced exon-skipping of 2′-OMePS with the order of PEA 06 > PEA 04, PEA 07 > PEA 03 > PEA 01 > others, and much higher than PEI 25k formulated 2′-OMePS. Exon-skipping efficiency of PMO in formulation with the PEAs were significantly enhanced in the order of PEA 02 > PEA 10 > PEA 01, PEA 03 > PEA 05, PEA 07, PEA 08 > others, with PEA 02 reaching fourfold of Endo-porter formulated PMO. PEAs improve PMO delivery more effectively than 2′-OMePS delivery in vivo, and the systemic delivery evaluation further highlight the efficiency of PEA for PMO delivery in all skeletal muscle. The results suggest that the flexibility of PEA polymers could be explored for delivery of different AO chemistries, especially for antisense therapy. PMID:27483024

Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

PubMed Central

Rockenstein, Edward; Nuber, Silke; Overk, Cassia R.; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H.; Campioni, Silvia; Riek, Roland; Winkler, Jürgen; Gage, Fred H.; Winner, Beate

2014-01-01

In Parkinson’s disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson’s disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction. PMID:24662516

Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo.

PubMed

Rockenstein, Edward; Nuber, Silke; Overk, Cassia R; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H; Campioni, Silvia; Riek, Roland; Winkler, Jürgen; Gage, Fred H; Winner, Beate; Masliah, Eliezer

2014-05-01

In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.

Role of the reaction of stabilized Criegee intermediates with peroxy radicals in particle formation and growth in air.

PubMed

Zhao, Yue; Wingen, Lisa M; Perraud, Véronique; Greaves, John; Finlayson-Pitts, Barbara J

2015-05-21

Ozonolysis of alkenes is an important source of secondary organic aerosol (SOA) in the atmosphere. However, the mechanisms by which stabilized Criegee intermediates (SCI) react to form and grow the particles, and in particular the contributions from oligomers, are not well understood. In this study, ozonolysis of trans-3-hexene (C6H12), as a proxy for small alkenes, was investigated with an emphasis on the mechanisms of particle formation and growth. Ozonolysis experiments were carried out both in static Teflon chambers (18-20 min reaction times) and in a glass flow reactor (24 s reaction time) in the absence and presence of OH or SCI scavengers, and under different relative humidity (RH) conditions. The chemical composition of polydisperse and size-selected SOA particles was probed using different mass spectrometric techniques and infrared spectroscopy. Oligomers having SCI as the chain unit are found to be the dominant components of such SOA particles. The formation mechanism for these oligomers suggested by our results follows the sequential addition of SCI to organic peroxy (RO2) radicals, in agreement with previous studies by Moortgat and coworkers. Smaller particles are shown to have a relatively greater contribution from longer oligomers. Higher O/C ratios are observed in smaller particles and are similar to those of oligomers resulting from RO2 + nSCI, supporting a significant role for longer oligomers in particle nucleation and early growth. Under atmospherically relevant RH of 30-80%, water vapor suppresses oligomer formation through scavenging SCI, but also enhances particle nucleation. Under humid conditions, or in the presence of formic or hydrochloric acid as SCI scavengers, peroxyhemiacetals are formed by the acid-catalyzed particle phase reaction between oligomers from RO2 + nSCI and a trans-3-hexene derived carbonyl product. In contrast to the ozonolysis of trans-3-hexene, oligomerization involving RO2 + nSCI does not appear to be prevalent in the ozonolysis of α-cedrene (C15H24), indicating different particle formation mechanisms for small and large complex alkenes that need to be taken into account in atmospheric models.

About the choice of Gibbs' potential for modelling of FCC ↔ HCP transformation in FeMnSi-based shape memory alloys

NASA Astrophysics Data System (ADS)

Evard, Margarita E.; Volkov, Aleksandr E.; Belyaev, Fedor S.; Ignatova, Anna D.

2018-05-01

The choice of Gibbs' potential for microstructural modeling of FCC ↔ HCP martensitic transformation in FeMn-based shape memory alloys is discussed. Threefold symmetry of the HCP phase is taken into account on specifying internal variables characterizing volume fractions of martensite variants. Constraints imposed on model constants by thermodynamic equilibrium conditions are formulated.

Hierarchical Theoretical Methods for Understanding and Predicting Anisotropic Thermal Transport Release in Rocket Propellant Formulations

DTIC Science & Technology

2016-12-08

mesoscopic models of interfaces and interphases, and microstructure-resolved representative volume element simulations. Atomic simulations were...title and subtitle with volume number and part number, if applicable. On classified documents, enter the title classification in parentheses. 5a...careful prediction of the pressure- volume -temperature equation of state, pressure- and temperature-dependent crystal and liquid thermal and transport

Uncapped silver nanoparticles synthesized by DC arc thermal plasma technique for conductor paste formulation

NASA Astrophysics Data System (ADS)

Shinde, Manish; Pawar, Amol; Karmakar, Soumen; Seth, Tanay; Raut, Varsha; Rane, Sunit; Bhoraskar, Sudha; Amalnerkar, Dinesh

2009-11-01

Uncapped silver nanoparticles were synthesized by DC arc thermal plasma technique. The synthesized nanoparticles were structurally cubic and showed wide particle size variation (between 20-150 nm). Thick film paste formulated from such uncapped silver nanoparticles was screen-printed on alumina substrates and the resultant `green' films were fired at different firing temperatures. The films fired at 600 °C revealed better microstructure properties and also yielded the lowest value of sheet resistance in comparison to those corresponding to conventional peak firing temperature of 850 °C. Our findings directly support the role of silver nanoparticles in substantially depressing the operative peak firing temperature involved in traditional conductor thick films technology.

A FFT-based formulation for discrete dislocation dynamics in heterogeneous media

NASA Astrophysics Data System (ADS)

Bertin, N.; Capolungo, L.

2018-02-01

In this paper, an extension of the DDD-FFT approach presented in [1] is developed for heterogeneous elasticity. For such a purpose, an iterative spectral formulation in which convolutions are calculated in the Fourier space is developed to solve for the mechanical state associated with the discrete eigenstrain-based microstructural representation. With this, the heterogeneous DDD-FFT approach is capable of treating anisotropic and heterogeneous elasticity in a computationally efficient manner. In addition, a GPU implementation is presented to allow for further acceleration. As a first example, the approach is used to investigate the interaction between dislocations and second-phase particles, thereby demonstrating its ability to inherently incorporate image forces arising from elastic inhomogeneities.

Charge delocalization characteristics of regioregular high mobility polymers

DOE PAGES

Coughlin, J. E.; Zhugayevych, A.; Wang, M.; ...

2017-01-01

Controlling the regioregularity among the structural units of narrow bandgap conjugated polymer backbones has led to improvements in optoelectronic properties, for example in the mobilities observed in field effect transistor devices. To investigate how the regioregularity affects quantities relevant to hole transport, regioregular and regiorandom oligomers representative of polymeric structures were studied using density functional theory. Several structural and electronic characteristics of the oligomers were compared, including chain planarity, cation spin density, excess charges on molecular units and internal reorganizational energy. The main difference between the regioregular and regiorandom oligomers is found to be the conjugated backbone planarity, while themore » reorganizational energies calculated are quite similar across the molecular family. Lastly, this work constitutes the first step on understanding the complex interplay of atomistic changes and an oligomer backbone structure toward modeling the charge transport properties.« less

Some photophysical properties of new oligomer obtained from anodic oxidation of 4,4‧-dimethoxychalcone

NASA Astrophysics Data System (ADS)

Ghomrasni, S.; Aribi, I.; Chemek, M.; Said, A. Haj; Alimi, K.

2018-04-01

Some photopysical properties of a new oligomer obtained from the anodic oxidation of the 4,4‧-dimethoxy-chalcone were investigated using different and complementary techniques. Firstly, TGA analysis and X-Ray diffraction experiments showed that the oligomer is thermally stable up to 500 K and partially organized at the solid state, respectively. Secondly, the optical properties of the oligomer were studied in solution and in the solid state. The optical band gap was estimated to be 3.17 eV in solution state and 2.70 eV in film state. What's more, the fluorescence decay is determined showing a considerably faster in the film state (0.183 ns) than in solution state (1.606 ns), due to the rapid non-radiative decay at inter-chain trap sites.

A mechanistic model of tau amyloid aggregation based on direct observation of oligomers

NASA Astrophysics Data System (ADS)

Shammas, Sarah L.; Garcia, Gonzalo A.; Kumar, Satish; Kjaergaard, Magnus; Horrocks, Mathew H.; Shivji, Nadia; Mandelkow, Eva; Knowles, Tuomas P. J.; Mandelkow, Eckhard; Klenerman, David

2015-04-01

Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. The fundamental microscopic reactions taking place during aggregation, and their rate constants, have been difficult to determine due to lack of suitable methods to identify and follow the low concentration of oligomers over time. Here we use single-molecule fluorescence to study the aggregation of the repeat domain of tau (K18), and two mutant forms linked with familial frontotemporal dementia, the deletion mutant ΔK280 and the point mutant P301L. Our kinetic analysis reveals that aggregation proceeds via monomeric assembly into small oligomers, and a subsequent slow structural conversion step before fibril formation. Using this approach, we have been able to quantitatively determine how these mutations alter the aggregation energy landscape.

Resin adhesion strengths to zirconia ceramics after primer treatment with silane coupling monomer or oligomer.

PubMed

Okada, Masahiro; Inoue, Kazusa; Irie, Masao; Taketa, Hiroaki; Torii, Yasuhiro; Matsumoto, Takuya

2017-09-26

Resin bonding to zirconia ceramics is difficult to achieve using the standard methods for conventional silica-based dental ceramics, which employ silane coupling monomers as primers. The hypothesis in this study was that a silane coupling oligomer -a condensed product of silane coupling monomers- would be a more suitable primer for zirconia. To prove this hypothesis, the shear bond strengths between a composite resin and zirconia were compared after applying either a silane coupling monomer or oligomer. The shear bond strength increased after applying a non-activated ethanol solution of the silane coupling oligomer compared with that achieved when applying the monomer. Thermal treatment of the zirconia at 110°C after application of the silane coupling agents was essential to improve the shear bond strength between the composite resin cement and zirconia.

Resveratrol Oligomers for the Prevention and Treatment of Cancers

PubMed Central

Xue, You-Qiu; Di, Jin-Ming; Luo, Yun; Cheng, Ke-Jun; Wei, Xing

2014-01-01

Resveratrol (3,4′,5-trihydroxystilbene) is a naturally derived phytoalexin stilbene isolated from grapes and other plants, playing an important role in human health and is well known for its extensive bioactivities, such as antioxidation, anti-inflammatory, anticancer. In addition to resveratrol, scientists also pay attention to resveratrol oligomers, derivatives of resveratrol, which are characterized by the polymerization of two to eight, or even more resveratrol units, and are the largest group of oligomeric stilbenes. Resveratrol oligomers have multiple beneficial properties, of which some are superior in activity, stability, and selectivity compared with resveratrol. The complicated structures and diverse biological activities are of significant interest for drug research and development and may provide promising prospects as cancer preventive and therapeutical agents. This review presents an overview on preventive or anticancer properties of resveratrol oligomers. PMID:24799982

EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

PubMed Central

Needham, Sarah R.; Roberts, Selene K.; Arkhipov, Anton; Mysore, Venkatesh P.; Tynan, Christopher J.; Zanetti-Domingues, Laura C.; Kim, Eric T.; Losasso, Valeria; Korovesis, Dimitrios; Hirsch, Michael; Rolfe, Daniel J.; Clarke, David T.; Winn, Martyn D.; Lajevardipour, Alireza; Clayton, Andrew H. A.; Pike, Linda J.; Perani, Michela; Parker, Peter J.; Shan, Yibing; Shaw, David E.; Martin-Fernandez, Marisa L.

2016-01-01

Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling. PMID:27796308

Probing the binding affinity of amyloids to reduce toxicity of oligomers in diabetes

PubMed Central

Smaoui, Mohamed Raef; Orland, Henri; Waldispühl, Jérôme

2015-01-01

Motivation: Amyloids play a role in the degradation of β-cells in diabetes patients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the β-cells to live longer. Results: We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length. The binding and extension lower toxicity and β-cell death. The amylin analog is designed through a parsimonious selection of mutations and is to be administered with the pramlintide drug, but not to interact with it. The mutations (T9K L12K S28H T30K) produce a stable native structure, strong binding affinity to oligomers, and long fibrils. We present an extended mathematical model for the insulin–glucose relationship and demonstrate how affecting the concentration of oligomers with such analog is strictly coupled with insulin release and β-cell fitness. Availability and implementation: SEMBA, the tool to probe the binding affinity of amyloid proteins and generate the binding affinity scoring matrices and R-scores is available at: http://amyloid.cs.mcgill.ca Contact: jeromew@cs.mcgill.ca Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25777526

Mechanisms leading to oligomers and SOA through aqueous photooxidation: insights from OH radical oxidation of acetic acid and methylglyoxal

NASA Astrophysics Data System (ADS)

Tan, Y.; Lim, Y. B.; Altieri, K. E.; Seitzinger, S. P.; Turpin, B. J.

2012-01-01

Previous experiments have demonstrated that the aqueous OH radical oxidation of methylglyoxal produces low volatility products including pyruvate, oxalate and oligomers. These products are found predominantly in the particle phase in the atmosphere, suggesting that methylglyoxal is a precursor of secondary organic aerosol (SOA). Acetic acid plays a central role in the aqueous oxidation of methylglyoxal and it is a ubiquitous product of gas phase photochemistry, making it a potential "aqueous" SOA precursor in its own right. However, the fate of acetic acid upon aqueous-phase oxidation is not well understood. In this research, acetic acid (20 μM-10 mM) was oxidized by OH radicals, and pyruvic acid and methylglyoxal experimental samples were analyzed using new analytical methods, in order to better understand the formation of SOA from acetic acid and methylglyoxal. Glyoxylic, glycolic, and oxalic acids formed from acetic acid and OH radicals. In contrast to the aqueous OH radical oxidation of methylglyoxal, the aqueous OH radical oxidation of acetic acid did not produce succinic acid and oligomers. This suggests that the methylgloxal-derived oligomers do not form through the acid catalyzed esterification pathway proposed previously. Using results from these experiments, radical mechanisms responsible for oligomer formation from methylglyoxal oxidation in clouds and wet aerosols are proposed. The importance of acetic acid/acetate as an SOA precursor is also discussed. We hypothesize that this and similar chemistry is central to the daytime formation of oligomers in wet aerosols.

Imide Oligomers Containing Pendent and Terminal Phenylethynyl Groups-2

NASA Technical Reports Server (NTRS)

Connell, J. W.; Smith, J. G., Jr.; Hergenrother, P. M.

1998-01-01

As part of a program to develop high-performance/high-temperature structural resins for aeronautical applications, imide oligomers containing pendent and terminal phenylethynyl groups were prepared, characterized and the cured resins evaluated as composite matrices. The oligomers were prepared at a calculated number-average molecular weight of 5000 g/mol and contained 15-20 mol% pendent phenylethynyl groups. In previous work, an oligomer containing pendent and terminal phenylethynyl groups exhibited a high glass transition temperature (approximately 313 C), and laminates therefrom exhibited high compressive properties, but processability, fracture toughness, microcrack resistance and damage tolerance were less than desired. In an attempt to improve these deficiencies, modifications in the oligomeric backbone involving the incorporation of 1,3-bis(3-aminophenoxy)benzene were investigated as a means of improving processability and toughness without detracting from the high glass transition temperature and high compressive properties. The amide acid oligomeric solutions were prepared in N-methyl-2-pyrrolidinone and were subsequently processed into imide powder, thin films, adhesive tape and carbon fiber prepreg. Neat resin plaques were fabricated from imide powder by compression moulding. The maximum processing pressure was 1.4 MPa and the cure temperature ranged from 350 to 371 C for 1 h for the mouldings, adhesives, films and composites. The properties of the 1,3-bis(3-aniinophenoxy)benzene modified cured imide oligomers containing pendent and terminal phenylethynyl groups are compared with those of previously prepared oligomers containing pendent and terminal phenylethynyl groups of similar composition and molecular weight.

Backbone conformation affects duplex initiation and duplex propagation in hybridisation of synthetic H-bonding oligomers.

PubMed

Iadevaia, Giulia; Núñez-Villanueva, Diego; Stross, Alexander E; Hunter, Christopher A

2018-06-06

Synthetic oligomers equipped with complementary H-bond donor and acceptor side chains form multiply H-bonded duplexes in organic solvents. Comparison of the duplex forming properties of four families of oligomers with different backbones shows that formation of an extended duplex with three or four inter-strand H-bonds is more challenging than formation of complexes that make only two H-bonds. The stabilities of 1 : 1 complexes formed between length complementary homo-oligomers equipped with either phosphine oxide or phenol recognition modules were measured in toluene. When the backbone is very flexible (pentane-1,5-diyl thioether), the stability increases uniformly by an order of magnitude for each additional base-pair added to the duplex: the effective molarities for formation of the first intramolecular H-bond (duplex initiation) and subsequent intramolecular H-bonds (duplex propagation) are similar. This flexible system is compared with three more rigid backbones that are isomeric combinations of an aromatic ring and methylene groups. One of the rigid systems behaves in exactly the same way as the flexible backbone, but the other two do not. For these systems, the effective molarity for formation of the first intramolecular H-bond is the same as that found for the other two backbones, but additional H-bonds are not formed between the longer oligomers. The effective molarities are too low for duplex propagation in these systems, because the oligomer backbones cannot adopt conformations compatible with formation of an extended duplex.

Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons.

PubMed

Zolezzi, Juan M; Lindsay, Carolina B; Serrano, Felipe G; Ureta, Roxana C; Theoduloz, Cristina; Schmeda-Hirschmann, Guillermo; Inestrosa, Nibaldo C

2018-01-01

Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

Rheological effect of gamma radiation on gel-like formulation: Appraisal for the construction of radiopharmaceuticals for cutaneous application

NASA Astrophysics Data System (ADS)

Saez, Vivian; Khoury, Helen Jamil; da Silva, Maria Isabel Barbosa; Mansur, Claudia Regina Elias; Santos-Oliveira, Ralph

2018-04-01

Skin cancer affects a lot of people being a malignant cutaneous melanoma one of the most aggressive neoplasms. Nowadays, the FDA-approved drugs to treat them are not as efficient as needed. Thus, the development of new agents or treatments is quite urgent. In that sense, the use of radioactive materials could represent a good alternative and especially Radium-223 is already been explored with promising results. Here, a Carbopol gel-like formulation was designed and irradiated with different doses in order to prove that it is suitable to include Radium-223 for its combined application by topic route. A formulation was obtained by the addition of triethanolamine to the Carbopol solution until pH 5.0. Physical and rheological tests showed that the formulation is a weak gel with a proper consistence to be administered by both routes. The formulation kept its appearance of transparent gel without change in color, presence of grits or syneresis after all tratments. The microstructure of gels was only slightly modified when the irradiation was made with 1000 Gy while the spreadability and viscosity were more deeply affected. Since the properties of this Carbopol gel-like formulation were maintained under irradiation doses until 100 Gy it is possible to consider that the formulation is suitable to include Radium-223 in order to evaluate its performance as localized drug delivery system for topical administration.

High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer.

PubMed

De Miguel, Diego; Gallego-Lleyda, Ana; Ayuso, José María; Pejenaute-Ochoa, Dolores; Jarauta, Vidal; Marzo, Isabel; Fernández, Luis J; Ochoa, Ignacio; Conde, Blanca; Anel, Alberto; Martinez-Lostao, Luis

2016-12-28

During the last years, a great effort has been invested into developing new TRAIL formulations with increased bioactivity, trying to overcome the resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumours. In our group, we have generated artificial lipid nanoparticles decorated with sTRAIL (LUV-TRAIL), emulating the physiological TRAIL-containing exosomes by which T-cells release TRAIL upon activation. We already demonstrated that LUV-TRAIL has greater cytotoxicity against both chemoresistant haematologic tumour cells and epithelial carcinoma cells compared to a form of sTRAIL similar to that used in clinical trials. In this study we have tested LUV-TRAIL in several human colon cancer cell lines with different sensitivity to sTRAIL. LUV-TRAIL significantly improved sTRAIL cytotoxicity in all colon cancer cell lines tested. Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity, we demonstrated that TRAIL-coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL, and this relied on LUV-TRAIL ability to promote DR5 clustering on the cell surface. Moreover, we show that TRAIL molecules are arranged in higher order oligomers only in LUV-TRAIL, which may explain their enhanced DR5 clustering ability. Finally, LUV-TRAIL showed significantly better antitumour activity than sTRAIL in an in vivo model using HCT-116 xenograft tumours in nude mice, validating its potential clinical application. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Blad-containing oligomer: a novel fungicide used in crop protection as an alternative treatment for tinea pedis and tinea versicolor.

PubMed

Carreira, Alexandra; Ferreira, João Boavida; Pereira, Iliana; Ferreira, João; Filipe, Paulo; Ferreira, Ricardo Boavida; Monteiro, Sara

2018-02-01

The lack of novel antifungal drugs and the increasing incidence and severity of fungal infections are major concerns worldwide. Herein, we tested the activity of the Blad-containing oligomer (BCO), a new antifungal molecule already in use for agriculture, on Malassezia spp. and dermatophytes, the causal agents of human tinea versicolor and tinea pedis. Given the lack of a standard method for Malassezia susceptibility testing and the plethora of published methods, we also developed an improved method for this genus. The efficacy of BCO was assessed in vitro and compared to that of the drugs currently utilized in the treatment of tinea versicolor (fluconazole and itraconazole) and tinea pedis (itraconazole and terbinafine). For dermatophytes, the standard microdilution broth-based method was used, with small adjustments, and several broth formulations and inocula sizes were tested to develop an improved susceptibility method for Malassezia spp. We successfully developed a microdilution broth-based method with considerable advantages over other available methods, and used it for all in vitro susceptibility tests of Malassezia spp. isolates. We report that, on a molar basis, BCO was more effective than fluconazole or itraconazole on most strains of Malassezia spp. isolated from clinical samples (n=29). By contrast, BCO was less effective than itraconazole or terbinafine on the common dermatophytes Trichophyton rubrum and Trichophyton interdigitale. These data place BCO as a promising drug for the treatment of Malassezia-associated skin diseases. Further in vivo studies are now required to ascertain its applicability in the clinical setting.

Structural Characterization of Monomers and Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion Mobility Mass Spectrometry

NASA Astrophysics Data System (ADS)

Pang, Xueqin; Jia, Chenxi; Chen, Zhengwei; Li, Lingjun

2017-01-01

The D-residues are crucial to biological function of D-amino acid containing peptides (DAACPs). Previous ion mobility mass spectrometry (IM-MS) studies revealing oligomerization patterns of amyloid cascade demonstrated conversion from native soluble unstructured assembly to fibril ß-sheet oligomers, which has been implicated in amyloid diseases, such as Alzheimer's disease and type 2 diabetes. Although neuropeptides are typically present at very low concentrations in circulation, their local concentrations could be much higher in large dense core vesicles, forming dimers or oligomers. We studied the oligomerization of protonated and metal-adducted achatin I and dermorphin peptide isomers with IM-MS. Our results suggested that dimerization, oligomerization, and metal adduction augment the structural differences between D/L peptide isomers compared to protonated monomers. Dimers and oligomers enhanced the structural differences between D/L peptide isomers in both aqueous and organic solvent system. Furthermore, some oligomer forms were only observed for either D- or L-isomers, indicating the importance of chiral center in oligomerization process. The oligomerization patterns of D/L isomers appear to be similar. Potassium adducts were detected to enlarge the structural differences between D/L isomers.

Structural Insights into Amyloid Oligomers of the Parkinson Disease-related Protein α-Synuclein*

PubMed Central

Gallea, J. Ignacio; Celej, M. Soledad

2014-01-01

The presence of intraneuronal deposits mainly formed by amyloid fibrils of the presynaptic protein α-synuclein (AS) is a hallmark of Parkinson disease. Currently, neurotoxicity is attributed to prefibrillar oligomeric species rather than the insoluble aggregates, although their mechanisms of toxicity remain elusive. Structural details of the supramolecular organization of AS oligomers are critically needed to decipher the structure-toxicity relationship underlying their pathogenicity. In this study, we employed site-specific fluorescence to get a deeper insight into the internal architecture of AS oligomeric intermediates. We demonstrate that AS oligomers are ordered assemblies possessing a well defined pattern of intermolecular contacts. Some of these contacts involve regions that form the β-sheet core in the fibrillar state, although their spatial arrangement may differ in the two aggregated forms. However, even though the two termini are excluded from the fibrillar core, they are engaged in a number of intermolecular interactions within the oligomer. Therefore, substantial structural remodeling of early oligomeric interactions is essential for fibril growth. The intermolecular contacts identified in AS oligomers can serve as targets for the rational design of anti-amyloid compounds directed at preventing oligomeric interactions/reorganizations. PMID:25143382

Toxic prefibrillar α-synuclein amyloid oligomers adopt a distinctive antiparallel β-sheet structure.

PubMed

Celej, María Soledad; Sarroukh, Rabia; Goormaghtigh, Erik; Fidelio, Gerardo D; Ruysschaert, Jean-Marie; Raussens, Vincent

2012-05-01

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early β-sheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Ultrafast Photoinduced Electron Transfer in a π-Conjugated Oligomer/Porphyrin Complex.

PubMed

Aly, Shawkat M; Goswami, Subhadip; Alsulami, Qana A; Schanze, Kirk S; Mohammed, Omar F

2014-10-02

Controlling charge transfer (CT), charge separation (CS), and charge recombination (CR) at the donor-acceptor interface is extremely important to optimize the conversion efficiency in solar cell devices. In general, ultrafast CT and slow CR are desirable for optimal device performance. In this Letter, the ultrafast excited-state CT between platinum oligomer (DPP-Pt(acac)) as a new electron donor and porphyrin as an electron acceptor is monitored for the first time using femtosecond (fs) transient absorption (TA) spectroscopy with broad-band capability and 120 fs temporal resolution. Turning the CT on/off has been shown to be possible either by switching from an organometallic oligomer to a metal-free oligomer or by controlling the charge density on the nitrogen atom of the porphyrin meso unit. Our time-resolved data show that the CT and CS between DPP-Pt(acac) and cationic porphyrin are ultrafast (approximately 1.5 ps), and the CR is slow (ns time scale), as inferred from the formation and the decay of the cationic and anionic species. We also found that the metallic center in the DPP-Pt(acac) oligomer and the positive charge on the porphyrin are the keys to switching on/off the ultrafast CT process.

Hydrolysis kinetics of secoisolariciresinol diglucoside oligomers from flaxseed.

PubMed

Yuan, Jian-Ping; Li, Xin; Xu, Shi-Ping; Wang, Jiang-Hai; Liu, Xin

2008-11-12

Flaxseed is the richest dietary source of the lignan secoisolariciresinol diglucoside (SDG) and contains the largest amount of SDG oligomers, which are often hydrolyzed to break the ester linkages for the release of SDG and the glycosidic bonds for the release of secoisolariciresinol (SECO). The alkaline hydrolysis reaction kinetics of SDG oligomers from flaxseed and the acid hydrolysis process of SDG and other glucosides were investigated. For the kinetic modeling, a pseudo-first-order reaction was assumed. The results showed that the alkaline hydrolysis of SDG oligomers followed first-order reaction kinetics under mild alkaline hydrolytic conditions and that the concentration of sodium hydroxide had a strong influence on the activation energy of the alkaline hydrolysis of SDG oligomers. The results also indicated that the main acid hydrolysates of SDG included secoisolariciresinol monoglucoside (SMG), SECO, and anhydrosecoisolariciresinol (anhydro-SECO) and that the extent and the main hydrolysates of the acid hydrolysis reaction depended on the acid concentration, hydrolysis temperature, and time. In addition, the production and change of p-coumaric acid glucoside, ferulic acid glucoside and their methyl esters and p-coumaric acid, ferulic acid, and their methyl esters during the process of hydrolysis was also investigated.

Stochastic modelling of microstructure formation in solidification processes

NASA Astrophysics Data System (ADS)

Nastac, Laurentiu; Stefanescu, Doru M.

1997-07-01

To relax many of the assumptions used in continuum approaches, a general stochastic model has been developed. The stochastic model can be used not only for an accurate description of the fraction of solid evolution, and therefore accurate cooling curves, but also for simulation of microstructure formation in castings. The advantage of using the stochastic approach is to give a time- and space-dependent description of solidification processes. Time- and space-dependent processes can also be described by partial differential equations. Unlike a differential formulation which, in most cases, has to be transformed into a difference equation and solved numerically, the stochastic approach is essentially a direct numerical algorithm. The stochastic model is comprehensive, since the competition between various phases is considered. Furthermore, grain impingement is directly included through the structure of the model. In the present research, all grain morphologies are simulated with this procedure. The relevance of the stochastic approach is that the simulated microstructures can be directly compared with microstructures obtained from experiments. The computer becomes a `dynamic metallographic microscope'. A comparison between deterministic and stochastic approaches has been performed. An important objective of this research was to answer the following general questions: (1) `Would fully deterministic approaches continue to be useful in solidification modelling?' and (2) `Would stochastic algorithms be capable of entirely replacing purely deterministic models?'

Modeling creep deformation of a two-phase TiAI/Ti3Al alloy with a lamellar microstructure

NASA Astrophysics Data System (ADS)

Bartholomeusz, Michael F.; Wert, John A.

1994-10-01

A two-phase TiAl/Ti3Al alloy with a lamellar microstructure has been previously shown to exhibit a lower minimum creep rate than the minimum creep rates of the constituent TiAl and Ti3Al single-phase alloys. Fiducial-line experiments described in the present article demonstrate that the creep rates of the constituent phases within the two-phase TiAl/Ti3Al lamellar alloy tested in compression are more than an order of magnitude lower than the creep rates of single-phase TiAl and Ti3Al alloys tested in compression at the same stress and temperature. Additionally, the fiducial-line experiments show that no interfacial sliding of the phases in the TiAl/Ti3Al lamellar alloy occurs during creep. The lower creep rate of the lamellar alloy is attributed to enhanced hardening of the constituent phases within the lamellar microstructure. A composite-strength model has been formulated to predict the creep rate of the lamellar alloy, taking into account the lower creep rates of the constituent phases within the lamellar micro-structure. Application of the model yields a very good correlation between predicted and experimentally observed minimum creep rates over moderate stress and temperature ranges.

Synthesis and Electronic Properties of Length-Defined 9,10-Anthrylene-Butadiynylene Oligomers.

PubMed

Nagaoka, Maiko; Tsurumaki, Eiji; Nishiuchi, Mai; Iwanaga, Tetsuo; Toyota, Shinji

2018-05-18

Linear π-conjugated oligomers consisting of anthracene and diacetylene units were readily synthesized by a one-pot process that involved desilylation and oxidative coupling from appropriate building units. We were able to isolate length-defined oligomers ranging from 2-mer to 6-mer as stable and soluble solids. The bathochromic shifts in the UV-vis spectra suggested that the π-conjugation was extended with elongation of the linear chain. Cyclic voltammetric measurements showed characteristic reversible oxidation waves that were dependent on the number of anthracene units.

Solution of free-boundary problems using finite-element/Newton methods and locally refined grids - Application to analysis of solidification microstructure

NASA Technical Reports Server (NTRS)

Tsiveriotis, K.; Brown, R. A.

1993-01-01

A new method is presented for the solution of free-boundary problems using Lagrangian finite element approximations defined on locally refined grids. The formulation allows for direct transition from coarse to fine grids without introducing non-conforming basis functions. The calculation of elemental stiffness matrices and residual vectors are unaffected by changes in the refinement level, which are accounted for in the loading of elemental data to the global stiffness matrix and residual vector. This technique for local mesh refinement is combined with recently developed mapping methods and Newton's method to form an efficient algorithm for the solution of free-boundary problems, as demonstrated here by sample calculations of cellular interfacial microstructure during directional solidification of a binary alloy.

Investigation into the Microstructure, Texture and Rheological Properties of Chocolate Ganache.

PubMed

McGill, Jade; Hartel, Rich W

2018-03-01

Ganache is a mixture of chocolate and dairy. Although a popular confection, little is known about how it functions as a system. Objectives were to (1) determine if dairy fats and cocoa butter mix in ganache, (2) characterize ganache microstructure, and how structure affects texture and rheology, and (3) identify how changes in chocolate composition alter ganache. Textural analysis, differential scanning calorimetry, stress sweep tests, and microscopy were used to examine ganache formulations that varied in dairy source (cream or butter) or in solid fat content (SFC), composition or type of chocolate. Melting temperatures for all ganache formulations were lower than for chocolate, indicating that cream milk fat globules rupture during processing, and mix with cocoa butter. Altering the SFC of chocolate affected ganache hardness, spreadability, melting enthalpy, and resistance to deformation. Chocolate systems made with constant fat content and greater amounts of defatted cocoa powder relative to sugar or nonfat milk powder yielded ganache that was harder, less spreadable, and more resistant to deformation. Ganache made with commercially produced dark, milk, and white chocolates behaved similarly to model chocolate systems. Ganache attributes are affected by chocolate crystalline fat content in addition to particle phase volume-greater levels of cocoa powder, which is mostly insoluble, strengthens ganache structure, producing a firmer product, whereas greater levels of milk powder and sugar, which dissolve in the aqueous cream component, produce a softer ganache. Understanding how ganache functions as a system and how differences in chocolate composition affect its textural and rheological properties may allow for greater control over the desired characteristics of the final product. For example, this research shows how changing cocoa content of the chocolate affects ganache, which is useful when developing formulations involving chocolates with different cocoa percentages. There may also be cost saving implications; for example, using a chocolate with a harder cocoa butter may allow less total chocolate to be used in a formulation, while still achieving an appropriate texture. © 2018 Institute of Food Technologists®.

A sequence-dependent rigid-base model of DNA

NASA Astrophysics Data System (ADS)

Gonzalez, O.; Petkevičiutė, D.; Maddocks, J. H.

2013-02-01

A novel hierarchy of coarse-grain, sequence-dependent, rigid-base models of B-form DNA in solution is introduced. The hierarchy depends on both the assumed range of energetic couplings, and the extent of sequence dependence of the model parameters. A significant feature of the models is that they exhibit the phenomenon of frustration: each base cannot simultaneously minimize the energy of all of its interactions. As a consequence, an arbitrary DNA oligomer has an intrinsic or pre-existing stress, with the level of this frustration dependent on the particular sequence of the oligomer. Attention is focussed on the particular model in the hierarchy that has nearest-neighbor interactions and dimer sequence dependence of the model parameters. For a Gaussian version of this model, a complete coarse-grain parameter set is estimated. The parameterized model allows, for an oligomer of arbitrary length and sequence, a simple and explicit construction of an approximation to the configuration-space equilibrium probability density function for the oligomer in solution. The training set leading to the coarse-grain parameter set is itself extracted from a recent and extensive database of a large number of independent, atomic-resolution molecular dynamics (MD) simulations of short DNA oligomers immersed in explicit solvent. The Kullback-Leibler divergence between probability density functions is used to make several quantitative assessments of our nearest-neighbor, dimer-dependent model, which is compared against others in the hierarchy to assess various assumptions pertaining both to the locality of the energetic couplings and to the level of sequence dependence of its parameters. It is also compared directly against all-atom MD simulation to assess its predictive capabilities. The results show that the nearest-neighbor, dimer-dependent model can successfully resolve sequence effects both within and between oligomers. For example, due to the presence of frustration, the model can successfully predict the nonlocal changes in the minimum energy configuration of an oligomer that are consequent upon a local change of sequence at the level of a single point mutation.

Preparation and characterization of chemically defined oligomers of rabbit immunoglobulin G molecules for the complement binding studies.

PubMed Central

Wright, J K; Tschopp, J; Jaton, J C

1980-01-01

Pure dimers, trimers, tetramers and pentamers of rabbit non-immune IgG (immunoglobulin G) or antibody IgG were prepared by polymerization in the presence of the bifunctional cross-linking reagent dithiobis (succinimidylpropionate). Oligomerization was performed either in the presence of polysaccharide antigen and specific monomeric antibody (method A) or by random cross-linking of non-immune rabbit IgG in the absence of antigen (method B). By repeated gel-filtration chromatography, samples prepared by both methods exhibited a single band in analytical sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The electrophoretic mobilities of samples prepared by method A were slightly greater than those for the corresponding samples prepared by method B. This might suggest a role played by antigen in the orientation of IgG molecules within the clusters, which may be more compact than those formed by random cross-linking. The average numbers of cross-linker molecules per oligomer varied between 3 and 6 for clusters made by method A and between 1 and 3 for clusters made by method B. Ultracentrifugal analyses of the oligomers yielded sedimentation coefficients (S20,w) of 9.6S for the dimer, 11.2S for the trimer, 13.6S for the tetramer and 16.1S for the pentamer. Comparison of the observed sedimentation coefficients with those predicted by various hydrodynamic models suggested these oligomers possessed open and linear structures. Reduction of the cross-linking molecules converted oligomers into monomeric species of IgG. C.d. spectra of some oligomers studied in the range 200-250 nm were essentially the same as that of monomeric IgG molecules, thus strongly suggesting no major conformation changes in IgG molecules within clusters. These oligomers were found to be stable for up to 2 months when stored at -70 degrees C. Images Fig. 1. Fig. 4. PMID:7188424

High-order oligomers of intrinsically disordered brain proteins BASP1 and GAP-43 preserve the structural disorder.

PubMed

Forsova, Oksana S; Zakharov, Vladislav V

2016-04-01

Brain acid-soluble protein-1 (BASP1) and growth-associated protein-43 (GAP-43) are presynaptic membrane proteins participating in axon guidance, neuroregeneration and synaptic plasticity. They are presumed to sequester phosphatidylinositol-4,5-bisphosphate (PIP2 ) in lipid rafts. Previously we have shown that the proteins form heterogeneously sized oligomers in the presence of anionic phospholipids or SDS at submicellar concentration. BASP1 and GAP-43 are intrinsically disordered proteins (IDPs). In light of this, we investigated the structure of their oligomers. Using partial cross-linking of the oligomers with glutaraldehyde, the aggregation numbers of BASP1 and GAP-43 were estimated as 10-14 and 6-7 monomer subunits, respectively. The cross-linking pattern indicated that the subunits are circularly arranged. The circular dichroism (CD) spectra of the monomers were characteristic of coil-like IDPs showing unordered structure with a high population of polyproline-II conformation. The oligomerization was accompanied by a minor CD spectral change attributable to formation of a small amount of α-helix. The number of residues in the α-helical conformation was estimated as 13 in BASP1 and 18 in GAP-43. However, the overall structure of the oligomers remained disordered, indicating a high degree of 'fuzziness'. This was confirmed by measuring the hydrodynamic dimensions of the oligomers using polyacrylamide gradient gel electrophoresis and size-exclusion chromatography, and by assaying their sensitivity to proteolytic digestion. There is evidence that the observed α-helical folding occurs within the basic effector domains, which are presumably tethered together via anionic molecules of SDS or PIP2 . We conclude that BASP1 and GAP-43 oligomers preserve a mostly disordered structure, which may be of great importance for their function in PIP2 signaling pathway. © 2016 Federation of European Biochemical Societies.

Interdependence of the kinetics of NTP hydrolysis and the stability of the RecA-ssDNA complex.

PubMed

Katz, F S; Bryant, F R

2001-09-18

The ssDNA-dependent NTP hydrolysis activity of the RecA protein was examined using a series of dTn oligomers ranging in size from dT10 to dT2000 as the ssDNA effector. There were three distinct manifestations of the dTn-dependent NTP hydrolysis reaction, depending on the length of the dTn effector that was used. With longer dTn oligomers, NTP hydrolysis occurred with a turnover number of 20-25 min(-1) and the observed S0.5 value for the NTP was independent of the concentration of the dTn oligomer (DNA concentration-independent hydrolysis). With dTn oligomers of intermediate length, NTP hydrolysis still occurred with a turnover number of 20-25 min(-1), but the observed S0.5 for the NTP decreased with increasing dTn concentration until reaching a value similar to that obtained with the longer dTn oligomers (DNA concentration-dependent hydrolysis). With shorter dTn oligomers, the NTP hydrolysis activity was effectively eliminated. Although this general progression of kinetic behavior was observed for the three structurally related NTPs (dATP, ATP, and GTP), the dTn oligomer length at which DNA concentration-independent, DNA concentration-dependent, and no NTP hydrolysis was observed depended on the NTP being considered. For example, dATP (S0.5 = 35 microM) was hydrolyzed in the presence of dT20, whereas ATP (S0.5 = 70 microM) and GTP (S0.5 = 1200 microM) required at least dT50 and dT200 for hydrolysis, respectively. These results are discussed in terms of a kinetic model in which the stability of the RecA-ssDNA-NTP complex is dependent on the intrinsic S0.5 value of the NTP being hydrolyzed.

A sequence-dependent rigid-base model of DNA.

PubMed

Gonzalez, O; Petkevičiūtė, D; Maddocks, J H

2013-02-07

A novel hierarchy of coarse-grain, sequence-dependent, rigid-base models of B-form DNA in solution is introduced. The hierarchy depends on both the assumed range of energetic couplings, and the extent of sequence dependence of the model parameters. A significant feature of the models is that they exhibit the phenomenon of frustration: each base cannot simultaneously minimize the energy of all of its interactions. As a consequence, an arbitrary DNA oligomer has an intrinsic or pre-existing stress, with the level of this frustration dependent on the particular sequence of the oligomer. Attention is focussed on the particular model in the hierarchy that has nearest-neighbor interactions and dimer sequence dependence of the model parameters. For a Gaussian version of this model, a complete coarse-grain parameter set is estimated. The parameterized model allows, for an oligomer of arbitrary length and sequence, a simple and explicit construction of an approximation to the configuration-space equilibrium probability density function for the oligomer in solution. The training set leading to the coarse-grain parameter set is itself extracted from a recent and extensive database of a large number of independent, atomic-resolution molecular dynamics (MD) simulations of short DNA oligomers immersed in explicit solvent. The Kullback-Leibler divergence between probability density functions is used to make several quantitative assessments of our nearest-neighbor, dimer-dependent model, which is compared against others in the hierarchy to assess various assumptions pertaining both to the locality of the energetic couplings and to the level of sequence dependence of its parameters. It is also compared directly against all-atom MD simulation to assess its predictive capabilities. The results show that the nearest-neighbor, dimer-dependent model can successfully resolve sequence effects both within and between oligomers. For example, due to the presence of frustration, the model can successfully predict the nonlocal changes in the minimum energy configuration of an oligomer that are consequent upon a local change of sequence at the level of a single point mutation.

Wnt-related SynGAP1 is a neuroprotective factor of glutamatergic synapses against Aβ oligomers

PubMed Central

Codocedo, Juan F.; Montecinos-Oliva, Carla; Inestrosa, Nibaldo C.

2015-01-01

Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Aβ oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored. That is why we aim to study the relationship between Wnt-5a and miRNAs in glutamatergic synapses. We performed in silico analysis which predicted that miR-101b may inhibit the expression of synaptic GTPase-Activating Protein (SynGAP1), a Ras GTPase-activating protein critical for the development of cognition and proper synaptic function. Through overexpression of miR-101b, we showed that miR-101b is able to regulate the expression of SynGAP1 in an hippocampal cell line. Moreover and consistent with a decrease of miR-101b, Wnt-5a enhances SynGAP expression in cultured hippocampal neurons. Additionally, Wnt-5a increases the activity of SynGAP in a time-dependent manner, with a similar kinetic to CaMKII phosphorylation. This also, correlates with a modulation in the SynGAP clusters density. On the other hand, Aβ oligomers permanently decrease the number of SynGAP clusters. Interestingly, when neurons are co-incubated with Wnt-5a and Aβ oligomers, we do not observe the detrimental effect of Aβ oligomers, indicating that, Wnt-5a protects neurons from the synaptic failure triggered by Aβ oligomers. Overall, our findings suggest that SynGAP1 is part of the signaling pathways induced by Wnt-5a. Therefore, possibility exists that SynGAP is involved in the synaptic protection against Aβ oligomers. PMID:26124704

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ngo, Sam; Guo, Zhefeng, E-mail: zhefeng@ucla.edu

Highlights: Black-Right-Pointing-Pointer A{beta} oligomers are neurotoxins and likely the causing agents for Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}42 fusion protein form globular oligomers. Black-Right-Pointing-Pointer A{beta}42 fusion protein oligomers contain SDS-resistant tetramers and hexamers. Black-Right-Pointing-Pointer Cysteine substitutions at residues 31, 32, 34, 39-41 disrupt A{beta}42 oligomerization. -- Abstract: Deposition of amyloid fibrils consisting of amyloid {beta} (A{beta}) protein as senile plaques in the brain is a pathological hallmark of Alzheimer's disease. However, a growing body of evidence shows that soluble A{beta} oligomers correlate better with dementia than fibrils, suggesting that A{beta} oligomers may be the primary toxic species. The structure and oligomerization mechanismmore » of these A{beta} oligomers are crucial for developing effective therapeutics. Here we investigated the oligomerization of A{beta}42 in the context of a fusion protein containing GroES and ubiquitin fused to the N-terminus of A{beta} sequence. The presence of fusion protein partners, in combination with a denaturing buffer containing 8 M urea at pH 10, is unfavorable for A{beta}42 aggregation, thus allowing only the most stable structures to be observed. Transmission electron microscopy showed that A{beta}42 fusion protein formed globular oligomers, which bound weakly to thioflavin T and Congo red. SDS-PAGE shows that A{beta}42 fusion protein formed SDS-resistant hexamers and tetramers. In contrast, A{beta}40 fusion protein remained as monomers on SDS gel, suggesting that the oligomerization of A{beta}42 fusion protein is not due to the fusion protein partners. Cysteine scanning mutagenesis at 22 residue positions further revealed that single cysteine substitutions of the C-terminal hydrophobic residues (I31, I32, L34, V39, V40, and I41) led to disruption of hexamer and tetramer formation, suggesting that hydrophobic interactions between these residues are most critical for A{beta}42 oligomerization.« less

Grape seed polyphenolic extract specifically decreases aβ*56 in the brains of Tg2576 mice.

PubMed

Liu, Peng; Kemper, Lisa J; Wang, Jun; Zahs, Kathleen R; Ashe, Karen H; Pasinetti, Giulio M

2011-01-01

Amyloid-β (Aβ) oligomers, found in the brains of Alzheimer's disease (AD) patients and transgenic mouse models of AD, cause synaptotoxicity and memory impairment. Grape seed polyphenolic extract (GSPE) inhibits Aβ oligomerization in vitro and attenuates cognitive impairment and AD-related neuropathology in the brains of transgenic mice. In the current study, GSPE was administered to Tg2576 mice for a period of five months. Treatment significantly decreased brain levels of Aβ*56, a 56-kDa Aβ oligomer previously shown to induce memory dysfunction in rodents, without changing the levels of transgenic amyloid-β protein precursor, monomeric Aβ, or other Aβ oligomers. These results thus provide the first demonstration that a safe and affordable intervention can lower the levels of a memory-impairing Aβ oligomer in vivo and strongly suggest that GSPE should be further tested as a potential prevention and/or therapy for AD.

Biodegradable polyester-based eco-composites containing hemp fibers modified with macrocyclic oligomers

NASA Astrophysics Data System (ADS)

Conzatti, Lucia; Utzeri, Roberto; Hodge, Philip; Stagnaro, Paola

2016-05-01

An original compatibilizing pathway for hemp fibers/poly(1,4-butylene adipate-co-terephtalate) (PBAT) eco-composites was explored exploiting the capability of macrocyclic oligomers (MCOs), obtained by cyclodepolymerization (CDP) of PBAT at high dilution, of being re-converted into linear chains by entropically-driven ring-opening polymerization (ED-ROP) that occurs simply heating the MCOS in the bulk. CDP reaction of PBAT was carried out varying solvent, catalyst and reaction time. Selected MCOs were used to adjust the conditions of the ED-ROP reaction. The best experimental conditions were then adopted to modify hemp fibers. Eco-composites based on PBAT and hemp fibers as obtained or modified with PBAT macrocyclics or oligomers were prepared by different process strategies. The best fiber-PBAT compatibility was observed when the fibers were modified with PBAT oligomers before incorporation in the polyester matrix.

Ab Initio Study of Polarizabilities of Oligothiophene, Oligocyclopentadiene and Oligofulvene and their Cyano Substituted Oligomers

NASA Astrophysics Data System (ADS)

Lagowski, Jolanta; Ferdous, Sultana

2005-03-01

Ab Initio polarizabilities of thiophene, fulvene and cyclopentadiene based conducting oligomers and polymers and their cyano derivatives have been calculated using the Hartree-Fock (HF), configuration interaction (singles) (CIS ) and density functional (DF) theories with 3-21G* basis using Gaussian software. The main motivation of this investigation is to determine the correlation between the excitation energies and polarizabilities for the conjugated systems studied. It has been found that HF and DF approaches give similar magnitudes for polarizabilities whereas CIS theory provides results that are considerably different. All three methods predict similar trends in polarizabilities as a function of oligomer length and bond alternation along the backbone of the oligomers. It has also been observed that the end groups and the number of `double' bonds have a significant effect on the magnitude of polarizability per C-C bond. Comparison with experimental results will be made where possible.

Prebiotic Polymerization: Oxidative Polymerization of 2,3 Dimercapto-1- Propanol on the Surface of Iron(III) Hydroxide Oxide

NASA Technical Reports Server (NTRS)

Weber, Arthur L.

1995-01-01

The oxidation of 2,3-dimercapto-1-propanol by ferric ions on the surface of iron(III) hydroxide oxide (Fe(OH)O) yielded polydisulfide oligomers. This polymerization occurred readily at low dithiol concentration under mild aqueous conditions. Polydisulfide polymers up to the 15-mer were synthesized from 1 mM dithiol in 5 ml water reacted with iron(III) hydroxide oxide (20 mg, 160 micromole Fe) for 3 days under anaerobic conditions at 40 C and pH 4. About 91% of the dithiol was converted to short soluble oligomers and 9% to insoluble larger oligomers that were isolated with the FE(OH)O phase. Reactions carried out at the same ratio of dithiol to FE(OH)O but at higher dithiol concentrations gave higher yields of the larger insoluble oligomers. The relationship of these results to prebiotic polymer synthesis is discussed.

Prebiotic polymerization: Oxidative polymerization of 2, 3-dimercapto-1-propanol on the surface of iron(III) hydroxide oxide

NASA Technical Reports Server (NTRS)

Weber, Arthur L.

1995-01-01

The oxidation of 2, 3-dimercapto-1-propanol by ferric ions on the surface of iron(III) hydroxide oxide (Fe(OH)O) yielded polydisulfide oligomers. This polymerization occurred readily at low dithiol concentration under mild aqueous conditions. Polydisulfide polymers up to the 15-mer were synthesized from 1 mM dithiol in 5 ml water reacted with iron(III) hydroxide oxide (20 mg, 160 micromole Fe) for 3 days under anaerobic conditions at 40 C and pH 4. About 91% of the dithiol was converted to short soluble oligomers and 9% to insoluble larger oligomers that were isolated with the Fe(OH)O phase. Reactions carried out at the same ratio of dithiol to Fe(OH)O but at higher dithiol concentrations gave higher yields of the larger insoluble oligomers. The relationship of these results to prebiotic polymer synthesis is discussed.

Combining Orthogonal Chain-End Deprotections and Thiol-Maleimide Michael Coupling: Engineering Discrete Oligomers by an Iterative Growth Strategy.

PubMed

Huang, Zhihao; Zhao, Junfei; Wang, Zimu; Meng, Fanying; Ding, Kunshan; Pan, Xiangqiang; Zhou, Nianchen; Li, Xiaopeng; Zhang, Zhengbiao; Zhu, Xiulin

2017-10-23

Orthogonal maleimide and thiol deprotections were combined with thiol-maleimide coupling to synthesize discrete oligomers/macromolecules on a gram scale with molecular weights up to 27.4 kDa (128mer, 7.9 g) using an iterative exponential growth strategy with a degree of polymerization (DP) of 2 n -1. Using the same chemistry, a "readable" sequence-defined oligomer and a discrete cyclic topology were also created. Furthermore, uniform dendrons were fabricated using sequential growth (DP=2 n -1) or double exponential dendrimer growth approaches (DP=22n -1) with significantly accelerated growth rates. A versatile, efficient, and metal-free method for construction of discrete oligomers with tailored structures and a high growth rate would greatly facilitate research into the structure-property relationships of sophisticated polymeric materials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseas

PubMed Central

Ferreira, Sergio T; Klein, William L

2015-01-01

Alzheimer's disease is the 3rd most costly disease and is estimated to be the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD. PMID:21914486

Formation of nitrogen-containing oligomers by methylglyoxal and amines in simulated evaporating cloud droplets.

PubMed

De Haan, David O; Hawkins, Lelia N; Kononenko, Julia A; Turley, Jacob J; Corrigan, Ashley L; Tolbert, Margaret A; Jimenez, Jose L

2011-02-01

Reactions of methylglyoxal with amino acids, methylamine, and ammonium sulfate can take place in aqueous aerosol and evaporating cloud droplets. These processes are simulated by drying droplets and bulk solutions of these compounds (at low millimolar and 1 M concentrations, respectively) and analyzing the residuals by scanning mobility particle sizing, nuclear magnetic resonance, aerosol mass spectrometry (AMS), and electrospray ionization MS. The results are consistent with imine (but not diimine) formation on a time scale of seconds, followed by the formation of nitrogen-containing oligomers, methylimidazole, and dimethylimidazole products on a time scale of minutes to hours. Measured elemental ratios are consistent with imidazoles and oligomers being major reaction products, while effective aerosol densities suggest extensive reactions take place within minutes. These reactions may be a source of the light-absorbing, nitrogen-containing oligomers observed in urban and biomass-burning aerosol particles.

Light-curing reinforcement for denture base resin using a glass fiber cloth pre-impregnated with various urethane oligomers.

PubMed

Kanie, Takahito; Arikawa, Hiroyuki; Fujii, Koichi; Ban, Seiji

2004-09-01

The purpose of this study was to investigate the flexural properties of denture base resin reinforced using glass fiber cloth and a urethane oligomer. The five types of oligomer used in this study were S5, S9, S3, U4, and U6, which have varying functional groups and viscosities. The flexural properties of S9 with glass fiber cloth could not be measured because S9 is elastic. In the heat-cured resin reinforced with S9, the reinforcement peeled away from the resin. In the self- and light-cured resins reinforced with S9, the flexural properties increased significantly. When reinforced with the other four oligomers (S5, S3, U4, and U6), the flexural strength and flexural modulus of the self-, heat-, and light-cured resins increased significantly (p<0.01).

Effect of polymer properties and adherend surfaces on adhesion

NASA Technical Reports Server (NTRS)

Dwight, D. W.; Wightman, J. P.

1976-01-01

High temperature polymer surface characteristics associated with joint strength were evaluated. Selected samples represented composite adherends, aluminum filler and fiber glass carrier cloth. Detailed analysis of fractured joint surfaces revealed unique characteristics typical of the specific adhesive formulations and test conditions. A fracture mechanism model was developed for correlating macroscopic shear strength and microstructure of fracture surfaces. Applications were made to unpublished data on polyimides and fluoropolymers.

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

PubMed Central

Shin, Thuzar M; Isas, J Mario; Hsieh, Chia-Ling; Kayed, Rakez; Glabe, Charles G; Langen, Ralf; Chen, Jeannie

2008-01-01

Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE) cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases. PMID:18939994

Alzheimer's-associated A{beta} oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pitt, Jason; Roth, William; Lacor, Pascale

2009-10-15

It now appears likely that soluble oligomers of amyloid-{beta}{sub 1-42} peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt A{beta} oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble A{beta} species, when assayed with both sequence- and conformation-specific A{beta} antibodies, indicating changes in oligomer structure. Analysismore » of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (A{beta}-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.« less

Addition polymers from 1,4,5,8-tetrahydro-1,4;5,8-diepoxyanthracene and Bis-dienes. 2: Evidence for thermal dehydration occurring in the cure process

NASA Technical Reports Server (NTRS)

Meador, Mary Ann B.; Olshavsky, Michael A.; Meador, Michael A.; Ahn, Myong-Ku

1988-01-01

Diels-Alder cycloaddition copolymers from 1,4,5,8-tetrahydro-1,4;5,8-diepoxyanthracene and anthracene end-capped polyimide oligomers appear, by thermogravimetric analysis (TGA), to undergo dehydration at elevated temperatures. This would produce thermally stable pentiptycene units along the polymer backbone, and render the polymers incapable of unzipping through a retro-Diels-Alder pathway. High resolution solid 13C nuclear magnetic resonance (NMR) of one formulation of the polymer system before and after heating at elevated temperatures, shows this to indeed be the case. NMR spectra of solid samples of the polymer before and after heating correlated well with those of the parent pentiptycene model compound before and after acid-catalyzed dehydration. Isothermal gravimetric analyses and viscosities of the polymer before and after heat treatment support dehydration as a mechanism for the cure reaction.

Synthesis and Properties of Cross-Linked Polyamide Aerogels

NASA Technical Reports Server (NTRS)

Williams, Jarrod C.; Meador, Mary Ann; McCorkle, Linda

2015-01-01

We report the first synthesis of cross-linked polyamide aerogels through step growth polymerization using a combination of diamines, diacid chloride and triacid chloride. Polyamide oligomers endcapped with amines are prepared as stable solutions in N-methylpyrrolidinone from several different diamine precursors and 1,3-benzenedicarbonyl dichloride. Addition of 1,3,5-benzenetricarbonyl trichloride yields gels which form in under five minutes according to the scheme shown. Solvent exchange of the gels into ethanol, followed by drying using supercritical CO2 extraction gives colorless aerogels with densities around 0.1 to 0.2 gcm3. Thicker monolithes of the polyamide aerogels are stiff and strong, while thin films of certain formulations are highly flexible, durable, and even translucent. These materials may have use as insulation for deployable space structures, rovers, habitats or extravehicular activity suits as well as in many terrestrial applications. Strucure property relationships of the aerogels, including surface area, mechanical properties, and thermal conductivity will be discussed.

Synthesis and electromechanical characterization of a new acrylic dielectric elastomer with high actuation strain and dielectric strength

NASA Astrophysics Data System (ADS)

Hu, Wei; Niu, Xiaofan; Yang, Xinguo; Zhang, Naifang; Pei, Qibing

2013-04-01

Dielectric Elastomers (DEs) can be actuated under high electric field to produce large strains. Most high-performing DE materials such as the 3M™ VHB™ membranes are commercial products designed for industrial pressure-sensitive adhesives. The limited knowledge of the exact chemical structures of these commercial materials has made it difficult to understand the relationship between molecular structures and electromechanical properties. In this work, new acrylic elastomers based on n-butyl acrylate and acrylic acid were synthesized from monomer solutions by UV-initiated bulk polymerization. The new acrylic copolymers have a potential to obtain high dielectric constant, actuation strain, dielectric strength, and a high energy density. Silicone and ester oligomer diacrylates were also added onto the copolymer structures to suppress crystallization and to crosslink the polymer chains. Four acrylic formulations were developed with different amounts of acrylic acid. This gives a tunable stiffness, while the dielectric constant is varied from 4.3 to 7.1. The figure-of-merit performance of the best formulation is 186 % area strain, 222 MV/m of dielectric strength, and 2.7 MJ/m3 of energy density. To overcome electromechanical instability, different prestrain ratios were investigated, and under the optimized prestrain, the material has a lifetime of thousands of cycles at 120 % area strain.

Microstructure-tunable highly conductive graphene-metal composites achieved by inkjet printing and low temperature annealing

NASA Astrophysics Data System (ADS)

Zhao, Jie; Song, Man; Wen, Chenyu; Majee, Subimal; Yang, Dong; Wu, Biao; Zhang, Shi-Li; Zhang, Zhi-Bin

2018-03-01

We present a method for fabricating highly conductive graphene-silver composite films with a tunable microstructure achieved by means of an inkjet printing process and low temperature annealing. This is implemented by starting from an aqueous ink formulation using a reactive silver solution mixed with graphene nanoplatelets (GNPs), followed by inkjet printing deposition and annealing at 100 °C for silver formation. Due to the hydrophilic surfaces and the aid of a polymer stabilizer in an aqueous solution, the GNPs are uniformly covered with a silver layer. Simply by adjusting the content of GNPs in the inks, highly conductive GNP/Ag composites (>106 S m-1), with their microstructure changed from a large-area porous network to a compact film, is formed. In addition, the printed composite films show superior quality on a variety of unconventional substrates compared to its counterpart without GNPs. The availability of composite films paves the way to the metallization in different printed devices, e.g. interconnects in printed circuits and electrodes in energy storage devices.

Montmorillonite Clay-Catalyzed Synthesis of RNA Oligomers

NASA Astrophysics Data System (ADS)

Ferris, J. P.; Miyakawa, S.; Huang, W.; Joshi, P.

2005-12-01

It is proposed that catalysis had a central role in the origins of life. This will be illustrated using the montmorillonite clay-catalyzed synthesis of oligomers of RNA from activated monomers, (Ferris and Ertem, 1993) a possible step in the origin of the RNA world (Ferris, 2005). Structural analysis of oligomers formed in the reaction of the activated monomer of 5'-AMP with that of 5'-CMP demonstrated that the oligomers formed were not produced by random synthesis but rather the sequences observed were directed by the montmorillonite catalyst (Miyakawa and Ferris, 2003). RNA oligomers containing up to 40 mers have been synthesized in reactions performed in water at 25 oC in the presence of montmorillonite (Huang and Ferris, 2003). Analysis of the structure elements in these oligomers from the 7 to 39 mers showed that they did not vary. Reaction of D, L-mixtures of the activated monomers of A and U resulted in the formation of greater amounts of the homochiral amounts of dimers and trimers of A than would be expected if there was no selectivity in the reaction. A limited number of the dimers and trimers of U were also formed but here the selectivity was for the formation of an excess of heterochiral products (Joshi et al., 2000). A postulate that explains why homochiral trimers of U are not formed and the significance of catalysis in prebiotic synthesis will be discussed. Ferris, J.P. (2005) Origins of life, molecular basis of. In R.A. Meyers, Ed. Encyclopedia of Molecular Cell Biology and Molecular Medicine, 10. Wiley-VCH Verlag, Weinheim, Germany. Ferris, J.P., and Ertem, G. (1993) Montmorillonite catalysis of RNA oligomer formation in aqueous solution. A model for the prebiotic formation of RNA. J. Am. Chem. Soc., 115, 12270-12275. Huang, W., and Ferris, J.P. (2003) Synthesis of 35-40 mers of RNA oligomers from unblocked monomers. A simple approach to the RNA world. Chem. Commun., 1458-1459. Joshi, P.C., Pitsch, S., and Ferris, J.P. (2000) Homochiral selection in the montmorillonite-catalyzed and uncatalyzed prebiotic synthesis of RNA. Chem. Commun., 2497-2498. Miyakawa, S., and Ferris, J.P. (2003) Sequence- and Regioselectivity in the montmorillonite-catalyzed synthesis of RNA. J. Am. Chem. Soc., 125, 8202-8208.

A discrete mathematical model for the aggregation of β-Amyloid.

PubMed

Dayeh, Maher A; Livadiotis, George; Elaydi, Saber

2018-01-01

Dementia associated with the Alzheimer's disease is thought to be correlated with the conversion of the β - Amyloid (Aβ) peptides from soluble monomers to aggregated oligomers and insoluble fibrils. We present a discrete-time mathematical model for the aggregation of Aβ monomers into oligomers using concepts from chemical kinetics and population dynamics. Conditions for the stability and instability of the equilibria of the model are established. A formula for the number of monomers that is required for producing oligomers is also given. This may provide compound designers a mechanism to inhibit the Aβ aggregation.

HCN - A plausible source of purines, pyrimidines and amino acids on the primitive earth

NASA Technical Reports Server (NTRS)

Ferris, J.-P.; Joshi, P. C.; Edelson, E. H.; Lawless, J. G.

1978-01-01

Dilute (0.1 M) solutions of HCN condense to oligomers at pH 9.2, and hydrolysis of these oligomers yields 4,5-dihydroxypyrimidine, orotic acid, 5-hydroxyuracil, adenine, 4-aminoimidazole-5-carboxamide, and amino acids. It is suggested that the three main classes of nitrogen-containing biomolecules - purines, pyrimidines, and amino acids may have originated from HCN on the primitive earth. It is also suggested that the presence of orotic acid and 4-aminoimidazole-5-carboxamide might indicate that contemporary biosynthetic pathways for nucleotides evolved from the compounds released on hydrolysis of HCN oligomers.

Non-Traditional Aromatic Topologies and Biomimetic Assembly Motifs as Components of Functional Pi-Conjugated Oligomers

PubMed Central

Tovar, John D.; Diegelmann, Stephen R.; Peart, Patricia A.

2010-01-01

This article will highlight our recent work using conjugated oligomers as precursors to electroactive polymer films and self-assembling nanomaterials. One area of investigation has focused on nonbenzenoid aromaticity in the context of charge delocalization in conjugated polymers. In these studies, polymerizable pi-conjugated units were coupled onto unusual aromatic cores such as methano[10]annulene. This article will also show how biologically-inspired assembly of molecularly well-defined oligopeptides that flank pi-conjugated oligomers has resulted in the aqueous construction of 1-dimensional nanomaterials that encourage electronic delocalization among the pi-electron systems.

Solid-Phase Synthesis of Diverse Peptide Tertiary Amides By Reductive Amination

PubMed Central

Pels, Kevin; Kodadek, Thomas

2015-01-01

The synthesis of libraries of conformationally-constrained peptide-like oligomers is an important goal in combinatorial chemistry. In this regard an attractive building block is the N-alkylated peptide, also known as peptide tertiary amide (PTA). PTAs are strongly biased conformationally due to allylic 1,3 strain interactions. We report here an improved synthesis of these species on solid supports through the use of reductive amination chemistry using amino acid-terminated, bead-displayed oligomers and diverse aldehydes. The utility of this chemistry is demonstrated by the synthesis of a library of 10,000 mixed peptoid-PTA oligomers. PMID:25695359

Solid-phase synthesis of diverse peptide tertiary amides by reductive amination.

PubMed

Pels, Kevin; Kodadek, Thomas

2015-03-09

The synthesis of libraries of conformationally constrained peptide-like oligomers is an important goal in combinatorial chemistry. In this regard an attractive building block is the N-alkylated peptide, also known as a peptide tertiary amide (PTA). PTAs are conformationally constrained because of allylic 1,3 strain interactions. We report here an improved synthesis of these species on solid supports through the use of reductive amination chemistry using amino acid-terminated, bead-displayed oligomers and diverse aldehydes. The utility of this chemistry is demonstrated by the synthesis of a library of 10,000 mixed peptoid-PTA oligomers.

Change of electric dipole moment in charge transfer transitions of ferrocene oligomers studied by ultrafast two-photon absorption

NASA Astrophysics Data System (ADS)

Mikhaylov, Alexander; Arias, Eduardo; Moggio, Ivana; Ziolo, Ronald; Uudsemaa, Merle; Trummal, Aleksander; Cooper, Thomas; Rebane, Aleksander

2017-02-01

Change of permanent electric dipole moment in the lower-energy charge transfer transitions for a series of symmetrical and non-symmetrical ferrocene-phenyleneethynylene oligomers were studied by measuring the corresponding femtosecond two-photon absorption cross section spectra, and were determined to be in the range Δμ = 3 - 10 D. Quantum-chemical calculations of Δμ for the non-symmetrical oligomers show good quantitative agreement with the experimental results, thus validating two-photon absorption spectroscopy as a viable experimental approach to study electrostatic properties of organometallics and other charge transfer systems.

Sequence-specific unusual (1-->2)-type helical turns in alpha/beta-hybrid peptides.

PubMed

Prabhakaran, Panchami; Kale, Sangram S; Puranik, Vedavati G; Rajamohanan, P R; Chetina, Olga; Howard, Judith A K; Hofmann, Hans-Jörg; Sanjayan, Gangadhar J

2008-12-31

This article describes novel conformationally ordered alpha/beta-hybrid peptides consisting of repeating l-proline-anthranilic acid building blocks. These oligomers adopt a compact, right-handed helical architecture determined by the intrinsic conformational preferences of the individual amino acid residues. The striking feature of these oligomers is their ability to display an unusual periodic pseudo beta-turn network of nine-membered hydrogen-bonded rings formed in the forward direction of the sequence by 1-->2 amino acid interactions both in solid-state and in solution. Conformational investigations of several of these oligomers by single-crystal X-ray diffraction, solution-state NMR, and ab initio MO theory suggest that the characteristic steric and dihedral angle restraints exerted by proline are essential for stabilizing the unusual pseudo beta-turn network found in these oligomers. Replacing proline by the conformationally flexible analogue alanine (Ala) or by the conformationally more constrained alpha-amino isobutyric acid (Aib) had an adverse effect on the stabilization of this structural architecture. These findings increase the potential to design novel secondary structure elements profiting from the steric and dihedral angle constraints of the amino acid constituents and help to augment the conformational space available for synthetic oligomer design with diverse backbone structures.

Template-directed synthesis of oligoguanylic acids - Metal ion catalysis

NASA Technical Reports Server (NTRS)

Bridson, P. K.; Fakhrai, H.; Lohrmann, R.; Orgel, L. E.; Van Roode, M.

1981-01-01

The effects of Zn(2+), Pb(2+) and other metal ions on the efficiency and stereo-selectivity of the template-directed oligomerization of guanosine 5'-phosphorimidazolide are investigated. Reactions were run in the presence of a polyC template in a 2,6-lutidine buffer, and products analyzed by high-performance liquid chromatography on an RPC-5 column. The presence of the Pb(2+) ion is found to lead to the formation of 2'-5' linked oligomers up to the 40-mer, while Zn(2+) favors the formation of predominantly 3'-5' linked oligomers up to the 35-mer. When amounts of uracil, cytidine or adenosine 5'-phosphorimidazole equal to those of the guanosine derivative are included in the reaction mixture, the incorrect base is incorporated into the oligomer about 10% of the time with a Pb(2+) catalyst, but less than 0.5% of the time with Zn(2+). The Sn(2+), Sb(3+) and Bi(3+) ions are also found to promote the formation of 2'-5' oligomers, although not as effectively as Pb(2+), while no metal ions other than Zn(2+) promote the formation of the 3'-5' oligomers. The results may be important for the understanding of the evolution of nucleic acid replication in the absence of enzymes.

A Nontoxic Polypeptide Oligomer with a Fungicide Potency under Agricultural Conditions Which Is Equal or Greater than That of Their Chemical Counterparts

PubMed Central

Monteiro, Sara; Carreira, Alexandra; Freitas, Regina; Pinheiro, Ana Margarida; Ferreira, Ricardo Boavida

2015-01-01

There are literally hundreds of polypeptides described in the literature which exhibit fungicide activity. Tens of them have had attempted protection by patent applications but none, as far as we are aware, have found application under real agricultural conditions. The reasons behind may be multiple where the sensitivity to the Sun UV radiation can come in first place. Here we describe a multifunctional glyco-oligomer with 210 kDa which is mainly composed by a 20 kDa polypeptide termed Blad that has been previously shown to be a stable intermediary product of β-conglutin catabolism. This oligomer accumulates exclusively in the cotyledons of Lupinus species, between days 4 and 12 after the onset of germination. Blad-oligomer reveals a plethora of biochemical properties, like lectin and catalytic activities, which are not unusual per si, but are remarkable when found to coexist in the same protein molecule. With this vast range of chemical characteristics, antifungal activity arises almost as a natural consequence. The biological significance and potential technological applications of Blad-oligomer as a plant fungicide to agriculture, its uniqueness stems from being of polypeptidic in nature, and with efficacies which are either equal or greater than the top fungicides currently in the market are addressed. PMID:25849076

Distinct symmetry and limited peptide refolding activity of the thermosomes from the acidothermophilic archaea Acidianus tengchongensis S5{sup T}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Li; Hu, Zhong-jun; Luo, Yuan-ming

Recombinant thermosomes from the Acidianus tengchongensis strain S5{sup T} were purified to homogeneity and assembled in vitro into homo-oligomers (rATcpn{alpha} or rATcpn{beta}) and hetero-oligomers (rATcpn{alpha}{beta}). The symmetries of these complexes were determined by electron microscopy and image analysis. The rATcpn{alpha} homo-oligomer was shown to possess 8-fold symmetry while both rATcpn{beta} and rATcpn{alpha}{beta} oligomers adopted 9-fold symmetry. rATcpn{alpha}{beta} oligomers were shown to contain the {alpha} and {beta} subunits in a 1:2 ratio. All of the complexes prevented the irreversible inactivation of yeast alcohol dehydrogenase at 55 {sup o}C and completely prevented the formation of aggregates during thermal inactivation of citrate synthasemore » at 45 {sup o}C. All rATcpn complexes showed trace ATP hydrolysis activity. Furthermore, rATcpn{beta} sequestered fully chemically denatured substrates (GFP and thermophilic malic dehydrogenase) in vitro without refolding them in an ATP-dependent manner. This property is similar to previously reported properties of chaperonins from Sulfolobus tokodaii and Sulfolobus acidocaldarius. These features are consistent with the slow growth rates of these species of archaea in their native environment.« less

Size-Dependent Affinity of Glycine and Its Short Oligomers to Pyrite Surface: A Model for Prebiotic Accumulation of Amino Acid Oligomers on a Mineral Surface

PubMed Central

Afrin, Rehana; Ganbaatar, Narangerel; Aono, Masashi; Cleaves, H. James; Yano, Taka-aki; Hara, Masahiko

2018-01-01

The interaction strength of progressively longer oligomers of glycine, (Gly), di-Gly, tri-Gly, and penta-Gly, with a natural pyrite surface was directly measured using the force mode of an atomic force microscope (AFM). In recent years, selective activation of abiotically formed amino acids on mineral surfaces, especially that of pyrite, has been proposed as an important step in many origins of life scenarios. To investigate such notions, we used AFM-based force measurements to probe possible non-covalent interactions between pyrite and amino acids, starting from the simplest amino acid, Gly. Although Gly itself interacted with the pyrite surface only weakly, progressively larger unbinding forces and binding frequencies were obtained using oligomers from di-Gly to penta-Gly. In addition to an expected increase of the configurational entropy and size-dependent van der Waals force, the increasing number of polar peptide bonds, among others, may be responsible for this observation. The effect of chain length was also investigated by performing similar experiments using l-lysine vs. poly-l-lysine (PLL), and l-glutamic acid vs. poly-l-glutamic acid. The results suggest that longer oligomers/polymers of amino acids can be preferentially adsorbed on pyrite surfaces. PMID:29370126

GalaxyHomomer: a web server for protein homo-oligomer structure prediction from a monomer sequence or structure.

PubMed

Baek, Minkyung; Park, Taeyong; Heo, Lim; Park, Chiwook; Seok, Chaok

2017-07-03

Homo-oligomerization of proteins is abundant in nature, and is often intimately related with the physiological functions of proteins, such as in metabolism, signal transduction or immunity. Information on the homo-oligomer structure is therefore important to obtain a molecular-level understanding of protein functions and their regulation. Currently available web servers predict protein homo-oligomer structures either by template-based modeling using homo-oligomer templates selected from the protein structure database or by ab initio docking of monomer structures resolved by experiment or predicted by computation. The GalaxyHomomer server, freely accessible at http://galaxy.seoklab.org/homomer, carries out template-based modeling, ab initio docking or both depending on the availability of proper oligomer templates. It also incorporates recently developed model refinement methods that can consistently improve model quality. Moreover, the server provides additional options that can be chosen by the user depending on the availability of information on the monomer structure, oligomeric state and locations of unreliable/flexible loops or termini. The performance of the server was better than or comparable to that of other available methods when tested on benchmark sets and in a recent CASP performed in a blind fashion. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Design and development of advanced castable refractory materials

NASA Astrophysics Data System (ADS)

Davis, Robert Bruce

New formulations of castable refractory composite materials were studied. This technology is used to produce low cost composite concrete structures designed for high temperature stability, superior wear resistance and improved strength. An in situ fired, castable cement installation is a heterogeneous structure divided into three zones according to the temperature history and microstructure. The properties of each zone depend on the predominant bonding mode between constituents. Each zone has a characteristic microstructure that influences the integrity of the monolith. The hot side may have a highly dense and developed network of ceramic bonds between constituent particles while the cold side may never reach temperatures sufficient to drive off free water. The thermal, structural and tribological properties depend on the microstructure and the type of bonding that holds the monolith together. The phase distributions are defined by sets of metastable phase conditions driven by the local hydrated chemistry, nearest neighbor oxide compounds, impurities and sintering temperature. Equilibrium phase diagrams were used to select optimum compositions based on higher melting point phases. The phase diagrams were also used to target high temperature phase fields that are stable over wide temperature and stoichiometric ranges. Materials selection of candidate hydraulic clinkers, high temperature oxides, and reinforcement phases were based on requirements for high temperature stability. The calcium aluminate (CaO-Al2O3) and calcium dialuminate (CaO-(Al2O3)2) are common refractory clinkers used in castable refractory cements. The thermodynamics and kinetics of cement hydrate formation are well studied and suited to become the building block of a design for a superior refractory castable cement. The inert oxides mixed with the calcium aluminate clinkers are magnesia (MgO), alumina (Al 2O3), spinel (MgAl2O4) and chromic (Cr2O3). The bulk of the experiments concentrated in the Al2O3--MgO--CaO ternary system. Materials selection criteria for reinforcement materials was based on improved high temperature stability, increased strength, reduced thermal expansion mismatch, low thermal conductivity and increasing wear resistance. The reinforcement phases selected for this investigation are zircon (ZrSiO4), zirconia (ZrO2), spinel (MgAl2O4) and dead burnt magnesia (MgO). Batches of the formulations were tested for thermal conductivity, wear resistance and mechanical strength. Relative rankings of the formulations against commercial products indicate improved or similar performance with increased maximum temperature limits and improved thermal insulating power. The new cement formulations proved to exhibit superior high temperature stability with an increasing volume fraction of high temperature oxides. The addition of reinforcement aggregates and powder sizing to offset the loss of strength. The room temperature compression strength and wear resistance of the optimized formulations exceeded the properties of conventional refractory, brick and castable cement tested concurrently.

Catalysis and prebiotic RNA synthesis

NASA Technical Reports Server (NTRS)

Ferris, James P.

1993-01-01

The essential role of catalysis for the origins of life is discussed. The status of the prebiotic synthesis of 2',5'- and 3'5'-linked oligomers of RNA is reviewed. Examples of the role of metal ion and mineral catalysis in RNA oligomer formation are discussed.

Hydroxyapatite moldable formulation using natural rubber latex as binder.

PubMed

Sailaja, G S; Ramesh, P; Varma, H K

2007-07-01

A simple but efficient processing method for shaping intricate bioceramic green bodies has been developed by using natural rubber latex as binder. Different shapes of hydroxyapatite Ca10(PO4)6(OH)2 (HAP) were molded from a composite formulation containing wet precipitated HAP, natural rubber latex (NRL), and a stabilizer. On controlled heat treatment followed by sintering, dense shapes of HAP contours were obtained. The thermal degradation profile of HAP-NRL composites shows that NRL degrades slowly without any abrupt exotherm. The results of energy dispersive X-ray analysis together with inductively coupled plasma (ICP) analysis indicate that the inorganic residue of NRL does not contain any heavy element. The sintered density of the samples increased with increased HAP content in the formulation and percentage shrinkage reduced accordingly. On varying the HAP content in the formulation from 35 to 95 wt %, the compositions with 85, 90, 92, and 95 wt % HAP showed better flexural strength in the range 40-54 MPa and a flexural modulus value in the range 36-50 GPa. The fracture morphology, as observed by the scanning electron microscope confirms that with increased HAP content in the formulation the sample microstructure attains higher uniformity. The Vickers microhardness for the samples sintered at two different temperatures (1150 and 1250 degrees C) showed that hardness increases with increase in the sintering temperature with a maximum for the highest HAP loaded formulation. Copyright 2006 Wiley Periodicals, Inc.

The Development of Expanded Snack Product Made from Pumpkin Flour-Corn Grits: Effect of Extrusion Conditions and Formulations on Physical Characteristics and Microstructure

PubMed Central

Md Nor, Norfezah; Carr, Alistair; Hardacre, Allan; Brennan, Charles S.

2013-01-01

Pumpkin products confer natural sweetness, desirable flavours and β-carotene, a vitamin A precursor when added as ingredients to extruded snacks. Therefore, a potential use for dried pumpkin flour is as an ingredient in ready-to-eat (RTE) snack foods. Growth in this market has driven food manufacturers to produce a variety of new high value snack foods incorporating diverse ingredients to enhance the appearance and nutritional properties of these foods. Ready-to-eat snacks were made by extruding corn grits with 5%, 10%, 15% and 20% of pumpkin flour. Snacks made from 100% corn grits were used as control products for this work. The effect of formulation and screw speeds of 250 rpm and 350 rpm on torque and specific mechanical energy (SME, kWh/kg), physical characteristics (expansion ratio, bulk density, true density and hardness) and the microstructure of the snacks were studied. Increasing the screw speed resulted in a decrease of torque for all formulations. When pumpkin flour was added the specific mechanical energy (SME) decreased by approximately 45%. Increasing the percentage of pumpkin flour at the higher screw speed resulted in a harder texture for the extruded products. X-ray tomography of pumpkin flour-corn grit snacks showed that increased levels of pumpkin flour decreased both the bubble area and bubble size. However, no significant differences (p > 0.05) in bubble wall thickness were measured. By understanding the conditions during extrusion, desirable nutritional characteristics can be incorporated while maximizing expansion to make a product with low bulk density, a fine bubble structure and acceptable organoleptic properties. PMID:28239106

The Development of Expanded Snack Product Made from Pumpkin Flour-Corn Grits: Effect of Extrusion Conditions and Formulations on Physical Characteristics and Microstructure.

PubMed

Nor, Norfezah Md; Carr, Alistair; Hardacre, Allan; Brennan, Charles S

2013-05-14

Pumpkin products confer natural sweetness, desirable flavours and β-carotene, a vitamin A precursor when added as ingredients to extruded snacks. Therefore, a potential use for dried pumpkin flour is as an ingredient in ready-to-eat (RTE) snack foods. Growth in this market has driven food manufacturers to produce a variety of new high value snack foods incorporating diverse ingredients to enhance the appearance and nutritional properties of these foods. Ready-to-eat snacks were made by extruding corn grits with 5%, 10%, 15% and 20% of pumpkin flour. Snacks made from 100% corn grits were used as control products for this work. The effect of formulation and screw speeds of 250 rpm and 350 rpm on torque and specific mechanical energy (SME, kWh/kg), physical characteristics (expansion ratio, bulk density, true density and hardness) and the microstructure of the snacks were studied. Increasing the screw speed resulted in a decrease of torque for all formulations. When pumpkin flour was added the specific mechanical energy (SME) decreased by approximately 45%. Increasing the percentage of pumpkin flour at the higher screw speed resulted in a harder texture for the extruded products. X-ray tomography of pumpkin flour-corn grit snacks showed that increased levels of pumpkin flour decreased both the bubble area and bubble size. However, no significant differences ( p > 0.05) in bubble wall thickness were measured. By understanding the conditions during extrusion, desirable nutritional characteristics can be incorporated while maximizing expansion to make a product with low bulk density, a fine bubble structure and acceptable organoleptic properties.

The type and composition of alginate and hyaluronic-based hydrogels influence the viability of stem cells of the apical papilla.

PubMed

Lambricht, Laure; De Berdt, Pauline; Vanacker, Julie; Leprince, Julian; Diogenes, Anibal; Goldansaz, Hadi; Bouzin, Caroline; Préat, Véronique; Dupont-Gillain, Christine; des Rieux, Anne

2014-12-01

The goal of the present work was to evaluate in vitro and in vivo the influence of various types and compositions of natural hydrogels on the viability and metabolic activity of SCAPs. Two alginate, three hyaluronic-based (Corgel™) hydrogel formulations and Matrigel were characterized for their mechanical, surface and microstructure properties using rheology, X-ray photoelectron spectroscopy and scanning electron microscopy, respectively. A characterized SCAP cell line (RP89 cells) was encapsulated in the different experimental hydrogel formulations. Cells were cultured in vitro, or implanted in cyclosporine treated mice. In vitro cell viability was evaluated using a Live/Dead assay and in vitro cellular metabolic activity was evaluated with a MTS assay. In vivo cell apoptosis was evaluated by a TUNEL test and RP89 cells were identified by human mitochondria immunostaining. Hydrogel composition influenced their mechanical and surface properties, and their microstructure. In vitro cell viability was above 80% after 2 days but decreased significantly after 7 days (60-40%). Viability at day 7 was the highest in Matrigel (70%) and then in Corgel 1.5 (60%). Metabolic activity increased over time in all the hydrogels, excepted in alginate SLM. SCAPs survived after 1 week in vivo with low apoptosis (<1%). The highest number of RP89 cells was found in Corgel 5.5 (140cells/mm(2)). Collectively, these data demonstrate that SCAP viability was directly modulated by hydrogel composition and suggest that a commercially available hyaluronic acid-based formulation might be a suitable delivery vehicle for SCAP-based dental pulp regeneration strategies. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Influence of the ratio of amphiphilic copolymers used as emulsifiers on the microstructure, physical stability and rheology of α-pinene emulsions stabilized with gellan gum.

PubMed

García, Maria Carmen; Alfaro, Maria Carmen; Muñoz, José

2015-11-01

α-Pinene is a terpenic solvent whose use in the formulation of emulsions entails a double benefit from the environmental point of view since it is a green solvent, easily biodegradable, which also has certain antimicrobial properties. In this work a combination of Atlas™ G-5000 and Atlox™ 4913 amphiphilic copolymers was used to obtain O/W emulsions formulated with α-pinene and gellan gum. These emulsions may find applications related to the design of complex biotechnological systems with different uses. In order to investigate the microstructure and the physical stability of these emulsions, a combination of different techniques such as rheology, microscopy, laser diffraction and multiple light scattering turn out to be a useful methodology. The results demonstrated the need to include a minimum amount of Atlas™ G-5000 copolymer in the formulation of these emulsions to improve their stability. These results were supported by the information revealed by optical micrographs, according to which Atlas™ G-5000 is directed to the continuous medium to structure water (this surfactant is particularly effective at forming hydrogen bonds with water). On the other hand Atlox™ 4913 is preferentially adsorbed at the α-pinene-water interface, such that a high Atlox™ 4913/Atlas™ G-5000 mass ratio slows down the kinetics of coalescence as shown by multiple light scattering. However, a very low relative concentration of Atlas™ G-5000 causes creaming to become the dominant destabilization mechanism. Increasing the Atlas™ G-5000/Atlox™ 4913 mass ratio yields emulsions with enhanced viscosity and viscoelasticity. Copyright © 2015 Elsevier B.V. All rights reserved.

Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis

PubMed Central

Gantz, Donald L.; Haupt, Christian; Gursky, Olga

2017-01-01

Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5–4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5–4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis. PMID:28743750

Construction and characterization of the hetero-oligomer of the group II chaperonin from the hyperthermophilic archaeon, Thermococcus sp. strain KS-1.

PubMed

Sahlan, Muhamad; Kanzaki, Taro; Yohda, Masafumi

2009-05-01

The hyperthermophilic archaeon Thermococcus sp. strain KS-1 (T. KS-1) expresses two different chaperonin subunits, alpha and beta, for the folding of its proteins. The composition of the subunits in the hexadecameric double ring changes with temperature. The content of the beta subunit significantly increases according to the increase in temperature. The homo-oligomer of the beta subunit, Cpn beta, is more thermostable than that of the alpha subunit, Cpn alpha. Since Cpn alpha and Cpn beta also have different protein folding activities and interactions with prefoldin, the hetero-oligomer is thought to exhibit different characteristics according to the content of subunits. The hetero-oligomer of the T. KS-1 chaperonin has not been studied, however, because the alpha and beta subunits form hetero-oligomers of varying compositions when they are expressed simultaneously. In this study, we characterized the T. KS-1 chaperonin hetero-oligomer, Cpn alphabeta, containing both alpha and beta in the alternate order, which was constructed by the expression of alpha and beta subunits in a coordinated fashion and protease digestion. Cpn alphabeta protected citrate synthase from thermal aggregation, promoted the folding of acid-denatured GFP in an ATP-dependent manner, and exhibited an ATP-dependent conformational change. The yield of refolded GFP generated by Cpn alphabeta was almost equivalent to that generated by Cpn beta but lower than that generated by Cpn alpha. In contrast, Cpn alphabeta exhibited almost the same level of thermal stability as Cpn alpha, which was lower than that of Cpn beta. The affinity of Cpn alphabeta to prefoldin was found to be between those of Cpn alpha and Cpn beta, as expected.

Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

PubMed Central

Trikha, Saurabh; Jeremic, Aleksandar M.

2013-01-01

Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells. PMID:24019897

Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols

PubMed Central

Pitt, Jason; Thorner, Michael; Brautigan, David; Larner, Joseph; Klein, William L.

2013-01-01

Alzheimer's disease (AD) is a progressive dementia that correlates highly with synapse loss. This loss appears due to the synaptic accumulation of toxic Aβ oligomers (ADDLs), which damages synapse structure and function. Although it has been reported that oligomer binding and toxicity can be prevented by stimulation of neuronal insulin signaling with PPARγ agonists, these agonists have problematic side effects. We therefore investigated the therapeutic potential of chiro-inositols, insulin-sensitizing compounds safe for human consumption. Chiro-inositols have been studied extensively for treatment of diseases associated with peripheral insulin resistance, but their insulin mimetic function in memory-relevant central nervous system (CNS) cells is unknown. Here we demonstrate that mature cultures of hippocampal neurons respond to d-chiro-inositol (DCI), pinitol (3-O-methyl DCI), and the inositol glycan INS-2 (pinitol β-1-4 galactosamine) with increased phosphorylation in key upstream components in the insulin-signaling pathway (insulin receptor, insulin receptor substrate-1, and Akt). Consistent with insulin stimulation, DCI treatment promotes rapid withdrawal of dendritic insulin receptors. With respect to neuroprotection, DCI greatly enhances the ability of insulin to prevent ADDL-induced synapse damage (EC50 of 90 nM). The mechanism comprises inhibition of oligomer binding at synapses and requires insulin/IGF signaling. DCI showed no effects on Aβ oligomerization. We propose that inositol glycans and DCI, a compound already established as safe for human consumption, have potential as AD therapeutics by protecting CNS synapses against Aβ oligomers through their insulin mimetic activity.—Pitt, J., Thorner, M., Brautigan, D., Larner, J., Klein, W. L. Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. PMID:23073831

Low Melt Viscosity Resins for Resin Transfer Molding

NASA Technical Reports Server (NTRS)

Harris, Frank W.

2002-01-01

In recent years, resin transfer molding (RTM) has become one of the methods of choice for high performance composites. Its cost effectiveness and ease of fabrication are major advantages of RTM. RTM process usually requires resins with very low melt viscosity (less than 10 Poise). The optimum RTM resins also need to display high thennal-oxidative stability, high glass transition temperature (T(sub g)), and good toughness. The traditional PMR-type polyimides (e.g. PMR-15) do not fit this requirement, because the viscosities are too high and the nadic endcap cures too fast. High T(sub g), low-melt viscosity resins are highly desirable for aerospace applications and NASA s Reusable Launch Vehicle (RLV) program. The objective of this work is to prepare low-melt viscosity polyimide resins for RTM or resin film infusion (RFI) processes. The approach involves the synthesis of phenylethynyl-terminated imide oligomers. These materials have been designed to minimize their melt viscosity so that they can be readily processed. During the cure, the oligomers undergo both chain extension and crosslinking via the thermal polymerization of the phenylethynyl groups. The Phenylethynyl endcap is preferred over the nadic group due to its high curing temperature, which provides broader processing windows. This work involved the synthesis and polymerization of oligomers containing zig-zag backbones and twisted biphenyl structures. Some A-B type precursors which possessed both nitro and anhydride functionality, or both nitro and amine functionality, were also synthesized in order to obtain the well defined oligomers. The resulting zig-zag structured oligomers were then end-capped with 4-phenylethynylphthalic anhydride (PEPA) for further cure. The properties of these novel imide oligomers are evaluated.

Oligomerization of uridine phosphorimidazolides on montmorillonite: a model for the prebiotic synthesis of RNA on minerals

NASA Technical Reports Server (NTRS)

Ding, P. Z.; Kawamura, K.; Ferris, J. P.

1996-01-01

The 5'-phosphorimidazolide of uridine reacts on Na(+)-montmorillonite 22A in aqueous solution to give oligomers as long as 7 mers. The maximum chain length increases to 9 mers and the overall oligomer yield increases when 9:1 ImpU, A5' ppA mixtures react under the same conditions. The oligomer yield and maximum chain length decreases with the structure of the added pyrophosphate in the order A5' ppA > A5' ppU > U5' ppU. Structure analysis of individual oligomer fractions was performed by selective enzymatic hydrolyses followed by HPLC analysis of the products. The regioselectivity for 3',5'-bond formation is 80-90% in the 9:1 ImpU, A5' ppA reaction, a percentage comparable to that observed in the 9:1 ImpA, A5' ppA reaction. Oligomerization of ImpU is inhibited by addition of dA5' ppdA, and MeppA. No oligomers containing A5' ppU were products of the 9:1 ImpU,A5' ppA reaction, a finding consistent with the simple addition of the ImpU to the A5' ppA and not the rearrangement of an ImpU-A5' ppA adduct. Concentrations of lysine or arginine which were close to that of the ImpU did not inhibit oligomer formation. Treatment of Na(+)-montmorillonite with 1 M arginine yielded arginine-montmorillonite, an amino acid-mineral adduct which did not catalyze ImpU oligomerization. Neither the 4-9 mers formed in the 9:1 ImpU, A5' ppA reaction nor the 4-9 mers formed by the base hydrolysis of poly(U) served as templates for the formation of oligo(A)s.

Porous Cross-Linked Polyimide Networks

NASA Technical Reports Server (NTRS)

Meador, Mary Ann B. (Inventor); Guo, Haiquan (Inventor)

2015-01-01

Porous cross-linked polyimide networks are provided. The networks comprise an anhydride end-capped polyamic acid oligomer. The oligomer (i) comprises a repeating unit of a dianhydride and a diamine and terminal anhydride groups, (ii) has an average degree of polymerization of 10 to 50, (iii) has been cross-linked via a cross-linking agent, comprising three or more amine groups, at a balanced stoichiometry of the amine groups to the terminal anhydride groups, and (iv) has been chemically imidized to yield the porous cross-linked polyimide network. Also provided are porous cross-linked polyimide aerogels comprising a cross-linked and imidized anhydride end-capped polyamic acid oligomer, wherein the oligomer comprises a repeating unit of a dianhydride and a diamine, and the aerogel has a density of 0.10 to 0.333 g/cm.sup.3 and a Young's modulus of 1.7 to 102 MPa. Also provided are thin films comprising aerogels, and methods of making porous cross-linked polyimide networks.

Computational Design of Self-Assembling Cyclic Protein Homo-oligomers

PubMed Central

Fallas, Jorge A.; Ueda, George; Sheffler, William; Nguyen, Vanessa; McNamara, Dan E.; Sankaran, Banumathi; Pereira, Jose Henrique; Parmeggiani, Fabio; Brunette, TJ; Cascio, Duilio; Yeates, Todd R.; Zwart, Peter; Baker, David

2016-01-01

Self-assembling cyclic protein homo-oligomers play important roles in biology and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue pair transform method for assessing the design ability of a protein-protein interface. This method is sufficiently rapid to enable systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were experimentally characterized, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (4 homodimers, 6 homotrimers, 6 homotetramers and 1 homopentamer) had solution small angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each of these were shown to be very close to their design model. PMID:28338692

Simple extrapolation method to predict the electronic structure of conjugated polymers from calculations on oligomers

DOE PAGES

Larsen, Ross E.

2016-04-12

In this study, we introduce two simple tight-binding models, which we call fragment frontier orbital extrapolations (FFOE), to extrapolate important electronic properties to the polymer limit using electronic structure calculations on only a few small oligomers. In particular, we demonstrate by comparison to explicit density functional theory calculations that for long oligomers the energies of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and of the first electronic excited state are accurately described as a function of number of repeat units by a simple effective Hamiltonian parameterized from electronic structure calculations on monomers, dimers and, optionally,more » tetramers. For the alternating copolymer materials that currently comprise some of the most efficient polymer organic photovoltaic devices one can use these simple but rigorous models to extrapolate computed properties to the polymer limit based on calculations on a small number of low-molecular-weight oligomers.« less

Stereocomplexes Formed From Select Oligomers of Polymer d-lactic Acid (PDLA) and l-lactate May Inhibit Growth of Cancer Cells and Help Diagnose Aggressive Cancers-Applications of the Warburg Effect.

PubMed

Goldberg, Joel S

2011-02-15

It is proposed that select oligomers of polymer d-lactic acid (PDLA) will form a stereocomplex with l-lactate in vivo, producing lactate deficiency in tumor cells. Those cancer cells that utilize transport of lactate to maintain electrical neutrality may cease to multiply or die because of lactate trapping, and those cancer cells that benefit from utilization of extracellular lactate may be impaired. Intracellular trapping of lactate produces a different physiology than inhibition of LDH because the cell loses the option of shuttling pyruvate to an alternative pathway to produce an anion. Conjugated with stains or fluorescent probes, PDLA oligomers may be an agent for the diagnosis of tissue lactate and possibly cell differentiation in biopsy specimens. Preliminary experimental evidence is presented confirming that PDLA in high concentrations is cytotoxic and that l-lactate forms a presumed stereocomplex with PDLA. Future work should be directed at isolation of biologically active oligomers of PDLA.

Regeneration of cello-oligomers via selective depolymerization of cellulose fibers derived from printed paper wastes.

PubMed

Voon, Lee Ken; Pang, Suh Cem; Chin, Suk Fun

2016-05-20

Cellulose extracted from printed paper wastes were selectively depolymerized under controlled conditions into cello-oligomers of controllable chain lengths via dissolution in an ionic liquid, 1-allyl-3-methylimidazolium chloride (AMIMCl), and in the presence of an acid catalyst, Amberlyst 15DRY. The depolymerization process was optimized against reaction temperature, concentration of acid catalyst, and reaction time. Despite rapid initial depolymerization process, the rate of cellulose depolymerization slowed down gradually upon prolonged reaction time, with 75.0 wt% yield of regenerated cello-oligomers (mean Viscosimetric Degree of Polymerization value of 81) obtained after 40 min. The depolymerization of cellulose fibers at 80 °C appeared to proceed via a second-order kinetic reaction with respect to the catalyst concentration of 0.23 mmol H3O(+). As such, the cellulose depolymerization process could afford some degree of control on the degree of polymerization or chain lengths of cello-oligomers formed. Copyright © 2016 Elsevier Ltd. All rights reserved.

STEM/EELS Imaging of Magnetic Hybridization in Symmetric and Symmetry-Broken Plasmon Oligomer Dimers and All-Magnetic Fano Interference

DOE PAGES

Cherqui, Charles; Wu, Yueying; Li, Guoliang; ...

2016-09-27

Negative-index metamaterials composed of magnetic plasmon oligomers are actively being investigated for their potential role in optical cloaking, superlensing, and nanolithography applications. A significant improvement to their practicality lies in the ability to function at multiple distinct wavelengths in the visible part of spectrum. Here we utilize the nanometer spatial-resolving power of electron energy-loss spectroscopy to conclusively demonstrate hybridization of magnetic plasmons in oligomer dimers that can achieve this goal. We also show that breaking the dimer’s symmetry can induce all-magnetic Fano interferences based solely on the interplay of bright and dark magnetic modes, allowing us to further tailor themore » system’s optical responses. These features are engineered through the design of the oligomer’s underlying nanoparticle elements as elongated Ag nanodisks with spectrally isolated long-axis plasmon resonances. The resulting magnetic plasmon oligomers and their hybridized assemblies establish a new design paradigm for optical metamaterials with rich functionality.« less

Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure.

PubMed

Horvath, Istvan; Sellstedt, Magnus; Weise, Christoph; Nordvall, Lina-Maria; Krishna Prasad, G; Olofsson, Anders; Larsson, Göran; Almqvist, Fredrik; Wittung-Stafshede, Pernilla

2013-04-15

In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation. Copyright © 2013 Elsevier Inc. All rights reserved.

Ring rolling process simulation for microstructure optimization

NASA Astrophysics Data System (ADS)

Franchi, Rodolfo; Del Prete, Antonio; Donatiello, Iolanda; Calabrese, Maurizio

2017-10-01

Metal undergoes complicated microstructural evolution during Hot Ring Rolling (HRR), which determines the quality, mechanical properties and life of the ring formed. One of the principal microstructure properties which mostly influences the structural performances of forged components, is the value of the average grain size. In the present paper a ring rolling process has been studied and optimized in order to obtain anular components to be used in aerospace applications. In particular, the influence of process input parameters (feed rate of the mandrel and angular velocity of driver roll) on microstructural and on geometrical features of the final ring has been evaluated. For this purpose, a three-dimensional finite element model for HRR has been developed in SFTC DEFORM V11, taking into account also microstructural development of the material used (the nickel superalloy Waspalloy). The Finite Element (FE) model has been used to formulate a proper optimization problem. The optimization procedure has been developed in order to find the combination of process parameters which allows to minimize the average grain size. The Response Surface Methodology (RSM) has been used to find the relationship between input and output parameters, by using the exact values of output parameters in the control points of a design space explored through FEM simulation. Once this relationship is known, the values of the output parameters can be calculated for each combination of the input parameters. Then, an optimization procedure based on Genetic Algorithms has been applied. At the end, the minimum value of average grain size with respect to the input parameters has been found.

Physical and Oxidative Stability of Flaxseed Oil-in-Water Emulsions Fabricated from Sunflower Lecithins: Impact of Blending Lecithins with Different Phospholipid Profiles.

PubMed

Liang, Li; Chen, Fang; Wang, Xingguo; Jin, Qingzhe; Decker, Eric Andrew; McClements, David Julian

2017-06-14

There is great interest in the formulation of plant-based foods enriched with nutrients that promote health, such as polyunsaturated fatty acids. This study evaluated the impact of sunflower phospholipid type on the formation and stability of flaxseed oil-in-water emulsions. Two sunflower lecithins (Sunlipon 50 and 90) with different phosphatidylcholine (PC) levels (59 and 90%, respectively) were used in varying ratios to form emulsions. Emulsion droplet size, charge, appearance, microstructure, and oxidation were measured during storage at 55 °C in the dark. The physical and chemical stability increased as the PC content of the lecithin blends decreased. The oxidative stability of emulsions formulated using Sunlipon 50 was better than emulsions formulated using synthetic surfactants (SDS or Tween 20). The results are interpreted in terms of the impact of emulsifier type on the colloidal interactions between oil droplets and on the molecular interactions between pro-oxidants and oil droplet surfaces.

A homogenization-based quasi-discrete method for the fracture of heterogeneous materials

NASA Astrophysics Data System (ADS)

Berke, P. Z.; Peerlings, R. H. J.; Massart, T. J.; Geers, M. G. D.

2014-05-01

The understanding and the prediction of the failure behaviour of materials with pronounced microstructural effects is of crucial importance. This paper presents a novel computational methodology for the handling of fracture on the basis of the microscale behaviour. The basic principles presented here allow the incorporation of an adaptive discretization scheme of the structure as a function of the evolution of strain localization in the underlying microstructure. The proposed quasi-discrete methodology bridges two scales: the scale of the material microstructure, modelled with a continuum type description; and the structural scale, where a discrete description of the material is adopted. The damaging material at the structural scale is divided into unit volumes, called cells, which are represented as a discrete network of points. The scale transition is inspired by computational homogenization techniques; however it does not rely on classical averaging theorems. The structural discrete equilibrium problem is formulated in terms of the underlying fine scale computations. Particular boundary conditions are developed on the scale of the material microstructure to address damage localization problems. The performance of this quasi-discrete method with the enhanced boundary conditions is assessed using different computational test cases. The predictions of the quasi-discrete scheme agree well with reference solutions obtained through direct numerical simulations, both in terms of crack patterns and load versus displacement responses.

Modeling of stress distributions on the microstructural level in Alloy 600

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozaczek, K.J.; Petrovic, B.G.; Ruud, C.O.

1995-04-01

Stress distribution in a random polycrystalline material (Alloy 600) was studied using a topologically correct microstructural model. Distributions of von Mises and hydrostatic stresses at the grain vertices, which could be important in intergranular stress corrosion cracking, were analyzed as functions of microstructure, grain orientations and loading conditions. Grain size, shape, and orientation had a more pronounced effect on stress distribution than loading conditions. At grain vertices the stress concentration factor was higher for hydrostatic stress (1.7) than for von Mises stress (1.5). The stress/strain distribution in the volume (grain interiors) is a normal distribution and does not depend onmore » the location of the studied material volume i.e., surface vs/bulk. The analysis of stress distribution in the volume showed the von Mises stress concentration of 1.75 and stress concentration of 2.2 for the hydrostatic pressure. The observed stress concentration is high enough to cause localized plastic microdeformation, even when the polycrystalline aggregate is in the macroscopic elastic regime. Modeling of stresses and strains in polycrystalline materials can identify the microstructures (grain size distributions, texture) intrinsically susceptible to stress/strain concentrations and justify the correctness of applied stress state during the stress corrosion cracking tests. Also, it supplies the information necessary to formulate the local failure criteria and interpret of nondestructive stress measurements.« less

Applications of oligomers for nanostructured conducting polymers.

PubMed

Wang, Yue; Tran, Henry D; Kaner, Richard B

2011-01-03

This Feature Article provides an overview of the distinctive nanostructures that aniline oligomers form and the applications of these oligomers for shaping the nanoscale morphologies and chirality of conducting polymers. We focus on the synthetic methods for achieving such goals and highlight the underlying mechanisms. The clear advantages of each method and their possible drawbacks are discussed. Assembly and applications of these novel organic (semi)conducting nanomaterials are also outlined. We conclude this article with our perspective on the main challenges, new opportunities, and future directions for this nascent yet vibrant field of research. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Alternating phenylene and furan/pyrrole/thiophene units-based oligomers: A computational study of the structures and optoelectronic properties

NASA Astrophysics Data System (ADS)

Sahu, Harikrishna; Shukla, Rishabh; Goswami, Juri; Gaur, Priyank; Panda, Aditya N.

2018-01-01

Structural and optoelectronic properties of phenylene-furan, phenylene-pyrrole and phenylene-thiophene oligomers are reported using density functional theory methods. Studies reveal that stabilities of conformers change with increasing chain length, and helical conformers are energetically feasible for large oligomers of the studied systems, due to stacking interactions between adjacent helical turns. Absorption spectra of helices are dominated by multiple number of electronic transitions other than the S0 →S1 , involving orbitals other than the HOMO/LUMO. All studied helices are optically active having similar pattern of negative and positive peaks in the CD spectra.

Phase transition in conjugated oligomers suspended in chloroform

NASA Astrophysics Data System (ADS)

Dwivedi, Shikha; Kumar, Anupam; Yadav, S. N. S.; Mishra, Pankaj

2015-08-01

Density functional theory (DFT) has been used to investigate the isotropic-nematic (I-N) phase transition in a system of high aspect ratio conjugated oligomers suspended in chloroform. The interaction between the oligomers is modeled using Gay-Berne potential in which effect of solvent is implicit. Percus-Yevick integral equation theory has been used to evaluate the pair correlation functions of the fluid phase at several temperatures and densities. These pair correlation function has been used in the DFT to evaluate the I-N freezing parameters. Highly oriented nematic is found to stabilize at low density. The results obtained are in qualitative agreement with the simulation and are verifiable.

Real-time investigation of cytochrome c release profiles in living neuronal cells undergoing amyloid beta oligomer-induced apoptosis

NASA Astrophysics Data System (ADS)

Lee, Jae Young; Park, Younggeun; Pun, San; Lee, Sung Sik; Lo, Joe F.; Lee, Luke P.

2015-06-01

Intracellular Cyt c release profiles in living human neuroblastoma undergoing amyloid β oligomer (AβO)-induced apoptosis, as a model Alzheimer's disease-associated pathogenic molecule, were analysed in a real-time manner using plasmon resonance energy transfer (PRET)-based spectroscopy.Intracellular Cyt c release profiles in living human neuroblastoma undergoing amyloid β oligomer (AβO)-induced apoptosis, as a model Alzheimer's disease-associated pathogenic molecule, were analysed in a real-time manner using plasmon resonance energy transfer (PRET)-based spectroscopy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr02390d

Phenylethynyl terminated reactive oligomer

NASA Technical Reports Server (NTRS)

Bryant, Robert G. (Inventor); Jensen, Brian J. (Inventor); Hergenrother, Paul M. (Inventor)

1995-01-01

A composition of matter having the general structure: ##STR1## (wherein X is F, Cl, or NO.sub.2, and Y is CO, SO.sub.2 or C(CF.sub.3).sub.2) is employed to terminate a nucleophilic reagent, resulting in the exclusive production of phenylethynyl terminated reactive oligomers which display unique thermal characteristics. A reactive diluent having the general structure: ##STR2## (wherein R is any aliphatic or aromatic moiety) is employed to decrease the melt viscosity of a phenylethynyl terminated reactive oligomer and to subsequently react therewith to provide a thermosetting material of enhanced density. These materials have features which make them attractive candidates for use as composite matrices and adhesives.

Reactions of peroxynitrite with cocoa procyanidin oligomers.

PubMed

Arteel, G E; Schroeder, P; Sies, H

2000-08-01

Peroxynitrite is a mediator molecule in inflammation, and its biological properties are being studied extensively. Flavonoids, which are natural plant constituents, protect against peroxynitrite and thereby could play an anti-inflammatory role. Procyanidin oligomers of different sizes (monomer through nonamer), isolated from the seeds of Theobroma cacao, were recently examined for their ability to protect against peroxynitrite-dependent oxidation of dihydrorhodamine 123 and nitration of tyrosine and were found to be effective in attenuating these reactions. The tetramer was particularly efficient at protecting against oxidation and nitration reactions. Epicatechin oligomers found in cocoa powder and chocolate may be a potent dietary source for defense against peroxynitrite.

Synthesis, characterization and optical properties of novel star azo-oligomers containing well-defined oligo(ethylene glycol) segments

NASA Astrophysics Data System (ADS)

González-Gómez, Roberto; Vonlanthen, Mireille; Ortíz-Palacios, Jesús; Ruiu, Andrea; Valderrama-García, Bianca X.; Rivera, Ernesto

2018-05-01

In this work, the synthesis and characterization of a series of star azo-oligomers bearing amino, amino-methoxy, amino-nitro and amino-cyano substituted azobenzene units and oligo(ethylene glycol) segments is reported. The full characterization of the obtained compounds was achieved by FTIR, 1H and 13C NMR spectroscopies, and their molecular weights were determined by MALDI-TOF mass spectrometry. The optical properties of these compounds were studied by absorption spectroscopy in solution. Finally, light polarized microscopy experiments as a function of the temperature were performed in order to study the liquid-crystalline behavior of these star azo-oligomers.

Atomic structures of corkscrew-forming segments of SOD1 reveal varied oligomer conformations.

PubMed

Sangwan, Smriti; Sawaya, Michael R; Murray, Kevin A; Hughes, Michael P; Eisenberg, David S

2018-02-17

The aggregation cascade of disease-related amyloidogenic proteins, terminating in insoluble amyloid fibrils, involves intermediate oligomeric states. The structural and biochemical details of these oligomers have been largely unknown. Here we report crystal structures of variants of the cytotoxic oligomer-forming segment residues 28-38 of the ALS-linked protein, SOD1. The crystal structures reveal three different architectures: corkscrew oligomeric structure, nontwisting curved sheet structure and a steric zipper proto-filament structure. Our work highlights the polymorphism of the segment 28-38 of SOD1 and identifies the molecular features of amyloidogenic entities. © 2018 The Protein Society.

Molecular Design of Squalene/Squalane Countertypes via the Controlled Oligomerization of Isoprene and Evaluation of Vaccine Adjuvant Applications.

PubMed

Adlington, Kevin; El Harfi, Jaouad; Li, Jianing; Carmichael, Kim; Guderian, Jeffrey A; Fox, Christopher B; Irvine, Derek J

2016-01-11

The potential to replace shark-derived squalene in vaccine adjuvant applications with synthetic squalene/poly(isoprene) oligomers, synthesized by the controlled oligomerization of isoprene is demonstrated. Following on from our previous work regarding the synthesis of poly(isoprene) oligomers, we demonstrate the ability to tune the molecular weight of the synthetic poly(isoprene) material beyond that of natural squalene, while retaining a final backbone structure that contained a minimum of 75% of 1,4 addition product and an acceptable polydispersity. The synthesis was successfully scaled from the 2 g to the 40 g scale both in the bulk (i.e., solvent free) and with the aid of additional solvent by utilizing catalytic chain transfer polymerization (CCTP) as the control method, such that the target molecular weight, acceptable dispersity levels, and the desired level of 1,4 addition in the backbone structure and an acceptable yield (∼60%) are achieved. Moreover, the stability and in vitro bioactivity of nanoemulsion adjuvant formulations manufactured with the synthetic poly(isoprene) material are evaluated in comparison to emulsions made with shark-derived squalene. Emulsions containing the synthetic poly(isoprene) achieved smaller particle size and equivalent or enhanced bioactivity (stimulation of cytokine production in human whole blood) compared to corresponding shark squalene emulsions. However, as opposed to the shark squalene-based emulsions, the poly(isoprene) emulsions demonstrated reduced long-term size stability and induced hemolysis at high concentrations. Finally, we demonstrate that the synthetic oligomeric poly(isoprene) material could successfully be hydrogenated such that >95% of the double bonds were successfully removed to give a representative poly(isoprene)-derived squalane mimic.

Subsite binding energies of an exo-polygalacturonase using isothermal titration calorimetry

USDA-ARS?s Scientific Manuscript database

Thermodynamic parameters for binding of a series of galacturonic acid oligomers to an exo-polygalacturonase, RPG16 from Rhizopus oryzae, were determined by isothermal titration calorimetry. Binding of oligomers varying in chain length from two to five galacturonic acid residues is an exothermic proc...

Nanofluidic Lab-On-Chip Technology for DNA Identification

DTIC Science & Technology

2013-09-30

samples Fluorescently labeled (FAM tag) DNA oligomers (10, 20, and 50 bases long) were purchased with standard desalting and additional HPLC purification...A.2 DNA samples: DNA oligomers (10, 20, 50 nt long) were purchased with standard desalting and additional HPLC purification for the 50 base

Iron-induced oligomerization of human FXN81-210 and bacterial CyaY frataxin and the effect of iron chelators

PubMed Central

Ahlgren, Eva-Christina; Fekry, Mostafa; Wiemann, Mathias; Söderberg, Christopher A.; Bernfur, Katja; Gakh, Olex; Rasmussen, Morten; Højrup, Peter; Emanuelsson, Cecilia; Isaya, Grazia

2017-01-01

Patients suffering from the progressive neurodegenerative disease Friedreich’s ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form. Both long forms, FXN42-210 and FXN56-210, have been shown to spontaneously form oligomeric particles stabilized by the extended N-terminal sequence. The short variant FXN81-210, on other hand, has only been observed in the monomeric state. However, a highly homologous E. coli frataxin CyaY, which also lacks an N-terminal extension, has been shown to oligomerize in the presence of iron. To explore the mechanisms of stabilization of short variant frataxin oligomers we compare here the effect of iron on the oligomerization of CyaY and FXN81-210. Using dynamic light scattering, small-angle X-ray scattering, electron microscopy (EM) and cross linking mass spectrometry (MS), we show that at aerobic conditions in the presence of iron both FXN81-210 and CyaY form oligomers. However, while CyaY oligomers are stable over time, FXN81-210 oligomers are unstable and dissociate into monomers after about 24 h. EM and MS studies suggest that within the oligomers FXN81-210 and CyaY monomers are packed in a head-to-tail fashion in ring-shaped structures with potential iron-binding sites located at the interface between monomers. The higher stability of CyaY oligomers can be explained by a higher number of acidic residues at the interface between monomers, which may result in a more stable iron binding. We also show that CyaY oligomers may be dissociated by ferric iron chelators deferiprone and DFO, as well as by the ferrous iron chelator BIPY. Surprisingly, deferiprone and DFO stimulate FXN81-210 oligomerization, while BIPY does not show any effect on oligomerization in this case. The results suggest that FXN81-210 oligomerization is primarily driven by ferric iron, while both ferric and ferrous iron participate in CyaY oligomer stabilization. Analysis of the amino acid sequences of bacterial and eukaryotic frataxins suggests that variations in the position of the acidic residues in helix 1, β-strand 1 and the loop between them may control the mode of frataxin oligomerization. PMID:29200434

Redox proteomic profiling of neuroketal-adducted proteins in human brain: Regional vulnerability at middle age increases in the elderly.

PubMed

Domínguez, Mayelín; de Oliveira, Eliandre; Odena, María Antonia; Portero, Manuel; Pamplona, Reinald; Ferrer, Isidro

2016-06-01

Protein lipoxidation was assessed in the parietal cortex (PC), frontal cortex (FC), and cingulate gyrus (CG) in middle-aged and old-aged individuals with no clinical manifestations of cognitive impairment, in order to increase understanding of regional brain vulnerability to oxidative damage during aging. Twenty-five lipoxidized proteins were identified in all the three regions although with regional specificities, by using redox proteomics to detect target proteins of neuroketals (NKT) adduction. The number of cases with NKT-adducted proteins was higher in old-aged individuals but most oxidized proteins were already present in middle-aged individuals. Differences in vulnerability to oxidation were dependent on the sub-cellular localization, secondary structure, and external exposition of certain amino acids. Lipoxidized proteins included those involved in energy metabolism, cytoskeleton, proteostasis, neurotransmission and O2/CO2, and heme metabolism. Total NKT and soluble oligomer levels were estimated employing slot-blot, and these were compared between age groups. Oligomers increased with age in PC and FC; NKT significantly increased with age in FC, whereas total NKT and oligomer levels were not modified in CG, thus highlighting differences in brain regional vulnerability with age. Oligomers significantly correlated with NKT levels in the three cortical regions, suggesting that protein NKT adduction parallels soluble oligomer formation. Copyright © 2016 Elsevier Inc. All rights reserved.

High-Capacity Conductive Nanocellulose Paper Sheets for Electrochemically Controlled Extraction of DNA Oligomers

PubMed Central

Razaq, Aamir; Nyström, Gustav; Strømme, Maria; Mihranyan, Albert; Nyholm, Leif

2011-01-01

Highly porous polypyrrole (PPy)-nanocellulose paper sheets have been evaluated as inexpensive and disposable electrochemically controlled three-dimensional solid phase extraction materials. The composites, which had a total anion exchange capacity of about 1.1 mol kg−1, were used for extraction and subsequent release of negatively charged fluorophore tagged DNA oligomers via galvanostatic oxidation and reduction of a 30–50 nm conformal PPy layer on the cellulose substrate. The ion exchange capacity, which was, at least, two orders of magnitude higher than those previously reached in electrochemically controlled extraction, originated from the high surface area (i.e. 80 m2 g−1) of the porous composites and the thin PPy layer which ensured excellent access to the ion exchange material. This enabled the extractions to be carried out faster and with better control of the PPy charge than with previously employed approaches. Experiments in equimolar mixtures of (dT)6, (dT)20, and (dT)40 DNA oligomers showed that all oligomers could be extracted, and that the smallest oligomer was preferentially released with an efficiency of up to 40% during the reduction of the PPy layer. These results indicate that the present material is very promising for the development of inexpensive and efficient electrochemically controlled ion-exchange membranes for batch-wise extraction of biomolecules. PMID:22195031

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification

NASA Astrophysics Data System (ADS)

Kotler, Samuel A.; Brender, Jeffrey R.; Vivekanandan, Subramanian; Suzuki, Yuta; Yamamoto, Kazutoshi; Monette, Martine; Krishnamoorthy, Janarthanan; Walsh, Patrick; Cauble, Meagan; Holl, Mark M. Banaszak; Marsh, E. Neil. G.; Ramamoorthy, Ayyalusamy

2015-07-01

Alzheimer’s disease is characterized by the misfolding and self-assembly of the amyloidogenic protein amyloid-β (Aβ). The aggregation of Aβ leads to diverse oligomeric states, each of which may be potential targets for intervention. Obtaining insight into Aβ oligomers at the atomic level has been a major challenge to most techniques. Here, we use magic angle spinning recoupling 1H-1H NMR experiments to overcome many of these limitations. Using 1H-1H dipolar couplings as a NMR spectral filter to remove both high and low molecular weight species, we provide atomic-level characterization of a non-fibrillar aggregation product of the Aβ1-40 peptide using non-frozen samples without isotopic labeling. Importantly, this spectral filter allows the detection of the specific oligomer signal without a separate purification procedure. In comparison to other solid-state NMR techniques, the experiment is extraordinarily selective and sensitive. A resolved 2D spectra could be acquired of a small population of oligomers (6 micrograms, 7% of the total) amongst a much larger population of monomers and fibers (93% of the total). By coupling real-time 1H-1H NMR experiments with other biophysical measurements, we show that a stable, primarily disordered Aβ1-40 oligomer 5-15 nm in diameter can form and coexist in parallel with the well-known cross-β-sheet fibrils.

Structural assemblies of the di- and oligomeric G-protein coupled receptor TGR5 in live cells: an MFIS-FRET and integrative modelling study

NASA Astrophysics Data System (ADS)

Greife, Annemarie; Felekyan, Suren; Ma, Qijun; Gertzen, Christoph G. W.; Spomer, Lina; Dimura, Mykola; Peulen, Thomas O.; Wöhler, Christina; Häussinger, Dieter; Gohlke, Holger; Keitel, Verena; Seidel, Claus A. M.

2016-11-01

TGR5 is the first identified bile acid-sensing G-protein coupled receptor, which has emerged as a potential therapeutic target for metabolic disorders. So far, structural and multimerization properties are largely unknown for TGR5. We used a combined strategy applying cellular biology, Multiparameter Image Fluorescence Spectroscopy (MFIS) for quantitative FRET analysis, and integrative modelling to obtain structural information about dimerization and higher-order oligomerization assemblies of TGR5 wildtype (wt) and Y111 variants fused to fluorescent proteins. Residue 111 is located in transmembrane helix 3 within the highly conserved ERY motif. Co-immunoprecipitation and MFIS-FRET measurements with gradually increasing acceptor to donor concentrations showed that TGR5 wt forms higher-order oligomers, a process disrupted in TGR5 Y111A variants. From the concentration dependence of the MFIS-FRET data we conclude that higher-order oligomers - likely with a tetramer organization - are formed from dimers, the smallest unit suggested for TGR5 Y111A variants. Higher-order oligomers likely have a linear arrangement with interaction sites involving transmembrane helix 1 and helix 8 as well as transmembrane helix 5. The latter interaction is suggested to be disrupted by the Y111A mutation. The proposed model of TGR5 oligomer assembly broadens our view of possible oligomer patterns and affinities of class A GPCRs.

Evidence of Aβ- and transgene-dependent defects in ERK-CREB signaling in Alzheimer’s models

PubMed Central

Ma, Qiu-Lan; Harris-White, Marni E.; Ubeda, Oliver J.; Simmons, Mychica; Beech, Walter; Lim, Giselle P.; Teter, Bruce; Frautschy, Sally A.; Cole, Greg M.

2008-01-01

Extracellular-signal regulated kinase (ERK) signaling is critical for memory and tightly regulated by acute environmental stimuli. In Alzheimer disease transgenic models, active ERK is shown to first be increased, then later reduced, but whether these baseline changes reflect disruptions in ERK signaling is less clear. We investigated the influence of the familial Alzheimer’s disease transgene APPsw and β-amyloid peptide (Aβ) immunoneutralization on cannulation injury-associated (i.c.v. infusion) ERK activation. At both 12 and 22 months of age, the trauma-associated activation of ERK observed in Tg− mice was dramatically attenuated in Tg+. In cortices of 22-month-old non-infused mice, a reduction in ERK activation was observed in Tg+, relative to Tg− mice. Intracerebroventricular (i.c.v.) anti-Aβ infusion significantly increased phosphorylated ERK, its substrate cAMP-response element-binding protein (CREB) and a downstream target, the NMDA receptor subunit. We also demonstrated that Aβ oligomer decreased active ERK and subsequently active CREB in human neuroblastoma cells, which could be prevented by oligomer immunoneutralization. Aβ oligomers also inhibited active ERK and CREB in primary neurons, in addition to reducing the downstream post-synaptic protein NMDA receptor subunit. These effects were reversed by anti-oligomer. Our data strongly support the existence of an APPsw transgene-dependent and Aβ oligomer-mediated defect in regulation of ERK activation. PMID:17760871

Mechanisms leading to oligomers and SOA through aqueous photooxidation: insights from OH radical oxidation of acetic acid

NASA Astrophysics Data System (ADS)

Tan, Y.; Lim, Y. B.; Altieri, K. E.; Seitzinger, S. P.; Turpin, B. J.

2011-06-01

Previous experiments have demonstrated that the aqueous OH radical oxidation of methylglyoxal produces low volatility products including oxalate and oligomers. These products are found predominantly in the particle phase in the atmosphere, suggesting that methylglyoxal is a precursor of secondary organic aerosol (SOA). Acetic acid is an important intermediate in aqueous methylglyoxal oxidation and a ubiquitous product of gas phase photochemistry, making it a potential "aqueous" SOA precursor in its own right. Altieri et al. (2008) proposed that acetic acid was the precursor of oligoesters observed in methylglyoxal oxidation. However, the fate of acetic acid upon aqueous-phase oxidation is not well understood. In this research, acetic acid at concentrations relevant to atmospheric waters (20 μM-10 mM) was oxidized by OH radical. Products were analyzed by ion chromatography (IC), electrospray ionization mass spectrometry (ESI-MS), and IC-ESI-MS. The formation of glyoxylic, glycolic, and oxalic acids were observed. In contrast to methylglyoxal oxidation, succinic acid and oligomers were not detected. Using results from these and methylglyoxal + OH radical experiments, radical mechanisms responsible for oligomer formation from methylglyoxal oxidation in clouds and wet aerosols are proposed. The importance of acetic acid/acetate as an SOA precursor is also discussed. We hypothesize that this and similar chemistry is central to the daytime formation of oligomers in wet aerosols.

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification

PubMed Central

Kotler, Samuel A.; Brender, Jeffrey R.; Vivekanandan, Subramanian; Suzuki, Yuta; Yamamoto, Kazutoshi; Monette, Martine; Krishnamoorthy, Janarthanan; Walsh, Patrick; Cauble, Meagan; Holl, Mark M. Banaszak; Marsh, E. Neil. G.; Ramamoorthy, Ayyalusamy

2015-01-01

Alzheimer’s disease is characterized by the misfolding and self-assembly of the amyloidogenic protein amyloid-β (Aβ). The aggregation of Aβ leads to diverse oligomeric states, each of which may be potential targets for intervention. Obtaining insight into Aβ oligomers at the atomic level has been a major challenge to most techniques. Here, we use magic angle spinning recoupling 1H-1H NMR experiments to overcome many of these limitations. Using 1H-1H dipolar couplings as a NMR spectral filter to remove both high and low molecular weight species, we provide atomic-level characterization of a non-fibrillar aggregation product of the Aβ1-40 peptide using non-frozen samples without isotopic labeling. Importantly, this spectral filter allows the detection of the specific oligomer signal without a separate purification procedure. In comparison to other solid-state NMR techniques, the experiment is extraordinarily selective and sensitive. A resolved 2D spectra could be acquired of a small population of oligomers (6 micrograms, 7% of the total) amongst a much larger population of monomers and fibers (93% of the total). By coupling real-time 1H-1H NMR experiments with other biophysical measurements, we show that a stable, primarily disordered Aβ1-40 oligomer 5–15 nm in diameter can form and coexist in parallel with the well-known cross-β-sheet fibrils. PMID:26138908

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification.

PubMed

Kotler, Samuel A; Brender, Jeffrey R; Vivekanandan, Subramanian; Suzuki, Yuta; Yamamoto, Kazutoshi; Monette, Martine; Krishnamoorthy, Janarthanan; Walsh, Patrick; Cauble, Meagan; Holl, Mark M Banaszak; Marsh, E Neil G; Ramamoorthy, Ayyalusamy

2015-07-03

Alzheimer's disease is characterized by the misfolding and self-assembly of the amyloidogenic protein amyloid-β (Aβ). The aggregation of Aβ leads to diverse oligomeric states, each of which may be potential targets for intervention. Obtaining insight into Aβ oligomers at the atomic level has been a major challenge to most techniques. Here, we use magic angle spinning recoupling (1)H-(1)H NMR experiments to overcome many of these limitations. Using (1)H-(1)H dipolar couplings as a NMR spectral filter to remove both high and low molecular weight species, we provide atomic-level characterization of a non-fibrillar aggregation product of the Aβ1-40 peptide using non-frozen samples without isotopic labeling. Importantly, this spectral filter allows the detection of the specific oligomer signal without a separate purification procedure. In comparison to other solid-state NMR techniques, the experiment is extraordinarily selective and sensitive. A resolved 2D spectra could be acquired of a small population of oligomers (6 micrograms, 7% of the total) amongst a much larger population of monomers and fibers (93% of the total). By coupling real-time (1)H-(1)H NMR experiments with other biophysical measurements, we show that a stable, primarily disordered Aβ1-40 oligomer 5-15 nm in diameter can form and coexist in parallel with the well-known cross-β-sheet fibrils.

Chemical evolution. XXII - The hydantoins released on hydrolysis of HCN oligomers

NASA Technical Reports Server (NTRS)

Ferris, J. P.; Wos, J. D.; Lobo, A. P.

1974-01-01

The isolation of three hydantoins from HCN oligomers is described. One of these hydantoins, 5-carboxymethylidine hydantoin (5-CMH), rearranges to pyrimidine orotic acid in basic solution. The isolation of 5-CMH suggests the possibility that pyrimidines were formed directly from HCN on the primitive earth.

Tissue microstructure estimation using a deep network inspired by a dictionary-based framework.

PubMed

Ye, Chuyang

2017-12-01

Diffusion magnetic resonance imaging (dMRI) captures the anisotropic pattern of water displacement in the neuronal tissue and allows noninvasive investigation of the complex tissue microstructure. A number of biophysical models have been proposed to relate the tissue organization with the observed diffusion signals, so that the tissue microstructure can be inferred. The Neurite Orientation Dispersion and Density Imaging (NODDI) model has been a popular choice and has been widely used for many neuroscientific studies. It models the diffusion signal with three compartments that are characterized by distinct diffusion properties, and the parameters in the model describe tissue microstructure. In NODDI, these parameters are estimated in a maximum likelihood framework, where the nonlinear model fitting is computationally intensive. Therefore, efforts have been made to develop efficient and accurate algorithms for NODDI microstructure estimation, which is still an open problem. In this work, we propose a deep network based approach that performs end-to-end estimation of NODDI microstructure, which is named Microstructure Estimation using a Deep Network (MEDN). MEDN comprises two cascaded stages and is motivated by the AMICO algorithm, where the NODDI microstructure estimation is formulated in a dictionary-based framework. The first stage computes the coefficients of the dictionary. It resembles the solution to a sparse reconstruction problem, where the iterative process in conventional estimation approaches is unfolded and truncated, and the weights are learned instead of predetermined by the dictionary. In the second stage, microstructure properties are computed from the output of the first stage, which resembles the weighted sum of normalized dictionary coefficients in AMICO, and the weights are also learned. Because spatial consistency of diffusion signals can be used to reduce the effect of noise, we also propose MEDN+, which is an extended version of MEDN. MEDN+ allows incorporation of neighborhood information by inserting a stage with learned weights before the MEDN structure, where the diffusion signals in the neighborhood of a voxel are processed. The weights in MEDN or MEDN+ are jointly learned from training samples that are acquired with diffusion gradients densely sampling the q-space. We performed MEDN and MEDN+ on brain dMRI scans, where two shells each with 30 gradient directions were used, and measured their accuracy with respect to the gold standard. Results demonstrate that the proposed networks outperform the competing methods. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficient solid rocket propulsion for access to space

NASA Astrophysics Data System (ADS)

Maggi, Filippo; Bandera, Alessio; Galfetti, Luciano; De Luca, Luigi T.; Jackson, Thomas L.

2010-06-01

Space launch activity is expected to grow in the next few years in order to follow the current trend of space exploitation for business purpose. Granting high specific thrust and volumetric specific impulse, and counting on decades of intense development, solid rocket propulsion is a good candidate for commercial access to space, even with common propellant formulations. Yet, some drawbacks such as low theoretical specific impulse, losses as well as safety issues, suggest more efficient propulsion systems, digging into the enhancement of consolidated techniques. Focusing the attention on delivered specific impulse, a consistent fraction of losses can be ascribed to the multiphase medium inside the nozzle which, in turn, is related to agglomeration; a reduction of agglomerate size is likely. The present paper proposes a model based on heterogeneity characterization capable of describing the agglomeration trend for a standard aluminized solid propellant formulation. Material microstructure is characterized through the use of two statistical descriptors (pair correlation function and near-contact particles) looking at the mean metal pocket size inside the bulk. Given the real formulation and density of a propellant, a packing code generates the material representative which is then statistically analyzed. Agglomerate predictions are successfully contrasted to experimental data at 5 bar for four different formulations.

Modeling of intragranular misorientation and grain fragmentation in polycrystalline materials using the viscoplastic self-consistent formulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zecevic, Miroslav; Lebensohn, Ricardo A.; McCabe, Rodney J.

In this paper, the recently established methodology to use known algorithmic expressions of the second moments of the stress field in the grains of a polycrystalline aggregate for calculating average fluctuations of lattice rotation rates and the associated average intragranular misorientation distributions using the mean-field viscoplastic self-consistent (VPSC) formulation is extended to solve the coupled problem of considering the effect of intragranular misorientations on stress and rotation rate fluctuations. In turn, these coupled expressions are used to formulate and implement a grain fragmentation (GF) model in VPSC. Case studies, including tension and plane-strain compression of face-centered cubic polycrystals are usedmore » to illustrate the capabilities of the new model. GF-VPSC predictions of intragranular misorientation distributions and texture evolution are compared with experiments and full-field numerical simulations, showing good agreement. In particular, the inclusion of misorientation spreads reduced the intensity of the deformed texture and thus improved the texture predictions. Finally and moreover, considering that intragranular misorientations act as driving forces for recrystallization, the new GF-VPSC formulation is shown to enable modeling of microstructure evolution during deformation and recrystallization, in a computationally efficient manner.« less

Modeling of intragranular misorientation and grain fragmentation in polycrystalline materials using the viscoplastic self-consistent formulation

DOE PAGES

Zecevic, Miroslav; Lebensohn, Ricardo A.; McCabe, Rodney J.; ...

2018-06-15

In this paper, the recently established methodology to use known algorithmic expressions of the second moments of the stress field in the grains of a polycrystalline aggregate for calculating average fluctuations of lattice rotation rates and the associated average intragranular misorientation distributions using the mean-field viscoplastic self-consistent (VPSC) formulation is extended to solve the coupled problem of considering the effect of intragranular misorientations on stress and rotation rate fluctuations. In turn, these coupled expressions are used to formulate and implement a grain fragmentation (GF) model in VPSC. Case studies, including tension and plane-strain compression of face-centered cubic polycrystals are usedmore » to illustrate the capabilities of the new model. GF-VPSC predictions of intragranular misorientation distributions and texture evolution are compared with experiments and full-field numerical simulations, showing good agreement. In particular, the inclusion of misorientation spreads reduced the intensity of the deformed texture and thus improved the texture predictions. Finally and moreover, considering that intragranular misorientations act as driving forces for recrystallization, the new GF-VPSC formulation is shown to enable modeling of microstructure evolution during deformation and recrystallization, in a computationally efficient manner.« less

Nouvelles bornes et estimations pour les milieux poreux à matrice rigide parfaitement plastique

NASA Astrophysics Data System (ADS)

Bilger, Nicolas; Auslender, François; Bornert, Michel; Masson, Renaud

We derive new rigorous bounds and self-consistent estimates for the effective yield surface of porous media with a rigid perfectly plastic matrix and a microstructure similar to Hashin's composite spheres assemblage. These results arise from a homogenisation technique that combines a pattern-based modelling for linear composite materials and a variational formulation for nonlinear media. To cite this article: N. Bilger et al., C. R. Mecanique 330 (2002) 127-132.

Microstructural investigation using synchrotron radiation X-ray microtomography reveals taste-masking mechanism of acetaminophen microspheres.

PubMed

Guo, Zhen; Yin, Xianzhen; Liu, Congbiao; Wu, Li; Zhu, Weifeng; Shao, Qun; York, Peter; Patterson, Laurence; Zhang, Jiwen

2016-02-29

The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-μCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-μCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking. Copyright © 2015 Elsevier B.V. All rights reserved.

Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging.

PubMed

Markl, Daniel; Zeitler, J Axel; Rasch, Cecilie; Michaelsen, Maria Høtoft; Müllertz, Anette; Rantanen, Jukka; Rades, Thomas; Bøtker, Johan

2017-05-01

A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI). Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined. A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 ± 0.75% larger than designed; n = 3). The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.

Poly(amidoamine) Dendrimer Nanocarriers and Their Aerosol Formulations for siRNA Delivery to the Lung Epithelium

PubMed Central

2015-01-01

Small interfering RNA (siRNA)-based therapies have great promise in the treatment of a number of prevalent pulmonary disorders including lung cancer, asthma and cystic fibrosis. However, progress in this area has been hindered due to the lack of carriers that can efficiently deliver siRNA to lung epithelial cells, and also due to challenges in developing oral inhalation (OI) formulations for the regional administration of siRNA and their carriers to the lungs. In this work we report the ability of generation four, amine-terminated poly(amidoamine) (PAMAM) dendrimer (G4NH2)–siRNA complexes (dendriplexes) to silence the enhanced green fluorescent protein (eGFP) gene on A549 lung alveolar epithelial cells stably expressing eGFP. We also report the formulation of the dendriplexes and their aerosol characteristics in propellant-based portable OI devices. The size and gene silencing ability of the dendriplexes was seen not to be a strong function of the N/P ratio. Silencing efficiencies of up to 40% are reported. Stable dispersions of the dendriplexes encapsulated in mannitol and also in a biodegradable and water-soluble co-oligomer were prepared in hydrofluoroalkane (HFA)-based pressurized metered-dose inhalers (pMDIs). Their aerosol characteristics were very favorable, and conducive to deep lung deposition, with respirable fractions of up to 77%. Importantly, siRNA formulated as dendriplexes in pMDIs was shown to keep its integrity after the particle preparation processes, and also after long-term exposures to HFA. The relevance of this study stems from the fact that this is the first work to report the formulation of inhalable siRNA with aerosol properties suitable to deep lung deposition using pMDIs devices that are the least expensive and most widely used portable inhalers. This study is relevant because, also for the first time, it shows that siRNA–G4NH2 dendriplexes can efficiently target lung alveolar epithelial A549 cells and silence genes even after siRNA has been exposed to the propellant environment. PMID:24811243

Influence of multi-walled carbon nanotubes on melting temperature and microstructural evolution of Pb-free Sn-5Sb/Cu solder joint

NASA Astrophysics Data System (ADS)

Dele-Afolabi, T. T.; Azmah Hanim, M. A.; Norkhairunnisa, M.; Suraya, M. T.; Yusoff, H. M.

2017-09-01

In this study, the effects of multi-walled carbon nanotubes on the melting temperature and microstructural evolution of the Sn-5Sb/Cu joints are evaluated. Plain and carbon nanotubes (CNTs) reinforced Sn-5Sb solder systems with solder formulations Sn-5Sb, Sn-5Sb-0.01CNT, Sn-5Sb-0.05CNT and Sn-5Sb-0.1CNT were prepared through the powder metallurgy route and thereafter samples were subjected to thermal and microstructural evaluation. As retrieved from the DSC scans, a slight decline in the peak temperature was observed in the composite solders which is indicative of the CNTs role in exciting surface instability in the host Sn matrix. In order to prepare the solder joints and analyze the interfacial intermetallic compound (IMC) evolution, respective solder systems were placed on copper (Cu) substrate and subjected to both reflow soldering and isothermal aging (170°C) conditions. From the IMC thickness result, considerable retardation in the IMC layer growth was observed in the CNTs reinforced solder joints, especially the 0.05wt.% CNTs solder system owing to the inhibition of Sn atoms diffusion by reinforcement material.

Concurrent topology optimization for minimization of total mass considering load-carrying capabilities and thermal insulation simultaneously

NASA Astrophysics Data System (ADS)

Long, Kai; Wang, Xuan; Gu, Xianguang

2017-09-01

The present work introduces a novel concurrent optimization formulation to meet the requirements of lightweight design and various constraints simultaneously. Nodal displacement of macrostructure and effective thermal conductivity of microstructure are regarded as the constraint functions, which means taking into account both the load-carrying capabilities and the thermal insulation properties. The effective properties of porous material derived from numerical homogenization are used for macrostructural analysis. Meanwhile, displacement vectors of macrostructures from original and adjoint load cases are used for sensitivity analysis of the microstructure. Design variables in the form of reciprocal functions of relative densities are introduced and used for linearization of the constraint function. The objective function of total mass is approximately expressed by the second order Taylor series expansion. Then, the proposed concurrent optimization problem is solved using a sequential quadratic programming algorithm, by splitting into a series of sub-problems in the form of the quadratic program. Finally, several numerical examples are presented to validate the effectiveness of the proposed optimization method. The various effects including initial designs, prescribed limits of nodal displacement, and effective thermal conductivity on optimized designs are also investigated. An amount of optimized macrostructures and their corresponding microstructures are achieved.

Separation of Uncharged Oligodeoxynucleotide Analogs by Anion-Exchange Chromatography at High pH

NASA Technical Reports Server (NTRS)

Schmidt, Jurgen G.; Nielsen, Peter E.; Orgel, Leslie

1996-01-01

Ion-exchange chromatography is a well-established method for the analysis and purification of phosphodiester-linked oligonucleotides. If elution is carried out under alkaline conditions, the secondary structure of G- and C-rich oligomers is disrupted. Furthermore, elution times become more sensitive to the G and T content of the oligomer, because G and T are deprotonated at pH 10. In recent work on peptide-nucleic acids (PNAs) we noted that mixtures of PNA oligomers G(sub 4), G(Sub 6), G(sub 8), and G(sub 10) are readily separated by elution at pH 12 on an RPC-5 column. Here we show that this separation method is more generally applicable.

Proteins from disassembled microtubules characterized by oligospecific antisera.

PubMed

Meier, E; Jorgensen, O S

1977-10-26

The immunochemical properties of in vitro reassembled microtubules were investigated by immunoelectrophoretic techniques. The tubulin dimer gave no measurable immunochemical response, but the tubulin oligomer, the tau-factor and an antigen of about 135 000 daltons all gave precipitating antibodies. Those four proteins were investigated in reassembled microtubules, in DEAE-cellulose purified tubulin, and after molecular sieve chromatography of disassembled and NaCl-dissociated microtubules. Reconstitution of tubulin oligomer from tubulin dimer and tau-factor was also performed. The presence of a unique antigenic structure on tubulin oligomer which was not found in the dissociated components and the role of this aggregate as a nucleation center or intermediate in the assembly of microtubules is discussed.

Monte Carlo Simulation of Endlinking Oligomers

NASA Technical Reports Server (NTRS)

Hinkley, Jeffrey A.; Young, Jennifer A.

1998-01-01

This report describes initial efforts to model the endlinking reaction of phenylethynyl-terminated oligomers. Several different molecular weights were simulated using the Bond Fluctuation Monte Carlo technique on a 20 x 20 x 20 unit lattice with periodic boundary conditions. After a monodisperse "melt" was equilibrated, chain ends were linked whenever they came within the allowed bond distance. Ends remained reactive throughout, so that multiple links were permitted. Even under these very liberal crosslinking assumptions, geometrical factors limited the degree of crosslinking. Average crosslink functionalities were 2.3 to 2.6; surprisingly, they did not depend strongly on the chain length. These results agreed well with the degrees of crosslinking inferred from experiment in a cured phenylethynyl-terminated polyimide oligomer.

Negative Differential Conductance in Polyporphyrin Oligomers with Nonlinear Backbones.

PubMed

Kuang, Guowen; Chen, Shi Zhang; Yan, Linghao; Chen, Ke Qiu; Shang, Xuesong; Liu, Pei Nian; Lin, Nian

2018-01-17

We study negative differential conductance (NDC) effects in polyporphyrin oligomers with nonlinear backbones. Using a low-temperature scanning tunneling microscope, we selectively controlled the charge transport path in single oligomer wires. We observed robust NDC when charge passed through a T-shape junction, bistable NDC when charge passed through a 90° kink and no NDC when charge passed through a 120° kink. Aided by density functional theory with nonequilibrium Green's functions simulations, we attributed this backbone-dependent NDC to bias-modulated hybridization of the electrode states with the resonant transport molecular orbital. We argue this mechanism is generic in molecular systems, which opens a new route of designing molecular NDC devices.

Characterization of green synthesized nano-formulation (ZnO-A. vera) and their antibacterial activity against pathogens.

PubMed

Qian, Yiguang; Yao, Jun; Russel, Mohammad; Chen, Ke; Wang, Xiaoyu

2015-03-01

The application of nanotechnology in medicine has recently been a breakthrough in therapeutic drugs formulation. This paper presents the structural and optical characterization of a new green nano-formulation (ZnO-Aloe vera) with considerable antibacterial activity against pathogenic bacteria. Its particle structure, size and morphology were characterized by XRD, TEM and SEM. And optical absorption spectra and photoluminescence were measured synchronously. Their antibacterial activity against Escherichia coli and Staphylococcus aureus was also investigated using thermokinetic profiling and agar well diffusion method. The nano-formulation is spherical shape and hexagonal with a particle size ranging from 25 to 65 nm as well as an increased crystallite size of 49 nm. For antibacterial activity, the maximum inhibition zones of ZnO and ZnO+A. vera are 18.33 and 26.45 mm for E. coli, 22.11 and 28.12 mm for S. aureus (p<0.05). Considering Pmax, Qt and k, ZnO+A. vera nano-formulation has a significant (p < 0.05) antibacterial effect against S. aureus almost at all concentration and against E. coli at 15 and 25mg/L. ZnO+A. vera nano-formulation is much more toxic against S. aureus than E. coli, with an IC50 of 13.12 mg/L and 21.31 mg/L, respectively. The overall results reveal that the ZnO-A. vera nano-formulation has good surface energy, crystallinity, transmission, and enriched antibacterial activities. Their antibacterial properties are possibly relevant to particle size, microstructural ionization, the crystal formation and the Gram property of pathogens. This ZnO-A. vera nano-formulation could be utilized effectively as a spectral and significant antibacterial agent for pathogens in future medical and environmental concerns. Copyright © 2015 Elsevier B.V. All rights reserved.

Toughening epoxy acrylate with polyurethane acrylates and hyper-branched polyester in three dimensional printing

NASA Astrophysics Data System (ADS)

Fang, Chao; Li, Ning; Liu, Yang; Lu, Gang

2018-05-01

In order to improve the toughness of epoxy acrylate (EA) in three dimensional printing (3D-printing), bifunctional polyurethane acrylate (PUA) and trifunctional PUA were firstly blended with EA. The multi-indicators orthogonal experiment, designed with the indicators of tensile strength, elongation at break and impact strength, was used to find out the optimal formulation. Then, hyper-branched polyesters (HBPs) was added to improve the toughness of the photocurable system. The microstructures of the cured specimens were characterized by optical microscopy and scanning electron microscopy. By analyzing their mechanical properties and microstructures, it was revealed that the best addition amounts of HBP are 10 wt%. Results indicated that their toughness improved a lot comparing with pure EA. The changes of mechanical properties were characterized by DMA. The addition of HBP could cause a loss in stiffness, elasticity modulus and thermostability.

Development and Application of Wood Flour-Filled Polylactic Acid Composite Filament for 3D Printing

PubMed Central

Tao, Yubo; Wang, Honglei; Li, Zelong; Li, Peng; Shi, Sheldon Q.

2017-01-01

This paper presents the development of wood flour (WF)-filled polylactic acid (PLA) composite filaments for a fused deposition modeling (FDM) process with the aim of application to 3D printing. The composite filament consists of wood flour (5 wt %) in a PLA matrix. The detailed formulation and characterization of the composite filament were investigated experimentally, including tensile properties, microstructure, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The feedstock filaments of this composite were produced and used successfully in an assembled FDM 3D printer. The research concludes that compared with pure PLA filament, adding WF changed the microstructure of material fracture surface, the initial deformation resistance of the composite was enhanced, the starting thermal degradation temperature of the composite decreased slightly, and there were no effects on the melting temperature. The WF/PLA composite filament is suitable to be printed by the FDM process. PMID:28772694

Visualizing In Situ Microstructure Dependent Crack Tip Stress Distribution in IN-617 Using Nano-mechanical Raman Spectroscopy

NASA Astrophysics Data System (ADS)

Zhang, Yang; Mohanty, Debapriya P.; Tomar, Vikas

2016-11-01

Inconel 617 (IN-617) is a solid solution alloy, which is widely used in applications that require high-temperature component operation due to its high-temperature stability and strength as well as strong resistance to oxidation and carburization. The current work focuses on in situ measurements of stress distribution under 3-point bending at elevated temperature in IN-617. A nanomechanical Raman spectroscopy measurement platform was designed and built based on a combination of a customized open Raman spectroscopy (NMRS) system incorporating a motorized scanning and imaging system with a nanomechanical loading platform. Based on the scanning of the crack tip notch area using the NMRS notch tip, stress distribution under applied load with micron-scale resolution for analyzed microstructures is predicted. A finite element method-based formulation to predict crack tip stresses is presented and validated using the presented experimental data.

DEVELOPMENT OF SEPARATION SYSTEMS FOR POLYNUCLEAR AROMATIC HYDROCARBON ENVIRONMENTAL CONTAMINANTS USING MICELLAR ELECTROKINETIC CHROMATOGRAPHY WITH MOLECULAR MICELLES AND FREE ZONE ELECTROPHORESIS

EPA Science Inventory

Of four systems available from the literature, based on cyclodextrins, dioctylsulfosuccinate, bile salts, and molecular micelles consisting of oligomers of undecylenic acid, the most successful separation system in our hands is based on the molecular micelles, oligomers of sodiu...

Student-Driven Design of Peptide Mimetics: Microwave-Assisted Synthesis of Peptoid Oligomers

ERIC Educational Resources Information Center

Pohl, Nicola L. B.; Kirshenbaum, Kent; Yoo, Barney; Schulz, Nathan; Zea, Corbin J.; Streff, Jennifer M.; Schwarz, Kimberly L.

2011-01-01

An experiment for the undergraduate organic laboratory is described in which peptide mimetic oligomers called "peptoids" are built stepwise on a solid-phase resin. Students employ two modern strategies to facilitate rapid multistep syntheses: solid-phase techniques to obviate the need for intermediate purifications and microwave irradiation to…

Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation*

PubMed Central

Tashiro, Erika; Zako, Tamotsu; Muto, Hideki; Itoo, Yoshinori; Sörgjerd, Karin; Terada, Naofumi; Abe, Akira; Miyazawa, Makoto; Kitamura, Akira; Kitaura, Hirotake; Kubota, Hiroshi; Maeda, Mizuo; Momoi, Takashi; Iguchi-Ariga, Sanae M. M.; Kinjo, Masataka; Ariga, Hiroyoshi

2013-01-01

Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1–6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells. PMID:23720755

Does Thioflavin-T Detect Oligomers Formed During Amyloid Fibril Assembly

NASA Astrophysics Data System (ADS)

Persichilli, Christopher; Hill, Shannon E.; Mast, Jason; Muschol, Martin

2011-03-01

Recent results have shown that oligomeric intermediates of amyloid fibril assembly represent the main toxic species in disorders such as Alzheimer's disease and type II diabetes. Thioflavin-T (ThT) is among the most commonly used indicator dyes for mature amyloid fibrils in vitro. We used ThT to monitor amyloid fibril formation of lysozyme (HEWL), and correlated ThT fluorescence to concurrent dynamic light scattering and atomic force microscopy measurements. Specifically, we tested the ability of ThT to discern among oligomer-free vs. oligomeric fibril assembly pathways. We found that ThT fluorescence did not detect oligomer growth; however, fluorescence increases did coincide with the formation of monomeric filaments in the oligomer-free assembly pathway. This implies that ThT fluorescence is not generally suitable for the detection of oligomeric intermediates. The results further suggest different internal structures for oligomeric vs. monomeric filaments. This research was supported, in part, by funding through the Byrd Alzheimer's Institute (ARG-2007-22) and the BITT-Florida Center of Excellence for M.M., an NSF-REU grant (DMR-1004873) for C. P. and an NSF-IGERT fellowship for S.H.

Concentrations of oligomers and polymers of proanthocyanidins in red and purple rice bran and their relationships to total phenolics, flavonoids, antioxidant capacity and whole grain color.

PubMed

Chen, Ming-Hsuan; McClung, Anna M; Bergman, Christine J

2016-10-01

Proanthocyanidins, a flavonoids subgroup, are proposed to have chronic disease modulation properties. With the eventual goal of enhancing rice phytonutrient concentrations, we investigated the genotypic variation of the concentrations of individual oligomers and polymers of proanthocyanidins in red and purple rice brans. A 4.3-fold variation in total proanthocyanidins (sum of oligomers and polymers) in the extractable fraction was found and the concentration was highly correlated with total phenolics, total flavonoids and antiradical capacity. Variation in the proportion of oligomers and polymers existed, with monomers to trimers, 4-6mers, 7-10mers and polymers accounting for 7, 18, 26.5 and 48.7%, respectively, of the total. The redness value a(∗) of whole grain rice measured in CIE L(∗)a(∗)b(∗) color space was negatively and positively correlated with extractable and non-extractable proanthocyanidins, respectively. The variation found indicates it is possible to select rice with bran containing high levels of total proanthocyanidins and specific degree of polymerization profiles. Published by Elsevier Ltd.

Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

PubMed Central

Wong, Michael; Daly, Seth M.; Greenberg, David E.; Toprak, Erdal

2016-01-01

The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene’s sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities. PMID:27631336

Separation of a chemically modified DNA oligomer bound by the carcinogen 2-Amino-1-methy-6-phenylimidazo [4,5-{beta}]pyridine using capillary gel electrophoresis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, T.N.

1994-05-06

We have optimized the reaction conditions under which unactivated metabolite of the food borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-{beta}]pyridine (PhIP) is covalently bound to the oligodeoxynucleotide d(CCTACGCATCC). Capillary electrophoresis (CE) was used to separate and characterize this DNA oligomer bound by PhIP. We observed 2 major and several minor PhIP adduct species. The 2 major adducts had different absorbance maxima; the major adduct eluates with faster and slower mobilities had absorbance maxima of 360 and 340 nm, respectively. One of the two major PhIP adduct species was resolvable but the peak was broad. Using detection at 260 nm, the other major PhIPmore » adduct with fastest electrophoretic mobility was not resolvable, but coelute with the huge broad unmodified DNA oligomer peak. However, at higher wavelengths (>320 nm) where DNA does not absorb, electropherograms generated by detection at these higher wavelengths showed very heterogeneous binding by PhIP to the DNA oligomer with no interfering absorbance by the DNA.« less

Contact lines on silicone elastomers promote contamination

NASA Astrophysics Data System (ADS)

Hourlier-Fargette, Aurelie; Antkowiak, Arnaud; Neukirch, Sebastien

2017-11-01

Silicone elastomers are used in contact with aqueous liquids in a large range of applications. Due to numerous advantages such as its flexibility, optical transparency, or gas permeability, polydimethylsiloxane is widely spread in rapid prototyping for microfluidics or elastocapillarity experiments. However, silicone elastomers are known to contain a small fraction of uncrosslinked low-molecular-weight oligomers, the effects of which are not completely understood. We show that in various setups involving an air-water-silicone elastomer contact line, a capillarity-induced extraction of uncrosslinked oligomers occurs, leading to a contamination of water-air interfaces. We investigate the case of a static air-water-PDMS contact line, before focusing on moving contact lines. A water droplet sliding down on a PDMS inclined plane or an air bubble rising on an immersed PDMS plane exhibits two successive speed regimes: the second regime is reached only when a monolayer of oligomers completely covers the water-air interface. These experiments involve processes occurring at the polymer network scale that have significant macroscopic consequences, and therefore provide a simple test to evaluate the presence of uncrosslinked oligomers in an elastomer sample.

Stable, Metastable, and Kinetically Trapped Amyloid Aggregate Phases

PubMed Central

2015-01-01

Self-assembly of proteins into amyloid fibrils plays a key role in a multitude of human disorders that range from Alzheimer’s disease to type II diabetes. Compact oligomeric species, observed early during amyloid formation, are reported as the molecular entities responsible for the toxic effects of amyloid self-assembly. However, the relation between early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. We show that these different structures occupy well-defined regions in a peculiar phase diagram. Lysozyme amyloid oligomers and their curvilinear fibrils only form after they cross a salt and protein concentration-dependent threshold. We also determine a boundary for the onset of amyloid oligomer precipitation. The oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. These experimentally determined boundaries match well with colloidal model predictions that account for salt-modulated charge repulsion. The model also incorporates the metastable and kinetic character of oligomer phases. Similarities and differences of amyloid oligomer assembly to metastable liquid–liquid phase separation of proteins and to surfactant aggregation are discussed. PMID:25469942

A quantitative evaluation of the iron-sulfur world and its relevance to life's origins.

PubMed

Ross, David S

2008-04-01

The significance of Wächtershäuser's iron-sulfur world to the origin of life and the limits to its notional autocatalytic cycles are examined in kinetic simulations of the chain polymerization sequence: primitive materials-->amino acids-->oligomers. The simulations were run for the formation of all oligomers up to the 20-mer over a 1 Gy interval from the end of the period of heavy bombardment, during which period life emerged. Upper-limit rate constant estimates developed from the studies of Huber and Wächtershäuser were employed. The simulations showed that oligomer production consistent with life's start within that interval emerges only with an autocatalyst exhibiting a catalytic proficiency comparable to that of contemporary enzymes. The simulations, moreover, ignored likely thermodynamic and statistical burdens which, if included, would have led to the need for catalytic capacities well in excess of those in present-day enzymes. Prebiotic oligomers with such levels of activity are clearly not likely, and it is apparent that the iron-sulfur scheme could not have played a role in life's beginnings.

Regulation of adhesion and growth of fibrosarcoma cells by NF-kappa B RelA involves transforming growth factor beta.

PubMed Central

Perez, J R; Higgins-Sochaski, K A; Maltese, J Y; Narayanan, R

1994-01-01

The NF-kappa B transcription factor is a pleiotropic activator that participates in the induction of a wide variety of cellular genes. Antisense oligomer inhibition of the RelA subunit of NF-kappa B results in a block of cellular adhesion and inhibition of tumor cell growth. Investigation of the molecular basis for these effects showed that in vitro inhibition of the growth of transformed fibroblasts by relA antisense oligonucleotides can be reversed by the parental-cell-conditioned medium. Cytokine profile analysis of these cells treated with relA antisense oligonucleotides revealed inhibition of transforming growth factor beta 1 (TGF-beta 1 to the transformed fibroblasts reversed the inhibitory effects of relA antisense oligomers on soft agar colony formation and cell adhesion to the substratum. Direct inhibition of TGF-beta 1 expression by antisense phosphorothioates to TGF-beta 1 mimicked the in vitro effects of blocking cell adhesion that are elicited by antisense relA oligomers. These results may explain the in vitro effects of relA antisense oligomers on fibrosarcoma cell growth and adhesion. Images PMID:8035811

Exciton–exciton annihilation as a probe of interchain interactions in PPV–oligomer aggregates

DOE PAGES

Peteanu, Linda A.; Chowdhury, Sanchari; Wildeman, Jurjen; ...

2017-01-20

One measure of exciton mobility in an aggregate is the efficiency of exciton–exciton annihilation (EEA). Both exciton mobilities and EEA are enhanced for aggregate morphologies in which the distances between chromophores and their relative orientations are favorable for Förster energy transfer. Here this principle is applied to gauge the strength of interchain interactions in aggregates of two substituted PPV oligomers of 7 (OPPV7) and 13 (OPPV13) phenylene rings. These are models of the semiconducting conjugated polymer MEH–PPV. The aggregates were formed by adding a poor solvent (methanol or water) to the oligomers dissolved in a good solvent. Aggregates formed frommore » the longer-chain oligomer and/or by addition of the more polar solvent showed the largest contribution of EEA in their emission decay dynamics. This was found to correlate with the degree to which the steady-state emission spectrum of the monomer is altered by aggregation. Furthermore, the wavelength dependence of the EEA signal was also shown to be useful in differentiating emission features due to monomeric and aggregated chains when their spectra overlap significantly.« less

Iterative divergent/convergent doubling approach to linear conjugated oligomers. A rapid route to a 128 A long potential molecular wire

NASA Astrophysics Data System (ADS)

Tour, James M.; Schumm, Jeffrey S.; Pearson, Darren L.

1994-06-01

Described is the synthesis of oligo (2-ethylphenylene ethynylene)s and oligo (2-(3'ethylheptyl) phenylene ethynylene)s via an iterative divergent convergent approach. Synthesized were the monomer, dimer, tetramer, and octamer of the ethyl derivative and the monomer, dimer, tetramer, octamer, and 16-mer of the ethylheptyl derivative. The 16-mer is 128 A long. At each stage in the iteration, the length of the framework doubles. Only three sets of reaction conditions are needed for the entire iterative synthetic sequence; an iodination, a protodesilylation, and a Pd/Cu-catalyzed cross coupling. The oligomers were characterized spectroscopically and by mass spectrometry. The optical properties are presented which show the stage of optical absorbance saturation. The size exclusion chromatography values for the number average weights, relative to polystyrene, illustrate the tremendous differences in the hydrodynamic volume of these rigid rod oligomers verses the random coils of polystyrene. These differences become quite apparent at the octamer stage. These oligomers may act as molecular wires in molecular electronic devices and they also serve as useful models for understanding related bulk polymers.

Stereocomplexes Formed From Select Oligomers of Polymer d-lactic Acid (PDLA) and l-lactate May Inhibit Growth of Cancer Cells and Help Diagnose Aggressive Cancers—Applications of the Warburg Effect

PubMed Central

Goldberg, Joel S.

2011-01-01

It is proposed that select oligomers of polymer d-lactic acid (PDLA) will form a stereocomplex with l-lactate in vivo, producing lactate deficiency in tumor cells. Those cancer cells that utilize transport of lactate to maintain electrical neutrality may cease to multiply or die because of lactate trapping, and those cancer cells that benefit from utilization of extracellular lactate may be impaired. Intracellular trapping of lactate produces a different physiology than inhibition of LDH because the cell loses the option of shuttling pyruvate to an alternative pathway to produce an anion. Conjugated with stains or fluorescent probes, PDLA oligomers may be an agent for the diagnosis of tissue lactate and possibly cell differentiation in biopsy specimens. Preliminary experimental evidence is presented confirming that PDLA in high concentrations is cytotoxic and that l-lactate forms a presumed stereocomplex with PDLA. Future work should be directed at isolation of biologically active oligomers of PDLA. PMID:21487535

Non-native Soluble Oligomers of Cu/Zn Superoxide Dismutase (SOD1) Contain a Conformational Epitope Linked to Cytotoxicity in Amyotrophic Lateral Sclerosis (ALS)

PubMed Central

2015-01-01

Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS. PMID:24660965

Stable, metastable, and kinetically trapped amyloid aggregate phases.

PubMed

Miti, Tatiana; Mulaj, Mentor; Schmit, Jeremy D; Muschol, Martin

2015-01-12

Self-assembly of proteins into amyloid fibrils plays a key role in a multitude of human disorders that range from Alzheimer's disease to type II diabetes. Compact oligomeric species, observed early during amyloid formation, are reported as the molecular entities responsible for the toxic effects of amyloid self-assembly. However, the relation between early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. We show that these different structures occupy well-defined regions in a peculiar phase diagram. Lysozyme amyloid oligomers and their curvilinear fibrils only form after they cross a salt and protein concentration-dependent threshold. We also determine a boundary for the onset of amyloid oligomer precipitation. The oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. These experimentally determined boundaries match well with colloidal model predictions that account for salt-modulated charge repulsion. The model also incorporates the metastable and kinetic character of oligomer phases. Similarities and differences of amyloid oligomer assembly to metastable liquid-liquid phase separation of proteins and to surfactant aggregation are discussed.

Exciton-Exciton Annihilation as a Probe of Interchain Interactions in PPV-Oligomer Aggregates.

PubMed

Peteanu, Linda A; Chowdhury, Sanchari; Wildeman, Jurjen; Sfeir, Matthew Y

2017-02-23

One measure of exciton mobility in an aggregate is the efficiency of exciton-exciton annihilation (EEA). Both exciton mobilities and EEA are enhanced for aggregate morphologies in which the distances between chromophores and their relative orientations are favorable for Förster energy transfer. Here this principle is applied to gauge the strength of interchain interactions in aggregates of two substituted PPV oligomers of 7 (OPPV7) and 13 (OPPV13) phenylene rings. These are models of the semiconducting conjugated polymer MEH-PPV. The aggregates were formed by adding a poor solvent (methanol or water) to the oligomers dissolved in a good solvent. Aggregates formed from the longer-chain oligomer and/or by addition of the more polar solvent showed the largest contribution of EEA in their emission decay dynamics. This was found to correlate with the degree to which the steady-state emission spectrum of the monomer is altered by aggregation. The wavelength dependence of the EEA signal was also shown to be useful in differentiating emission features due to monomeric and aggregated chains when their spectra overlap significantly.

Computational Design of High-χ Block Oligomers for Accessing 1 nm Domains.

PubMed

Chen, Qile P; Barreda, Leonel; Oquendo, Luis E; Hillmyer, Marc A; Lodge, Timothy P; Siepmann, J Ilja

2018-05-22

Molecular dynamics simulations are used to design a series of high-χ block oligomers (HCBOs) that can self-assemble into a variety of mesophases with domain sizes as small as 1 nm. The exploration of these oligomers with various chain lengths, volume fractions, and chain architectures at multiple temperatures reveals the presence of ordered lamellae, perforated lamellae, and hexagonally packed cylinders. The achieved periods are as small as 3.0 and 2.1 nm for lamellae and cylinders, respectively, which correspond to polar domains of approximately 1 nm. Interestingly, the detailed phase behavior of these oligomers is distinct from that of either solvent-free surfactants or block polymers. The simulations reveal that the behavior of these HCBOs is a product of an interplay between both "surfactant factors" (headgroup interactions, chain flexibility, and interfacial curvature) and "block polymer factors" (χ, chain length N, and volume fraction f). This insight promotes the understanding of molecular features pivotal for mesophase formation at the sub-5 nm length scale, which facilitates the design of HCBOs tailored toward particular desired morphologies.

A quantitative evaluation of the iron-sulfur world and its relevance to life's origins

USGS Publications Warehouse

Ross, D.S.

2008-01-01

The significance of Wa??chtersha??user's iron-sulfur world to the origin of life and the limits to its notional autocatalytic cycles are examined in kinetic simulations of the chain polymerization sequence primitive materials ??? amino acids ??? oligomers The simulations were run for the formation of all oligomers up to the 20-mer over a 1 Gy interval from the end of the period of heavy bombardment, during which period life emerged. Upper-limit rate constant estimates developed from the studies of Huber and Wa??chtersha?? user were employed. The simulations showed that oligomer production consistent with life's start within that interval emerges only with an autocatalyst exhibiting a catalytic proficiency comparable to that of contemporary enzymes. The simulations, moreover, ignored likely thermodynamic and statistical burdens which, if included, would have led to the need for catalytic capacities well in excess of those in present-day enzymes. Prebiotic oligomers with such levels of activity are clearly not likely, and it is apparent that the iron-sulfur scheme could not have played a role in life's beginnings. ?? 2008 Mary Ann Liebert, Inc.

Oligomers, organosulfates, and nitroxy organosulfates identified in rainwater

NASA Astrophysics Data System (ADS)

Altieri, K. E.; Turpin, B. J.; Seitzinger, S. P.

2008-12-01

Wet deposition is an important removal mechanism for atmospheric organic matter, and a potentially important input for receiving ecosystems, yet less than 50 percent of rainwater organic matter is considered chemically characterized. Precipitation samples collected in New Jersey, USA, were analyzed by negative ion ultra-high resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). We document the presence of 552 unique compounds in the rainwater over a mass range of 50-500 Da, in four compound classes (i.e., CHO, CHOS, CHON, and CHONS). The presence of oligomers, organosulfates, nitroxy organosulfates, organic acids, and linear alkylbenzene sulfonates is reported. Some compounds detected have distinct primary sources; however, the composition of the bulk of this material suggests it is formed in the atmosphere and composed of known contributors to secondary organic aerosol. For example, eight oligomer series known to form through aqueous photooxidation of methylglyoxal and organosulfate compounds known to form from 4 precursors in smog chamber experiments were identified in the rainwater samples. The oligomers, organosulfates, and nitroxy organosulfates detected in the rainwater could all contribute to the HULIS fraction of atmospheric organic matter.

N-vinylpyrrolidone modified glass-ionomer resins for improved dental restoratives

NASA Astrophysics Data System (ADS)

Xie, Dong

The studies described in this dissertation focus on improvement of mechanical properties of current glass-ionomer cements. Thermal properties and microstructures of the cements were correlated with their mechanical strengths. The first study evaluated mechanical properties of selected commercial glass-ionomer cements and examined their microstructures. The results showed that resin-modified glass-ionomer cements (RM GICs) exhibited much higher flexural (FS) and diametral tensile strengths (DTS), compared to conventional GICs (C GICs). In addition, they exhibited comparable compressive strength (CS), relatively low microhardness and less wear resistance than C GICs. The C GICs exhibited brittle behavior, whereas the RM GICs underwent substantial plastic deformation in compression. The mechanical properties of the GICs were closely related to their microstructures. Factors such as the density of the microstructure, the integrity of the interface between the glass particles and polymer matrix, particle size and the number and size of voids have important roles in determining the mechanical properties. The second study evaluated thermal properties of these GICs. The results showed that the RM GICs exhibited higher thermal transition temperatures than those of the C GICs, thermal expansion coefficients of these cements were close to those of human teeth, and the indentation creep of the RM GICs were higher than the C GICs. The third study explored and evaluated the effect of a water-soluble monomer, N-vinylpyrrolidone (NVP), on the performance of current C GICs, indicating a significant improvement in both mechanical and working properties. The fourth study demonstrated the process of determining the optimal molar ratio of the NVP-containing copolymers, using design of experiment. The results showed that the optimal molar ratio for these copolymers was 7:1:3 for poly(acrylic acid-co-itaconic acid-co-N-vinylpyrrolidone), based on the FS test. The molar ratio of 8:2:1 (AA:IA:NVP) was considered as the best molar ratio for these copolymers, based on the DTS and CS tests. The fifth study formulated the NVP-containing RM GICs using a statistical design of experiment. The results indicated that the best graft ratio for 2-isocyanatoethyl methacrylate (IEM) in this system was 15% of the terpolymer by a molar ratio. The optimal formulation was found to be at the weight ratio of 55:15:30 (RM NVP-containing terpolymer: 2-hydroxyethyl methacrylate (HEMA): Hsb2O). Stress-strain curves showed that a relatively high amount of water in the formulation led to higher elastic modulus and proportional limit and lower malleability, whereas a relatively high amount of HEMA gave the opposite results. The sixth study evaluated the NVP modified GICs (NVPM GICs) with the best molar ratios and optimal formulations in the mechanical, thermal and working properties. The results showed that the effect of molecular weight on mechanical properties of the NVPM GICs were evident. Different glass powders exhibited different effects on properties of the NVPM GICs, due to different compositions, size and affinity. Powder/liquid ratios had significant effects on the mechanical properties of NVPM GICs, especially on FS. P/W ratios are only beneficial to the NVPM GICs mixed with the Fuji II glass powders. The NVPM GICs showed a higher WT than the models, due to water retention of the NVP ring. Thermal expansion coefficients for the NVPM GICs were close to those for the natural tooth. Mismatch between the glass powders used and the polymer matrix was a big concern in this study and should be solved in the future.

Stereolithography of perfluoropolyethers for the microfabrication of robust omniphobic surfaces

NASA Astrophysics Data System (ADS)

Credi, Caterina; Levi, Marinella; Turri, Stefano; Simeone, Giovanni

2017-05-01

In this work, we provide a simple and straightforward method for the fabrication of stable highly hydrophobic and oleophobic surfaces by applying stereolithography (SL) to perfluoropolyethers (PFPEs). Inspired by the liquid repellency widely shown in nature, our approach enables to easily mimic the interplay between the chemistry and physics by microtexturing low surface tension PFPEs. To this end, UV-curable resins suitable for SL-processing were formulated by blending multifunctional (meth-)acrylates PFPEs oligomers with photoinitiator and visible dyes whose content was tuned to tailor resin SL sensitivities. Photocalorimetric studies were also performed to investigate the curing behavior of the different formulations upon SL light exposure. Being the first example of stereolithography applied to PFPEs, stereolithographic processability of new developed PFPEs photopolymer was compared with a standard photoresist taken as benchmark (DL260®). Optimized formulations were characterized by reduced laser penetration depth (<75 μm) and small critical energies thus enabling for fast printing of micrometric structures. Arrays of cylindrical pillars (85 μm diameter, 400 μm height) characterized by varied pillars spacing (200 ÷ 350 μm) were rapidly printed with high fidelity as attested by SEM examination. Contact angle measurements in static and dynamic conditions were performed to investigate the surface properties of textured samples using water and oil as the probing liquids. PFPEs liquid repellent performances were compared with those from DL260® textured surfaces arrayed by SL. High water contact angles coupled with low hysteresis asserted that high hydrophobic surfaces were successfully obtained and best-performing textured surfaces were also characterized by high oil repellency. Finally, this study demonstrated that omniphobic surfaces can be easily realized via a single-step, cost-effective, and time-saving process.

Delivery of Dual Drug Loaded Lipid Based Nanoparticles across the Blood-Brain Barrier Impart Enhanced Neuroprotection in a Rotenone Induced Mouse Model of Parkinson's Disease.

PubMed

Kundu, Paromita; Das, Manasi; Tripathy, Kalpalata; Sahoo, Sanjeeb K

2016-12-21

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Modulation of hematopoietic progenitor cell fate in vitro by varying collagen oligomer matrix stiffness in the presence or absence of osteoblasts.

PubMed

Chitteti, Brahmananda Reddy; Kacena, Melissa A; Voytik-Harbin, Sherry L; Srour, Edward F

2015-10-01

To recreate the in vivo hematopoietic cell microenvironment or niche and to study the impact of extracellular matrix (ECM) biophysical properties on hematopoietic progenitor cell (HPC) proliferation and function, mouse bone-marrow derived HPC (Lin-Sca1+cKit+/(LSK) were cultured within three-dimensional (3D) type I collagen oligomer matrices. To generate a more physiologic milieu, 3D cultures were established in both the presence and absence of calvariae-derived osteoblasts (OB). Collagen oligomers were polymerized at varying concentration to give rise to matrices of different fibril densities and therefore matrix stiffness (shear storage modulus, 50-800 Pa). Decreased proliferation and increased clonogenicity of LSK cells was associated with increase of matrix stiffness regardless of whether OB were present or absent from the 3D culture system. Also, regardless of whether OB were or were not added to the 3D co-culture system, LSK within 800 Pa collagen oligomer matrices maintained the highest percentage of Lin-Sca1+ cells as well as higher percentage of cells in quiescent state (G0/G1) compared to 50 Pa or 200Pa matrices. Collectively, these data illustrate that biophysical features of collagen oligomer matrices, specifically fibril density-induced modulation of matrix stiffness, provide important guidance cues in terms of LSK expansion and differentiation and therefore maintenance of progenitor cell function. Copyright © 2015. Published by Elsevier B.V.

Comparative inhibition of rabbit globin mRNA translation by modified antisense oligodeoxynucleotides.

PubMed Central

Cazenave, C; Stein, C A; Loreau, N; Thuong, N T; Neckers, L M; Subasinghe, C; Hélène, C; Cohen, J S; Toulmé, J J

1989-01-01

We have studied the translation of rabbit globin mRNA in cell free systems (reticulocyte lysate and wheat germ extract) and in microinjected Xenopus oocytes in the presence of anti-sense oligodeoxynucleotides. Results obtained with the unmodified all-oxygen compounds were compared with those obtained when phosphorothioate or alpha-DNA was used. In the wheat germ system a 17-mer sequence targeted to the coding region of beta-globin mRNA was specifically inhibitory when either the unmodified phosphodiester oligonucleotide or its phosphorothioate analogue were used. In contrast no effect was observed with the alpha-oligomer. These results were ascribed to the fact that phosphorothioate oligomers elicit an RNase-H activity comparable to the all-oxygen congeners, while alpha-DNA/mRNA hybrids were a poor substrate. Microinjected Xenopus oocytes followed a similar pattern. The phosphorothioate oligomer was more efficient to prevent translation than the unmodified 17-mer. Inhibition of beta-globin synthesis was observed in the nanomolar concentration range. This result can be ascribed to the nuclease resistance of phosphorothioates as compared to natural phosphodiester linkages, alpha-oligomers were devoid of any inhibitory effect up to 30 microM. Phosphorothioate oligodeoxyribonucleotides were shown to be non-specific inhibitors of protein translation, at concentrations in the micromolar range, in both cell-free systems and oocytes. Non-specific inhibition of translation was dependent on the length of the phosphorothioate oligomer. These non-specific effects were not observed with the unmodified or the alpha-oligonucleotides. Images PMID:2472605

Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation.

PubMed

Feng, Ying; Wang, Xiao-ping; Yang, Shi-gao; Wang, Yu-jiong; Zhang, Xi; Du, Xue-ting; Sun, Xiao-xia; Zhao, Min; Huang, Lei; Liu, Rui-tian

2009-11-01

Beta-amyloid (Abeta) aggregation has been strongly associated with the neurodegenerative pathology and a cascade of harmful event rated to Alzheimer's disease (AD). Inhibition of Abeta assembly, destabilization of preformed Abeta aggregates and attenuation of the cytotoxicity of Abeta oligomers and fibrils could be valuable therapeutics of patients with AD. Recent studies suggested that moderate consumption of red wine and intake of dietary polyphenols, such as resveratrol, may benefit AD phenotypes in animal models and reduce the relative risk for AD clinical dementia. To understand the mechanism of this neuroprotection, we studied the effects of resveratrol, an active ingredient of polyphenols in wine and many plants, on the polymerization of Abeta42 monomer, the destabilization of Abeta42 fibril and the cell toxicity of Abeta42 in vitro using fluorescence spectroscopic analysis with thioflavin T (ThT), transmission electron microscope (TEM), circular dichroism (CD) and MTT assay. The results showed that resveratrol could dose-dependently inhibit Abeta42 fibril formation and cytotoxicity but could not prevent Abeta42 oligomerization. The studies by Western-blot, dot-blot and ELISA confirmed that the addition of resveratrol resulted in numerous Abeta42 oligomer formation. In conjunction with the concept that Abeta oligomers are linked to Abeta toxicity, we speculate that aside from potential antioxidant activities, resveratrol may directly bind to Abeta42, interfere in Abeta42 aggregation, change the Abeta42 oligomer conformation and attenuate Abeta42 oligomeric cytotoxicity.

A Helical Structural Nucleus Is the Primary Elongating Unit of Insulin Amyloid Fibrils

PubMed Central

Roessle, Manfred; Kastrup, Jette S; van de Weert, Marco; Flink, James M; Frokjaer, Sven; Gajhede, Michael; Svergun, Dmitri I

2007-01-01

Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are indications that oligomeric aggregated precursors of fibrillation, and not mature fibrils, are the main cause of cytotoxicity in amyloid disease. This further emphasizes the importance of characterizing early fibrillation events. Here we present a kinetic x-ray solution scattering study of insulin fibrillation, revealing three major components: insulin monomers, mature fibrils, and an oligomeric species. Low-resolution three-dimensional structures are determined for the fibril repeating unit and for the oligomer, the latter being a helical unit composed of five to six insulin monomers. This helical oligomer is likely to be a structural nucleus, which accumulates above the supercritical concentration used in our experiments. The growth rate of the fibrils is proportional to the amount of the helical oligomer present in solution, suggesting that these oligomers elongate the fibrils. Hence, the structural nucleus and elongating unit in insulin amyloid fibrillation may be the same structural component above supercritical concentrations. A novel elongation pathway of insulin amyloid fibrils is proposed, based on the shape and size of the fibrillation precursor. The distinct helical oligomer described in this study defines a conceptually new basis of structure-based drug design against amyloid diseases. PMID:17472440

Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.

PubMed

Diógenes, Maria José; Dias, Raquel B; Rombo, Diogo M; Vicente Miranda, Hugo; Maiolino, Francesca; Guerreiro, Patrícia; Näsström, Thomas; Franquelim, Henri G; Oliveira, Luís M A; Castanho, Miguel A R B; Lannfelt, Lars; Bergström, Joakim; Ingelsson, Martin; Quintas, Alexandre; Sebastião, Ana M; Lopes, Luísa V; Outeiro, Tiago Fleming

2012-08-22

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

Enzyme-specific sensors via aggregation of charged p-phenylene ethynylenes.

PubMed

Hill, Eric H; Zhang, Yue; Evans, Deborah G; Whitten, David G

2015-03-11

Chemical and biological sensors are sought for their ability to detect enzymes as biomarkers for symptoms of various disorders, or the presence of chemical pollutants or poisons. p-Phenylene ethynylene oligomers with pendant charged groups have been recently shown to have ideal photophysical properties for sensing. In this study, one anionic and one cationic oligomer are combined with substrates that are susceptible to enzymatic degradation by phospholipases or acetylcholinesterases. The photophysical properties of the J-aggregated oligomers with the substrate are ideal for sensing, with fluorescence quantum yields of the sensors enhanced between 30 and 66 times compared to the oligomers without substrate. The phospholipase sensor was used to monitor the activity of phospholipase A1 and A2 and obtain kinetic information, though phospholipase C did not degrade the sensor. The acetylcholinesterase sensor was used to monitor enzyme activity and was also used to detect the inhibition of acetylcholinesterase by three different inhibitors. Phospholipase A2 is a biomarker for heart and circulatory disease, and acetylcholinesterase is a biomarker for Alzheimer's, and indicative of exposure to certain pesticides and nerve agents. This work shows that phenylene ethynylene oligomers can be tailored to enzyme-specific sensors by careful selection of substrates that induce formation of a molecular aggregate, and that the sensing of enzymes can be extended to enzyme kinetics and detection of inhibition. Furthermore, the aggregates were studied through all-atom molecular dynamics, providing a molecular-level view of the formation of the molecular aggregates and their structure.

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

PubMed Central

Zheng, Weihua; Tsai, Min-Yeh; Chen, Mingchen; Wolynes, Peter G.

2016-01-01

A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1–40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer’s disease. PMID:27698130

Template-directed synthesis of linear porphyrin oligomers: classical, Vernier and mutual Vernier† †Electronic supplementary information (ESI) available: Synthesis and characterization of new compounds, ladder complexes, UV-vis-NIR titrations and binding data for reference compounds and for the formation of linear oligomer complexes, calculation of effective molarities, analytical GPC calibration and molar absorption coefficients. See DOI: 10.1039/c6sc05355f Click here for additional data file.

PubMed Central

Kamonsutthipaijit, Nuntaporn

2017-01-01

Three different types of template-directed syntheses of linear porphyrin oligomers are presented. In the classical approach the product has the same number of binding sites as the template, whereas in Vernier reactions the product has the lowest common multiple of the numbers of binding sites in the template and the building block. Mutual Vernier templating is like Vernier templating except that both strands of the Vernier complex undergo coupling simultaneously, so that it becomes impossible to say which is the ‘template’ and which is the ‘building block’. The template-directed synthesis of monodisperse linear oligomers is more difficult than that of cyclic oligomers, because the products of linear templating have reactive ends. All three types of templating are demonstrated here, and used to prepare a nickel(ii) porphyrin dodecamer with 4-pyridyl substituents on all twelve porphyrin units. The stabilities and cooperativities of the double-strand complexes involved in these reactions were investigated by UV-vis-NIR titration. The four-rung ladder duplex has a stability constant of about 2 × 1018 M–1 in dichloromethane at 298 K. PMID:28553508

A sensitive detection assay based on signal amplification technology for Alzheimer's disease's early biomarker in exosome.

PubMed

Zhou, Jie; Meng, Lingchang; Ye, Weiran; Wang, Qiaolei; Geng, Shizhen; Sun, Chong

2018-08-31

Alzheimer's disease (AD) considered as the third health "killer" has seriously threatened the health of the elderly. However, the modern diagnostic strategies of AD present several disadvantages: the low accuracy and specificity resulting in some false-negative diagnoses, and the poor sensitivity leading to a delayed treatment. In view of this situation, a enzyme-free and target-triggered signal amplification strategy, based on graphene oxide (GO) and entropy-driven strand displacement reaction (ESDR) principle, was proposed. In this strategy, when the hairpin structure probes (H)specially binds with beta-amyloid-(1-42) oligomers (Aβ42 oligomers), it's structure will be opened, causing the bases complementary to FAM-labeled replacement probes R (R1 and R2) exposed. At this time, R1 and R2 will hybridize with H, resulting in the bound Aβ42 oligomers released. The released Aβ42 oligomers would participate in the next cycle reaction, making the signal amplified. As a quencher, GO could absorb the free single-stranded DNA R1 and R2 and quench their fluorescence; however, the DNA duplex still exists free and keeps its signal-on. Through the detection of Aβ42 oligomers in exosomes, this ultrasensitive detection method with the advantages of low limit of detection (LOD, 20 pM), great accuracy, excellent precision and convenience provides an excellent prospect for AD's early diagnosis. Copyright © 2018 Elsevier B.V. All rights reserved.

The Volumetric Diversity of Misfolded Prion Protein Oligomers Revealed by Pressure Dissociation*

PubMed Central

Torrent, Joan; Lange, Reinhard; Rezaei, Human

2015-01-01

Protein oligomerization has been associated with a wide range of diseases. High pressure approaches offer a powerful tool for deciphering the underlying molecular mechanisms by revealing volume changes associated with the misfolding and assembly reactions. We applied high pressure to induce conformational changes in three distinct β-sheet-rich oligomers of the prion protein PrP, a protein characterized by a variety of infectious quaternary structures that can propagate stably and faithfully and cause diseases with specific phenotypic traits. We show that pressure induces dissociation of the oligomers and leads to a lower volume monomeric PrP state that refolds into the native conformation after pressure release. By measuring the different pressure and temperature sensitivity of the tested PrP oligomers, we demonstrate significantly different void volumes in their quaternary structure. In addition, by focusing on the kinetic and energetic behavior of the pressure-induced dissociation of one specific PrP oligomer, we reveal a large negative activation volume and an increase in both apparent activation enthalpy and entropy. This suggests a transition state ensemble that is less structured and significantly more hydrated than the oligomeric state. Finally, we found that site-specific fluorescent labeling allows monitoring of the transient population of a kinetic intermediate in the dissociation reaction. Our results indicate that defects in atomic packing may deserve consideration as a new factor that influences differences between PrP assemblies and that could be relevant also for explaining the origin of prion strains. PMID:26126829

The effect of molecular shape on oligomerization of hydrophobic drugs: Molecular simulations of ciprofloxacin and nutlin

NASA Astrophysics Data System (ADS)

Li, Jianguo; Beuerman, Roger; Verma, Chandra

2018-03-01

Molecular aggregation plays a significant role in modulating the solubility, permeability, and bioactivity of drugs. The propensity to aggregate depends on hydrophobicity and on molecular shape. Molecular dynamics simulations coupled with enhanced sampling methods are used to explore the early stages of oligomerization of two drug molecules which have a strong aggregation propensity, but with contrasting molecule shapes: the antibiotic ciprofloxacin and the anticancer drug Nutlin-3A. The planar shape of ciprofloxacin induces the formation of stable oligomers at all cluster sizes. The aggregation of ciprofloxacin is driven by two-body interactions, and transferring one ciprofloxacin molecule to an existing cluster involves the desolvation of two faces and the concomitant hydrophobic interactions between the two faces; thus, the corresponding free energy of oligomerization weakly depends on the oligomer size. By contrast, Nutlin-3A has a star-shape and hence can only form stable oligomers when the cluster size is greater than 8. Free energy simulations further confirmed that the free energy of oligomer formation for Nutlin-3A becomes more favorable as the oligomer becomes larger. The aggregation of star-shaped Nutlin-3A results from many-body interactions and hence the free energy of cluster formation is strongly dependent on the size. The findings of this study provide atomistic insights into how molecular shape modulates the aggregation behavior of molecules and may be factored into the design of drugs or nano-particles.

Inactivation of lipoprotein lipase occurs on the surface of THP-1 macrophages where oligomers of angiopoietin-like protein 4 are formed

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makoveichuk, Elena; Sukonina, Valentina; Kroupa, Olessia

2012-08-24

Highlights: Black-Right-Pointing-Pointer Lipoprotein lipase (LPL) activity is controlled by ANGPTL4 in THP-1 macrophages. Black-Right-Pointing-Pointer Both LPL and ANGPTL4 bind to THP-1 macrophages in a heparin-releasable fashion. Black-Right-Pointing-Pointer Only monomers of ANGPTL4 are present within THP-1 macrophages. Black-Right-Pointing-Pointer Covalent oligomers of ANGPTL4 appear on cell surface and in medium. Black-Right-Pointing-Pointer Inactivation of LPL coincide with ANGPTL4 oligomer formation on cell surfaces. -- Abstract: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like proteinmore » (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPAR{delta} agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL. Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed.« less

High-molecular weight Aβ oligomers and protofibrils are the predominant Aβ species in the native soluble protein fraction of the AD brain.

PubMed

Upadhaya, Ajeet Rijal; Lungrin, Irina; Yamaguchi, Haruyasu; Fändrich, Marcus; Thal, Dietmar Rudolf

2012-02-01

Alzheimer's disease (AD) is characterized by the aggregation and deposition of amyloid β protein (Aβ) in the brain. Soluble Aβ oligomers are thought to be toxic. To investigate the predominant species of Aβ protein that may play a role in AD pathogenesis, we performed biochemical analysis of AD and control brains. Sucrose buffer-soluble brain lysates were characterized in native form using blue native (BN)-PAGE and also in denatured form using SDS-PAGE followed by Western blot analysis. BN-PAGE analysis revealed a high-molecular weight smear (>1000 kD) of Aβ(42) -positive material in the AD brain, whereas low-molecular weight and monomeric Aβ species were not detected. SDS-PAGE analysis, on the other hand, allowed the detection of prominent Aβ monomer and dimer bands in AD cases but not in controls. Immunoelectron microscopy of immunoprecipitated oligomers and protofibrils/fibrils showed spherical and protofibrillar Aβ-positive material, thereby confirming the presence of high-molecular weight Aβ (hiMWAβ) aggregates in the AD brain. In vitro analysis of synthetic Aβ(40) - and Aβ(42) preparations revealed Aβ fibrils, protofibrils, and hiMWAβ oligomers that were detectable at the electron microscopic level and after BN-PAGE. Further, BN-PAGE analysis exhibited a monomer band and less prominent low-molecular weight Aβ (loMWAβ) oligomers. In contrast, SDS-PAGE showed large amounts of loMWAβ but no hiMWAβ(40) and strikingly reduced levels of hiMWAβ(42) . These results indicate that hiMWAβ aggregates, particularly Aβ(42) species, are most prevalent in the soluble fraction of the AD brain. Thus, soluble hiMWAβ aggregates may play an important role in the pathogenesis of AD either independently or as a reservoir for release of loMWAβ oligomers. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Aqueous phase oligomerization of methyl vinyl ketone through photooxidation - Part 1: Aging processes of oligomers

NASA Astrophysics Data System (ADS)

Renard, P.; Siekmann, F.; Salque, G.; Smaani, A.; Demelas, C.; Coulomb, B.; Vassalo, L.; Ravier, S.; Temime-Roussel, B.; Voisin, D.; Monod, A.

2014-06-01

Secondary organic aerosol (SOA) represents a substantial part of organic aerosol, which affects climate and human health. It is now accepted that one of the important pathways of SOA formation occurs via aqueous phase chemistry in the atmosphere. Recently, we have shown in a previous study (Renard et al., 2013) the mechanism of oligomerization of MVK (methyl vinyl ketone), and suggested that unsaturated water soluble organic compounds (UWSOC) might efficiently form SOA in wet aerosol particles, even for weakly soluble ones like MVK. The atmospheric relevance of these processes is explored by means of process model studies (in a companion paper). In the present study we investigate the aging of these aqueous phase MVK-oligomers (Part 1). We compared aqueous phase composition and SOA composition after nebulization, mainly by means of UPLC-ESI-MS and AMS, respectively. Both instruments match and show similar trend of oligomer formation and aging. The SMPS analysis performed on the nebulized solutions allow to quantify these SOA and to measure their mass yields. We have highlighted in the current study that MVK •OH-oxidation undergoes kinetic competition between functionalization and oligomerization. The SOA composition and its evolution highly depend on the precursor initial concentration. We determined the threshold of MVK concentration, i.e. 2 mM, from which oligomerization prevails over functionalization. Hence, at these concentrations, •OH-oxidation of MVK forms oligomers that are SV-OOA, with low O / C and high f43. Oligomers are then fragmented, via unidentified intermediates that have the properties of LV-OOA which then end into succinic, malonic and oxalic diacids. For lower initial MVK concentrations, the oligomerization is not the major process, and functionalization dominates, resulting in small carbonyls, dicarbonyls and mainly monoacids. The aging of these oligomers could be an explanation for the presence of a part of the diacids observed in aerosol.

High-molecular weight Aβ oligomers and protofibrils are the predominant Aβ species in the native soluble protein fraction of the AD brain

PubMed Central

Upadhaya, Ajeet Rijal; Lungrin, Irina; Yamaguchi, Haruyasu; Fändrich, Marcus; Thal, Dietmar Rudolf

2012-01-01

Abstract Alzheimer’s disease (AD) is characterized by the aggregation and deposition of amyloid β protein (Aβ) in the brain. Soluble Aβ oligomers are thought to be toxic. To investigate the predominant species of Aβ protein that may play a role in AD pathogenesis, we performed biochemical analysis of AD and control brains. Sucrose buffer-soluble brain lysates were characterized in native form using blue native (BN)-PAGE and also in denatured form using SDS-PAGE followed by Western blot analysis. BN-PAGE analysis revealed a high-molecular weight smear (>1000 kD) of Aβ42-positive material in the AD brain, whereas low-molecular weight and monomeric Aβ species were not detected. SDS-PAGE analysis, on the other hand, allowed the detection of prominent Aβ monomer and dimer bands in AD cases but not in controls. Immunoelectron microscopy of immunoprecipitated oligomers and protofibrils/fibrils showed spherical and protofibrillar Aβ-positive material, thereby confirming the presence of high-molecular weight Aβ (hiMWAβ) aggregates in the AD brain. In vitro analysis of synthetic Aβ40- and Aβ42 preparations revealed Aβ fibrils, protofibrils, and hiMWAβ oligomers that were detectable at the electron microscopic level and after BN-PAGE. Further, BN-PAGE analysis exhibited a monomer band and less prominent low-molecular weight Aβ (loMWAβ) oligomers. In contrast, SDS-PAGE showed large amounts of loMWAβ but no hiMWAβ40 and strikingly reduced levels of hiMWAβ42. These results indicate that hiMWAβ aggregates, particularly Aβ42 species, are most prevalent in the soluble fraction of the AD brain. Thus, soluble hiMWAβ aggregates may play an important role in the pathogenesis of AD either independently or as a reservoir for release of loMWAβ oligomers. PMID:21418518

The Impact of HA Oligomer Content on Physical, Mechanical, and Biologic Properties of Divinyl Sulfone-Crosslinked HA Hydrogels

PubMed Central

Ibrahim, Samir; Kang, Qian K; Ramamurthi, Anand

2009-01-01

In recent studies, we showed that exogenous hyaluronic acid oligomers (HA-o) stimulate functional endothelialization, though native long-chain HA is more bioinert and possibly more biocompatible. Thus, in this study, hydrogels containing high molecular weight (HMW) HA (1×106 Da) and HA oligomer mixtures (HA-o: 0.75–10 kDa) were created by crosslinking with divinyl sulfone (DVS). The incorporation of HA oligomers was found to compromise the physical and mechanical properties of the gels (rheology, apparent crosslinking density, swelling ratio, degradation) and to very mildly enhance inflammatory cell recruitment in vivo; increasing the DVS crosslinker content within the gels in general, had the opposite effect, though the relatively high concentration of DVS within these gels (necessary to create a solid gel) also stimulated a mild sub-cutaneous inflammatory response in vivo and VCAM-1 expression by ECs cultured atop; ICAM-expression levels remained very low irrespective extent of DVS crosslinking or HA-o content. The greatest EC attachment and proliferation (MTT assay) was observed on gels that contained the highest amount of HA-o. The study shows that the beneficial EC response to HA oligomers and biocompatibility of HA is mostly unaltered by their chemical derivatization and crosslinking into a hydrogel. However, the study also demonstrates that the relatively high concentrations of DVS, necessary to create solid gels, compromises their biocompatibility. Moreover, the poor mechanics of even these heavily crosslinked gels, in the context of vascular implantation, necessitates the investigation of other, more appropriate crosslinking agents. Alternately, the outcomes of this study may be used to guide an approach based on chemical immobilization and controlled surface-presentation of both bioactive HA oligomers and more biocompatible HMW HAon synthetic or tissue engineered grafts already in use, without the use of a crosslinker, so that improved, predictable, and functional endothelialization can be achieved, and the need to create a mechanically compliant biomaterial for standalone use, circumvented. PMID:20186732

Cohesive zone model for intergranular slow crack growth in ceramics: influence of the process and the microstructure

NASA Astrophysics Data System (ADS)

Romero de la Osa, M.; Estevez, R.; Olagnon, C.; Chevalier, J.; Tallaron, C.

2011-10-01

Ceramic polycrystals are prone to slow crack growth (SCG) which is stress and environmentally assisted, similarly to observations reported for silica glasses. The kinetics of fracture are known to be dependent on the load level, the temperature and the relative humidity. In addition, evidence is available on the influence of the microstructure on the SCG rate with an increase in the crack velocity with decreasing the grain size. Crack propagation takes place beyond a load threshold, which is grain size dependent. We present a cohesive zone model for the intergranular failure process. The methodology accounts for an intrinsic opening that governs the length of the cohesive zone and allows the investigation of grain size effects. A rate and temperature-dependent cohesive model is proposed (Romero de la Osa M, Estevez R et al 2009 J. Mech. Adv. Mater. Struct. 16 623-31) to mimic the reaction-rupture mechanism. The formulation is inspired by Michalske and Freiman's picture (Michalske and Freiman 1983 J. Am. Ceram. Soc. 66 284-8) together with a recent study by Zhu et al (2005 J. Mech. Phys. Solids 53 1597-623) of the reaction-rupture mechanism. The present investigation extends a previous work (Romero de la Osa et al 2009 Int. J. Fracture 158 157-67) in which the problem is formulated. Here, we explore the influence of the microstructure in terms of grain size, their elastic properties and residual thermal stresses originating from the cooling from the sintering temperature down to ambient conditions. Their influence on SCG for static loadings is reported and the predictions compared with experimental trends. We show that the initial stress state is responsible for the grain size dependence reported experimentally for SCG. Furthermore, the account for the initial stresses enables the prediction of a load threshold below which no crack growth is observed: a crack arrest takes place when the crack path meets a region in compression.

Preparation and Characterization of Ceramizable Kaolin/VMQ and Kaolin/ZB/VMQ Composites

NASA Astrophysics Data System (ADS)

Zhang, X.; Qin, Y.; Pei, Y.; Huang, Z. X.

Ceramizable silicone-based composite was prepared by using methyl vinyl silicone rubber (VMQ) as matrix, calcined Kaolin and zinc borate (ZB) as additives. This composition can form interpenetrating network structures after crosslinking, and then improve heat-resistant properties by firing in air. The results of different formulations were investigated by FTIR. TG-DTG SEM and XRD. It showed that when the temperature above 600°C. the fillers and silicon rubber started to transform from organic to inorganic and internal microstructure became denser.

Low-Temperature Reactivities of Ultra-High Temperature Ceramics (Hf-X System)

DTIC Science & Technology

2005-12-01

as interacting fillers with the preceramic polymer formulations. In situ formation of the SiC phase was also evaluated as a practical approach in...led to a renewal of activities to fabricate MB2/ SiC composites as the materials of choice, because of their high thermal and oxidation resistance...HfB2/ SiC composite microstructures (and also HfC, ZrB2, and ZrC composites ) under pressureless conditions. These can be employed in reactive and

Size effects in martensitic microstructures: Finite-strain phase field model versus sharp-interface approach

NASA Astrophysics Data System (ADS)

Tůma, K.; Stupkiewicz, S.; Petryk, H.

2016-10-01

A finite-strain phase field model for martensitic phase transformation and twinning in shape memory alloys is developed and confronted with the corresponding sharp-interface approach extended to interfacial energy effects. The model is set in the energy framework so that the kinetic equations and conditions of mechanical equilibrium are fully defined by specifying the free energy and dissipation potentials. The free energy density involves the bulk and interfacial energy contributions, the latter describing the energy of diffuse interfaces in a manner typical for phase-field approaches. To ensure volume preservation during martensite reorientation at finite deformation within a diffuse interface, it is proposed to apply linear mixing of the logarithmic transformation strains. The physically different nature of phase interfaces and twin boundaries in the martensitic phase is reflected by introducing two order-parameters in a hierarchical manner, one as the reference volume fraction of austenite, and thus of the whole martensite, and the second as the volume fraction of one variant of martensite in the martensitic phase only. The microstructure evolution problem is given a variational formulation in terms of incremental fields of displacement and order parameters, with unilateral constraints on volume fractions explicitly enforced by applying the augmented Lagrangian method. As an application, size-dependent microstructures with diffuse interfaces are calculated for the cubic-to-orthorhombic transformation in a CuAlNi shape memory alloy and compared with the sharp-interface microstructures with interfacial energy effects.

Concentrations of oligomers and polymers of proanthocyanidins in red and purple rice bran and their relationships to total phenolics, flavonoids, antioxidant capacity and whole grain color

USDA-ARS?s Scientific Manuscript database

Proanthocyanidins, a flavonoids subgroup, are proposed to have chronic disease modulation properties. With the eventual goal of enhancing rice phytonutrient concentrations, we investigated the genotypic variation of the concentrations of individual oligomers and polymers of proanthocyanidins in dark...

A method for the 32P labeling of peptides or peptide nucleic acid oligomers

NASA Technical Reports Server (NTRS)

Kozlov, I. A.; Nielsen, P. E.; Orgel, L. E.; Bada, J. L. (Principal Investigator)

1998-01-01

A novel approach to the radioactive labeling of peptides and PNA oligomers is described. It is based on the conjugation of a deoxynucleoside 3'-phosphate with the terminal amine of the substrate, followed by phosphorylation of the 5'-hydroxyl group of the nucleotide using T4 polynucleotide kinase and [gamma-32P]ATP.

Separation of 'Uncharged' Oligodeoxynucleotide Analogs by Anion-Exchange Chromatography at High pH

NASA Technical Reports Server (NTRS)

Schmidt, Jurgen G.; Orgel, Leslie E.; Nielsen, Peter E.

1996-01-01

Ion-exchange chromatography is a well-established method for the analysis and purification of phosphodiester-linked oligonucleotides. If elution is carried out under alkaline conditions, the secondary structure of G- and C-rich oligomers is disrupted. Furthermore, elution times become more sensitive to the G and T content of the oligomer, because G and T are deprotonated at pH 10. In recent work on peptide-nucleic acids (PNAs) we noted that mixtures of PNA oligomers G(sub 4), G(sub 6), G(sub 8), and G9(sub 10) are readily separated by elution at pH 12 on an RPC-5 column. Here we show that this separation method is more generally applicable.

Chitovibrin: a chitin-binding lectin from Vibrio parahemolyticus.

PubMed

Gildemeister, O S; Zhu, B C; Laine, R A

1994-12-01

A novel 134 kDa, calcium-independent chitin-binding lectin, 'chitovibrin', is secreted by the marine bacterium Vibrio parahemolyticus, inducible with chitin or chitin-oligomers. Chitovibrin shows no apparent enzymatic activity but exhibits a strong affinity for chitin and chito-oligomers > dp9. The protein has an isoelectric pH of 3.6, shows thermal tolerance, binds chitin with an optimum at pH 6 and is active in 0-4 M NaCl. Chitovibrin appears to be completely different from other reported Vibrio lectins and may function to bind V. parahemolyticus to chitin substrates, or to capture or sequester chito-oligomers. It may be a member of a large group of recently described proteins in Vibrios related to a complex chitinoclastic (chitinivorous) system.

Adhesive and composite evaluation of acetylene-terminated phenylquinoxaline resins

NASA Technical Reports Server (NTRS)

Hergenrother, P. M.

1981-01-01

A series of acetylene-terminated phenylquinoxaline (ATPQ) oligomers of various molecular weights were prepared and subsequently chain extended by the thermally induced reaction of the ethynyl groups. The processability and thermal properties of these oligomers and their cured resins were compared with that of a relatively high molecular weight linear polyphenylquinoxaline (PPQ) with the same chemical backbone. The ATPQ oligomers exhibited significantly better processability than the linear PPQ but the PPQ displayed substantially better thermooxidative stability. Adhesive (Ti/Ti) and composite (graphite filament reinforcement) work was performed to evaluate the potential of these materials for structural applications. The PPQ exhibited better retention of adhesive and laminate properties than the ATPQ resins at 260 C after aging for 500 hr at 260 C in circulating air.

Anticoagulant flavonoid oligomers from the rhizomes of Alpinia platychilus.

PubMed

Shen, Chuan-Pu; Luo, Jian-Guang; Yang, Ming-Hua; Kong, Ling-Yi

2015-10-01

Two pairs of enantiomers of flavonoid oligomers (1a and 1b, 2a and 2b) along with one known chalcone (3) were isolated from the rhizomes of Alpinia platychilus. Their structures were elucidated on the basis of spectroscopic data (MS and 1D/2D NMR). The absolute configurations of the flavonoid oligomers were established by their ECD spectra. Separation of the enantiomeric mixtures (1a and 1b, 2a and 2b) was achieved on a chiral column using hexane:isopropyl alcohol:ethanol (7:2:1) as eluents. The anticoagulant assay showed that 2a, 2b and 3 exhibited potent activities to prolong the prothrombin times (PT) and the thrombin times (TT). Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibition of Human Immunodeficiency Virus Replication by Antisense Oligodeoxynucleotides

NASA Astrophysics Data System (ADS)

Goodchild, John; Agrawal, Sudhir; Civeira, Maria P.; Sarin, Prem S.; Sun, Daisy; Zamecnik, Paul C.

1988-08-01

Twenty different target sites within human immunodeficiency virus (HIV) RNA were selected for studies of inhibition of HIV replication by antisense oligonucleotides. Target sites were selected based on their potential capacity to block recognition functions during viral replication. Antisense oligomers complementary to sites within or near the sequence repeated at the ends of retrovirus RNA (R region) and to certain splice sites were most effective. The effect of antisense oligomer length on inhibiting virus replication was also investigated, and preliminary toxicity studies in mice show that these compounds are toxic only at high levels. The results indicate potential usefulness for these oligomers in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex either alone or in combination with other drugs.

Chemical evolution. XXIX - Pyrimidines from hydrogen cyanide

NASA Technical Reports Server (NTRS)

Ferris, J. P.; Joshi, P. C.; Lawless, J. G.

1978-01-01

Compounds obtained by hydrolysis of HCN oligomers formed by allowing pH 9.2, 0.1 M cyanide to stand at room temperature for 4 to 12 months were analyzed. Hydrolysis of HCN oligomers yielded 4,5-dihydroxypyrimidine and 5-hydroxyuracil; orotic acid was detected after hydrolysis at pH 8.5. A unified pathway from diaminofumaronitrile to the pyrimidines observed is suggested. As purines, pyrimidines and amino acids are released by hydrolysis of HCN oligomers in either acidic or mildly basic aqueous solutions, they could have been formed on the primitive earth in spite of fluctuations in pH. 4,5-dihydroxypyrimidines appear to be likely candidates for incorporation into primitive nucleic acids, as they should undergo Watson-Crick hydrogen bonding with adenine.

Synthesis and Characterization of Modified Phenylethynyl Terminated Polyimides

NASA Technical Reports Server (NTRS)

Chang, Alice C.

1998-01-01

As an ongoing effort to develop structural adhesives for high performance aerospace applications, recent work has focused on phenylethynyl terminated imide (PETI) oligomers. The work reported herein involves the synthesis and characterization of a series of phenylethynyl containing oligomers designated LARC (TM) MPEI (Modified Phenylethynyl Terminated Polyimide). These oligomers contain mixtures of linear, branched and star-shaped molecules. The fully imidized polymers exhibited minimum melt viscosity as low as 600 poise at 335 C. Ti/Ti lap shear specimens processed at 288 C under 15 psi showed tensile shear strength of approx. 6000 psi and 5200 psi at ambient and 350 F temperatures, respectively. The chemistry and properties of these new MPEIs are presented and compared to an optimized linear PETI, LaRC(Tm) -PETI-5.

A Cosserat crystal plasticity and phase field theory for grain boundary migration

NASA Astrophysics Data System (ADS)

Ask, Anna; Forest, Samuel; Appolaire, Benoit; Ammar, Kais; Salman, Oguz Umut

2018-06-01

The microstructure evolution due to thermomechanical treatment of metals can largely be described by viscoplastic deformation, nucleation and grain growth. These processes take place over different length and time scales which present significant challenges when formulating simulation models. In particular, no overall unified field framework exists to model concurrent viscoplastic deformation and recrystallization and grain growth in metal polycrystals. In this work a thermodynamically consistent diffuse interface framework incorporating crystal viscoplasticity and grain boundary migration is elaborated. The Kobayashi-Warren-Carter (KWC) phase field model is extended to incorporate the full mechanical coupling with material and lattice rotations and evolution of dislocation densities. The Cosserat crystal plasticity theory is shown to be the appropriate framework to formulate the coupling between phase field and mechanics with proper distinction between bulk and grain boundary behaviour.

Graft-crosslinked copolymers based on poly(arylene ether ketone)-gc-sulfonated poly(arylene ether sulfone) for PEMFC applications.

PubMed

Zhang, Xuan; Hu, Zhaoxia; Luo, Linqiang; Chen, Shanshan; Liu, Jianmei; Chen, Shouwen; Wang, Lianjun

2011-07-15

Novel poly(arylene ether ketone) polymers with fluorophenyl pendants and phenoxide-terminated wholly sulfonated poly(arylene ether sulfone) oligomers are prepared via Ni(0)-catalyzed and nucleophilic polymerization, respectively, and subsequently used as starting materials to obtain graft-crosslinked membranes as polymer electrolyte membranes. The phenoxide-terminated sulfonated moieties are introduced as hydrophilic parts as well as crosslinking units. The chemical structure and morphology of the obtained membranes are confirmed by (1) H NMR and tapping-mode AFM. The properties required for fuel cell applications, including water uptake and dimensional change, as well as proton conductivity, are investigated. AFM results show a clear nanoscale phase-separation microstructure of the obtained membranes. The membranes show good dimensional stability and reasonably high proton conductivities under 30-90% relative humidity. The anisotropic proton conductivity ratios (σ(formula see text) ) of the membranes in water are in the range 0.65-0.92, and increase with an increase in hydrophilic block length. The results indicate that the graft-crosslinked membranes are promising candidates for applications as polymer electrolyte membranes. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formulation of a medical food cocktail for Alzheimer's disease: beneficial effects on cognition and neuropathology in a mouse model of the disease.

PubMed

Parachikova, Anna; Green, Kim N; Hendrix, Curt; LaFerla, Frank M

2010-11-17

Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitamins, vitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease. The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning. In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.

Maleate/vinyl ether UV-cured coatings: Effects of composition on curing and properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noren, G.K.

1996-10-01

The effect of the composition of the maleate polyester and the vinyl ether terminated compound on their UV-curing and properties has been investigated. Linear unsaturated polyester resins based on maleic anhydride and 1,5-pentane diol were synthesized. The molecular weight of the unsaturated polyesters was varied by changing the ratio of maleic anhydride to 1,5-pentane diol and the double bond equivalent weight was varied by replacing maleic anhydride with succinic anhydride. Coating formulations containing these unsaturated polyesters, triethylene glycol divinyl ether and a free radical photoinitiator were crosslinked in the presence of UV light. The coatings were very brittle, exhibiting tensilemore » strengths in the range of 1.5-4.0 MPa and elongations of only 3-7%. Diethyl maleate and isobutyl vinyl ether were effective diluents for reducing viscosity but reduced the cure speed. A vinyl ether urethane oligomer was synthesized and enhanced the flexibility and toughness of the coatings when substituted for triethylene glycol divinyl ether.« less

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

PubMed

Hey, John A; Yu, Jeremy Y; Versavel, Mark; Abushakra, Susan; Kocis, Petr; Power, Aidan; Kaplan, Paul L; Amedio, John; Tolar, Martin

2018-03-01

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia.

PubMed

Fessel, Jeffrey

2018-01-01

The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD). Published studies were examined. The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid-centric treatments have provided no clinical benefit and about one-third of cognitively normal, older persons have cerebral amyloid plaques. Also problematic is the alternative hypothesis that, instead of amyloid plaques, it is oligomers of amyloid precursor protein that cause AD.Evidence is presented suggesting amyloid/oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, requires the addition of cofactors known to be associated with AD. Those cofactors include several subcellular processes: mitochondrial impairments; the Wnt signaling system; the unfolded protein response; the ubiquitin proteasome system; the Notch signaling system; and tau, calcium, and oxidative damage. A modified amyloid/oligomer hypothesis for the pathogenesis of AD is that activation of one or more of the aforementioned cofactors creates a burden of functional impairments that, in conjunction with amyloid/oligomers, now crosses a threshold of dysfunction that results in clinical dementia. Of considerable importance, several treatments that might reverse the activation of some of the subcellular processes are available, for example, lithium, pioglitazone, erythropoietin, and prazosin; they should be given in combination in a clinical trial to test their safety and efficacy. © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2*

PubMed Central

Srinivasan, Saipraveen; Patke, Sanket; Wang, Yun; Ye, Zhuqiu; Litt, Jeffrey; Srivastava, Sunit K.; Lopez, Maria M.; Kurouski, Dmitry; Lednev, Igor K.; Kane, Ravi S.; Colón, Wilfredo

2013-01-01

Serum amyloid A (SAA) is best known for being the main component of amyloid in the inflammation-related disease amyloid A (AA) amyloidosis. Despite the high sequence identity among different SAA isoforms, not all SAA proteins are pathogenic. In most mouse strains, the AA deposits mostly consist of SAA1.1. Conversely, the CE/J type mouse expresses a single non-pathogenic SAA2.2 protein that is 94% identical to SAA1.1. Here we show that SAA1.1 and SAA2.2 differ in their quaternary structure, fibrillation kinetics, prefibrillar oligomers, and fibril morphology. At 37 °C and inflammation-related SAA concentrations, SAA1.1 exhibits an oligomer-rich fibrillation lag phase of a few days, whereas SAA2.2 shows virtually no lag phase and forms small fibrils within a few hours. Deep UV resonance Raman, far UV-circular dichroism, atomic force microscopy, and fibrillation cross-seeding experiments suggest that SAA1.1 and SAA2.2 fibrils possess different morphology. Both the long-lived oligomers of pathogenic SAA1.1 and the fleeting prefibrillar oligomers of non-pathogenic SAA2.2, but not their respective amyloid fibrils, permeabilized synthetic bilayer membranes in vitro. This study represents the first comprehensive comparison between the biophysical properties of SAA isoforms with distinct pathogenicities, and the results suggest that structural and kinetic differences in the oligomerization-fibrillation of SAA1.1 and SAA2.2, more than their intrinsic amyloidogenicity, may contribute to their diverse pathogenicity. PMID:23223242

Detection of Mutant Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules

PubMed Central

Sontag, Emily Mitchell; Lotz, Gregor P.; Yang, Guocheng; Sontag, Christopher J.; Cummings, Brian J.; Glabe, Charles G.; Muchowski, Paul J.; Thompson, Leslie Michels

2012-01-01

The Huntington’s disease (HD) mutation leads to a complex process of Huntingtin (Htt) aggregation into multimeric species that eventually form visible inclusions in cytoplasm, nuclei and neuronal processes. One hypothesis is that smaller, soluble forms of amyloid proteins confer toxic effects and contribute to early cell dysfunction. However, analysis of mutant Htt aggregation intermediates to identify conformers that may represent toxic forms of the protein and represent potential drug targets remains difficult. We performed a detailed analysis of aggregation conformers in multiple in vitro, cell and ex vivo models of HD. Conformation-specific antibodies were used to identify and characterize aggregation species, allowing assessment of multiple conformers present during the aggregation process. Using a series of assays together with these antibodies, several forms could be identified. Fibrillar oligomers, defined as having a β-sheet rich conformation, are observed in vitro using recombinant protein and in protein extracts from cells in culture or mouse brain and shown to be globular, soluble and non-sedimentable structures. Compounds previously described to modulate visible inclusion body formation and reduce toxicity in HD models were also tested and consistently found to alter the formation of fibrillar oligomers. Interestingly, these compounds did not alter the rate of visible inclusion formation, indicating that fibrillar oligomers are not necessarily the rate limiting step of inclusion body formation. Taken together, we provide insights into the structure and formation of mutant Htt fibrillar oligomers that are modulated by small molecules with protective potential in HD models. PMID:24086178

Structural Conversion of Aβ17–42 Peptides from Disordered Oligomers to U-Shape Protofilaments via Multiple Kinetic Pathways

PubMed Central

Cheon, Mookyung; Hall, Carol K.; Chang, Iksoo

2015-01-01

Discovering the mechanisms by which proteins aggregate into fibrils is an essential first step in understanding the molecular level processes underlying neurodegenerative diseases such as Alzheimer’s and Parkinson's. The goal of this work is to provide insights into the structural changes that characterize the kinetic pathways by which amyloid-β peptides convert from monomers to oligomers to fibrils. By applying discontinuous molecular dynamics simulations to PRIME20, a force field designed to capture the chemical and physical aspects of protein aggregation, we have been able to trace out the entire aggregation process for a system containing 8 Aβ17–42 peptides. We uncovered two fibrillization mechanisms that govern the structural conversion of Aβ17–42 peptides from disordered oligomers into protofilaments. The first mechanism is monomeric conversion templated by a U-shape oligomeric nucleus into U-shape protofilament. The second mechanism involves a long-lived and on-pathway metastable oligomer with S-shape chains, having a C-terminal turn, en route to the final U-shape protofilament. Oligomers with this C-terminal turn have been regarded in recent experiments as a major contributing element to cell toxicity in Alzheimer’s disease. The internal structures of the U-shape protofilaments from our PRIME20/DMD simulation agree well with those from solid state NMR experiments. The approach presented here offers a simple molecular-level framework to describe protein aggregation in general and to visualize the kinetic evolution of a putative toxic element in Alzheimer’s disease in particular. PMID:25955249

Structure and function of small heat shock/alpha-crystallin proteins: established concepts and emerging ideas.

PubMed

MacRae, T H

2000-06-01

Small heat shock/alpha-crystallin proteins are defined by conserved sequence of approximately 90 amino acid residues, termed the alpha-crystallin domain, which is bounded by variable amino- and carboxy-terminal extensions. These proteins form oligomers, most of uncertain quaternary structure, and oligomerization is prerequisite to their function as molecular chaperones. Sequence modelling and physical analyses show that the secondary structure of small heat shock/alpha-crystallin proteins is predominately beta-pleated sheet. Crystallography, site-directed spin-labelling and yeast two-hybrid selection demonstrate regions of secondary structure within the alpha-crystallin domain that interact during oligomer assembly, a process also dependent on the amino terminus. Oligomers are dynamic, exhibiting subunit exchange and organizational plasticity, perhaps leading to functional diversity. Exposure of hydrophobic residues by structural modification facilitates chaperoning where denaturing proteins in the molten globule state associate with oligomers. The flexible carboxy-terminal extension contributes to chaperone activity by enhancing the solubility of small heat shock/alpha-crystallin proteins. Site-directed mutagenesis has yielded proteins where the effect of the change on structure and function depends upon the residue modified, the organism under study and the analytical techniques used. Most revealing, substitution of a conserved arginine residue within the alpha-crystallin domain has a major impact on quaternary structure and chaperone action probably through realignment of beta-sheets. These mutations are linked to inherited diseases. Oligomer size is regulated by a stress-responsive cascade including MAPKAP kinase 2/3 and p38. Phosphorylation of small heat shock/alpha-crystallin proteins has important consequences within stressed cells, especially for microfilaments.

Eckmaxol, a Phlorotannin Extracted from Ecklonia maxima, Produces Anti-β-amyloid Oligomer Neuroprotective Effects Possibly via Directly Acting on Glycogen Synthase Kinase 3β.

PubMed

Wang, Jialing; Zheng, Jiachen; Huang, Chunhui; Zhao, Jiaying; Lin, Jiajia; Zhou, Xuezhen; Naman, C Benjamin; Wang, Ning; Gerwick, William H; Wang, Qinwen; Yan, Xiaojun; Cui, Wei; He, Shan

2018-04-10

Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble β-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, could produce neuroprotective effects in SH-SY5Y cells. Eckmaxol effectively prevented but did not rescue β-amyloid oligomer-induced neuronal apoptosis and increase of intracellular reactive oxygen species. Eckmaxol also significantly reversed the decreased expression of phospho-Ser9-glycogen synthase kinase 3β and increased expression of phospho-extracellular signal-regulated kinase, which was induced by Aβ oligomer. Moreover, both glycogen synthase kinase 3β and mitogen activated protein kinase inhibitors produced neuroprotective effects in SH-SY5Y cells. Furthermore, eckmaxol showed favorable interaction in the ATP binding site of glycogen synthase kinase 3β and mitogen activated protein kinase. These results suggested that eckmaxol might produce neuroprotective effects via concurrent inhibition of glycogen synthase kinase 3β and extracellular signal-regulated kinase pathways, possibly via directly acting on glycogen synthase kinase 3β and mitogen activated protein kinase. Based on the central role that β-amyloid oligomers play in the pathogenesis of Alzheimer's disease and the high annual production of Ecklonia maxima for alginate and other nutritional ingredients, this report represents a new candidate for the treatment of Alzheimer's disease, and also expands the potential application of Ecklonia maxima and its constituents in the field of pharmacology.

Single-molecule studies of oligomer extraction and uptake of dyes in poly(dimethylsiloxane) films.

PubMed

Lange, Jeffrey J; Collinson, Maryanne M; Culbertson, Christopher T; Higgins, Daniel A

2009-12-15

Single-molecule microscopic methods were used to probe the uptake, mobility, and entrapment of dye molecules in cured poly(dimethylsiloxane) (PDMS) films as a function of oligomer extraction. The results are relevant to the use of PDMS in microfluidic separations, pervaporation, solid-phase microextraction, and nanofiltration. PDMS films were prepared by spin-casting dilute solutions of Sylgard 184 onto glass coverslips, yielding approximately 1.4 microm thick films after curing. Residual oligomers were subsequently extracted from the films by "spin extraction". In this procedure, 200 microL aliquots of isopropyl alcohol were repeatedly dropped onto the film surface and spun off at 2000 rpm. Samples extracted 5, 10, 20, and 40 times were investigated. Dye molecules were loaded into these films by spin-casting nanomolar dye solutions onto the films. Both neutral perylene diimide (N,N'-bis(butoxypropyl)perylene-3,4,9,10-tetracarboxylic diimide) and cationic rhodamine 6G (R6G) dyes were employed. The films were imaged by confocal fluorescence microscopy. The images obtained depict nonzero populations of fixed and mobile molecules in all films. Cross-correlation methods were used to quantitatively determine the population of fixed molecules in a given region, while a Bayesian burst analysis was used to obtain the total population of molecules. The results show that the total amount of dye loaded increases with increased oligomer extraction, while the relative populations of fixed and mobile molecules decrease and increase, respectively. Bulk R6G data also show greater dye loading with increased oligomer extraction.

Dielectric Characteristics of Microstructural Changes and Property Evolution in Engineered Materials

NASA Astrophysics Data System (ADS)

Clifford, Jallisa Janet

Heterogeneous materials are increasingly used in a wide range of applications such as aerospace, civil infrastructure, fuel cells and many others. The ability to take properties from two or more materials to create a material with properties engineered to needs is always very attractive. Hence heterogeneous materials are evolving into more complex formulations in multiple disciplines. Design of microstructure at multiple scales control the global functional properties of these materials and their structures. However, local microstructural changes do not directly cause a proportional change to the global properties (such as strength and stiffness). Instead, local changes follow an evolution process including significant interactions. Therefore, in order to understand property evolution of engineered materials, microstructural changes need to be effectively captured. Characterizing these changes and representing them by material variables will enable us to further improve our material level understanding. In this work, we will demonstrate how microstructural features of heterogeneous materials can be described quantitatively using broadband dielectric spectroscopy (BbDS). The frequency dependent dielectric properties can capture the change in material microstructure and represent these changes in terms of material variables, such as complex permittivity. These changes in terms of material properties can then be linked to a number of different conditions, such as increasing damage due to impact or fatigue. Two different broadband dielectric spectroscopy scanning modes are presented: bulk measurements and continuous scanning to measure dielectric property change as a function of position across the specimen. In this study, we will focus on ceramic materials and fiber reinforced polymer matrix composites as test bed material systems. In the first part of the thesis, we will present how different micro-structural design of porous ceramic materials can be captured quantitatively using BbDS. These materials are typically used in solid oxide fuel cells (SOFC). Results show significant effect of microstructural design on material properties at multiple temperatures (up to 800 °C). In the later part of the thesis, we will focus on microstructural changes of fiber reinforced composite materials due to impact and static loading. The changes in dielectric response can then be linked to the bulk mechanical properties of the material and various damage modes. Observing trends in dielectric response enables us to further determine local mechanisms and distribution of properties throughout the damaged specimens. A 3D X-ray microscope and a digital microscope have been used to visualize these changes in material microstructure and validate experimental observations. The increase in damage observed in the material microstructure can then also be linked to the changes in dielectric response. Results show that BbDS is an extremely useful tool for identifying microstructural changes within a heterogeneous material and particularly useful in relating remaining properties. Dielectric material variables can be used directly in property degradation laws and help develop a framework for future predictive modeling methodologies.

Unified approach to catechin hetero-oligomers: first total synthesis of trimer EZ-EG-CA isolated from Ziziphus jujuba.

PubMed

Yano, Takahisa; Ohmori, Ken; Takahashi, Haruko; Kusumi, Takenori; Suzuki, Keisuke

2012-10-14

A catechin hetero-trimer isolated from Ziziphus jujuba has been synthesized. Among three constituent monomers, (-)-epiafzelechin and (-)-epigallocatechin were prepared by de novo synthesis. Trimer formation relied on the unified approach to oligomers based on the bromo-capping and the orthogonal activation, reaching the reported structure of the natural product.

The subunit structure of horse spleen apoferritin: the molecular weight of the oligomer and its stability to dissociation by dilution (Short Communication)

PubMed Central

Crichton, Robert R.; Eason, Robert; Barclay, Allan; Bryce, Charles F. A.

1973-01-01

The oligomer molecular weight of horse spleen apoferritin was determined by sedimentation-equilibrium techniques and a value of 443000 found. It is concluded that the apoferritin molecule consists of 24 subunits. At concentrations as low as 0.01μm there is no evidence of subunit dissociation. PMID:4737327

Kinetic properties of two Rhizopus exo-polygalacturonase enzymes hydrolyzing galacturonic acid oligomers using isothermal titration calorimetry

USDA-ARS?s Scientific Manuscript database

The kinetic characteristics of two Rhizopus oryzae exo-polygalacturonases acting on galacturonic acid oligomers (GalpA) were determined using isothermal titration calorimetry (ITC). RPG15 hydrolyzing (GalpA)2 demonstrated a Km of 55 uM and kcat of 10.3 s^-1^ while RPG16 was shown to have greater af...

Ethylene sensing by silver(I) salt-impregnated luminescent films

USDA-ARS?s Scientific Manuscript database

Luminescent oligomer /polymer films impregnated with Ag(I) salts are effective sensors for small gas molecules such as ethylene. Films composed of various Ag(I) salts (i.e. AgBF4, AgSbF6, AgB(C6F5)4, AgClO4 and AgOTf) and polymers (i.e. poly(vinylphenylketone) (PVPK), polystyrene (PS) or oligomers (...

Comparative Toxicity of Halogenated Hydrocarbons: Molecular Aspects

DTIC Science & Technology

1993-07-13

peroxisome proliferators, namely perfluorooctanoic acid ( PFOA ), perfluorodecanoic acid ( PFDA ) and the tri-and tetra-oligomers of chlorotrifluooethylene...ACID ( PFOA ), PERFLUORO - DECANOIC ACID ( PFDA ) AND THE TRI-AND TETRA-OLIGOMERS OF CHLORO -TR.tLUORO ETHYLENE (CTFE) HAVE BEEN INVESTIGATED IN THE RAT AND...AVAILABILITY STATEMENT 12b. DISTRIBUTION CODE NO LIMITATION NOT KNOWN 13. ABSTRACT (Maximum 200 words) THE COMPARATIVE HEPATOTOXICITIES OF PERFLUOROOCTANOIC

Detection of Amyloid Beta (Aβ) Oligomeric Composition Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS)

NASA Astrophysics Data System (ADS)

Wang, Jasmine S.-H.; Whitehead, Shawn N.; Yeung, Ken K.-C.

2018-02-01

The use of MALDI MS as a fast and direct method to detect the Aβ oligomers of different masses is examined in this paper. Experimental results suggest that Aβ oligomers are ionized and detected as singly charged ions, and thus, the resulting mass spectrum directly reports the oligomer size distribution. Validation experiments were performed to verify the MS data against artifacts. Mass spectra collected from modified Aβ peptides with different propensities for aggregation were compared. Generally, the relative intensities of multimers were higher from samples where oligomerization was expected to be more favorable, and vice versa. MALDI MS was also able to detect the differences in oligomeric composition before and after the incubation/oligomerization step. Such differences in sample composition were also independently confirmed with an in vitro Aβ toxicity study on primary rat cortical neurons. An additional validation was accomplished through removal of oligomers from the sample using molecular weight cutoff filters; the resulting MS data correctly reflected the removal at the expected cutoff points. The results collectively validated the ability of MALDI MS to assess the monomeric/multimeric composition of Aβ samples. [Figure not available: see fulltext.

Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model.

PubMed

Hamilton, Alison; Vasefi, Maryam; Vander Tuin, Cheryl; McQuaid, Robyn J; Anisman, Hymie; Ferguson, Stephen S G

2016-05-31

Beta-amyloid (Aβ) oligomers contribute to the pathophysiology of Alzheimer disease (AD), and metabotropic glutamate receptor 5 (mGluR5) has been shown to act as a receptor for both Aβ oligomers and cellular prion proteins. Furthermore, the genetic deletion of mGluR5 in an APPswe/PS1ΔE9 mouse model of AD improves cognitive function and reduces Aβ plaques and Aβ oligomer concentrations. Here, we show that chronic administration of the orally bioavailable mGluR5-selective negative allosteric modulator CTEP, which is similar in structure, potency, and selectivity to Basimglurant (RO4917523), which is currently in phase II clinical development for major depressive disorder and fragile X syndrome, reverses cognitive decline in APPswe/PS1ΔE9 mice and reduces Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1ΔE9 and 3xTg-AD male mice. These findings suggest that CTEP or its analogue Basimglutant might potentially be an effective therapeutic for the treatment of AD patients. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice.

PubMed

Hou, Ting-Ting; Yang, He-Yun; Wang, Wei; Wu, Qiao-Qi; Tian, Yuan-Ruhua; Jia, Jian-Ping

2018-01-01

Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD.

Benzothienobenzothiophene-based conjugated oligomers as semiconductors for stable organic thin-film transistors.

PubMed

Yu, Han; Li, Weili; Tian, Hongkun; Wang, Haibo; Yan, Donghang; Zhang, Jingping; Geng, Yanhou; Wang, Fosong

2014-04-09

Two benzothienobenzothiophene (BTBT)-based conjugated oligomers, i.e., 2,2'-bi[1]benzothieno[3,2-b][1]benzothiophene (1) and 5,5'-bis([1]benzothieno[3,2-b][1]benzothiophen-2-yl)-2,2'-bithiophene (2), were prepared and characterized. Both oligomers exhibit excellent thermal stability, with 5% weight-loss temperatures (T(L)) above 370 °C; no phase transition was observed before decomposition. The highest occupied molecular orbital (HOMO) levels of 1 and 2 are -5.3 and -4.9 eV, respectively, as measured by ultraviolet photoelectron spectroscopy. Thin-film X-ray diffraction and atomic force microscopy characterizations indicate that both oligomers form highly crystalline films with large domain sizes on octadecyltrimethoxysilane-modified substrates. Organic thin-film transistors with top-contact and bottom-gate geometry based on 1 and 2 exhibited mobilities up to 2.12 cm(2)/V·s for 1 and 1.39 cm(2)/V·s for 2 in an ambient atmosphere. 1-based devices exhibited great air and thermal stabilities, as evidenced by the slight performance degradation after 2 months of storage under ambient conditions and after thermal annealing at temperatures below 250 °C.

Enzymatic generation of galactose-rich oligosaccharides/oligomers from potato rhamnogalacturonan I pectic polysaccharides.

PubMed

Khodaei, Nastaran; Karboune, Salwa

2016-04-15

Potato pulp by-product rich in galactan-rich rhamnogalacturonan I (RG I) was investigated as a new source of oligosaccharides with potential prebiotic properties. The efficiency of selected monocomponent enzymes and multi-enzymatic preparations to generate oligosaccharides/oligomers from potato RG I was evaluated. These overall results of yield were dependent on the activity profile of the multi-enzymatic preparations. Highest oligo-RG I yield of 93.9% was achieved using multi-enzymatic preparation (Depol 670L) with higher hydrolytic activity toward side chains of RG I as compared to its backbone. Main oligo-RG I products were oligosaccharides with DP of 2-12 (79.8-100%), while the oligomers with DP of 13-70 comprised smaller proportion (0.0-20.2%). Galactose (58.9-91.2%, w/w) was the main monosaccharide of oligo-RG I, while arabinose represented 0.0-12.1%. An understanding of the relationship between the activity profile of multi-enzymatic preparations and the yield/DP of oligo-RG I was achieved. This is expected to provide the capability to generate galacto- and galacto(arabino) oligosaccharides and their corresponding oligomers from an abundant by-product. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sulfatide-Hsp70 Interaction Promotes Hsp70 Clustering and Stabilizes Binding to Unfolded Protein

PubMed Central

Harada, Yoichiro; Sato, Chihiro; Kitajima, Ken

2015-01-01

The 70-kDa heat shock protein (Hsp70), one of the major stress-inducible molecular chaperones, is localized not only in the cytosol, but also in extracellular milieu in mammals. Hsp70 interacts with various cell surface glycolipids including sulfatide (3'-sulfogalactosphingolipid). However, the molecular mechanism, as well as the biological relevance, underlying the glycolipid-Hsp70 interaction is unknown. Here we report that sulfatide promotes Hsp70 oligomerization through the N-terminal ATPase domain, which stabilizes the binding of Hsp70 to unfolded protein in vitro. We find that the Hsp70 oligomer has apparent molecular masses ranging from 440 kDa to greater than 669 kDa. The C-terminal peptide-binding domain is dispensable for the sulfatide-induced oligomer formation. The oligomer formation is impaired in the presence of ATP, while the Hsp70 oligomer, once formed, is unable to bind to ATP. These results suggest that sulfatide locks Hsp70 in a high-affinity state to unfolded proteins by clustering the peptide-binding domain and blocking the binding to ATP that induces the dissociation of Hsp70 from protein substrates. PMID:25989600

SERS Detection of Amyloid Oligomers on Metallorganic-Decorated Plasmonic Beads.

PubMed

Guerrini, Luca; Arenal, Raul; Mannini, Benedetta; Chiti, Fabrizio; Pini, Roberto; Matteini, Paolo; Alvarez-Puebla, Ramon A

2015-05-13

Protein misfolded proteins are among the most toxic endogenous species of macromolecules. These chemical entities are responsible for neurodegenerative disorders such as Alzheimer's, Parkinson's, Creutzfeldt-Jakob's and different non-neurophatic amyloidosis. Notably, these oligomers show a combination of marked heterogeneity and low abundance in body fluids, which have prevented a reliable detection by immunological methods so far. Herein we exploit the selectivity of proteins to react with metallic ions and the sensitivity of surface-enhanced Raman spectroscopy (SERS) toward small electronic changes in coordination compounds to design and engineer a reliable optical sensor for protein misfolded oligomers. Our strategy relies on the functionalization of Au nanoparticle-decorated polystyrene beads with an effective metallorganic Raman chemoreceptor, composed by Al(3+) ions coordinated to 4-mercaptobenzoic acid (MBA) with high Raman cross-section, that selectively binds aberrant protein oligomers. The mechanical deformations of the MBA phenyl ring upon complexation with the oligomeric species are registered in its SERS spectrum and can be quantitatively correlated with the concentration of the target biomolecule. The SERS platform used here appears promising for future implementation of diagnostic tools of aberrant species associated with protein deposition diseases, including those with a strong social and economic impact, such as Alzheimer's and Parkinson's diseases.

Biodegradable and adjustable sol-gel glass based hybrid scaffolds from multi-armed oligomeric building blocks.

PubMed

Kascholke, Christian; Hendrikx, Stephan; Flath, Tobias; Kuzmenka, Dzmitry; Dörfler, Hans-Martin; Schumann, Dirk; Gressenbuch, Mathias; Schulze, F Peter; Schulz-Siegmund, Michaela; Hacker, Michael C

2017-11-01

Biodegradability is a crucial characteristic to improve the clinical potential of sol-gel-derived glass materials. To this end, a set of degradable organic/inorganic class II hybrids from a tetraethoxysilane(TEOS)-derived silica sol and oligovalent cross-linker oligomers containing oligo(d,l-lactide) domains was developed and characterized. A series of 18 oligomers (Mn: 1100-3200Da) with different degrees of ethoxylation and varying length of oligoester units was established and chemical composition was determined. Applicability of an established indirect rapid prototyping method enabled fabrication of a total of 85 different hybrid scaffold formulations from 3-isocyanatopropyltriethoxysilane-functionalized macromers. In vitro degradation was analyzed over 12months and a continuous linear weight loss (0.2-0.5wt%/d) combined with only moderate material swelling was detected which was controlled by oligo(lactide) content and matrix hydrophilicity. Compressive strength (2-30MPa) and compressive modulus (44-716MPa) were determined and total content, oligo(ethylene oxide) content, oligo(lactide) content and molecular weight of the oligomeric cross-linkers as well as material porosity were identified as the main factors determining hybrid mechanics. Cytocompatibility was assessed by cell culture experiments with human adipose tissue-derived stem cells (hASC). Cell migration into the entire scaffold pore network was indicated and continuous proliferation over 14days was found. ALP activity linearly increased over 2weeks indicating osteogenic differentiation. The presented glass-based hybrid concept with precisely adjustable material properties holds promise for regenerative purposes. Adaption of degradation kinetics toward physiological relevance is still an unmet challenge of (bio-)glass engineering. We therefore present a glass-derived hybrid material with adjustable degradation. A flexible design concept based on degradable multi-armed oligomers was combined with an established indirect rapid prototyping method to produce a systematic set of porous sol-gel-derived class II hybrid scaffolds. Mechanical properties in the range of cancellous bone were narrowly controlled by hybrid composition. The oligoester introduction resulted in significantly increased compressive moduli. Cytocompatible hybrids degraded in physiologically relevant time frames and a promising linear and controllable weight loss profile was found. To our knowledge, our degradation study represents the most extensive long-term investigation of sol-gel-derived class II hybrids. Due to the broad adjustability of material properties, our concept offers potential for engineering of biodegradable hybrid materials for versatile applications. Copyright © 2017. Published by Elsevier Ltd.

Chemistry and Properties of Imide Oligomers from Phenylethynyl-Containing Diamines

NASA Technical Reports Server (NTRS)

Smith, J. G., Jr.; Connell, J. W.

2000-01-01

As an extension of work on pendent phenylethynlyl-containing imide oligomer, three new diamines containing pendent phenylethynyl groups were prepared and characterized. These diamines were used to prepare pendent and pendent and terminal phenylethynyl imide oliogomers via the amide acid route in N-methyl-2-pyrrolidinone at a calculated number average molecular weight of 5000 g mol (exp -1). The pendent phenylethynyl groups were randomly distributed along the oliogomer backbone and provided a means of controlling the distance between reactive sites. The imide oligomers were characterized and thermally cured, and the cured polymers evaluated as thin films and compared with materials of similar composition prepared from 3,5-diamino-4'-phenylethynylbenzophenone. This work was performed as part of a continuing research effort to develop structural resins for potential aeronautical applications.

Hydrogenation and hydrodeoxygenation of biomass-derived oxygenates to liquid alkanes for transportation fuels.

PubMed

Sun, Shaohui; Yang, Ruishu; Wang, Xin; Yan, Shaokang

2018-04-01

An attractive approach for the production of transportation fuels from renewable biomass resources is to convert oxygenates into alkanes. In this paper, C 5 -C 20 alkanes formed via the hydrogenation and hydrodeoxygenation of the oligomers of furfuryl alcohol(FA) can be used as gasoline, diesel and jet fuel fraction. The first step of the process is the oligomers of FA convert into hydrogenated products over Raney Ni catalyst in a batch reactor. The second step of the process converts hydrogenated products to alkanes via hydrodeoxygenation over different bi-functional catalysts include hydrogenation and acidic deoxidization active sites. After this process, the oxygen content decreased from 22.1 wt% in the oligomers of FA to 0.58 wt% in the hydrodeoxygenation products.

Divalent cation interactions with oligogalacturonides.

PubMed

Cescutti, P; Rizzo, R

2001-07-01

The conformational properties of high and low molecular weight galacturonides were investigated in relation to the ability of oligomers with degree of polymerization >10 to act as elicitors of plant defense mechanisms. Oligomers from polygalacturonate were obtained by means of enzymatic hydrolysis. Two fractions exhibiting high and low average degrees of polymerization were isolated by solvent fractionation and characterized by means of electrospray mass spectrometry. The conformational behaviors of the two fractions were investigated in the presence of different divalent cations using circular dichroism. Calcium, copper, and zinc ions were able to induce a conformational transition in both fractions. When in the presence of the high molecular weight fraction, copper and zinc ions were much more effective than calcium ions, whereas the efficiency was much reduced with low molecular weight oligomers.

QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

PubMed Central

Brener, Oleksandr; Dunkelmann, Tina; Gremer, Lothar; van Groen, Thomas; Mirecka, Ewa A.; Kadish, Inga; Willuweit, Antje; Kutzsche, Janine; Jürgens, Dagmar; Rudolph, Stephan; Tusche, Markus; Bongen, Patrick; Pietruszka, Jörg; Oesterhelt, Filipp; Langen, Karl-Josef; Demuth, Hans-Ulrich; Janssen, Arnold; Hoyer, Wolfgang; Funke, Susanne A.; Nagel-Steger, Luitgard; Willbold, Dieter

2015-01-01

Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease. PMID:26394756

An Improved Method for Generating Consistent Soluble Amyloid-beta Oligomer Preparations for In Vitro Neurotoxicity Studies

PubMed Central

Ryan, Deborah A.; Narrow, Wade C.; Federoff, Howard J.; Bowers, William J.

2010-01-01

Soluble Aβ oligomers are recognized as playing a key role in Alzheimer’s disease (AD) pathophysiology. Despite their significance, many investigators encounter difficulty generating reliable preparations for in vitro and in vivo experiments. Solutions of Aβ are often unstable and soluble conformer profiles inconsistent. In this study we describe detailed methods for preparing Aβ oligomers that are stable for several weeks and are enriched for low and high molecular weight oligomeric forms, including the 56-kDa form, a conformer implicated in AD-related cognitive impairment. We characterize their structural and functional properties using Western blot, dot blot, atomic force microscopy, Thioflavine T fluorescence, and primary neuronal culture toxicity assays. These synthetic preparations should prove valuable to many studying Aβ-mediated mechanisms underlying AD. PMID:20452375

Predictions and Experimental Microstructural Characterization of High Strain Rate Failure Modes in Layered Aluminum Composites

NASA Astrophysics Data System (ADS)

Khanikar, Prasenjit

Different aluminum alloys can be combined, as composites, for tailored dynamic applications. Most investigations pertaining to metallic alloy layered composites, however, have been based on quasi-static approaches. The dynamic failure of layered metallic composites, therefore, needs to be characterized in terms of strength, toughness, and fracture response. A dislocation-density based crystalline plasticity formulation, finite-element techniques, rational crystallographic orientation relations and a new fracture methodology were used to predict the failure modes associated with the high strain rate behavior of aluminum layered composites. Two alloy layers, a high strength alloy, aluminum 2195, and an aluminum alloy 2139, with high toughness, were modeled with representative microstructures that included precipitates, dispersed particles, and different grain boundary (GB) distributions. The new fracture methodology, based on an overlap method and phantom nodes, is used with a fracture criteria specialized for fracture on different cleavage planes. One of the objectives of this investigation, therefore, was to determine the optimal arrangements of the 2139 and 2195 aluminum alloys for a metallic layered composite that would combine strength, toughness and fracture resistance for high strain-rate applications. Different layer arrangements were investigated for high strain-rate applications, and the optimal arrangement was with the high toughness 2139 layer on the bottom, which provided extensive shear strain localization, and the high strength 2195 layer on the top for high strength resistance. The layer thickness of the bottom high toughness layer also affected the bending behavior of the roll-boned interface and the potential delamination of the layers. Shear strain localization, dynamic cracking and delamination were the mutually competing failure mechanisms for the layered metallic composite, and control of these failure modes can be optimized for high strain-rate applications. The second major objective of this investigation was the use of recently developed dynamic fracture formulations to model and analyze the crack nucleation and propagation of aluminum layered composites subjected to high strain rate loading conditions and how microstructural effects, such as precipitates, dispersed particles, and GB orientations affect failure evolution. This dynamic fracture approach is used to investigate crack nucleation and crack growth as a function of the different microstructural characteristics of each alloy in layered composites with and without pre-existing cracks. The zigzag nature of the crack paths were mainly due to the microstructural features, such as precipitates and dispersed particles distributions and orientations ahead of the crack front, and it underscored the capabilities of the fracture methodology. The evolution of dislocation density and the formation of localized shear slip contributed to the blunting of the propagating crack. Extensive geometrical and thermal softening due to the localized plastic slip also affected crack path orientations and directions. These softening mechanisms resulted in the switching of cleavage planes, which affected crack path orientations. Interface delamination can also have an important role in the failure and toughening of the layered composites. Different scenarios of delamination were investigated, such as planar crack growth and crack penetration into the layers. The presence of brittle surface oxide platelets in the interface region also significantly influenced the interface delamination process. Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) and Optical Microscopy (OM) characterization provided further physical insights and validation of the predictive capabilities. The inherent microstructural features of each alloy play a significant role in the dynamic fracture, shear strain localization, and interface delamination of the layered metallic composite. These microstructural features, such as precipitates, dispersed particles, and GB orientations and distributions can be optimized for desired behavior of metallic composites.

Radiopaque Resists for Two-Photon Lithography To Enable Submicron 3D Imaging of Polymer Parts via X-ray Computed Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saha, Sourabh K.; Oakdale, James S.; Cuadra, Jefferson A.

Two-photon lithography (TPL) is a high-resolution additive manufacturing (AM) technique capable of producing arbitrarily complex three-dimensional (3D) microstructures with features 2–3 orders of magnitude finer than human hair. This process finds numerous applications as a direct route toward the fabrication of novel optical and mechanical metamaterials, miniaturized optics, microfluidics, biological scaffolds, and various other intricate 3D parts. As TPL matures, metrology and inspection become a crucial step in the manufacturing process to ensure that the geometric form of the end product meets design specifications. X-ray-based computed tomography (CT) is a nondestructive technique that can provide this inspection capability for themore » evaluation of complex internal 3D structure. However, polymeric photoresists commonly used for TPL, as well as other forms of stereolithography, poorly attenuate X-rays due to the low atomic number (Z) of their constituent elements and therefore appear relatively transparent during imaging. We present the development of optically clear yet radiopaque photoresists for enhanced contrast under X-ray CT. We have synthesized iodinated acrylate monomers to formulate high-Z photoresist materials that are capable of forming 3D microstructures with sub-150 nm features. In addition, we have developed a formulation protocol to match the refractive index of the photoresists to the immersion medium of the objective lens so as to enable dip-in laser lithography, a direct laser writing technique for producing millimeter-tall structures. Our radiopaque photopolymer then resists increase X-ray attenuation by a factor of more than 10 times without sacrificing the sub-150 nm feature resolution or the millimeter-scale part height. Thus, our resists can successfully replace existing photopolymers to generate AM parts that are suitable for inspection via X-ray CT. By providing the “feedstock” for radiopaque AM parts, our resist formulation is expected to play a critical role in enabling fabrication of functional polymer parts to tight design tolerances.« less

Radiopaque Resists for Two-Photon Lithography To Enable Submicron 3D Imaging of Polymer Parts via X-ray Computed Tomography

DOE PAGES

Saha, Sourabh K.; Oakdale, James S.; Cuadra, Jefferson A.; ...

2017-11-24

Two-photon lithography (TPL) is a high-resolution additive manufacturing (AM) technique capable of producing arbitrarily complex three-dimensional (3D) microstructures with features 2–3 orders of magnitude finer than human hair. This process finds numerous applications as a direct route toward the fabrication of novel optical and mechanical metamaterials, miniaturized optics, microfluidics, biological scaffolds, and various other intricate 3D parts. As TPL matures, metrology and inspection become a crucial step in the manufacturing process to ensure that the geometric form of the end product meets design specifications. X-ray-based computed tomography (CT) is a nondestructive technique that can provide this inspection capability for themore » evaluation of complex internal 3D structure. However, polymeric photoresists commonly used for TPL, as well as other forms of stereolithography, poorly attenuate X-rays due to the low atomic number (Z) of their constituent elements and therefore appear relatively transparent during imaging. We present the development of optically clear yet radiopaque photoresists for enhanced contrast under X-ray CT. We have synthesized iodinated acrylate monomers to formulate high-Z photoresist materials that are capable of forming 3D microstructures with sub-150 nm features. In addition, we have developed a formulation protocol to match the refractive index of the photoresists to the immersion medium of the objective lens so as to enable dip-in laser lithography, a direct laser writing technique for producing millimeter-tall structures. Our radiopaque photopolymer then resists increase X-ray attenuation by a factor of more than 10 times without sacrificing the sub-150 nm feature resolution or the millimeter-scale part height. Thus, our resists can successfully replace existing photopolymers to generate AM parts that are suitable for inspection via X-ray CT. By providing the “feedstock” for radiopaque AM parts, our resist formulation is expected to play a critical role in enabling fabrication of functional polymer parts to tight design tolerances.« less

Design and fabrication of an elliptical micro-lens array with grating for laser safety

NASA Astrophysics Data System (ADS)

Li, L. H.; Wu, B. Q.; Chan, C. Y.; Lee, W. B.; Dong, L. H.

2015-10-01

With the enormous expansion of laser usage in medicine, industry and research, all facilities must formulate and adhere to specific safety methods that appropriately address user protection. The protective ellipticalal microstructure with grating is a novel technology which can provide the principal means of ensuring against ocular injury, and must be worn at all times during laser operation. On the basis of Fresnel's law and the diffractive law, Solidworks and Lighttools software are applied to design the elliptical micro-lens array and correspondent grating. The height of the microstructure is 100um and its period is 3mm. The period of grating is 5um. It is shown that the amount of emergent light of a specific wavelength (1064nm) can reflect more than 40° from the incident light through simulation, while the incident light is perpendicular to the microstructure. The fabrication adopts the ultra-precision single point diamond method and injection molding method. However, it is found in the test that the surface roughness has a serious effect on the angle between the emergent and incident light. As a result, the element can reflect the vertical incidence beam into a tilted emergent beam with a certain angular degree , as well as protecting users from laser damage injures.

Ethynyl-terminated ester oligomers and polymers therefrom

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Havens, Stephen J. (Inventor)

1986-01-01

A class of ethynyl terminated oligomers and the process for preparing the same are disclosed. Upon the application of heat, with or without a catalyst, the ethynyl groups react to provide crosslinking and chain extension to increase the polymer use temperature and improve the polymer solvent resistance. These polyesters are potentially useful in packaging, magnetic tapes, capacitors, industrial belting, protective coatings, structural adhesives and composite matrices.

Ethynyl terminated ester oligomers and polymers therefrom

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); hesives and composite matrices. (Inventor)

1987-01-01

A new class of ethynyl-terminated oligomers and the process for preparing same are disclosed. Upon the application of heat, with or without a catalyst, the ethynyl groups react to provide crosslinking and chain extension to increase the polymer use temperature and improve the polymer solvent resistance. These improved polyesters are potentially useful in packaging, magnetic tapes, capacitors, industrial belting, protective coatings, structural adhesives and composite matrices.

Computationally Designed Oligomers for High Contrast Black Electrochromic Polymers

DTIC Science & Technology

2017-05-05

SUBJECT TERMS electrochromics, DFf, TDDFT, organic electronics , oligomer, organic polymers 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF 18. NUMBER... electron -withdrawing behaviors. Another finding was that the same dication was produced regardless of the color or peak morphology of the neutral 5...radical cation states present in the chromophore upon oxidation. The two-ring electron rich dioxythiophene portions of the chromophore (EAc) and/or the

Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples

PubMed Central

Liu, Zhandong; Venkatesh, Santosh S; Maley, Carlo C

2008-01-01

Background Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. Results We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (> 98%) 12 bp oligomers appear in vertebrate genomes while < 2% of 19 bp oligomers are present. Other species showed different ranges of > 98% to < 2% of possible oligomers in D. melanogaster (12–17 bp), C. elegans (11–17 bp), A. thaliana (11–17 bp), S. cerevisiae (10–16 bp) and E. coli (9–15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Conclusion Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues. PMID:18973670

Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples.

PubMed

Liu, Zhandong; Venkatesh, Santosh S; Maley, Carlo C

2008-10-30

Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (> 98%) 12 bp oligomers appear in vertebrate genomes while < 2% of 19 bp oligomers are present. Other species showed different ranges of > 98% to < 2% of possible oligomers in D. melanogaster (12-17 bp), C. elegans (11-17 bp), A. thaliana (11-17 bp), S. cerevisiae (10-16 bp) and E. coli (9-15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues.

The Disintegration Process in Microcrystalline Cellulose Based Tablets, Part 1: Influence of Temperature, Porosity and Superdisintegrants

PubMed Central

Yassin, Samy; Goodwin, Daniel J; Anderson, Andrew; Sibik, Juraj; Wilson, D Ian; Gladden, Lynn F; Zeitler, J Axel

2015-01-01

Disintegration performance was measured by analysing both water ingress and tablet swelling of pure microcrystalline cellulose (MCC) and in mixture with croscarmellose sodium using terahertz pulsed imaging (TPI). Tablets made from pure MCC with porosities of 10% and 15% showed similar swelling and transport kinetics: within the first 15 s, tablets had swollen by up to 33% of their original thickness and water had fully penetrated the tablet following Darcy flow kinetics. In contrast, MCC tablets with a porosity of 5% exhibited much slower transport kinetics, with swelling to only 17% of their original thickness and full water penetration reached after 100 s, dominated by case II transport kinetics. The effect of adding superdisintegrant to the formulation and varying the temperature of the dissolution medium between 20°C and 37°C on the swelling and transport process was quantified. We have demonstrated that TPI can be used to non-invasively analyse the complex disintegration kinetics of formulations that take place on timescales of seconds and is a promising tool to better understand the effect of dosage form microstructure on its performance. By relating immediate-release formulations to mathematical models used to describe controlled release formulations, it becomes possible to use this data for formulation design. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3440–3450, 2015 PMID:26073446

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miner, Jacob Carlson; Garcia, Angel Enrique

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1–3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients andmore » Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5–3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.« less

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

DOE PAGES

Miner, Jacob Carlson; Garcia, Angel Enrique

2018-05-29

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1–3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients andmore » Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5–3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.« less

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

NASA Astrophysics Data System (ADS)

Miner, Jacob Carlson; García, Angel Enrique

2018-06-01

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Structural basis for the auxin-induced transcriptional regulation by Aux/IAA17.

PubMed

Han, Mookyoung; Park, Yangshin; Kim, Iktae; Kim, Eun-Hee; Yu, Tae-Kyung; Rhee, Sangkee; Suh, Jeong-Yong

2014-12-30

Auxin is the central hormone that regulates plant growth and organ development. Transcriptional regulation by auxin is mediated by the auxin response factor (ARF) and the repressor, AUX/IAA. Aux/IAA associates with ARF via domain III-IV for transcriptional repression that is reversed by auxin-induced Aux/IAA degradation. It has been known that Aux/IAA and ARF form homo- and hetero-oligomers for the transcriptional regulation, but what determines their association states is poorly understood. Here we report, to our knowledge, the first solution structure of domain III-IV of Aux/IAA17 (IAA17), and characterize molecular interactions underlying the homotypic and heterotypic oligomerization. The structure exhibits a compact β-grasp fold with a highly dynamic insert helix that is unique in Aux/IAA family proteins. IAA17 associates to form a heterogeneous ensemble of front-to-back oligomers in a concentration-dependent manner. IAA17 and ARF5 associate to form homo- or hetero-oligomers using a common scaffold and binding interfaces, but their affinities vary significantly. The equilibrium dissociation constants (KD) for homo-oligomerization are 6.6 μM and 0.87 μM for IAA17 and ARF5, respectively, whereas hetero-oligomerization reveals a ∼ 10- to ∼ 100-fold greater affinity (KD = 73 nM). Thus, individual homo-oligomers of IAA17 and ARF5 spontaneously exchange their subunits to form alternating hetero-oligomers for transcriptional repression. Oligomerization is mainly driven by electrostatic interactions, so that charge complementarity at the interface determines the binding affinity. Variable binding affinity by surface charge modulation may effectively regulate the complex interaction network between Aux/IAA and ARF family proteins required for the transcriptional control of auxin-response genes.

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

PubMed Central

Foley, Joseph; Hill, Shannon E.; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

2013-01-01

Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway. PMID:24089713

Polydopamine and eumelanin molecular structures investigated with ab initio calculations† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc04692d Click here for additional data file.

PubMed Central

Chen, Chun-Teh; Martin-Martinez, Francisco J.; Jung, Gang Seob

2017-01-01

A set of computational methods that contains a brute-force algorithmic generation of chemical isomers, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations is reported and applied to investigate nearly 3000 probable molecular structures of polydopamine (PDA) and eumelanin. All probable early-polymerized 5,6-dihydroxyindole (DHI) oligomers, ranging from dimers to tetramers, have been systematically analyzed to find the most stable geometry connections as well as to propose a set of molecular models that represents the chemically diverse nature of PDA and eumelanin. Our results indicate that more planar oligomers have a tendency to be more stable. This finding is in good agreement with recent experimental observations, which suggested that PDA and eumelanin are composed of nearly planar oligomers that appear to be stacked together via π–π interactions to form graphite-like layered aggregates. We also show that there is a group of tetramers notably more stable than the others, implying that even though there is an inherent chemical diversity in PDA and eumelanin, the molecular structures of the majority of the species are quite repetitive. Our results also suggest that larger oligomers are less likely to form. This observation is also consistent with experimental measurements, supporting the existence of small oligomers instead of large polymers as main components of PDA and eumelanin. In summary, this work brings an insight into the controversial structure of PDA and eumelanin, explaining some of the most important structural features, and providing a set of molecular models for more accurate modeling of eumelanin-like materials. PMID:28451292

Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures

PubMed Central

Fraietta, Joseph A.; Mueller, Yvonne M.; Lozenski, Karissa L.; Ratner, Deena; Boesteanu, Alina C.; Hancock, Aidan S.; Lackman-Smith, Carol; Zentner, Isaac J.; Chaiken, Irwin M.; Chung, Suhman; LeGrice, Stuart F. J.; Snyder, Beth A.; Mankowski, Marie K.; Jones, Natalie M.; Hope, Jennifer L.; Gupta, Phalguni; Anderson, Sharon H.; Wigdahl, Brian

2014-01-01

In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer the most immediate hope for controlling the AIDS pandemic. The most advanced and clinically effective microbicides are based on ARV agents that interfere with the earliest stages of HIV-1 replication. Our objective was to identify and characterize novel ARV-like inhibitors, as well as demonstrate their efficacy at blocking HIV-1 transmission. Abasic phosphorothioate 2′ deoxyribose backbone (PDB) oligomers were evaluated in a variety of mechanistic assays and for their ability to inhibit HIV-1 infection and virus transmission through primary human cervical mucosa. Cellular and biochemical assays were used to elucidate the antiviral mechanisms of action of PDB oligomers against both lab-adapted and primary CCR5- and CXCR4-utilizing HIV-1 strains, including a multidrug-resistant isolate. A polarized cervical organ culture was used to test the ability of PDB compounds to block HIV-1 transmission to primary immune cell populations across ectocervical tissue. The antiviral activity and mechanisms of action of PDB-based compounds were dependent on oligomer size, with smaller molecules preventing reverse transcription and larger oligomers blocking viral entry. Importantly, irrespective of molecular size, PDBs potently inhibited virus infection and transmission within genital tissue samples. Furthermore, the PDB inhibitors exhibited excellent toxicity and stability profiles and were found to be safe for vaginal application in vivo. These results, coupled with the previously reported intrinsic anti-inflammatory properties of PDBs, support further investigations in the development of PDB-based topical microbicides for preventing the global spread of HIV-1. PMID:25224013

Rhynchophylline Protects Against the Amyloid β-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats.

PubMed

Shao, Hui; Mi, Ze; Ji, Wei-gang; Zhang, Cheng-huan; Zhang, Teng; Ren, Shuan-cheng; Zhu, Zhi-ru

2015-11-01

Accumulated soluble amyloid β (Aβ)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Aβ oligomers. Our recent study showed that soluble Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Aβ1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 μM soluble Aβ1-42 oligomers; (2) 30 μM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Aβ1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 μM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Aβ and counteract the deleterious effect of Aβ1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD.

β-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin

PubMed Central

Ma, Qiu-Lan; Yang, Fusheng; Rosario, Emily R.; Ubeda, Oliver J.; Beech, Walter; Gant, Dana J.; Chen, Ping Ping; Hudspeth, Beverly; Chen, Cory; Zhao, Yongle; Vinters, Harry V.; Frautschy, Sally A.

2009-01-01

Both insulin resistance (type II diabetes) and β-amyloid (Aβ) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Aβ oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics. Here, we report Aβ oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze performance. Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. These data indicate JNK mediates Aβ oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. PMID:19605645

Comparison of neurotoxicity of different aggregated forms of Aβ40, Aβ42 and Aβ43 in cell cultures.

PubMed

Fu, Lu; Sun, Yao; Guo, Yongqing; Chen, Yan; Yu, Bin; Zhang, Haihong; Wu, Jiaxin; Yu, Xianghui; Kong, Wei; Wu, Hui

2017-03-01

The abnormal deposition of amyloid-β (Aβ) peptides in the brain is the main neuropathological hallmark of Alzheimer's disease (AD). Amyloid deposits are formed by a heterogeneous mixture of Aβ peptides, among which the most studied are Aβ40 and Aβ42. Aβ40 is abundantly produced in the human brain, but the level of Aβ42 is remarkably increased in the brain of AD patients. Aside from Aβ40 and Aβ42, recent data have raised the possibility that Aβ43 peptides may be instrumental in AD pathogenesis. Besides its length, whether the Aβ aggregated form accounts for the neurotoxicity is also particularly controversial. Aβ fibrils are generally considered as key pathogenic substances in AD pathogenesis. Nevertheless, recent data implicated soluble Aβ oligomers as the main cause of synaptic dysfunction and memory loss in AD. To further address this uncertainty, we analyzed the neurotoxicity of different Aβ species and Aβ forms at the cellular level. The results showed that Aβ42 could form oligomers significantly faster than Aβ40 and Aβ43 and Aβ42 oligomers showed the greatest level of neurotoxicity. Regardless of the length of Aβ peptides, Aβ oligomers induced significantly higher cytotoxicity compared with the other two Aβ forms. Surprisingly, the neurotoxicity of fibrils in PC12 cells was only marginally but not significantly stronger than monomers, contrary to previous reports. Altogether, our findings demonstrate the high pathogenicity of Aβ42 among the three Aβ species and support the idea that Aβ42 oligomers contribute to the pathological events leading to neurodegeneration in AD. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Correlation Between the Extent of Catalytic Activity and Charge Density of Montmorillonites

PubMed Central

Steudel, Annett; Emmerich, Katja; Lagaly, Gerhard; Schuhmann, Rainer

2010-01-01

Abstract The clay mineral montmorillonite is a member of the phyllosilicate group of minerals, which has been detected on martian soil. Montmorillonite catalyzes the condensation of activated monomers to form RNA-like oligomers. Extent of catalysis, that is, the yield of oligomers, and the length of the longest oligomer formed in these reactions widely varies with the source of montmorillonite (i.e., the locality where the mineral is mined). This study was undertaken to establish whether there exists a correlation between the extent of catalytic property and the charge density of montmorillonites. Charge density was determined by saturating the montmorillonites with alkyl ammonium cations that contained increasing lengths of alkyl chains, [CH3-(CH2)n-NH3]+, where n = 3–16 and 18, and then measuring d(001), interlayer spacing of the resulting montmorillonite-alkyl ammonium-montmorillonite complex by X-ray diffractometry (XRD). Results demonstrate that catalytic activity of montmorillonites with lower charge density is superior to that of higher charge density montmorillonite. They produce longer oligomers that contain 9 to 10 monomer units, while montmorillonite with high charge density catalyzes the formation of oligomers that contain only 4 monomer units. The charge density of montmorillonites can also be calculated from the chemical composition if elemental analysis data of the pure mineral are available. In the next mission to Mars, CheMin (Chemistry and Mineralogy), a combined X-ray diffraction/X-ray fluorescence instrument, will provide information on the mineralogical and elemental analysis of the samples. Possible significance of these results for planning the future missions to Mars for the search of organic compounds and extinct or extant life is discussed. Key Words: Mars—Origin of life—Montmorillonite—Mineral catalysis—Layer charge density—X–ray diffractometry. Astrobiology 10, 743–749. PMID:20854214

Correlation between the extent of catalytic activity and charge density of montmorillonites.

PubMed

Ertem, Gözen; Steudel, Annett; Emmerich, Katja; Lagaly, Gerhard; Schuhmann, Rainer

2010-09-01

The clay mineral montmorillonite is a member of the phyllosilicate group of minerals, which has been detected on martian soil. Montmorillonite catalyzes the condensation of activated monomers to form RNA-like oligomers. Extent of catalysis, that is, the yield of oligomers, and the length of the longest oligomer formed in these reactions widely varies with the source of montmorillonite (i.e., the locality where the mineral is mined). This study was undertaken to establish whether there exists a correlation between the extent of catalytic property and the charge density of montmorillonites. Charge density was determined by saturating the montmorillonites with alkyl ammonium cations that contained increasing lengths of alkyl chains, [CH₃-(CH₂)(n)-NH₃](+), where n = 3-16 and 18, and then measuring d(₀₀₁), interlayer spacing of the resulting montmorillonite-alkyl ammonium-montmorillonite complex by X-ray diffractometry (XRD). Results demonstrate that catalytic activity of montmorillonites with lower charge density is superior to that of higher charge density montmorillonite. They produce longer oligomers that contain 9 to 10 monomer units, while montmorillonite with high charge density catalyzes the formation of oligomers that contain only 4 monomer units. The charge density of montmorillonites can also be calculated from the chemical composition if elemental analysis data of the pure mineral are available. In the next mission to Mars, CheMin (Chemistry and Mineralogy), a combined X-ray diffraction/X-ray fluorescence instrument, will provide information on the mineralogical and elemental analysis of the samples. Possible significance of these results for planning the future missions to Mars for the search of organic compounds and extinct or extant life is discussed.

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

NASA Astrophysics Data System (ADS)

Foley, Joseph; Hill, Shannon E.; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

2013-09-01

Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway.

NADP+ Binding to the Regulatory Subunit of Methionine Adenosyltransferase II Increases Intersubunit Binding Affinity in the Hetero-Trimer

PubMed Central

Ortega, Rebeca; Martínez-Júlvez, Marta; Revilla-Guarinos, Ainhoa; Pérez-Pertejo, Yolanda; Velázquez-Campoy, Adrián; Sanz-Aparicio, Julia; Pajares, María A.

2012-01-01

Mammalian methionine adenosyltransferase II (MAT II) is the only hetero-oligomer in this family of enzymes that synthesize S-adenosylmethionine using methionine and ATP as substrates. Binding of regulatory β subunits and catalytic α2 dimers is known to increase the affinity for methionine, although scarce additional information about this interaction is available. This work reports the use of recombinant α2 and β subunits to produce oligomers showing kinetic parameters comparable to MAT II purified from several tissues. According to isothermal titration calorimetry data and densitometric scanning of the stained hetero-oligomer bands on denatured gels, the composition of these oligomers is that of a hetero-trimer with α2 dimers associated to single β subunits. Additionally, the regulatory subunit is able to bind NADP+ with a 1∶1 stoichiometry, the cofactor enhancing β to α2-dimer binding affinity. Mutants lacking residues involved in NADP+ binding and N-terminal truncations of the β subunit were able to oligomerize with α2-dimers, although the kinetic properties appeared altered. These data together suggest a role for both parts of the sequence in the regulatory role exerted by the β subunit on catalysis. Moreover, preparation of a structural model for the hetero-oligomer, using the available crystal data, allowed prediction of the regions involved in β to α2-dimer interaction. Finally, the implications that the presence of different N-terminals in the β subunit could have on MAT II behavior are discussed in light of the recent identification of several splicing forms of this subunit in hepatoma cells. PMID:23189196

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth.

PubMed

Foley, Joseph; Hill, Shannon E; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

2013-09-28

Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway.

Inhibiting nucleation of amyloid structure in a huntingtin fragment by targeting α-helix rich oligomeric intermediates

PubMed Central

Mishra, Rakesh; Jayaraman, Murali; Roland, Bartholomew P.; Landrum, Elizabeth; Fullam, Timothy; Kodali, Ravindra; Thakur, Ashwani K.; Arduini, Irene; Wetzel, Ronald

2011-01-01

Although oligomeric intermediates are transiently formed in almost all known amyloid assembly reactions, their mechanistic roles are poorly understood. Recently we demonstrated a critical role for the 17 amino acid N-terminal segment (httNT) of huntingtin (htt) in oligomer-mediated amyloid assembly of htt N-terminal fragments. In this mechanism, the httNT segment forms the α-helix rich core of the oligomers, leaving most or all of each polyglutamine (polyQ) segment disordered and solvent-exposed. Nucleation of amyloid structure occurs within this local high concentration of disordered polyQ. Here we demonstrate the kinetic importance of httNT self-assembly by describing inhibitory httNT-containing peptides that appear to work by targeting nucleation within the oligomer fraction. These molecules inhibit amyloid nucleation by forming mixed oligomers with the httNT domains of polyQ-containing htt N-terminal fragments. In one class of inhibitor, nucleation is passively suppressed due to the reduced local concentration of polyQ within the mixed oligomer. In the other class, nucleation is actively suppressed by a proline-rich polyQ segment covalently attached to httNT. Studies with D-amino acid and scrambled sequence versions of httNT suggest that inhibition activity is strongly linked to the propensity of inhibitory peptides to make amphipathic α-helices. HttNT derivatives with C-terminal cell penetrating peptide segments, also exhibit excellent inhibitory activity. The httNT-based peptides described here, especially those with protease-resistant D-amino acids and/or with cell penetrating sequences, may prove useful as lead therapeutics for inhibiting nucleation of amyloid formation in Huntington’s disease. PMID:22178478

Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats.

PubMed

Kalra, Jaspreet; Kumar, Puneet; Majeed, Abu Bakar Abdul; Prakash, Atish

2016-01-01

Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop.

PubMed

Miner, Jacob Carlson; García, Angel Enrique

2018-06-14

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Liquid chromatography/mass spectrometry investigation of the impact of thermal processing and storage on peach procyanidins.

PubMed

Hong, Yun-Jeong; Barrett, Diane M; Mitchell, Alyson E

2004-04-21

Normal-phase liquid chromatography/mass spectrometry (LC/MS) was used to determine the levels and fate of procyanidins in frozen and canned Ross clingstone peaches as well as in the syrup used in the canning over a 3 month period. Procyanidin oligomers, monomers through undecamers, were identified in Ross clingstone peaches. Optimized methods allowed for the quantitation of oligomers through octamers. The profile of procyanidins in peaches is similar to profiles found in grapes, chocolate, and beverages linked to health benefits such as tea and wine. The monomer content in frozen peeled peaches was found to be 19.59 mg/kg. Dimers (39.59 mg/kg) and trimers (38.81 mg/kg) constituted the largest percent composition of oligomers in the peaches. Tetramers through octamers were present in levels of 17.81, 12.43, 10.62, 3.94 and 1.75 mg/kg, respectively. Thermal processing resulted in an 11% reduction in monomers, a 9% reduction in dimers, a 12% reduction in trimers, a 6% reduction in tetramers, and a 5% reduction in pentamers. Hexamers and heptamers demonstrated an approximate 30% loss, and octamers were no longer detected. Analysis of the syrup after thermal processing indicates that there is a migration of procyanidin monomers through hexamers into the syrup that can account for the losses observed during the canning process. Storage of canned peaches for 3 months demonstrated a time-related loss in higher oligomers and that by 3 months oligomers larger than tetramers are not observed. At 3 months postcanning, levels of monomers had decreased by 10%, dimers by 16%, trimers by 45%, and tetramers by 80%. A similar trend was observed in the canning syrup.