Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.

Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture.

Correction of precursor and product ion relative abundances in order to standardize CID spectra and improve Ecom accuracy for non-targeted metabolomics.

Quantitative biases in the abundance of precursor and product ions due to mass discrimination in RF-only ion guides results in inaccurate collision induced dissociation (CID) spectra. We evaluated the effects of collision cell RF voltage and collision energy on CID spectra using ten singly protonated compounds (46-854 Da) in an orthogonal acceleration time-of-flight mass spectrometer. The relative ion transfer efficiency, i.

Comprehensive bioimaging with fluorinated nanoparticles using breathable liquids.

Fluorocarbons are lipophobic and non-polar molecules that exhibit remarkable biocompatibility, with applications in liquid ventilation and synthetic blood. The unique properties of these compounds have also enabled mass spectrometry imaging of tissues where the fluorocarbons act as a Teflon-like coating for nanostructured surfaces to assist in desorption/ionization. Here we report fluorinated gold nanoparticles (f-AuNPs) designed to facilitate nanostructure imaging mass spectrometry.

Heat shock protein-90 inhibitors enhance antigen expression on melanomas and increase T cell recognition of tumor cells.

In an effort to enhance antigen-specific T cell recognition of cancer cells, we have examined numerous modulators of antigen-expression. In this report we demonstrate that twelve different Hsp90 inhibitors (iHsp90) share the ability to increase the expression of differentiation antigens and MHC Class I antigens. These iHsp90 are active in several molecular and cellular assays on a series of tumor cell lines, including eleven human melanomas, a murine B16 melanoma, and two human glioma-derived cell lines.

Photosynthetic and morphological acclimation of seedlings of tropical lianas to changes in the light environment.

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Premise Of The Study: Few studies have analyzed the physiological performance of different life stages and the expression of ontogenetic niche shifts in lianas. Here, we analyzed the photosynthetic and morphological acclimation of seedlings of Stigmaphyllon lindenianum, Combretum fruticosum, and Bonamia trichantha to distinctive light conditions in a tropical dry forest and compared their response with the acclimation response of adult canopy lianas of the same species. We expected acclimation to occur faster through changes in leaf photochemistry relative to adaptation in morphology, consistent with the life history strategies of these lianas.

Demographic variation across successional stages and their effects on the population dynamics of the neotropical palm Euterpe precatoria.

• Premise of the study: Environmental heterogeneity is a strong selective force shaping adaptation and population dynamics across temporal and spatial scales. Natural and anthropogenic gradients influence the variation of environmental and biotic factors, which determine population demography and dynamics. Successional gradients are expected to influence demographic parameters, but the relationship between these gradients and the species life history, habitat requirements, and degree of variation in demographic traits remains elusive.

Detection of genetic variations in coagulopathy-related genes using ramified rolling circle amplification.

We evaluated single nucleotide polymorphism (SNP) detection via a target-capture, C-probe ligation, and RAM assay in a single-blind comparison to clinical samples that had been tested with FDA-cleared tests for up to 4 different vascular disease-related SNPs. In the RAM assay circulizable linear probes (C- or padlock probes) were annealed directly to genomic DNA, processed on a largely automated platform, and ligated C-probes were amplified by real-time RAM. After allele determinations were made with the experimental system, the sample genotypes were unblinded and the experimentally determined genotypes were found to be completely consistent with the FDA-cleared test results.

Are molecular alphabets universal enabling factors for the evolution of complex life?

Terrestrial biosystems depend on macromolecules, and this feature is often considered as a likely universal aspect of life. While opinions differ regarding the importance of small-molecule systems in abiogenesis, escalating biological functional demands are linked with increasing complexity in key molecules participating in biosystem operations, and many such requirements cannot be efficiently mediated by relatively small compounds. It has long been recognized that known life is associated with the evolution of two distinct molecular alphabets (nucleic acid and protein), specific sequence combinations of which serve as informational and functional polymers.

Near instrument-free, simple molecular device for rapid detection of herpes simplex viruses.

The first near instrument-free, inexpensive and simple molecular diagnostic device (IsoAmp HSV, BioHelix Corp., MA, USA) recently received US FDA clearance for use in the detection of herpes simplex viruses (HSV) in genital and oral lesion specimens. The IsoAmp HSV assay uses isothermal helicase-dependent amplification in combination with a disposable, hermetically-sealed, vertical-flow strip identification.

Pleiotropic effects of calcium channel blockers.

Clinical trials have reported reduced cardiovascular events with certain antihypertensive agents at a rate that could not be predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by pleiotropic effects of these agents and modulation of central blood pressures. This review focuses on the mechanisms by which calcium channel blockers exert pleiotropic effects, both alone and in combination with statins and inhibitors of the renin-angiotensin system.

Silicon photodiodes with high photoconductive gain at room temperature.

Silicon photodiodes with high photoconductive gain are demonstrated. The photodiodes are fabricated in a complementary metal-oxide-semiconductor (CMOS)-compatible process. The typical room temperature responsivity at 940 nm is >20 A/W and the dark current density is ≈ 100 nA/cm2 at 5 V reverse bias, yielding a detectivity of ≈ 10(14) Jones.

An UPLC-ESI-MS/MS Assay Using 6-Aminoquinolyl-N-Hydroxysuccinimidyl Carbamate Derivatization for Targeted Amino Acid Analysis: Application to Screening of Arabidopsis thaliana Mutants.

In spite of the large arsenal of methodologies developed for amino acid assessment in complex matrices, their implementation in metabolomics studies involving wide-ranging mutant screening is hampered by their lack of high-throughput, sensitivity, reproducibility, and/or wide dynamic range. In response to the challenge of developing amino acid analysis methods that satisfy the criteria required for metabolomic studies, improved reverse-phase high-performance liquid chromatography-mass spectrometry (RPHPLC-MS) methods have been recently reported for large-scale screening of metabolic phenotypes. However, these methods focus on the direct analysis of underivatized amino acids and, therefore, problems associated with insufficient retention and resolution are observed due to the hydrophilic nature of amino acids.

RNA templating of molecular assembly and covalent modification patterning in early molecular evolution and modern biosystems.

The Direct RNA Template (DRT) hypothesis proposes that an early stage of genetic code evolution involved RNA molecules acting as stereochemical recognition templates for assembly of specific amino acids in sequence-ordered arrays, providing a framework for directed covalent peptide bond formation. It is hypothesized here that modern biological precedents may exist for RNA-based structural templating with functional analogies to hypothetical DRT systems. Beyond covalent molecular assembly, an extension of the DRT concept can include RNA molecules acting as dynamic structural template guides for the specific non-covalent assembly of multi-subunit complexes, equivalent to structural assembly chaperones.

Glucose promotes membrane cholesterol crystalline domain formation by lipid peroxidation.

Oxidative damage to vascular cell membrane phospholipids causes physicochemical changes in membrane structure and lipid organization, contributing to atherogenesis. Oxidative stress combined with hyperglycemia has been shown to further increase the risk of vascular and metabolic diseases. In this study, the effects of glucose on oxidative stress-induced cholesterol domain formation were tested in model membranes containing polyunsaturated fatty acids and physiologic levels of cholesterol.

Bacterial glycosidases for the production of universal red blood cells.

Enzymatic removal of blood group ABO antigens to develop universal red blood cells (RBCs) was a pioneering vision originally proposed more than 25 years ago. Although the feasibility of this approach was demonstrated in clinical trials for group B RBCs, a major obstacle in translating this technology to clinical practice has been the lack of efficient glycosidase enzymes. Here we report two bacterial glycosidase gene families that provide enzymes capable of efficient removal of A and B antigens at neutral pH with low consumption of recombinant enzymes.

Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis.

The biological benefits of certain carotenoids may be due to their potent antioxidant properties attributed to specific physico-chemical interactions with membranes. To test this hypothesis, we measured the effects of various carotenoids on rates of lipid peroxidation and correlated these findings with their membrane interactions, as determined by small angle X-ray diffraction approaches. The effects of the homochiral carotenoids (astaxanthin, zeaxanthin, lutein, beta-carotene, lycopene) on lipid hydroperoxide (LOOH) generation were evaluated in membranes enriched with polyunsaturated fatty acids.

Analysis of gene ontology features in microarray data using the Proteome BioKnowledge Library.

Microarray technology has resulted in an explosion of complex, valuable data. Integrating data analysis tools with a comprehensive underlying database would allow efficient identification of common properties among differentially regulated genes. In this study we sought to compare the utility of various databases in microarray analysis.

Cerebrospinal fluid may mediate CNS ischemic injury.

Background: The central nervous system (CNS) is extremely vulnerable to ischemic injury. The details underlying this susceptibility are not completely understood. Since the CNS is surrounded by cerebrospinal fluid (CSF) that contains a low concentration of plasma protein, we examined the effect of changing the CSF in the evolution of CNS injury during ischemic insult.

Evaluation of CML model cell lines and imatinib mesylate response: determinants of signaling profiles.

Our understanding of the mechanisms by which BCR-ABL drives CML is based, in part, on the use of model cell lines such as the K562 cell line. However, the BCR-ABL translocation may occur via a number of different junction points. In addition, CML is a disease of hematopoietic stem cells and, as a result, can give rise to multiple lineages of tumor cells.

Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone.

Novel indeno[1,2-c]isoquinolinone derivatives were synthesized and evaluated as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). These potent nonmutagenic PARP-1 inhibitors possess an additional five-membered ring between the B and C rings of 6(5H)-phenanthridinone. The most potent PARP-1 inhibitors were obtained from the substitution of the D ring at the C-9 position, in particular sulfonamide and N-acyl analogues (6 and 11).

Roles of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and its complications.

Activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of beta-cell necrosis that occurs in response to autoimmune disease associated with Type I diabetes. In addition, PARP activation also plays a role in the pathogenesis of endothelial injury that underlies the ethiology of various diabetic complications (vasculopathy, cardiomyopathy, retinopathy, neuropathy), which develop on the basis of chronically elevated circulating glucose levels in diabetes. Both during the pathogenesis of diabetes and during the pathogenesis of diabetic complications, free radical and oxidant production leads to DNA strand-breakage which activates the nuclear enzyme PARP and initiates an energy consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors.

Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors.

Poly(ADP-ribose) polymerases (PARPs) are involved in the regulation of many cellular functions. Three consequences of the activation of PARP1, which is the main isoform of the PARP family, are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of pro-inflammatory genes. Consequently, pharmacological inhibitors of PARP have the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce parenchymal cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications).

Facile and convenient syntheses of 6,11-dihydro-5H-indeno[1,2-c]isoquinolin- 5-ones and 6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-one.

[reaction: see text] The synthesis of 6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-ones from the base-promoted condensation reaction of homophthalic anhydride and 2-(bromomethyl)-benzonitrile and a convenient method for the synthesis of indolo[3,2-c]isoquinolinones are described.

Cytokines stimulate expression of inducible nitric oxide synthase in DLD-1 human adenocarcinoma cells by activating poly(A) polymerase.

Objective: The stimulation of epithelial cells by cytokines or lipopolysaccharide results in a marked increase in cellular mRNA and protein levels of inducible nitric oxide synthase (iNOS) disproportionate to the small upregulation in transcriptional activity. The molecular mechanisms by which cytokines increase iNOS expression are not well characterized.

Methods: DLD-1 cells were treated with cytokines and we studied the expression patterns of various genes by using western blot analysis and RT-PCR assay method.