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Biomedical subjects

Zygmunt Gryczynski

Publications and source records attributed to Zygmunt Gryczynski.

At least 19 recordsLinked to original sources

Protonation of excited state pyrene-1-carboxylate by phosphate and organic acids in aqueous solution studied by fluorescence spectroscopy.

Pyrene-1-carboxylic acid has a pK of 4.0 in the ground state and 8.1 in the singlet electronic excited state. In the pH range of physiological interest (pH approximately 5-8), the ground state compound is largely ionized as pyrene-1-carboxylate, but protonation of the excited state molecule occurs when a proton donor reacts with the carboxylate during the excited state lifetime of the fluorophore. Both forms of the pyrene derivatives are fluorescent, and in this work the protonation reaction was measured by monitoring steady-state and time-resolved fluorescence. The rate of protonation of pyrene-COO(-) by acetic, chloroacetic, lactic, and cacodylic acids is a function of DeltapK, as predicted by Marcus theory. The rate of proton transfer from these acids saturates at high concentration, as expected for the existence of an encounter complex. Trihydrogen-phosphate is a much better proton donor than dihydrogen- and monohydrogen-phosphate, as can be seen by the pH dependence. The proton-donating ability of phosphate does not saturate at high concentrations, but increases with increasing phosphate concentration. We suggest that enhanced rate of proton transfer at high phosphate concentrations may be due to the dual proton donating and accepting nature of phosphate, in analogy to the Grotthuss mechanism for proton transfer in water. It is suggested that in molecular structures containing multiple phosphates, such as membrane surfaces and DNA, proton transfer rates will be enhanced by this mechanism.

Acids↗

Dye-labeled silver nanoshell-bright particle.

Silica beads with average diameters of 40-600 nm were prepared, and Ru(bpy)3(2+) complexes were incorporated into the beads. These beads were coated by silver layer by layer to generate porous but continuous metal nanoshells. The thicknesses of these metal shells were 5-50 nm. The emission band from the dyes in the silica cores was more narrow and the intensity was enhanced with growth of silver shell thickness due to coupling of the emission light from Ru(bpy)3(2+) in the cores with the metal plasmon from the silver shells. The enhancement of emission intensity was also dependent on the size of the silica core, showing that the enhancement efficiency decreased with an increase in the size of the silica beads. Lifetime measurements support the coupling mechanism between the dye and metal shell. This study can be used to develop novel dye-labeled metal particles with bright and narrow emission bands.

Fluorescent Dyes↗

Pressure effect on the stability and the conformational dynamics of the D-Galactose/D-Glucose-binding protein from Escherichia coli.

The effect of the pressure on the structure and stability of the D-Galactose/D-Glucose binding protein (GGBP) from Escherichia coli was studied by steady-state and time-resolved fluorescence spectroscopy, and the ability of glucose ligand to stabilize the GGBP structure was also investigated. Steady-state fluorescence experiments showed a marked quenching of fluorescence emission of GGBP in the absence of glucose. Instead, the presence of glucose seems to stabilize the structure of GGBP at low and moderate pressure values. Time-resolved fluorescence measurements showed that the GGBP taumean in the absence of glucose varies significantly up to 600 bar, while in the presence of the ligand it is almost unaffected by pressure increase up to 600 bar. The effect of the pressure on GGBP was also studied by molecular dynamics simulations. The simulation data support the spectroscopic results and confirm that the presence of glucose is able to contrast the negative effects of pressure on the protein structure. Taken together, the spectroscopic and computer simulation studies suggest that at pressure values up to 2000 bar the structure of GGBP in the absence of glucose remains folded, but a significant perturbation of the protein secondary structures can be detected. The binding of glucose reduces the negative effect of pressure on protein structure and confers protection from perturbation especially at moderate pressure values.

Computer Simulation↗

One- and two-photon induced fluorescence of Pacific Blue-labeled human serum albumin deposited on different core size silver colloids.

We studied one- and two-photon induced fluorescence of Pacific Blue (PB)-labeled human serum albumin (HSA) in the presence of different size silver colloids. The PB fluorescence emission intensity was observed with small (30-40 nm) and large (about 120 nm) colloids and compared with PB emission in absence of colloids. For the system with a small core size colloids we did not detect any fluorescence enhancement with one-photon excitation and the enhancement observed with two-photon excitation was about 2.5-fold. In contrast, for large silver colloids we observed about a 2-fold increase in PB fluorescence brightness for one-photon excitation, and the enhancement with two-photon excitation excided 13-folds. Much stronger increases in brightness observed with two-photon excitation, compared to one-photon excitation, indicate a dominant role of enhanced local field in fluorescence enhancement on silver colloids in solutions.

Colloids↗

Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors.

Essential, protein-protein complexes between the large subunit of the U2 small nuclear RNA auxiliary factor (U2AF65) with the splicing factor 1 (SF1) or the spliceosomal component SF3b155 are exchanged during a critical, ATP-dependent step of pre-mRNA splicing. Both SF1 and the N-terminal domain of SF3b155 interact with a U2AF homology motif (UHM) of U2AF65. SF3b155 contains seven tryptophan-containing sites with sequence similarity to the previously characterized U2AF65-binding domain of SF1. We show that the SF3b155 domain lacks detectable secondary structure using circular dichroism spectroscopy, and demonstrate that five of the tryptophan-containing SF3b155 sites are recognized by the U2AF65-UHM using intrinsic tryptophan fluorescence experiments with SF3b155 variants. When compared with SF1, similar spectral shifts and sequence requirements indicate that U2AF65 interactions with each of the SF3b155 sites are similar to the minimal SF1 site. However, thermodynamic comparison of SF1 or SF3b155 proteins with minimal peptides demonstrates that formation the SF1/U2AF65 complex is likely to affect regions of SF1 beyond the previously identified, linear interaction site, in a remarkably distinct manner from the local U2AF65 binding mode of SF3b155. Furthermore, the complex of the SF1/U2AF65 interacting domains is stabilized by 3.3 kcal mol-1 relative to the complex of the SF3b155/U2AF65 interacting domains, consistent with the need for ATP hydrolysis to drive exchange of these partners during pre-mRNA splicing. We propose that the multiple U2AF65 binding sites within SF3b155 regulate conformational rearrangements during spliceosome assembly. Comparison of the SF3b155 sites defines an (R/K)nXRW(DE) consensus sequence for predicting U2AF65-UHM ligands from genomic sequences, where parentheses denote residues that contribute to, but are not required for binding.

Amino Acid Sequence↗

First observation of surface plasmon-coupled emission due to LED excitation.

Detection limitations for fluorescence methods are normally determined by the phenomenon itself rather than the sensitivity of the instrumentation. These limitations make it necessary to have high sensitivity, high cost equipment causing fluorescence methods to remain lab-oriented. Alleviation of the limitations can be achieved through the phenomenon of surface plasmon-coupled emission (SPCE), which displays enhanced, directional, polarized fluorescence. Here we present the excitation of SPCE from Rhodamine B with a light-emitting diode (LED). Incorporating the gains in sensitivity due to SPCE with LED excitation, it could be possible to design low-cost, high-sensitivity sensors that would allow measurements to be performed in the field.

Journal Article↗

Directional surface plasmon-coupled emission: application for an immunoassay in whole blood.

We present a new approach for performing fluorescence immunoassay in whole blood using fluorescently labeled anti-rabbit immunoglobulin G (IgG) on a silver surface. This approach, which is based on surface plasmon-coupled emission (SPCE), provides increased sensitivity and substantial background reduction due to exclusive selection of the signal from the fluorophores located near a bioaffinity surface. This article describes the effect of an optically dense sample matrix, namely human whole blood and serum, on the intensity of the SPCE. An antigen (rabbit IgG) was adsorbed to a slide covered with a thin silver metal layer, and the SPCE signal from the fluorophore-labeled anti-rabbit antibody, binding to the immobilized antigen, was detected. The effect of the sample matrix (buffer, human serum, or human whole blood) on the end-point immunoassay SPCE signal was studied. It was demonstrated that the kinetics of binding could be monitored directly in whole blood or serum. The results showed that human serum and human whole blood attenuate the SPCE end-point signal and the immunoassay kinetic signal only approximately two- and threefold, respectively, as compared with buffer, resulting in signals that are easily detectable even in whole blood. The high optical absorption of the hemoglobin can be tolerated because only fluorophores within a couple of hundred nanometers from the metallic film contribute to SPCE. Excited fluorophores outside the 200-nm layer do not contribute to SPCE, and their free space emission is not transmitted through the opaque metallic film into the glass substrate. We believe that SPCE has the potential of becoming a powerful approach for performing immunoassays based on surface-bound analytes or antibodies for many biomarkers directly in dense samples such as whole blood with no need for washing steps.

Animals↗

Spectroscopic characterization of the EF-hand domain of phospholipase C delta1: identification of a lipid interacting domain.

The interaction of the isolated EF-hand domain of phospholipase C delta1 with arachidonic acid (AA) was characterized using circular dichroism (CD) and fluorescence spectroscopy. The far-UV CD spectral changes indicate that AA binds to the EF domain. The near-UV CD spectra suggest that the orientations of aromatic residues in the peptide are affected when AA binds to the protein. The fluorescence of the single intrinsic tryptophan located in EF1 was enhanced by the addition of dodecylmaltoside (DDM) and AA suggesting that this region of the protein is involved in hydrophobic interactions. In the presence of a low concentration of DDM it was found that AA induced a change in fluorescence resonance energy transfer, which is indicative of a conformational change. The lipid induced conformational change may play a role in calcium binding because the isolated EF-hand domain did not bind Ca2+ in the absence of lipids, but Ca2+-dependent changes in the intrinsic tryptophan emission were observed when free fatty acids were present. These studies identify specific EF-hand domains as allosteric regulatory domains that require hydrophobic ligands such as lipids.

Amino Acid Sequence↗

Plasmonic technology: novel approach to ultrasensitive immunoassays.

At the Center for Fluorescence Spectroscopy, we have taken advantage of the favorable properties of surface plasmon-coupled emission (SPCE) to improve fluorescence-based immunoassays. SPCE occurs when excited fluorophores near conducting metallic structures efficiently couple to surface plasmons. These surface plasmons, appearing as free electron oscillations in the metallic layer, produce electromagnetic radiation that preserves the spectral properties of fluorophores but is highly polarized and directional. SPCE immunoassays provide several advantages over other fluorescence-based methods. This review explains new approaches to fluorescence immunoassays, including our own use of SPCE for simultaneous detection of more than one fluorescent marker and performance of immunoassays in the presence of an optically dense medium, such as whole blood.

Humans↗

Two-photon induced fluorescence of Cy5-DNA in buffer solution and on silver island films.

We report the observation of a strong two-photon induced fluorescence emission of Cy5-DNA within the tunable range of a Ti:Sapphire laser. The estimated two-photon cross-section for Cy5-DNA of 400GM is about 3.5-fold higher than it was reported for rhodamine B. The fundamental anisotropies of Cy5-DNA are close to the theoretical limits of 2/5 and 4/7 for one- and two-photon excitation, respectively. We also observed an enhanced two-photon induced fluorescence (TPIF) of Cy5-DNA deposited on silver island films (SIFs). In the presence of SIFs, the TPIF is about 100-fold brighter. The brightness increase of Cy5-DNA TPIF near SIFs is mostly due to enhanced local field.

Buffers↗

Surface-plasmon-coupled emission of quantum dots.

We studied surface plasmon-coupled emission (SPCE) of semiconductor quantum dots (QDs). These QDs are water-soluble ZnS-capped CdSe nanoparticles stabilized using lysine cross-linked mercaptoundecanoic acid. The QDs were spin-coated from 0.75% PVA solution on a glass slide covered with 50 nm of silver and a 5-nm protective SiO(2) layer. Excited QDs induced surface plasmons in a thin silver layer. Surface plasmons emitted a hollow cone of radiation into an attached hemispherical glass prism at a narrow angle of 48.5 degrees. This directional radiation (SPCE) preserves the spectral properties of QD emission and is highly p-polarized irrespective of the excitation polarization. The SPCE spectrum depends on the observation angle because of the intrinsic dispersive properties of SPCE phenomenon. The remarkable photostability can make QDs superior to organic fluorophores when long exposure to the intense excitation is needed. The nanosize QDs also introduce a roughness near the metal layer, which results in a many-fold increase of the coupling of the incident light to the surface plasmons. This scattered incident illumination transformed into directional, polarized radiation can be used simultaneously with SPCE to develop devices based on both quantum dot emission and light scattered from surface plasmons on a rough surface.

Cadmium Compounds↗

A conformational change in the eukaryotic translation preinitiation complex and release of eIF1 signal recognition of the start codon.

During eukaryotic translation initiation, ribosomal 43S complexes scan mRNAs for the correct AUG codon at which to begin translation. Start codon recognition triggers GTP hydrolysis, committing the complex to engagement at that point on the mRNA. While fidelity at this step is essential, the nature of the codon recognition event and the mechanism by which it activates GTP hydrolysis are poorly understood. Here we report the changes that occur within the 43S.mRNA complex in response to AUG codon recognition. eIF1 and eIF1A are key players in assembly of 43S.mRNA complexes capable of locating initiation codons. We observed FRET between these two factors when bound to the 40S subunit. Using steady-state FRET, anisotropy, and kinetic analyses, we demonstrate that start codon recognition results in a conformational change and release of eIF1 from the ribosome. These rearrangements probably play a role in triggering GTP hydrolysis and committing the complex to downstream events.

Codon, Initiator↗

Plastic versus glass support for an immunoassay on metal-coated surfaces in optically dense samples utilizing directional surface plasmon-coupled emission.

We compared plastic (polycarbonate) and high-quality glass support materials for gold-coated slides, when performing a model immunoassay against rabbit IgG using fluorescently labeled (AlexaFluor-647) anti-rabbit IgG, and detecting surface plasmon-coupled emission (SPCE) signals. Both, glass and plastic slides were simultaneously coated with a 48-nm layer of gold and protected with a 10-nm layer of silica. The maximum SPCE signal of AlexaFluor-647 was only two- to three-fold smaller on plastic slides than on glass slides. A small difference in the SPCE angles on glass (theta (F) = 55 degrees ) and plastic (theta (F) = 52.5 degrees ) slides was observed and can be explained with a slightly smaller refractive index of the plastic. We have not found any difference in the angle distribution (sharpness of the fluorescence signal at optimal SPCE angle) for the plastic slide compared to the glass slide. The kinetics of binding was monitored on the plastic slide as well as on the glass slide. Optically dense samples, a 4% red blood cell suspension and a 15% hemoglobin solution, are causing a reduction in the immunoassay SPCE signal by approximately 15% and three times, respectively, and the percentage of the reduction is the same for plastic and for glass slides. We believe that plastic substrates can be readily used in any SPCE assay, with only marginally lower total signal compared to high-quality glass slides.

Animals↗

Myoglobin immunoassay based on metal particle-enhanced fluorescence.

Enhanced fluorescence on silver island films (SIFs) is utilized to develop a sandwich-format immunoassay for the cardiac marker myoglobin (Myo). Myoglobin was first captured on surfaces coated with anti-Myo antibodies; the surface was then incubated with fluorescently labeled anti-Myo antibodies. The system was examined on glass surfaces and on SIFs. We observed the enhancement of the signal from SIFs in the range of 10-15-fold if compared to the signal from the glass substrate not modified with a SIF. A kinetic immunoassay for Myo on SIF-modified surface results in a decreased background signal. The initial results show that it is possible to detect Myoglobin concentrations below 50 ng/mL, which is lower than clinical cut-off for Myoglobin in healthy patients. We suggest the use of SIF-modified substrates for increasing the sensitivity of surface assays with fluorescence detection.

Antibodies, Monoclonal↗

Metal-enhanced fluorescence immunoassays using total internal reflection and silver island-coated surfaces.

We present a generic immunoassay platform that uses enhanced total internal reflection fluorescence in the proximity of silver island films (SIFs), a surface coating consisting of metal (silver) particles. This platform is used with a model immunoassay where a protein antigen, rabbit immunoglobulin G, was immobilized on the SIF-coated glass surface. The signal from a fluorescent dye-labeled anti-rabbit antibody binding to the surface antigen was detected; different color dyes have been tested. Close placement of the fluorophore to surface-bound silver nanostructures results in dramatic signal enhancement (up to 40-fold) on the SIFs as compared with the glass slides. Use of the total internal reflection mode of excitation has significant advantages (over classic front-face excitation) for practical assay development. The limited evanescent wave excitation volume makes it possible to minimize the background signal and use the immunoassay with no need for any washing steps.

Antibodies↗

Myoglobin immunoassay utilizing directional surface plasmon-coupled emission.

We described an immunoassay for the cardiac marker myoglobin on a thin silver mirror surface using surface plasmon-coupled emission (SPCE). SPCE occurs for fluorophores in proximity (within approximately 200 nm) of a thin metal film (in our case, silver) and results in a highly directional radiation through a glass substrate at a well-defined angle from the normal axis. We used the effect of SPCE to develop a myoglobin immunoassay on the silver mirror surface deposited on a glass substrate. Binding of the labeled anti-myoglobin antibodies led to the enhanced fluorescence emission at a specific angle of 72 degrees . The directional and enhanced directional fluorescence emission enables detection of myoglobin over a wide range of concentrations from subnormal to the elevated level of this cardiac marker. Utilizing SPCE allowed us also to demonstrate significant background suppression (from serum or whole blood) in the myoglobin immunoassay. We expect SPCE to become a powerful technique for performing immunoassays for many biomarkers in surface-bound assays.

Immunoassay↗

Ultrabright fluorescein-labeled antibodies near silver metallic surfaces.

Fluorescein-labeled antibodies are widely used in clinical assays and fluorescence microscopy. The fluorescent signal per labeled antibody is limited by fluorescein self-quenching, which occurs when the antibody is heavily labeled with multiple fluoresceins. We examined immunoglobulin G (IgG) when labeled with 0.7 to about 30 fluoresceins per antibody molecule. The extent of self-quenching was decreased, and the signal increased, when the labeled antibody was in close proximity to metallic silver particles. Time-resolved measurements showed that the intensity increase was due in part to a silver-induced increase in the radiative decay rate. These results suggest the use of labeled antibodies conjugated to silver particles as ultrabright probes for imaging or analytical applications.

Antibodies↗

Ultraviolet surface plasmon-coupled emission using thin aluminum films.

Surface plasmon-coupled emission (SPCE) is the directional radiation of light into a substrate due to excited fluorophores above a thin metal film. To date, SPCE has only been observed with visible wavelengths using silver or gold films. We now show that SPCE can be observed in the ultraviolet region of the spectrum using thin (20 nm) aluminum films. We observed directional emission in a quartz substrate from the DNA base analogue 2-aminopurine (2-AP). The SPCE radiation occurs within a narrow angle at 59 degrees from the normal to the hemicylindrical prism. The excitation conditions precluded the creation of surface plasmons by the incident light. The directional emission at 59 degrees is almost completely p-polarized, consistent with its origin from surface plasmons due to coupling of excited 2-AP with the aluminum. The emission spectra and lifetimes of the SPCE are those characteristic of 2-AP. Different emission wavelengths radiate at slightly different angles on the prism providing intrinsic spectral resolution from the aluminum film. These results indicate that SPCE can be used with numerous UV-absorbing fluorophores, suggesting biochemical applications with simultaneous surface plasmon resonance and SPCE binding assays.

2-Aminopurine↗