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Recently, a flow-based selectin-dependent method for the capture and enrichment of specific types of cells (CD34+ hematopoetic stem and progenitor cells and human leukemia HL60) from peripheral blood was demonstrated. However, these devices depend on a monolayer of selectin protein, which has been shown to have a maximum binding efficiency as a function of surface area. A novel surface coating of colloidal silica nanoparticles was designed that alters the surface roughness resulting in increased surface area. The nanoparticles were adhered using either an inorganic titanate resinous coating or an organic polymer of poly-L-lysine. Using Alexa Fluor 647 conjugated P-selectin, an increase in protein adsorption of up to 35% when compared to control was observed. During perfusion experiments using P-selectin-coated microtubes, we observed increased cell capture and greatly decreased rolling velocity at equivalent protein concentration compared to nonparticle control. Atomic force microscopy showed increased surface roughness consistent with the nanoparticle mean diameter, suggesting a monolayer of particles. These results support the coating's potential to improve existing cell capture implantable devices for a variety of therapeutic and scientific uses.
ACS Nano 2010 Jan 26
PMID:Nanoparticle coatings for enhanced capture of flowing cells in microtubes. 2001 20

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.
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PMID:SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. 2020 11

Spontaneous embedding of gold nanoparticle (NP) aggregates or polyelectrolyte microcapsules modified with NPs in biocompatible hyaluronic acid/poly(l-lysine) films is reported. The NPs were adsorbed in the aggregated state to induce near-IR light absorption. The films functionalized with gold NPs become active in response to a "biologically friendly" near-IR laser at a power of about 20 mW. The activation is characterized by a localized temperature increase in the film, allowing conversion of light energy to heat into confined volumes. Microcapsules adsorbed onto the film can release its cargo under stimulation with near-IR light because of localized permeability changes in their walls. This work is aimed at layer-by-layer film-based biomedical coatings and active surfaces with light-sensitive features wherein metal NPs and microcapsules are used as active centers or carriers with remote control of functionalities.
ACS Appl Mater Interfaces 2009 Aug
PMID:Remote near-IR light activation of a hyaluronic acid/poly(l-lysine) multilayered film and film-entrapped microcapsules. 2035 86

We have characterized the adsorption and lubricating properties of the polycation-PEG graft copolymer poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) on human-hair surfaces by means of X-ray photoelectron spectroscopy (XPS), fluorescence microscopy, and atomic force microscopy (AFM). XPS measurements indicated that PLL-g-PEG copolymers spontaneously adsorbed onto the surface of bleached-hair samples (a good model of a weathered, damaged hair surface for cosmetic care applications) from an aqueous solution. Further treatment with cationic surfactants present in common shampoo formulations removed the adsorbed PLL-g-PEG from the hair samples. Fluorescence microscopy showed that the adsorption of PLL-g-PEG onto the hair samples from an aqueous polymer solution occurred inhomogeneously. Nanotribological studies with AFM (friction vs load plots) revealed that the relationship between load and friction was approximately linear for all hair samples, while the slopes of the plots varied considerably along the hair sample surface. Under ambient, "dry" conditions, the frictional properties of the bleached, bleached + PLL-g-PEG-treated, and bleached + PLL-g-PEG-treated and subsequently surfactant-treated hair samples did not reveal a clear difference. In distilled water, however, the bleached + PLL-g-PEG-treated hair samples showed statistically lower frictional properties than simply bleached or bleached + PLL-g-PEG-treated and subsequently surfactant-treated hair samples. Overall, the three instrumental techniques have consistently shown that the adsorption of PLL-g-PEG onto the hair sample surface occurs unevenly, which can be ascribed to the intrinsically heterogeneous properties of the human-hair surface. A control experiment, involving an injection of concentrated PLL-g-PEG solution into a liquid cell where an AFM tip was already scanning over a specific area (line scan mode), revealed an immediate and apparent reduction in the frictional force. Despite the inhomogeneity of the hair surface, the adsorption of the polymer seems to be extremely effective in promoting lubrication of the fiber. This suggests that the adsorbed graft copolymers act as a boundary lubricant on the hair surface. The presence of a more organized, brushlike layer of polymers contrasts with the usual random adsorption of chains that is believed to be present in the case of linear polyelectrolytes that are nowadays applied for shampoos and conditioners in the cosmetic or textile industries.
ACS Appl Mater Interfaces 2009 Sep
PMID:Adsorption and lubricating properties of poly(l-lysine)-graft-poly(ethylene glycol) on human-hair surfaces. 2035 18

The tribological properties of poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG)-coated oxide interfaces have been investigated with atomic force microscopy (AFM) as a function of the molecular structure. Polymer-bearing surfaces were obtained via spontaneous adsorption of the polymer onto the oxide substrate from a buffered solution of physiological pH. Interfacial friction of these PLL-g-PEG-coated surfaces was found to be highly dependent on the duration of deposition and the architecture of PLL-g-PEG. In terms of the architecture, the PEG chain length and the grafting ratio (i.e., the molar ratio of L-lysine monomer to PEG side chain) of adsorbed PLL-g-PEG significantly influence the interfacial friction; specifically, friction is reduced as the PEG chain length increases and as the molar ratio of L-lysine monomer to PEG side chain decreases. The characteristics of the polymer deposition time and the influence of the lysine/PEG grafting ratio are rationalized in terms of spatial packing density considerations.
ACS Appl Mater Interfaces 2009 Jun
PMID:Tribological properties of poly(L-lysine)-graft-poly(ethylene glycol) films: influence of polymer architecture and adsorbed conformation. 2035 17

Colloidal particles that have nonuniform bulk or surface compositions are of emerging interest because of their potential applications involving advanced chemical storage and delivery and the self-assembly of novel functional materials. Experimental realization of anisotropic particles is much more difficult than that for particles with uniform bulk and surface composition, however. A new wet-chemical synthesis method to anisotropic microparticles is presented. This approach makes convenient use of the unusual observation of a salt-triggered separation of two water-solubilized polyamines into colloidal aggregates with nonuniform polymer composition. The anisotropic structure of these ionically cross-linked aggregates is explained by the difference in surface tensions of the contained single-polymer domains. Contacting the polymer aggregates with silicic acid or 13-nm silica nanoparticles leads to the charge-driven formation of solid or hollow microspheres, respectively. Depending on the poly(lysine)/poly(allylamine) ratio, the nonuniformity of the polymer aggregates translates to surface patches or internal compartments found in the resultant silica/polymer microparticles. Such hybrid materials with their unique structure could serve as a new basis for targeted chemical delivery and controlled release for potential applications in medicine, food, and cosmetics.
ACS Appl Mater Interfaces 2009 Mar
PMID:Polyamine-guided synthesis of anisotropic, multicompartment microparticles. 2035 80

Poly(L-lysine) (PLL) is a commonly used polymer for nonviral gene delivery. However, the polymer exhibits significant toxicity and is not very effective for transgene expression. To enhance the gene delivery efficiency of the polymer, we imparted an amphiphilic property to PLL by substituting approximately 10% of epsilon-NH2 with several endogenous lipids of variable chain lengths (lipid carbon chain ranging from 8 to 18). Lipid-modified PLL with high molecular weight (approximately 25 vs 4 kDa) was found to be more effective in delivering plasmid DNA intracellularly in clinically relevant bone marrow stromal cells (BMSC). For lipid-substituted 25 kDa PLL, a correlation between the extent of lipid substitution and the plasmid DNA delivery efficiency was obtained. Additionally, transgene expression by BMSC significantly increased (20-25%) when amphiphilic PLLs were used for plasmid delivery as compared to native PLL and the commercial transfection agent Lipofectamine-2000. The transfection efficiency of the polymers was positively correlated with the extent of lipid substitution. The amphiphilic polymers were able to modify the cells up to 7 days after transfection, after which the expression was decreased to background levels within 1 week. We conclude that lipid-substituted PLL can be used effectively as a nonviral carrier for DNA, and the extent of lipid substitution was an important determinant of gene delivery.
ACS Appl Mater Interfaces 2009 Apr
PMID:Relationship between the extent of lipid substitution on poly(L-lysine) and the DNA delivery efficiency. 2035 10

Chiral polyelectrolyte multilayers (PEMs) consisting of poly(l-lysine) (PLL), poly(N-(S)alkylated 4-vinylpyridinium iodide), or poly(ethyleneimine maltose) (PEI-m) as polycations and poly(styrenesulfonic acid) sodium salt (PSS) or poly(vinyl sulfate) as polyanions, as well as a nonchiral PEM composed of poly(ethyleneimine) (PEI) and PSS were deposited on silicon substrates and poly(tetrafluoroethylene) membranes using the layer-by-layer method. For these PEMs, enantiospecific interaction toward one enantiomer of either l/d-glutamic acid (l/d-GLU), l/d-tryptophan, or l/d-ascorbic acid (l/d-ASC), respectively, was studied under variation of the concentration, pH, and ionic strength. Both deposition and enantiospecific interaction were analyzed by attenuated total reflection Fourier transform infrared spectroscopy. Our results show a significant enantiospecific preference of d-GLU over l-GLU at PEMs containing PLL and of d-ASC over l-ASC at PEMs containing PEI-m. No such enantiospecific preference was found for nonchiral PEMs containing PEI. The enantiospecificity of PEMs of PLL/PSS toward l/d-GLU could be significantly influenced by the ionic strength and pH values, so that increasing attractive electrostatic interactions resulted in higher enantiospecificity.
ACS Appl Mater Interfaces 2009 Dec
PMID:In situ ATR-FTIR investigation on the preparation and enantiospecificity of chiral polyelectrolyte multilayers. 2035 70

Isoprenoid compounds are ubiquitous in nature, participating in important biological phenomena such as signal transduction, aerobic cellular respiration, photosynthesis, insect communication, and many others. They are derived from the 5-carbon isoprenoid substrates isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). In Archaea and Eukarya, these building blocks are synthesized via the mevalonate pathway. However, the genes required to convert mevalonate phosphate (MP) to IPP are missing in several species of Archaea. An enzyme with isopentenyl phosphate kinase (IPK) activity was recently discovered in Methanocaldococcus jannaschii (MJ), suggesting a departure from the classical sequence of converting MP to IPP. We have determined the high-resolution crystal structures of isopentenyl phosphate kinases in complex with both substrates and products from Thermoplasma acidophilum (THA), as well as the IPK from Methanothermobacter thermautotrophicus (MTH), by means of single-wavelength anomalous diffraction (SAD) and molecular replacement. A histidine residue (His50) in THA IPK makes a hydrogen bond with the terminal phosphates of IP and IPP, poising these molecules for phosphoryl transfer through an in-line geometry. Moreover, a lysine residue (Lys14) makes hydrogen bonds with nonbridging oxygen atoms at P(alpha) and P(gamma) and with the P(beta)-P(gamma) bridging oxygen atom in ATP. These interactions suggest a transition-state-stabilizing role for this residue. Lys14 is a part of a newly discovered "lysine triangle" catalytic motif in IPKs that also includes Lys5 and Lys205. Moreover, His50, Lys5, Lys14, and Lys205 are conserved in all IPKs and can therefore serve as fingerprints for identifying new homologues.
ACS Chem Biol 2010 May 21
PMID:X-ray structures of isopentenyl phosphate kinase. 2040 38

Moenomycin A (MmA) belongs to a family of natural products that inhibit peptidoglycan biosynthesis by binding to the peptidoglycan glycosyltransferases, the enzymes that make the glycan chains of peptidoglycan. MmA is remarkably potent, but its clinical utility has been hampered by poor physicochemical properties. Moenomycin contains three structurally distinct regions: a pentasaccharide, a phosphoglycerate, and a C25 isoprenyl (moenocinyl) lipid tail that gives the molecule its name. The phosphoglycerate moiety links the pentasaccharide to the moenocinyl chain. This moiety contains two negatively charged groups, a phosphoryl group and a carboxylate. Both the phosphoryl group and the carboxylate have previously been implicated in target binding but the role of the carboxylate has not been explored in detail. Here we report the synthesis of six MmA analogues designed to probe the importance of the phosphoglycerate. These analogues were evaluated for antibacterial and enzyme inhibitory activity; the specific contacts between the phosphoglycerate and the protein target were assessed by X-ray crystallography in conjunction with molecular modeling. Both the phosphoryl group and the carboxylate of the phosphoglycerate chain play roles in target binding. The negative charge of the carboxylate, and not its specific structure, appears to be the critical feature in binding since replacing it with a negatively charged acylsulfonamide group produces a more active compound than replacing it with the isosteric amide. Analysis of the ligand-protein contacts suggests that the carboxylate makes a critical contact with an invariant lysine in the active site. The reported work provides information and validated computational methods critical for the design of analogues based on moenomycin scaffolds.
ACS Chem Biol 2010 Jul 16
PMID:Functional and structural analysis of a key region of the cell wall inhibitor moenomycin. 2049 48


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