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At least 235 records · Page 13Linked to original sources

PubMed2005

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi-synthetic anthelmintics such as emodepside.

The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

Animals↗

PubMed2005

Exploration of jasmonate signalling via automated and standardized transient expression assays in tobacco cells.

Although sequence information and genome annotation are improving at an impressive pace, functional ontology is still non-existent or rudimentary for most genes. In this regard, transient expression assays are very valuable for identification of short functional segments in particular pathways, because they can be performed rapidly and at a scale unattainable in stably transformed tissues. Vectors were constructed and protocols developed for systematic transient assays in plant protoplasts. To enhance throughput and reproducibility, protoplast treatments were performed entirely by a liquid-handling robot in multiwell plates, including polyethylene glycol/Ca2+ cell transfection with plasmid mixtures, washes and lysis. All transcriptional readouts were measured using a dual firefly/Renilla luciferase assay, in which the former was controlled by a reporter promoter and the latter by the 35S CaMV promoter, which served as internal normalization standard. The automated protocols were suitable for transient assays in protoplasts prepared from cell cultures of Nicotiana tabacum Bright Yellow-2 and Arabidopsis thaliana. They were implemented in a screen to discover potential regulators of genes coding for key enzymes in nicotine biosynthesis. Two novel tobacco transcription factors were found, NtORC1 and NtJAP1, that positively regulate the putrescine N-methyltransferase (PMT) promoter. In addition, combinatorial tests showed that these two factors act synergistically to induce PMT transcriptional activity. The development and use of high-throughput plant transient expression assays are discussed.

Arabidopsis↗

PubMed2006

From genomics to chemical genomics: new developments in KEGG.

The increasing amount of genomic and molecular information is the basis for understanding higher-order biological systems, such as the cell and the organism, and their interactions with the environment, as well as for medical, industrial and other practical applications. The KEGG resource (http://www.genome.jp/kegg/) provides a reference knowledge base for linking genomes to biological systems, categorized as building blocks in the genomic space (KEGG GENES) and the chemical space (KEGG LIGAND), and wiring diagrams of interaction networks and reaction networks (KEGG PATHWAY). A fourth component, KEGG BRITE, has been formally added to the KEGG suite of databases. This reflects our attempt to computerize functional interpretations as part of the pathway reconstruction process based on the hierarchically structured knowledge about the genomic, chemical and network spaces. In accordance with the new chemical genomics initiatives, the scope of KEGG LIGAND has been significantly expanded to cover both endogenous and exogenous molecules. Specifically, RPAIR contains curated chemical structure transformation patterns extracted from known enzymatic reactions, which would enable analysis of genome-environment interactions, such as the prediction of new reactions and new enzyme genes that would degrade new environmental compounds. Additionally, drug information is now stored separately and linked to new KEGG DRUG structure maps.

Biotransformation↗

PubMed1998

Transformation of binaural response properties in the ascending auditory pathway: influence of time-varying interaural phase disparity.

Transformation of binaural response properties in the ascending auditory pathway: influence of time-varying interaural phase disparity. J. Neurophysiol. 80: 3062-3076, 1998. Previous studies demonstrated that tuning of inferior colliculus (IC) neurons to interaural phase disparity (IPD) is often profoundly influenced by temporal variation of IPD, which simulates the binaural cue produced by a moving sound source. To determine whether sensitivity to simulated motion arises in IC or at an earlier stage of binaural processing we compared responses in IC with those of two major IPD-sensitive neuronal classes in the superior olivary complex (SOC), neurons whose discharges were phase locked (PL) to tonal stimuli and those that were nonphase locked (NPL). Time-varying IPD stimuli consisted of binaural beats, generated by presenting tones of slightly different frequencies to the two ears, and interaural phase modulation (IPM), generated by presenting a pure tone to one ear and a phase modulated tone to the other. IC neurons and NPL-SOC neurons were more sharply tuned to time-varying than to static IPD, whereas PL-SOC neurons were essentially uninfluenced by the mode of stimulus presentation. Preferred IPD was generally similar in responses to static and time-varying IPD for all unit populations. A few IC neurons were highly influenced by the direction and rate of simulated motion, but the major effect for most IC neurons and all SOC neurons was a linear shift of preferred IPD at high rates-attributable to response latency. Most IC and NPL-SOC neurons were strongly influenced by IPM stimuli simulating motion through restricted ranges of azimuth; simulated motion through partially overlapping azimuthal ranges elicited discharge profiles that were highly discontiguous, indicating that the response associated with a particular IPD is dependent on preceding portions of the stimulus. In contrast, PL-SOC responses tracked instantaneous IPD throughout the trajectory of simulated motion, resulting in highly contiguous discharge profiles for overlapping stimuli. This finding indicates that responses of PL-SOC units to time-varying IPD reflect only instantaneous IPD with no additional influence of dynamic stimulus attributes. Thus the neuronal representation of auditory spatial information undergoes a major transformation as interaural delay is initially processed in the SOC and subsequently reprocessed in IC. The finding that motion sensitivity in IC emerges from motion-insensitive input suggests that information about change of position is crucial to spatial processing at higher levels of the auditory system.

Acoustic Stimulation↗

PubMed2006

Mass spectral characterization of phloroglucinol derivatives hyperforin and adhyperforin.

Active phloroglucinol constituents of Hypericum perforatum (St. John's wort) extracts, hyperforin and adhyperforin, have been studied following ion activation using tandem mass spectrometry (MS/MS) and complemented by accurate mass measurements. These two compounds were readily analyzed as protonated and deprotonated molecules with electrospray ionization. MS/MS and MS3 data from a quadrupole-linear ion trap tandem mass spectrometer were employed to elucidate fragmentation pathways. Fourier transform ion cyclotron resonance measurements afforded excellent mass accuracies for the confirmation of elemental formulae of product ions formed via infrared multiphoton dissociation and sustained off-resonance irradiation collision-induced dissociation. Fragmentation schemes have been devised for the dissociation of hyperforin and adhyperforin in negative and positive ion modes. This information is expected to be especially valuable for the characterization of related compounds, such as degradation products, metabolites and novel synthetic analogs of hyperforin.

Bridged Bicyclo Compounds↗

PubMed1995

Analysis of delay times of hemagglutinin-mediated fusion between influenza virus and cell membranes.

We have studied the kinetics of low pH-induced fusion between influenza virus A/PR 8/34 and human erythrocyte membranes in suspension by using an assay based on fluorescence dequenching (FDQ) of the lipophilic dye octadecylrhodamine B chloride (R 18). As shown previously (Clague et al. 1991) the onset of FDQ is preceded by a characteristic lag time (tlag) following pH reduction. Whereas tlag represents only a subpopulation of fusing viruses with the shortest delay time we suggest here that a representative mean lag time mu lag of virus-cell fusion can be deduced from the R 18-assay. Kinetics of FDQ reflects the cumulative distribution function of lag times tau lag of single fusion events with the mean value mu lag. We show that tau lag obtained from the onset of FDQ does not always reflect the fusion behaviour of the whole population of fusing viruses. While both lag times, taulag and mu lag, exhibit a similar temperature dependence we found a significantly different dependence of both delay times on virus inactivation by low pH-pretreatment. We conclude that the mean lag time mu lag appears to be a more appropriate parameter describing the kinetics of virus-cell fusion. The analysis of delay times offers a new approach to test the validity of different kinetic models of HA-mediated fusion and to gain valuable information about HA-mediated fusion. The analysis confirms that the inactivation process proceeds via steps of the formation of the fusion pore. Although the increase of lag times can be explained by a depletion of fusion competent HA's, our data suggest that intermediate structures of HA along the inactivation pathway can still transform into a fusion site.

Cells, Cultured↗

PubMed2006

Paths to and from poverty in late 19th century novels.

Late 19th century novels provide graphic descriptions of working and living conditions and their impact on population health, in particular the detrimental effects of hunger, poor housing, environmental conditions, hazardous work and poor pay, smoking and alcohol and crime, but also the transformative possibilities of social and political action. The popularity of these novels helped raise the collective conscience of citizens and illuminated the direction for 20th century welfare reforms. Yet many of these problems remain and the pathways to and from poverty are still recognisable today. Although novels are now less central in conveying social information, re-reading these novels enables us to understand how social and economic circumstances were understood at the time and what led to social and political change.

Female↗

PubMed1998

Spatially restricted activation of the SAX receptor by SCW modulates DPP/TKV signaling in Drosophila dorsal-ventral patterning.

Dorsal-ventral patterning within the embryonic ectoderm of Drosophila requires two TGFbeta ligands, DPP and SCW, and two type I TGFbeta receptors, TKV and SAX. In embryos lacking dpp signaling, increasing the level of TKV activity promotes progressively more dorsal cell types, while activation of SAX alone has no phenotypic consequences. However, SAX activity synergizes with TKV activity to promote dorsal development. Functional experiments suggest the two receptors have different ligands: DPP acts through TKV, and SCW acts through SAX. Furthermore, SOG, a negative regulator of this patterning process, preferentially blocks SCW activity. We propose that spatial regulation of the SAX pathway modulates TKV signaling to create positional information over the embryonic ectoderm.

Animals↗

PubMed1992

Isolation and kinetic properties of acetohydroxy acid isomeroreductase from spinach (Spinacia oleracea) chloroplasts overexpressed in Escherichia coli.

Acetohydroxy acid isomeroreductase catalyses a two-step reaction, an alkyl migration and a NADPH-dependent reduction, in the assembly of the carbon skeletons of branched-chain amino acids. Detailed investigations of acetohydroxy acid isomeroreductase aimed at elucidating the biosynthetic pathway of branched-chain amino acids and at designing new inhibitors of the enzyme having herbicidal potency have so far been conducted with the enzymes isolated from bacteria. To gain more information on a plant system, the gene encoding the mature acetohydroxy acid isomeroreductase from spinach (Spinacia oleracea) leaf chloroplasts has been used to transform Escherichia coli cells and to overexpress the enzyme. A rapid protocol is described that allows the preparation of large quantities of pure spinach chloroplast acetohydroxy acid isomeroreductase. Kinetic and structural properties of the plant enzyme expressed in Escherichia coli are compared with those reported in our previous studies on the native enzymes purified from spinach chloroplasts and with those reported for the corresponding enzymes isolated from Escherichia coli and Salmonella typhimurium. Both the plant and the bacterial enzymes obey an ordered mechanism in which NADPH binds first, followed by substrate (either 2-acetolactate or 2-aceto-2-hydroxybutyrate). Inhibition studies employing an inactive substrate analogue, 2-hydroxy-2-methyl-3-oxopentanoate, showed, however, that the binding of 2-hydroxy-2-methyl-3-oxopentanoate and NADPH occurs randomly, suggestive of some flexibility of the plant enzyme active site. The observed preference of the enzyme for 2-aceto-2-hydroxybutyrate over 2-acetolactate is discussed with regard to the contribution of acetohydroxy acid isomeroreductase activity in the partitioning between isoleucine and valine biosyntheses. Moreover, the kinetic properties of the chloroplast enzyme support the notion that biosynthesis of branched-chain amino acids in plants is controlled by light. As judged by analytical-ultracentrifugation and gel-filtration analyses the overexpressed plant enzyme is a dimer of identical subunits.

2-Acetolactate Mutase↗

PubMed2002

A comparative investigation of the metabolism of the herbicide glufosinate in cell cultures of transgenic glufosinate-resistant and non-transgenic oilseed rape (Brassica napus) and corn (Zea mays).

To obtain information on differences between the metabolic pathways of the herbicide glufosinate (trade names: BASTA, LIBERTY) in non-transgenic, glufosinate-sensitive plants and in transgenic, glufosinate-resistant plants, the metabolism of 14C-labeled glufosinate and its enantiomers L- and D-glufosinate was studied using cell cultures of oilseed rape and corn. Transformation of glufosinate in both sensitive and transgenic rape cells remained at a low rate of about 3-10% in contrast to corn cells, where 20% was transformed in sensitive and 43% in transgenic cells after 14 days of incubation, the rest remaining as unchanged glufosinate. In sensitive rape and corn cells the main metabolite was 4-methylphosphinico-2-oxo-butanoic acid (PPO) with 7.3 and 16.4%, respectively, together with low amounts of 3-methylphosphinicopropionic acid (MPP), 4-methylphosphinico-2-hydroxybutanoic acid (MHB), 4-methylphosphinicobutanoic acid (MPB) and 2-methylphosphinicoacetic acid (MPA). An additional metabolite formed in transgenic cell cultures was 2-acetamido-4-methylbutanoic acid (N-acetyl-L-glufosinate, NGA), which was formed at rates of 3.2% in rape and 16.1% in corn. A further minor metabolite, not yet identified, was detected in both cell types. The liberation of 0.2% 14CO2 indicates further metabolic steps prior to a limited mineralization in plant cell cultures. L-glufosinate was transformed into the same metabolites as the glufosinate racemate. D-glufosinate was not metabolized.

Aminobutyrates↗

PubMed1996

Spatial, behavioral and sensory correlates of hippocampal CA1 complex spike cell activity: implications for information processing functions.

The aim of this review is to better understand hippocampal function drawing almost entirely from single unit recording studies of pyramidal cells in areas CA1 and CA3 of behaving animals. Hippocampal location-selectivity ("place cell activity") as well as place-independent behavioral correlates and sensory-triggered discharges are demonstrated to have common features: (1) abstraction, that is, development within the hippocampal circuit of novel, cue-invariant supramodal representations; (2) varying degrees of generalization or specificity; (3) capacity for abrupt changes in discharge correlates of individual neurons as the animal changes its behavior pattern or its environment changes dramatically; (4) though individual neurons discharge when the subject occupies a certain place, or performs a certain behavior, the ensemble of hippocampal neurons comprehensively represent the whole environment and all behaviors required for the task at hand. A concordance is proposed: hippocampal neuronal discharge correlates represent elements partitioned from information abstracted along one or more systems of categorization or "information domains": the physical structure of the environment, regularities in the behavioral exigencies of the current situation. (Sensory stimuli can be considered as temporally varying features of the environment) Location-selectivity and behavioral correlates are extreme cases, and mixed correlates occur. The hippocampus is proposed to carry out several fundamental processes that transform information: abstraction, partitioning and recombination, that is, formation of conjunctive associations between events. Simultaneously activated neurons could then promote extrahippocampal associations linking together the diverse brain regions at the origin of these signals.

Animals↗

PubMed2001

Molecular genetics of lung cancer.

Lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, or the workplace. Recent studies suggest that histologically apparent lung cancer is due to the sequential accumulation of specific genetic and morphologic changes to the normal epithelial cells of the lung. Positive signallers, such as those mediated by the oncogene RAS, and negative signallers, such as those mediated by the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell growth and proliferation. Other key molecular derangements can also be considered hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis, tissue invasion, and metastases. Epigenetic inactivation of genes via DNA methylation provides another novel way of evading normal cellular control mechanisms. The new knowledge of the human genome coupled with global methods of detecting genetic abnormalities and profiling gene expression in tumor cells may enable us to understand the signaling pathways of lung cancer cells. These are molecular targets for new cancer therapeutics such as receptor tyrosine kinase inhibitors. This information could advance risk assessment, early detection, prognosis, and therapy for lung cancer.

Cell Transformation, Neoplastic↗

PubMed2001

Learning Hough transform: a neural network model.

A single-layered Hough transform network is proposed that accepts image coordinates of each object pixel as input and produces a set of outputs that indicate the belongingness of the pixel to a particular structure (e.g., a straight line). The network is able to learn adaptively the parametric forms of the linear segments present in the image. It is designed for learning and identification not only of linear segments in two-dimensional images but also the planes and hyperplanes in the higher-dimensional spaces. It provides an efficient representation of visual information embedded in the connection weights. The network not only reduces the large space requirement, as in the case of classical Hough transform, but also represents the parameters with high precision.

Algorithms↗

PubMed2003

Pyridoxine 5'-phosphate synthase: de novo synthesis of vitamin B6 and beyond.

Vitamin B(6) is an essential component in human diet. However, some organisms have the required machinery for its synthesis. There are two independent and autoexclusive groups of genes, pdx and SOR1. Pyridoxine 5'-phosphate (PNP) synthase is the key enzyme in the pdx group. It catalyses a multistep ring closure reaction yielding PNP and inorganic phosphate (Pi). This is the last step in the de novo synthetic pathway; afterwards, PNP enters the salvage pathway to be transformed to the pyridoxal 5'-phosphate cofactor. Because PNP synthase is not present in humans but is found in many human pathogens, the enzyme can be regarded as a potential target for the development of novel drugs. We have recently solved the structure of PNP synthase in complex with several ligands. The structural information allowed us to characterise the active site of the enzyme and identify the catalytically important residues. Furthermore, a detailed reaction mechanism could be proposed.

Bacterial Proteins↗

PubMed2006

Genetics of human heterotaxias.

The past decade has seen remarkable advances in defining the molecular mechanisms underlying formation of the embryonic left right (LR) axis. This information is slowly transforming our understanding of human birth defects that are caused by disturbed LR axis patterning. Reversals, isomerisms, or segmental discordances of thoraco-abdominal organ position, that is, classic heterotaxy, clearly indicate embryonic disruption of normal LR patterning. Other isolated birth defects, particularly cardiovascular malformations, may be caused by deficiencies in the same pathways. Here, we review the distinctive clinical features of human heterotaxias and try to summarize the known connections between them and the corresponding developmental pathways.

Body Patterning↗

PubMed1997

"... On the basis of velocity clues alone": some perceptual themes 1946-1996.

Three factors that have transformed perceptual research in the last fifty years are the digital computer, single-unit electrophysiology, and molecular biology. Amongst the developments in which members of the Experimental Psychology Society have been central are: the recognition of the role of optic flow in spatial vision; the demonstration that our perceptual systems contain parallel pathways extracting different information from the sensory array; the identification of specific detectors that can be selectively adapted in psychophysical experiments; and the transfer of the concepts of fourier analysis from audition to vision. The history of Opponent Process Theory offers an example where experimental psychologists have been misled by too simple an interpretation of physiological recordings.

Animals↗

PubMed1983

Yeast recombination: the association between double-strand gap repair and crossing-over.

In previous experiments, we have used yeast transformation to study the recombinogenic repair of double-strand breaks and gaps. A plasmid containing a double-strand gap within sequences homologous to the yeast genome integrates efficiently by crossing-over. During the process of integration, the double-strand gap is repaired, using chromosomal information as a template. This repair reaction results in the transfer of genetic information from one DNA duplex to another and is therefore a pathway for gene conversion. Because meiotic gene conversion is associated with a high frequency (up to 50%) of crossing-over, we wished to determine the degree of association of double-strand gap repair with crossing-over. Only the class of repair events resulting in crossovers (plasmid integration) were detected in our earlier experiments with nonreplicating plasmids. In this paper, we describe the outcome of double-strand gap repair in plasmids that are capable of autonomous replication and therefore allow recovery of both crossover and noncrossover products. After the correct repair of a double-strand gap, we recover approximately equal numbers of integrated and nonintegrated plasmids. Thus, gene conversion by double-strand gap repair can occur either with or without crossing-over, and it is similar in this respect to meiotic gene conversion. Circularization of linear plasmid DNA by ligation is also observed, suggesting that yeast has an additional repair pathway for double-strand breaks that is independent of recombination. Gap repair on replicating plasmids permits rapid cloning of chromosomal alleles.

Alleles↗

PubMed2005

A moving new role for the sodium pump in epithelial cells and carcinomas.

The Na,K-ATPase, or sodium pump, is a ubiquitous plasma membrane protein in higher eukaryotes, including humans, that carries out the coupled active transport of Na+ ions out of the cell and of K+ ions into the cell, using the energy of hydrolysis of adenosine triphosphate. In recent years, it has been suggested that that this protein may also be involved in various other functions, such as transducing information from the extracellular milieu to intracellular signaling pathways, much like a growth factor receptor. It has also been suggested that the sodium pump may be essential to the formation and function of junctional complexes in epithelial cells, and, most recently, it has been shown to play a role in epithelial cell motility. Maloney sarcoma virus-transformed Madin Darby canine kidney cells have depressed Na,K-ATPase beta subunit abundance and enhanced motility as compared with untransformed cells. Repletion of Na,K-ATPase beta subunits in the transformed cells results in suppression of motility. The most recent work, discussed here, demonstrates that the Na,K-ATPase alpha and beta subunits play distinct and separate roles, interacting with proteins in the phosphatidylinositol 3-kinase pathway and leading to the remodeling of the cytoskeleton and lamellipodia formation. The sodium pump subunits thus seem to play a role in regulating carcinoma cell motility and may be involved in cell motility suppression in many epithelial cells.

Animals↗