Distribution by Scientific Domains
Distribution within Chemistry

Kinds of Elucidation

  • complete elucidation
  • full elucidation
  • structural elucidation
  • structure elucidation

  • Selected Abstracts


    MING DONG GUArticle first published online: 15 NOV 200

    Glucose homeostasis and the gastrointestinal tract: insights into the treatment of diabetes

    D. Maggs
    The gastrointestinal tract is increasingly viewed as a critical organ in glucose metabolism because of its role in delivering glucose to the circulation and in secreting multiple glucoregulatory hormones that, in concert with insulin and glucagon, regulate glucose homeostasis. Under normal conditions, a complex interplay of these hormones acts to maintain plasma glucose within a narrow range despite large variations in the availability of glucose, particularly during transition from the fasting to fed state. In the fed state, the rate at which nutrients are passed from the stomach to the duodenum, termed gastric emptying rate, is a key determinant of postprandial glucose flux. In patients with diabetes, the regulation of glucose metabolism is disrupted resulting in fasting and postprandial hyperglycaemia. Elucidation of the role of the gastrointestinal tract, gut-derived glucoregulatory peptides and gastric emptying rate offers a new perspective on glucose homeostasis and the respective importance of these factors in the diabetes state. This review will highlight the importance of the gastrointestinal tract in playing a key role in glucose homeostasis, particularly in the postprandial period, and the role of established or new therapies that either leverage or modify gastrointestinal function to improve glycaemic state. [source]

    Role of mitogen-activated protein kinase cascades in P2Y receptor-mediated trophic activation of astroglial cells ,

    Joseph T. Neary
    Abstract The trophic actions of extracellular nucleotides and nucleosides on astroglial cells in the central nervous system may be important in development as well as injury and repair. Here we summarize recent findings on the signal transduction mechanisms and gene expression that mediate the trophic effects of extracellular ATP on astrocyte cultures, with a particular emphasis on mitogenesis. Activation of ATP/P2Y receptors leads to the stimulation of mitogen-activated protein kinase (MAPK) cascades, which play a crucial role in cellular proliferation, differentiation, and survival. Inhibition of ERK and p38, members of two distinct MAPK cascades, interferes with the ability of extracellular ATP to stimulate astrocyte proliferation, thereby indicating their importance in mitogenic signaling by P2Y receptors. Signaling from P2Y receptors to ERK involves phospholipase D and a calcium-independent protein kinase C isoform, PKC; this pathway is independent of the phosphatidylinositol-phospholipase C / calcium pathway which is also coupled to P2Y receptors. Pharmacological studies suggest that astrocytes may express an as-yet uncloned P2Y receptor that recruits a novel MEK activator in the ERK cascade. Extracellular ATP can also potentiate fibroblast growth factor (FGF)-2-induced proliferation, and studies on interactions between ATP and FGF-2 signaling pathways have revealed that although ATP does not activate cRaf-1, the first protein kinase in the ERK cascade, it can reduce cRaf-1 activation by FGF-2. As intermediate levels of Raf activity stimulate the cell cycle, the partial inhibition of FGF-induced Raf activity by ATP may contribute to the enhancing effect of ATP on FGF-2-induced astrocyte proliferation. Activation of P2Y receptors also leads to nuclear signaling, and the use of DNA arrays has shown that treatment of astrocytes with extracellular ATP results in the up- and downregulation of a number of genes; studies to determine which of these genes are regulated by MAPKs are now in progress. Elucidation of the components of MAPK pathways linked to P2Y receptors and subsequent changes in gene expression may provide targets for a new avenue of drug development aimed at the management of astrogliosis which occurs in many types of neurological disorders and neurodegeneration. Drug Dev. Res. 53:158,165, 2001. Published 2001 Wiley-Liss, Inc. [source]

    Complete Elucidation of Electrode Reaction Mechanisms by Using Differential Pulse Polarography

    ELECTROANALYSIS, Issue 17-18 2010
    Miguel, Rodríguez Mellado
    Abstract By exploring the different parameters of the technique, it is shown that Differential Pulse Polarography (DPP) can be used for the elucidation of the reaction mechanisms of the electrochemical processes (with the evident exception of the product and intermediate identification). So, the type of transport towards or from the electrode can be identified from the dependence of the intensities with the pulse amplitude, the electrochemical reaction order with respect to the electroactive species from the shape of the polarogram, the type of rate-determining step from the dependence of the peak potentials on the pulse duration, the electrochemical reaction order with respect to other species, such as the H+ion, from the dependence of the peak potentials on their concentrations etc. [source]

    Electrochemical Elucidation of the Facilitated Ion Transport Across a Bilayer Lipid Membrane in the Presence of Neutral Carrier Compounds

    ELECTROANALYSIS, Issue 11 2010
    Jun Onishi
    Abstract The ion transport facilitated by neutral carrier compounds (valinomycin, nonactin) has been investigated by cyclic voltammetry in the several electrolyte solutions (KF, KCl, KBr, KNO3, KSCN, KClO4), and we demonstrated the effect of the counter anions on the facilitated transport of K+ from the viewpoint of electroneutrality. Voltammograms for the ion transport were generated at steady state and the current density between W1 and W2, jW1,W2, increased with the absolute value of the applied membrane potential, EW1,W2. Then, the magnitude of jW1,W2 at a certain EW1,W2 increased with the hydrophobicity of the counter anion. It was proved that the logarithm of |jW1,W2|at a certain EW1,W2 is almost proportional to the hydration energy of the counter anion. This indicates that not only K+ but also the counter anion distributes into the BLM. Therefore, the magnitude of jW1,W2 at a certain EW1,W2 increased with an increase of pH, because the hydroxide ion was served as a counter anion. Based on the variation of the zero-current potential in case of various asymmetrical ionic compositions, it is found that the amount of cation transport is much larger than that of anion transport. [source]

    Voltammetric Elucidation of Ion Transfer Through an Extremely Thin Membrane

    ELECTROANALYSIS, Issue 9 2004
    Nobuyuki Ichieda
    Abstract Digital simulation of the cyclic voltammogram for the ion transfer through a liquid membrane of thickness from 1,mm to 10,nm was performed. The magnitude of current and the shape of the voltammogram simulated for extremely thin membrane (10,nm thick) were similar to those observed experimentally with a bilayer lipid membrane, BLM, of about 10,nm in thick, when the diffusion coefficient of an ion in the BLM was assumed to be extraordinary small (10,13 to 10,14,cm2 s,1). [source]

    Sonovoltammetric Elucidation of Electron Transfer Rates: The Oxidation of Dimethyl- p -phenylenediamine in Aqueous Solution

    ELECTROANALYSIS, Issue 4 2003
    Abstract The electrochemical oxidation of dimethyl- p -phenylenediamine (DMPD) in aqueous solution (pH 7 phosphate buffer) has been studied under conventional hydrodynamic and microelectrode voltammetric conditions and found to undergo a two-electron electrochemically reversible oxidation. Upon the application of ultrasound to the system an observed shoulder emerges in the oxidation wave. This effect has been attributed to the resolution of the two-electron transfer processes occurring: the first a relatively fast electron transfer (0.1,cm s,1) followed by a second slower (10,3 cm s,1) electron transfer: under the very high mass transport rates induced by insonation an overpotential develops for the second electron transfer so leading to the observed voltammetric resolution. The range of mass transport conditions accessible via sonication allows the estimation of the two rate constants reported. [source]

    Temperature and Ca2+ ion as modulators in cellular immunity of the Sunn pest Eurygaster integriceps Puton (Heteroptera: Scutelleridae)

    Arash ZIBAEE
    Abstract Environmental conditions in addition to divalent cations may affect the interactions between pathogens and insects. Elucidation of factors which modulate insect immune responses could be a significant part of investigations in this area. In this study, adults of Eurygaster integriceps, as the destructive pest of wheat, were kept at different temperatures in addition to injection with different concentrations of Ca2+ to find the effect on cellular immune reactions against Beauveria bassiana. Results showed that total and differentiate hemocyte numbers, nodule formation and phenoloxidase activity increased with elevation of temperature so that the higher values were obtained at 30 and 40°C at various intervals. Higher concentrations of Ca2+ ion (5 mM) caused an increase in plasmatocyte length and width especially after 60 min. Similar results were observed for nodule formation and phenoloxidase activity of E. integriceps adults after injection by B. bassiana spores and phenoloxidase activity. It is clear from the current study that thermoregulation and Ca2+ ion can positively affect the hemocyte numbers especially plasmatocytes and granulocytes, nodule formation and phenoloxidase activity in E. integriceps. The understanding of modulators of the insect immune response may directly influence novel approaches to obtain safe and effective biological control agents. [source]

    Worldwide distribution of Pseudomonas aeruginosa clone C strains in the aquatic environment and cystic fibrosis patients

    Ute Römling
    Summary Highly successful bacterial clones have the ability to effectively colonize environmental niches and patients. However, the factors which determine the complex interplay between the colonization of environmental niches and patients are mainly unknown. In this study we show that Pseudomonas aeruginosa clone C strains are distributed worldwide and highly prone to infect cystic fibrosis (CF) patients in Canada, England, France and Germany. In Hanover, Germany and Vancouver, Canada, clone C strains are highly prevalent in the CF patient community, although the mechanisms of acquisition may have been different. All clone C strains showed highly related macrorestriction fragment pattern of the whole genome as visualized by pulsed-field gel electrophoresis and harboured the 102 kbp plasmid pKLC102. Comparison of three prevalent P. aeruginosa clones with different distribution between the environment and patients revealed that neither enhanced biofilm formation nor antibiotic resistance was responsible for the spread of clone C. Clone M, which was highly prevalent in the clinical environment such as sanitary facilities, lacked motility, which could explain its relatively low prevalence in CF patients. Elucidation of the mechanisms which lead to the prevalence of clone C strain in patients and the environment requires the investigation of additional phenotypes. [source]

    Variable expression of CYP and Pgp genes in the human small intestine

    M. Lindell
    Abstract Background ,The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. Methods ,The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. Results ,Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. Conclusions ,Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation. [source]

    Asymmetric Homoaldol Reactions with Cyclohex-2-enyl N,N -Diisopropylcarbamate: Kinetic Resolution, Elucidation of the Stereochemical Course and Applications in the Synthesis of Hexahydroisobenzofuran-4-(1H)-ones

    Jochen Becker
    Abstract Enantio-enriched cyclohex-2-enyl N,N -diisopropylcarbamate (5) is stereospecifically deprotonated by sec -butyllithium/(,)-sparteine (9) to form the configurationally stable lithium complex 7·9. A kinetic resolution of rac - 5 by n -butyllithium/(,)-sparteine (9) yielded (R)- 5 with up to 99,% ee. Electrophilic substitution with tin electrophiles proceeds in a anti -SE, fashion as shown by chemical correlations. The synthesized allylstannanes 10 undergo a highly stereospecific TiCl4 -mediated homoaldol reaction with various aldehydes, yielding syn -configured homoaldol products 12. These were transferred into all - cis -configured hexahydroisobenzofuran-4(1H)-ones 22 by BF3·OEt2 -mediated reactions with aldehydes. The configurations of several products were determined by X-ray structure analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source]

    Archazolid-7- O -,- D -glucopyranoside , Isolation, Structural Elucidation and Solution Conformation of a Novel V-ATPase Inhibitor from the Myxobacterium Cystobacter violaceus

    Dirk Menche
    Abstract The novel polyketide macrolide archazolid-7- O -,- D -glucopyranoside (3) has been isolated from the myxobacterium Cystobacter violaceus and the structure of this first archazolid-glycoside has been determined by spectroscopic and degradative methods. A synthesis of simplified 7- O analogues, based on regioselective derivatisation of archazolid A, was elaborated. These structurally novel archazolids of natural and synthetic origin were evaluated in detail for V-ATPase inhibition and their biological activities are discussed in terms of their solution conformations, as determined by high-field NMR studies, including J -based conformation analysis and constrained molecular dynamics simulations. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source]

    Cyrmenins, Novel Antifungal Peptides Containing a Nitrogen-Linked ,-Methoxyacrylate Pharmacophore: Isolation and Structural Elucidation

    Thomas Leibold
    Abstract The novel antifungal metabolites cyrmenin A, B1, and B2 (1,3) were isolated from Archangium gephyra and Cystobacter armeniaca strains (myxobacteria). The cyrmenins are modified N -acyldipeptide esters containing a didehydroalanine, a 3- O -methyl-didehydroserine and a (2E,4Z)-undecadienoic or -dodecadienoic acid residue. These compounds represent the first bacterial counterparts of strobilurins that are characterized by an ,-substituted ,-methoxyacrylate pharmacophore. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source]

    Human evolution at the Matuyama-Brunhes boundary

    Article first published online: 12 FEB 200, Giorgio Manzi
    Abstract The cranial morphology of fossil hominids between the end of the Early Pleistocene and the beginning of the Middle Pleistocene provides crucial evidence to understand the distribution in time and space of the genus Homo. This evidence is critical for evaluating the competing models regarding diversity within our genus. The debate focuses on two alternative hypotheses, one basically anagenetic and the other cladogenetic. The first suggests that morphological change is so diffused, slow, and steady that it is meaningless to apply species names to segments of a single lineage. The second is that the morphological variation observed in the fossil record can best be described as a number of distinct species that are not connected in a linear ancestor-descendant sequence. Today much more fossil evidence is available than was in the past to test these alternative hypotheses, as well as intermediate variants. Special attention must be paid to Africa because this is the most probable continental homeland for both the origin of the genus Homo (around 2.5,2 Ma),1 as well as the site, two million or so years later, of the emergence of the species H. sapiens.2 However, the African fossil record is very poorly represented between 1 Ma and 600 ka. Europe furnishes recent discoveries in this time range around the Matuyama-Brunhes chron boundary (780,000 years ago), a period for which, at present, we have no noteworthy fossil evidence in Africa or the Levant. Two penecontemporaneous sources of European fossil evidence, the Ceprano calvaria (Italy)3 and the TD6 fossil assemblage of Atapuerca (Spain)4 are thus of great interest for testing hypotheses about human evolution in the fundamental time span bracketed between the late Early and the Middle Pleistocene. This paper is based on a phenetic approach to cranial variation aimed at reviewing the Early-to-Middle Pleistocene trajectories of human evolution. The focus of the paper is on neither the origin nor the end of the story of the genus Homo, but rather its chronological and phylogenetic core. Elucidation of the evolutionary events that happened around 780 ka during the transition from the Early to Middle Pleistocene is one of the new frontiers for human paleontology, and is critical for understanding the processes that ultimately led to the origin of H. sapiens. [source]

    Expression of melanoma-associated antigens in melanoma cell cultures

    Mirjana Urosevic
    Abstract:, The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA , Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 , by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2. Melan-A, tyrosinase and gp100 expression was frequently reduced in melanoma cell cultures, compared to that in foreskin melanocytes, whereas MAGE-1 and MAGE-3 expression showed variable degree of upregulation, compared to that in foreskin melanocytes. The expression of all tested MAA demonstrated high interindividual variability. We further show that cell cultures derived from the same tissue sample are oligoclonal in nature, by demonstrating the presence of up to three cell populations bearing distinct MAA profile. Analysing samples derived from the same patient but each at a different time point, we show that MAA expression profile changes over time either in positive (increase) or in negative (decrease) direction. Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P -value range: 0.05,0.001). Elucidation of the MAA expression patterns and the kinetics within the same patient as well as during the course of the disease may help improve current and develop new immunotherapeutic strategies. [source]

    The role of group bulkiness in the catalytic activity of psychrophile cold-active protein tyrosine phosphatase

    FEBS JOURNAL, Issue 17 2008
    Hiroki Tsuruta
    The cold-active protein tyrosine phosphatase found in psychrophilic Shewanella species exhibits high catalytic efficiency at low temperatures as well as low thermostability, both of which are characteristics shared by many cold-active enzymes. The structure of cold-active protein tyrosine phosphatase is notable for the presence of three hydrophobic sites (termed the CA, Zn-1 and Zn-2 sites) behind the loop structures comprising the catalytic region. To identify the structural components responsible for specific enzyme characteristics, we determined the structure of wild-type cold-active protein tyrosine phosphatase at high resolution (1.1 Å) and measured the catalytic efficiencies of enzymes containing mutations in the three hydrophobic sites. The bulkiness of the amino acid side chains in the core region of the Zn-1 site strongly affects the thermostability and the catalytic efficiency at low temperatures. The mutant enzyme I115M possessed a higher kcat at low temperatures. Elucidation of the crystal structure of I115M at a resolution of 1.5 Å revealed that the loop structures involved in retaining the nucleophilic group and the acid catalyst are more flexible than in the wild-type enzyme. [source]

    Elucidation of the role of Grr1p in glucose sensing by Saccharomyces cerevisiae through genome-wide transcription analysis

    FEMS YEAST RESEARCH, Issue 3 2004
    Steen L. Westergaard
    Abstract The role of Grr1p in glucose sensing in Saccharomyces cerevisiae was elucidated through genome-wide transcription analysis. From triplicate analysis of a strain with deletion of the GRR1 -gene from the genome and an isogenic reference strain, 68 genes were identified to have significantly altered expression using a Student's t -test with Bonferroni correction. These 68 genes were widely distributed across different parts of the cellular metabolism and GRR1 -deletion is therefore concluded to result in polytrophic effects, indicating multiple roles for Grr1p. Using a less conservative statistical test, namely the SAM test, 232 genes were identified as having significantly altered expression, and also these genes were widely distributed across different parts of the cellular metabolism. Promoter analyses on a genome-wide scale and on the genes with significant changes revealed an over-representation of DNA-binding motifs for the transcriptional regulators Mig1p and Rgt1p in the promoter region of the significantly altered genes, indicating that Grr1p plays an important role in the regulatory pathways that ultimately lead to transcriptional regulation by each of the components Mig1p and Rgt1p. [source]

    Lipopolysaccharide binding of the mite allergen Der f 2

    GENES TO CELLS, Issue 9 2009
    Saori Ichikawa
    Lipid-binding properties and/or involvement with host defense are often found in allergen proteins, implying that these intrinsic biological functions likely contribute to the allergenicity of allergens. The group 2 major mite allergens, Der f 2 and Der p 2, show structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex. Elucidation of the ligand-binding properties of group 2 mite allergens and identification of interaction sites by structural studies are important to explore the relationship between allergenicity and biological function. Here, we report a ligand-fishing approach in which His-tagged Der f 2 was incubated with sonicated stable isotope-labelled Escherichia coli as a potential ligand source, followed by isolation of Der f 2-bound material by a HisTrap column and NMR analysis. We found that Der f 2 binds to LPS with a nanomolar affinity and, using fluorescence and gel filtration assays that LPS binds to Der f 2 in a molar ratio of 1 : 1. We mapped the LPS-binding interface of Der f 2 by NMR perturbation studies, which suggested that LPS binds Der f 2 between the two large ,-sheets, similar to its binding to MD-2, the LPS-binding component of the innate immunity receptor TLR4. [source]

    Elucidation of the molecular mechanism of platelet activation: Dense granule secretion is regulated by small guanosine triphosphate-binding protein Rab27 and its effector Munc13-4

    Hisanori Horiuchi
    Cardiovascular diseases such as myocardial and cerebral infarction are common critical diseases occurring more frequently in the elderly. The trigger of the diseases is platelet activation following plaque rupture or erosion. Investigation of the molecular mechanism in platelet activation has been exclusively performed pharmacologically. We have succeeded in establishing the granule secretion and aggregation assays using permeabilized platelets. These systems enabled us to examine the molecular mechanism in platelet activation with molecular biological and biochemical methods. Using these assay systems, we have been investigating the molecular mechanism of platelet activation. With a support grant from the Novartis Foundation for Gerontological Research, we found several molecules involved in the regulation. In this report, I present the progress in the research of the granule secretion mechanism in activated platelets, which was reported in the Japanese Geriatric Society Meeting in 2005. [source]

    Isolation and Structure Elucidation of Enniatins L, M1, M2, and N: Novel Hydroxy Analogs

    Pornrapee Vongvilai
    Four new cyclohexadepsipeptides, enniatins L (1), M1 (2), M2 (3), and N (4), have been isolated from an unidentified fungus (BCC 2629), together with the known enniatins B (5), H (6), and I (7), MK1688 (8), and enniatin B4 (9). Compounds 1,4 are the first enniatin analogs with an OH group at the side chain of one of the 2-hydroxycarboxylic acid residues. The structures of 1,4 were elucidated by spectroscopic means and by X-ray crystallography. [source]

    Difference in somatosensory evoked fields elicited by mechanical and electrical stimulations: Elucidation of the human homunculus by a noninvasive method

    HUMAN BRAIN MAPPING, Issue 4 2005
    Ken Inoue
    Abstract We recently recorded somatosensory evoked fields (SEFs) elicited by compressing the glabrous skin of the finger and decompressing it by using a photosensor trigger. In that study, the equivalent current dipoles (ECDs) for these evoked fields appeared to be physiologically similar to the ECDs of P30m in median nerve stimulation. We sought to determine the relations of evoked fields elicited by mechanically stimulating the glabrous skin of the great toe and those of electrically produced P40m. We studied SEFs elicited by mechanical and electrical stimulations from the median and tibial nerves. The orientations of dipoles from the mechanical stimulations were from anterior-to-posterior, similar to the orientations of dipoles for P30m. The direction of the dipole around the peak of N20m from median nerve electrical stimulation was opposite to these directions. The orientations of dipoles around the peak of P40m by tibial nerve stimulation were transverse, whereas those by the compression and decompression stimulation of the toe were directed from anterior-to-posterior. The concordance of the orientations in ECDs for evoked fields elicited by mechanical and electrical stimulations suggests that the ECDs of P40m are physiologically similar to those of P30m but not to those of N20m. The discrepancy in orientations in ECDs for evoked field elicited by these stimulations in the lower extremity suggests that electrical and compression stimulations elicit evoked fields responding to fast surface rubbing stimuli and/or stimuli to the muscle and joint. Hum. Brain Mapping 24:274,283, 2005. © 2005 Wiley-Liss, Inc. [source]

    Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunities

    Stephen B Hanauer MD
    Abstract Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD. [source]

    Elucidation of a protein signature discriminating six common types of adenocarcinoma

    Gregory C. Bloom
    Abstract Pathologists are commonly facing the problem of attempting to identify the site of origin of a metastatic cancer when no primary tumor has been identified, yet few markers have been identified to date. Multitumor classifiers based on microarray based RNA expression have recently been described. Here we describe the first approximation of a tumor classifier based entirely on protein expression quantified by two-dimensional gel electrophoresis (2DE). The 2DE was used to analyze the proteomic expression pattern of 77 similarly appearing (using histomorphology) adenocarcinomas encompassing 6 types or sites of origin: ovary, colon, kidney, breast, lung and stomach. Discriminating sets of proteins were identified and used to train an artificial neural network (ANN). A leave-one-out cross validation (LOOCV) method was used to test the ability of the constructed network to predict the single held out sample from each iteration with a maximum predictive accuracy of 87% and an average predictive accuracy of 82% over the range of proteins chosen for its construction. These findings demonstrate the use of proteomics to construct a highly accurate ANN-based classifier for the detection of an individual tumor type, as well as distinguishing between 6 common tumor types in an unknown primary diagnosis setting. © 2006 Wiley-Liss, Inc. [source]

    Elucidation of Architectural Requirements from a Spacer in Supported Proline-Based Catalysts of Enantioselective Aldol Reaction

    Kerem Goren
    Abstract In order to delineate the properties of the spacer architecture responsible for the strong positive dendritic effect exhibited by polymer-supported proline-based catalysts, we prepared two series of polystyrene-bound model catalysts. The first series was based on a linear and partially dendritic spacers (of reduced branching and valency) imitating the length of the second generation spacer, while the second series was based on the first generation dendron spacer with one functional (proline-terminated) and one non-functional arm. Comparative studies of the model and original (fully dendritic) catalysts in the asymmetric aldol reaction of aromatic aldehydes with acetone disclose the features characteristic to the dendritic architecture, such as proximity between the terminal catalytic units and enhanced branching, as crucial for inducing higher yield and enantioselectivity in catalysis. [source]

    Highly Stereoselective Synthesis of Novel Multistereogenic Bis - Bifunctional Ligands Based on [2.2]Paracyclophane- 4,7-quinone, their Structure Elucidation and Application in Asymmetric Catalysis

    Natalia Vorontsova
    Abstract Bis - bifunctional cis -4,7-diarylsubstituted-4,7-dihydroxy-4,7-dihydro[2.2]paracyclophanes 3,6 were synthesized by a highly diastereoselective reaction of ortho -substituted aryllithium reagents with [2.2]paracyclophane-4,7-quinone (1). Enantiomerically pure diols 3,5 were tested as chiral inductors in the enantioselective addition of diethylzinc to benzaldehyde (up to 93.5% ee). Acid dehydration of cis -4,7-di(2-methoxyphenyl)-4,7-dihydroxy-4,7-dihydro[2.2]paracyclophane (3) results in 4,7-dihydro-7,8-di(2-methoxyphenyl)[2.2]paracyclophane-4-one (8) , a planar chiral cyclohexadienone of the [2.2]paracyclophane series with a para -semiquinoid substructure. X-Ray investigations of compounds 3, 4 and 8 were performed. [source]

    Elucidation of zeolite microstructure by synchrotron X-ray diffuse scattering

    B. J. Campbell
    Single-crystal diffuse scattering measurements can now rapidly probe the three-dimensional structure of subtle defects in microporous framework materials. Diffuse scattering data from natural mordenite crystals are shown to exhibit a complex distribution of weak features which have been mapped out using a synchrotron X-ray source and a CCD detector. Comparison with computer-simulated diffuse scattering patterns yields a detailed three-dimensional columnar defect structure and reveals that roughly one third of the mordenite's columnar defects cooperate to form a block-mosaic pattern of {110} stacking faults. [source]

    Conundrums in mixed woody,herbaceous plant systems

    Joanna I. House
    Abstract Aims To identify approaches to improve our understanding of, and predictive capability for, mixed tree,grass systems. Elucidation of the interactions, dynamics and determinants, and identification of robust generalizations that can be broadly applied to tree,grass systems would benefit ecological theory, modelling and land management. Methods A series of workshops brought together scientific expertise to review theory, data availability, modelling approaches and key questions. Location Ecosystems characterized by mixtures of herbaceous and woody plant life-forms, often termed ,savannas', range from open grasslands with few woody plants, to woodlands or forests with a grass layer. These ecosystems represent a substantial portion of the terrestrial biosphere, an important wildlife habitat, and a major resource for provision of livestock, fuel wood and other products. Results Although many concepts and principles developed for grassland and forest systems are relevant to these dual life-form communities, the novel, complex, nonlinear behaviour of mixed tree,grass systems cannot be accounted for by simply studying or modelling woody and herbaceous components independently. A more robust understanding requires addressing three fundamental conundrums: (1) The ,treeness' conundrum. What controls the relative abundance of woody and herbaceous plants for a given set of conditions at given site? (2) The coexistence conundrum. How do the life-forms interact with each other? Is a given woody,herbaceous ratio dynamically stable and persistent under a particular set of conditions? (3) The net primary productivity (NPP) conundrum. How does NPP of the woody vegetation, the herbaceous vegetation, and the total ecosystem (woody + herbaceous) change with changes in the tree,grass ratio? Tests of the theory and conceptual models of determinants of mixed woody,herbaceous systems have been largely site- or region-specific and have seldom been broadly or quantitatively evaluated. Cross-site syntheses based on data and modelling are required to address the conundrums and identify emerging patterns, yet, there are very few data sets for which either biomass or NPP have been quantified for both the woody and the herbaceous components of tree,grass systems. Furthermore, there are few cross-site comparisons spanning the diverse array of woody,herbaceous mixtures. Hence, initial synthesis studies should focus on compiling and standardizing a global data base which could be (1) explored to ascertain if robust generalizations and consistent patterns exist; and (2) used to evaluate the performance of savanna simulation models over a range of woody,herbaceous mixtures. Savanna structure and productivity are the result of complex and dynamic interactions between climate, soils and disturbances, notably fire and herbivory. Such factors are difficult to isolate or experimentally manipulate in order to evaluate their impacts at spatial and temporal scales appropriate for assessing ecosystem dynamics. These factors can, however, be evaluated with simulation models. Existing savanna models vary markedly with respect to their conceptual approach, their data requirements and the extent to which they incorporate mechanistic processes. Model intercomparisons can elucidate those approaches most suitable for various research questions and management applications. Conclusion Theoretical and conceptual advances could be achieved by considering a broad continuum of grass,shrub,tree combinations using data meta-analysis techniques and modelling. [source]

    Regulation of Osteogenesis-Angiogenesis Coupling by HIFs and VEGF,,

    Ernestina Schipani
    Abstract Bone is a highly vascularized tissue, but the function of angiogenesis in bone modeling and remodeling is still poorly defined, and the molecular mechanisms that regulate angiogenesis in bone are only partially elucidated. Genetic manipulations in mice have recently highlighted the critical role of the hypoxia-inducible-factor/vascular endothelial growth factor pathway in coupling angiogenesis and osteogenesis. In this brief perspective, we review the current understanding of the mechanisms responsible for this coupling. Elucidation of such mechanisms will expand our knowledge of bone development and homeostasis, and it may aid in the design of new therapies for accelerating bone regeneration and repair. [source]

    Identification of Novel Regulators Associated With Early-Phase Osteoblast Differentiation,

    Diana S de Jong
    Abstract Key regulatory components of the BMP-induced osteoblast differentiation cascade remain to be established. Microarray and subsequent expression analyses in mice identified two transcription factors, Hey1 and Tcf7, with in vitro and in vivo expression characteristics very similar to Cbfa1. Transfection studies suggest that Tcf7 modulates BMP2-induced osteoblast differentiation. This study contributes to a better definition of the onset of BMP-induced osteoblast differentiation. Introduction: Elucidation of the genetic cascade guiding mesenchymal stem cells to become osteoblasts is of extreme importance for improving the treatment of bone-related diseases such as osteoporosis. The aim of this study was to identify regulators of the early phases of bone morphogenetic protein (BMP)2-induced osteoblast differentiation. Materials and Methods: Osteoblast differentiation of mouse C2C12 cells was induced by treatment with BMP2, and regulation of gene expression was studied during the subsequent 24 h using high-density microarrays. The regulated genes were grouped by means of model-based clustering, and protein functions were assigned. Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells. Osteoblast specificity was studied by comparing these expression patterns with those in C3H10T1/2 and NIH3T3 cells under similar conditions. In situ hybridization of mRNA in embryos at embryonic day (E)14.5 and E16.5 of gestation and on newborn mouse tails were used to study in vivo expression patterns. Cells constitutively expressing the regulated gene Tcf7 were used to investigate its influence on BMP-induced osteoblast differentiation. Results and Conclusions: A total of 184 genes and expressed sequence tags (ESTs) were differentially expressed in the first 24 h after BMP2 treatment and grouped in subsets of immediate early, intermediate early, and late early response genes. Signal transduction regulatory factors mainly represented the subset of immediate early genes. Regulation of expression of these genes was direct, independent of de novo protein synthesis and independent of the cell type studied. The intermediate early and late early genes consisted primarily of genes related to processes that modulate morphology, basement membrane formation, and synthesis of extracellular calcified matrix. The late early genes require de novo protein synthesis and show osteoblast specificity. In vivo and in vitro experiments showed that the transcription factors Hey1 and Tcf7 exhibited expression characteristics and cell type specificity very similar to those of the osteoblast specific transcription factor Cbfa1, and constitutive expression of Tcf7 in C2C12 cells differentially regulated osteoblast differentiation marker genes. [source]

    Risk factors for drug-induced gingival overgrowth

    R. A. Seymour
    Abstract Background/Aims: Drug-induced gingival overgrowth remains a significant problem for the periodontologist. Many patients medicated with the drugs implicated in this unwanted effect experience significant, recurrent gingival problems that require repeated surgical excisions. In this review, we attempt to identify and quantify the various "risk factors" associated with both the development and expression of the drug-induced gingival changes. Method: The risk factors appraised include age, sex, drug variables, concomitant medication, periodontal variables and genetic factors. Elucidation of such factors may help to identify "at risk patients" and then develop appropriate treatment strategies. Results: Of the factors identified, the only one that can be affected by the periodontologist is the patents' periodontal condition. However, drug variables and concomitant medication do impact upon the expression of gingival overgrowth. Conclusion: The identificatioin of risk factors associated with both the prevalence and severity of drug-induced gingival overgrowth is important for all parties involved with this unwanted effect. Both periodontologist and patient have an important rôle to play in improving oral hygiene and gingival health. Likewise, there is always an opportinity to establish a close liaison between the patient's physician and the periodontologist to try and identify alternative drug regimens that can help reduce the impact of this unwanted effect. [source]