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At least 1,387 records · Page 77Linked to original sources
PubMed2001

Characterization of a DNA-cleaving deoxyribozyme.

A copper-dependent self-cleaving DNA that was isolated by in vitro selection has been minimized to its smallest active domain using both in vitro selection and rational design methods. The minimized 46-nucleotide deoxyribozyme forms duplex and triplex substructures that flank a highly conserved catalytic core. This self-cleaving construct can be converted into a bimolecular complex that comprises separate substrate and enzyme domains. Substrate cleavage is directed at one of two adjacent nucleotides and proceeds via an oxidative cleavage mechanism that is unique to the position cleaved. The structural, kinetic and mechanistic characteristics of this DNA-cleaving deoxyribozyme are reported.

Base Sequence↗
PubMedDate not supplied

Molecular diversity in chemical databases: comparison of medicinal chemistry knowledge bases and databases of commercially available compounds.

A molecular descriptor space has been developed which describes structural diversity. Large databases of molecules have been mapped into it and compared. This analysis used five chemical databases, CMC and MDDR, which represent knowledge bases containing active medicinal agents, ACD and SPECS, two databases of commercially available compounds, and finally the Wellcome Registry. Together these databases contained more than 300,000 structures. Topological indices and the free energy of solvation were computed for each compound in the databases. Factor analysis was used to reduce the dimensionality of the descriptor space. Low density observations were deleted as a way of removing outliers, which allowed a further reduction in the descriptor space of interest. The five databases could then be compared on an efficient basis using a metric developed for this purpose. A Riemann gridding scheme was used to subdivide the factor space into subhypercubes to obtain accurate comparisons. Most of the 300,000 structures were highly clustered, but unique structures were found. An analysis of overlap between the biological and commercial databases was carried out. The metric provides a useful algorithm for choosing screening sets of diverse compounds from large databases.

Artificial Intelligence↗
PubMed2003

Changes in green coffee protein profiles during roasting.

To reveal its flavor, coffee has to be roasted. In fact, the green coffee bean contains all ingredients necessary for the later development of coffee flavor. It is now widely accepted that free amino acids and peptides are required for the generation of coffee aroma. However, the mechanisms leading to defined mixtures of free amino acids and peptides remain unknown. Information pertaining to the identification of precursor proteins is also lacking. To answer some of these questions, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) was used to follow the fate of green coffee proteins. Two conditions were considered: roasting and incubation of green coffee suspensions at 37 degrees C. Coffee beans were observed to acquire the potential to spontaneously release H(2)O(2) upon polymerization of their proteins during roasting. Fragmentation of proteins was also observed. Conversely, H(2)O(2) was found to control polymerization and fragmentation of green coffee proteins in solution at 37 degrees C. Polymerization and fragmentation patterns under the two conditions were comparable. These observations suggest that the two conditions under study triggered, at least to some extent, similar biochemical mechanisms involving autoxidation. Throughout this study, a unique fragmentation cascade involving the 11S coffee storage protein was identified. Generated fragments shared an atypical staining behavior linked to their sensitivity to redox conditions.

Coffea↗
PubMed2006

Evaluation of toxicological monitoring markers using proteomic analysis in rats exposed to formaldehyde.

Formaldehyde (FA) is known as a low molecule weight organic compound and one of major components that causes sick building syndrome (SBS), and it has been reported that FA has cytotoxic, hemotoxic, immunotoxic, and genotoxic properties. The International Agency for Research on Cancer (IARC) has characterized FA as a carcinogen. In this study, we investigated the effects of FA on rat plasma proteins by using proteomic approach. Rats were exposed to three different concentrations of FA (0, 5, 10 ppm) for 2 weeks at 6 hours/day and 5 days/week in an inhalation chamber. Malondialdehyde (MDA) assay and carbonyl spectrometric assay were conducted to determine lipid peroxidation and protein oxidation levels and Comet assays were used for genotoxicity evaluation. Level of MDA, carbonyl insertion and DNA damage in plasma, livers, and in the lymphocytes of rats exposed to FA were found to be dose dependently increased. Proteomic analysis using three different pI ranges (3.5-5.6, 5.3-6.9, 6-9) and large size two-dimensional gel electrophoresis (2-DE) showed the presence of 3491 protein spots. A total of 32 (19 up- and 13 down-regulated) proteins were identified as biomarkers of FA, all showed dose dependent expressions in the plasma of rats exposed to FA and of these, 27 protein spots were identified by MALDI-TOF/MS. Several differentiated protein groups were found. Proteins involved in apoptosis, transportation, signaling, energy metabolism, and cell structure and motility were found to be up- or down-regulated. Among these, the identities of SNAP 23, apolipoprotein A-1 and E, clusterin, kinesin, and fibrinogen gamma were confirmed by Western blot assay, and apo E was further analyzed by using 2-DE immunoblot assays to determine isoform patterns. Two cytokine including IL4 and INF-gamma were measured in plasma with respect to fibrinogen gamma changes. In summary, cytotoxicity, and genotoxicity assays, namely MDA lipid peroxidation assay, the carbonyl protein oxidation assay, and Comet genotoxic assay showed that these effects increased on increasing FA levels. Proteomic analysis with three different pI ranges and long size 2-DE gel electrophoresis showed that 32 protein spots were up-or down-regulated. Of these 32 proteins, 7 proteins were confirmed by western blot assay. They could be potential biomarkers for human diseases associated with FA exposure.

Administration, Inhalation↗
PubMed2003

Volterra series in pharmacokinetics and pharmacodynamics.

Nonparametric black-box modeling has a long successful history of applications in pharmacokinetics (PK) (notably in deconvolution), but is rarely used in pharmacodynamics (PD). The main reason is associated with the fact that PK systems are often linear in respect to drug inputs, while the reverse is true for many PK/PD systems. In the PK/PD field existing non-parametric methods can deal with linear systems, but they cannot describe non-linear systems. Our purpose is to describe a novel implementation of a general nonparametric model which can represent non-linear systems, and in particular non-linear PK/PD systems, The model is based on a Volterra series, which is an integral series expansion of the response of a system in terms of its kernels and the inputs to the system. In PK we are familiar with the first term of the Volterra series, the convolution of the first kernel of the system (the so-called PK disposition function) with drug input rates. The main advantages of higher order Volterra representations is that they are general representations and can be used to describe and predict the response of an arbitrary (PK/ PD) system without any prior knowledge on the structure of the system. The main problem of the representation is that in a non-parametric representation of the kernels the number of parameters to be estimated grows geometrically with the order of the kernel. We developed a method to estimate the kernels in a Volterra-series which overcomes this problem. The method (i) is fully non-parametric (the kernels are represented using multivariate splines), (ii) is maximum-likelihood based, (iii) is adaptive (the order of the series and the dimensionality of each kernel is selected by the method), and (iv) allows for non-equispaced observations (thus allowing a reduction of the number of parameters in the representation, and the analysis of, e.g., PK/PD observations). The method is based on an adaptation of Friedmans's Multivariate Adaptive Regression Spline method. Examples demonstrate the possible application of the approach to the analysis of different PK/PD systems.

Algorithms↗
PubMed1998

Evaluation of optic disc cupping using high-resolution ocular ultrasound.

BACKGROUND/PURPOSE: The new Biovision B-Scan Probe has greater resolution than its predecessors because of its posteriorly placed focus (25 mm inside the eye) and the consequent reduction in size of the sound field. We investigated the accuracy, reproducibility and test-retest variability of two-dimensional optic cup measurements using this new-generation B-scanner. METHODS: One randomly selected eye of 20 patients underwent five repeated measurements of vertical (VOCD) and horizontal optic cup diameters (HOCD), and optic cup depth, using confocal scanning laser tomography (Heidelberg Retinal Tomograph) and high-resolution ultrasound (Biovision, Chiron Vision, UK) on two separate occasions. There was one operator per instrument who was masked to all clinical data and previous measurements. Accuracy of ultrasound readings was quantified by comparing the results with those of Heidelberg Retinal Tomography (HRT). RESULTS: The 95% confidence interval for the bias of echographic vertical and horizontal cup diameter measurements was -95 +/- 48 microns and -19 +/- 72 microns respectively, and -87 +/- 328 microns for cup depth readings. The indices of reproducibility (mean coefficient of repeatability +/- SD) were: VOCD: 177 +/- 105 microns [B-scan] 209 +/- 100 microns [HRT]; HOCD: 179 +/- 61 microns [B-scan], 205 +/- 101 microns [HRT]; cup depth: 206 +/- 63 microns [B-scan], 204 +/- 124 microns [HRT]. Ninety-five per cent limits of agreements between initial and retest values for ultrasound were 18 +/- 136 microns [VOCD], 2 +/- 144 microns [HOCD] and 4 +/- 156 microns [cup depth], compared with 1 +/- 104 microns [VOCD], 20 +/- 102 microns [HOCD] and 3 +/- 168 microns [cup depth] for scanning laser tomography. CONCLUSION: The results demonstrate that measurements of optic cup diameter and depth using ultrasound correlate strongly with corresponding HRT readings. These echographic measurements are reproducible, and not subject to clinically meaningful test-retest variability. This technique of measuring two-dimensional cup parameters does not require expensive specialist equipment and has many potential clinical applications which are discussed.

Aged↗
PubMed2004

Selectivity of protein carbonylation in the apoptotic response to oxidative stress associated with photodynamic therapy: a cell biochemical and proteomic investigation.

We previously reported that photodynamic therapy (PDT) using Purpurin-18 (Pu-18) induces apoptosis in HL60 cells. Using flow cytometry, two-dimensional electrophoresis coupled with immunodetection of carbonylated proteins and mass spectrometry, we now show that PDT-induced apoptosis is associated with increased reactive oxygen species generation, glutathione depletion, changes in mitochondrial transmembrane potential, simultaneous downregulation of mitofilin and carbonylation of specific proteins: glucose-regulated protein-78, heat-shock protein 60, heat-shock protein cognate 71, phosphate disulphide isomerase, calreticulin, beta-actin, tubulin-alpha-1-chain and enolase-alpha. Interestingly, all carbonylated proteins except calreticulin and enolase-alpha showed a pI shift in the proteome maps. Our results suggest that PDT with Pu-18 perturbs the normal redox balance and shifts HL60 cells into a state of oxidative stress, which systematically induces the carbonylation of specific chaperones. As these proteins normally produce a prosurvival signal during oxidative stress, we hypothesize that their carbonylation represents a signalling mechanism for apoptosis induced by PDT.

Actins↗
PubMed2004

Assembly modulates dissociation: electrokinetic experiments reveal peculiarities of the charge formation at monolayer films.

Self-assembled monomolecular films of alkanethiols chemisorbed on gold were used as a two-dimensional model system to study the effects of spatial confinement of surface functional groups on their acid-base behaviour; reduction of the surface charge density by mixed assemblies revealed an increase of the acidity of carboxy groups; surfaces with low amounts of charged groups show the interplay of dissociation of functional groups and preferential adsorption of ions in terms of surface charge formation.

Journal Article↗
PubMed2002

Fibre-optic two-photon scanning fluorescence microscopy.

Two geometries of a novel two-photon fluorescence microscope incorporating single-mode fibre optics for the delivery of ultrashort-pulsed illumination to a remote sample are characterized. First, a 785 nm single-mode optical fibre is implemented in a scanning microscope, which demonstrates that an improvement in axial resolution is achieved due to the non-linear response of the fibre to intense ultrashort-pulsed light. Second, a 785 nm single-mode optical fibre coupler is adapted, in which case spectral broadening and blue shifting of the ultrashort-pulsed laser beam caused by the non-linear response of the fibre to ultrashort-pulsed illumination are experimentally characterized. An investigation into the impact of temporal broadening of the ultrashort-pulsed beam on the systems is also considered. The coupling efficiency of both geometries for various illumination wavelengths is also presented. The introduction of the fibre coupler to the system has significant advantages, including an improved optical sectioning effect and a reduction in the number of bulk optical components resulting in a low-cost, compact instrument. Sets of three-dimensional images of fluorescent polymer microspheres and biological material confirm these features.

Eukaryota↗
PubMed1976

[Ultrasound examination in obstructive biliary disease (author's transl)].

Ultrasound examination with a two-dimensional recording technique has proved increasingly useful in obstructive biliary disease and in abnormalities of the liver parenchyma causing a reduction in biliary contrast excretion. In particular, hydrops of the gall bladder, cholelithiasis and choledocholithiasis and choledocholithiasis can be demonstrated where there is biliary obstruction. Analysis of various planes of section is particularly useful in showing obstruction due to the head of the pancreas. The introduction of grey scale techniques and focussed transducers of various frequencies and sizes, suggests that there will be further improvements in the sonographic diagnosis of the hilum of the liver and of the intrahepatic biliary passages.

Adult↗
PubMed2006

Distinct metastable atmospheric regimes despite nearly Gaussian statistics: a paradigm model.

A controversial topic in the recent climate modeling literature is the fashion in which metastable low-frequency regimes in the atmosphere occur despite nearly Gaussian statistics for these planetary waves. Here a simple 57-mode paradigm model for such metastable atmospheric regime behavior is introduced and analyzed through hidden Markov model (HMM) analysis of the time series of suitable low-frequency planetary waves. The analysis of this paradigm model elucidates how statistically significant metastable regime transitions between blocked and zonal statistical states occur despite nearly Gaussian behavior in the associated probability distribution function and without a significant role for the low-order truncated nonlinear dynamics alone; turbulent backscatter onto the three-dimensional subspace of low-frequency modes is responsible for these effects. It also is demonstrated that suitable stochastic mode reduction strategies, which include both augmented cubic nonlinearity and multiplicative noise, are also capable of capturing the metastable low-frequency regime behavior through a single stochastic differential equation compared with the full turbulent chaotic 57-mode model. This feature is attractive for issues such as long-term weather predictability. Although there have been many applications of HMM in other sciences, this work presents a previously undescribed application of HMM analysis to atmospheric low-frequency variability and points the way for further applications including their use in extended range predictability.

Journal Article↗
PubMed1999

Proteomic definition of normal human luminal and myoepithelial breast cells purified from reduction mammoplasties.

Normal human luminal and myoepithelial breast cells separately purified from a set of 10 reduction mammoplasties by using a double antibody magnetic affinity cell sorting and Dynabead immunomagnetic technique were used in two-dimensional gel proteome studies. A total of 43,302 proteins were detected across the 20 samples, and a master image for each cell type comprising a total of 1,738 unique proteins was derived. Differential analysis identified 170 proteins that were elevated 2-fold or more between the two breast cell types, and 51 of these were annotated by tandem mass spectrometry. Muscle-specific enzyme isoforms and contractile intermediate filaments including tropomyosin and smooth muscle (SM22) alpha protein were detected in the myoepithelial cells, and a large number of cytokeratin subclasses and isoforms characteristic of luminal cells were detected in this cell type. A further 134 nondifferentially regulated proteins were also annotated from the two breast cell types, making this the most extensive study to date of the protein expression map of the normal human breast and the basis for future studies of purified breast cancer cells.

Adult↗
PubMed2004

Classification using partial least squares with penalized logistic regression.

MOTIVATION: One important aspect of data-mining of microarray data is to discover the molecular variation among cancers. In microarray studies, the number n of samples is relatively small compared to the number p of genes per sample (usually in thousands). It is known that standard statistical methods in classification are efficient (i.e. in the present case, yield successful classifiers) particularly when n is (far) larger than p. This naturally calls for the use of a dimension reduction procedure together with the classification one. RESULTS: In this paper, the question of classification in such a high-dimensional setting is addressed. We view the classification problem as a regression one with few observations and many predictor variables. We propose a new method combining partial least squares (PLS) and Ridge penalized logistic regression. We review the existing methods based on PLS and/or penalized likelihood techniques, outline their interest in some cases and theoretically explain their sometimes poor behavior. Our procedure is compared with these other classifiers. The predictive performance of the resulting classification rule is illustrated on three data sets: Leukemia, Colon and Prostate.

Algorithms↗
PubMed1996

Analysis of protein carbonyls with 2,4-dinitrophenyl hydrazine and its antibodies by immunoblot in two-dimensional gel electrophoresis.

Protein carbonyls are reported to increase in aging and in pathologies such as Alzheimer's disease and ischemic injury. Detailed study of this important issue has, however, been hampered by lack of an appropriate method to identify individual carbonylated proteins. We describe here an immunoblot method to identify individual carbonylated proteins. We describe here an immunoblot method to investigate protein carbonyls reactive to 2,4-dinitrophenyl hydrazine. Rabbit polyclonal antibodies against 2,4-dinitrophenyl hydrazine were used to study the proteins derivatized by the reagent in one- or two-dimensional polyacrylamide gel electrophoresis followed by immunoblotting. More than 25 proteins with high carbonyl contents were clearly demonstrated in two-dimensional immunoblot of rat tissue soluble proteins. The method could detect concentrations as low as 1 pmol of carbonyls. The signals were mostly abolished by prior treatment of tissue proteins with sodium borohydride to reduce carbonyls. Fragments generated by V8 protease digestion of a single protein exhibited signal intensities of varying degrees, indicating that carbonylation is not uniform in different amino acid sequences. Proteins treated with glucose or aldehydes gave rise to positive signals, suggesting that the finding of carbonyls in tissue proteins is not necessarily an indication of direct oxidation of side chains of amino acid residues.

Acetaldehyde↗
PubMed1995

Three-dimensional magnetic resonance techniques for evaluating the cervical spine.

The general technique of three-dimensional magnetic resonance imaging is briefly described, as is a variety of specific three-dimensional sequences useful in the evaluation of spinal disease, particularly related to degenerative disc disease. Advantages of three-dimensional imaging include an increase in signal-to-noise ratio, thin contiguous slices, more accurate slice thickness, and a reduction in susceptibility artifacts. Computer post-processing allows reformatting of the data along any desired imaging plane, with minimal degradation in image quality.

Cervical Vertebrae↗
PubMed1997

Lumbar-hip flexion motion. A comparative study between asymptomatic and chronic low back pain in 18- to 36-year-old men.

STUDY DESIGN: The amount of lumbar and hip flexion and the relative contribution within movement during standing forward bending was recorded on a group of asymptomatic men and a group of men with a history of chronic low back pain. OBJECTIVES: To compare the relative contribution of the hip and lumbar spine to forward bending in the two groups. SUMMARY OF BACKGROUND DATA: The hips and lumbar spine both contribute to the forward bending motion, and an aberrant pattern of contribution in one or both regions could be related to the presence of chronic low back pain. METHODS: Thirty-two white men aged 18-36 years (15 with chronic low back pain and 17 asymptomatic) were assessed using a three-dimensional motion analysis system that allowed uninterrupted forward bending. RESULTS: The men with chronic low back pain demonstrated a significant reduction in the mean total range and mean maximum lumbar flexion relative to the asymptomatic group. Mean hip flexion was not significantly different. Data analysis for 120 degrees of gross flexion revealed a subgroup of men with chronic low back pain with a significant decrease in hip flexion. CONCLUSIONS: When assessing the relative motion of the lumbar spine and hips in standing forward flexion, there was measurable difference between asymptomatic men and a group of chronic low back pain patients. In particular, two subgroups of individuals with chronic low back pain appeared; one moved relatively similarly to the asymptomatic group, whereas the other sub-group demonstrated reduced hip mobility. These findings indicate the importance of assessing the lumbar and hip flexion motion in chronic low back pain patients to determine if a movement abnormality is present.

Adolescent↗
PubMed1999

Characterization of a vanillic acid non-oxidative decarboxylation gene cluster from Streptomyces sp. D7.

The genetics of non-oxidative decarboxylation of aromatic acids are poorly understood in both prokaryotes and eukaryotes. Although such reactions have been observed in numerous micro-organisms acting on a variety of substrates, the genes encoding enzymes responsible for these processes have not, to our knowledge, been reported in the literature. Here, the isolation of a streptomycete from soil (Streptomyces sp. D7) which efficiently converts 4-hydroxy-3-methoxybenzoic acid (vanillic acid) to 2-methoxyphenol (guaiacol) is described. Protein two-dimensional gel analysis revealed that several proteins were synthesized in response to vanillic acid. One of these was characterized by partial amino-terminal sequencing, leading to the cloning of a gene cluster from a genomic DNA lambda phage library, consisting of three ORFs, vdcB (602 bp), vdcC (1424 bp) and vdcD (239 bp). Protein sequence comparisons suggest that the product of vdcB (201 aa) is similar to phenylacrylate decarboxylase of yeast; the putative products of vdcC (475 aa) and vdcD (80 aa) are similar to hypothetical proteins of unknown function from various micro-organisms, and are found in a similar cluster in Bacillus subtilis. Northern blot analysis revealed the synthesis of a 2.5 kb mRNA transcript in vanillic-acid-induced cells, suggesting that the cluster is under the control of a single inducible promoter. Expression of the entire vdc gene cluster in Streptomyces lividans 1326 as a heterologous host resulted in that strain acquiring the ability to decarboxylate vanillic acid to guaiacol non-oxidatively. Both Streptomyces sp. strain D7 and recombinant S. lividans 1326 expressing the vdc gene cluster do not, however, decarboxylate structurally similar aromatic acids, suggesting that the system is specific for vanillic acid. This catabolic system may be useful as a component for pathway engineering research focused towards the production of valuable chemicals from forestry and agricultural by-products.

Amino Acid Sequence↗
PubMed2002

Structure of silica in matt water-based lacquer.

A model for the structure of silica matting agent in water-based lacquers is presented. It is assumed that, during film formation, the air that lies between the silica particles in the dry powder is replaced by polymer. At a critical concentration this leads to a silica structure similar to that of the dry powder. We assume the bulk volume occupied by the dry silica powder (silica and air) equals the dried lacquer film (polymer, silica, and residual air). Since the silica structure in the dry powder percolates, the silica in the dried lacquer is tested for percolation. Experimentally, a percolation threshold is found close to the critical concentration predicted by the model. Two further silica structures are also seen under different conditions. At low silica concentrations, the silica particles are suspended in the lacquer matrix and isolated. Above the percolation threshold, where the bulk volume of the dry silica exceeds that of the film, the silica structure can undergo collapse. This is caused by volume reduction in the lacquer as water evaporates. The lacquer is imaged with confocal laser scanning microscopy, to produce three-dimensional images of the bulk of the 50-microm film. Resolution is enhanced with image reconstruction via deconvolution. Computational image analysis is then used to investigate the structure quantitatively.

Journal Article↗