Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biologic pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,081 records · Page 60Linked to original sources
PubMed2000

Higher cardol homologs (5-alkylresorcinols) in rye seedlings.

The occurrence of alkylresorcinols, polyketide compounds that in the same homologous series as cardol isolated from Anacardium occidentale (cashew) or bilobol from Ginkgo biloba which are derivatives of 1,3-dihydroxy-5-alk(en)ylbenzene, have been demonstrated in developing rye (Secale cereale L.) kernels. The 3-day-old seedlings grown in sterile conditions already contain detectable amounts of phenolic compounds that were identified as alkylresorcinols. This fraction is the mixture of saturated and enoic homologs of various lengths of the aliphatic side chain. The composition of homologs is similar to that determined in mature grains. The relatively high level of alkylresorcinols in mitochondria and plastids (enhanced approximately twice in the absence of light) suggests that their synthetic pathway and/or biological function may be related to these cellular compartments. Resorcinolic lipids, when present in the external medium, are taken up by seedlings in the energy-dependent manner.

Chromatography, Thin Layer↗
PubMed2003

A Wnt-Wnt situation.

A recent Juan March Foundation workshop on "wnt genes and Wnt signaling" brought developmental and cancer biologists together to share some of the latest advances in Wnt research. Discussion topics included molecular, genetic, and genomic dissections of wnt genes in embryogenesis and cancer, Wnt signaling components and downstream targets, interactions with other signaling pathways, cell biological aspects of Wnt signaling, and a first glimpse of a purified Wnt protein.

Animals↗
PubMed1998

Social context in developmental psychopathology: recommendations for future research from the MacArthur Network on Psychopathology and Development. The MacArthur Foundation Research Network on Psychopathology and Development.

Accumulating evidence suggests that social contexts in early life have important and complex effects on childhood psychopathology. Spurred by the lack of an explicit operational definition that could guide the study of such effects, we define a social context operationally as "a set of interpersonal conditions, relevant to a particular behavior or disorder and external to, but shaped and interpreted by, the individual child." Building on this definition, we offer a series of recommendations for future research, based on five theoretically derived propositions: (a) Contexts are nested and multidimensional; (b) contexts broaden, differentiate, and deepen with age, becoming more specific in their effects; (c) contexts and children are mutually determining; (d) a context's meaning to the child determines its effects on the child and arises from the context's ability to provide for fundamental needs; and (e) contexts should be selected for assessment in light of specific questions or outcomes. As reflected in an increasingly rich legacy of literature on child development and psychopathology, social contexts appear to influence emerging mental disorders through dynamic, bidirectional interactions with individual children. Future research will benefit from examining not only statistical interactions between child- and context-specific factors, but also the actual transactions between children and contexts and the transduction of contextual influences into pathways of biological mediation. Because adverse contexts exert powerful effects on the mental health of children, it is important for the field to generate new, more theoretically grounded research addressing the contextual determinants of psychological well-being and disorder.

Child↗
PubMed1997

An optical method for evaluating ion selectivity for calcium signaling pathways in the cell.

A method for evaluating a physiologically relevant ion selectivity of Ca2+ signaling pathways in biological cells based on a Ca(2+)-dependent on/off switch for cellular processes via calmodulin (CaM) chemistry is described. CaM serves as a primary ion receptor for Ca2+ and a given CaM-binding peptide as a target for a CaM-Ca2+ complex. Upon accommodating four Ca2+ ions in its binding sites, CaM undergoes a conformational change to form a CaM-Ca(2+)-target peptide ternary complex. This Ca(2+)-induced selective binding of the Ca(2+)-CaM complex to the target peptide was monitored by a surface plasmon resonance (SPR) technique. As a target peptide, a 26-amino acid residue of M13 derived from skeletal muscle myosin light-chain kinase was used. The target peptide was covalently immobilized in the dextran matrix on top of gold, over which sample solutions containing Ca2+ and CaM were injected in a flow system. Ca(2+)-dependent SPR signals were observed for Ca2+ concentrations from 3.2 x 10(-8) to 1.1 x 10(-5) M and it leveled off. The observed SPR signals were explained as due to an increase in the refractive indexes caused by a Ca2+ ion-switched protein/ peptide interaction, i.e., Ca2+ ion to CaM and subsequent additional binding of the thus formed complex with immobilized M13. No SPR signals were however, induced by Mg2+, K+, and Li+ at concentrations as high as 1.0 x 10(-1) M; these results and previous spectroscopic data taken together conclude that these ions do not induce CaM/peptide interaction. Large changes in SPR signals were observed with a Sr2+ ion concentration over 5.1 x 10(-4) M; Sr2+ ion behaved in this case as a strong agonist toward the Ca(2+)-dependent on/off switch of CaM. The present system thus exhibited "physiologically more relevant" ion selectivity in that relevant metal ions could switch on the CaM/peptide or -protein interaction rather than merely be bound to CaM causing no further signal transduction. The potential use of this finding for more widely evaluating cation selectivity toward the Ca2+ signaling process was discussed.

Amino Acid Sequence↗
PubMed2003

The cell cycle of Entamoeba histolytica.

Entamoeba histolytica, is a microaerophilic protist, which causes amoebic dysentery in humans. This unicellular organism proliferates in the human intestine as the motile trophozoite and survives the hostile environment outside the human host as the dormant quadri-nucleate cyst. Lack of organelles--such as mitochondria and Golgi bodies--and an unequal mode of cell division, led to the popular belief, that this organism preceded other eukaryotes during evolution. However, data from several laboratories have shown that, contrary to this belief, E. histolytica is remarkable in its divergence from other eukaryotes. This uniqueness is witnessed in many aspects of its biochemical pathways, cellular biology and genetic diversity. In this context, I have analysed the cell division cycle of this organism and compared it to that of other eukaryotes. Studies on E. histolytica, suggest that in its proliferative phase, this organism may accumulate polyploid cells. Thus 'checkpoints' regulating alternation of genome duplication and cell division appear to be absent in this unicellular protist. Sequence homologs of several cell cycle regulating proteins have been identified in amoeba, but their structural divergence suggests that they may not have equivalent function in this organism. The regulation of cell proliferation in E. histolytica, may be ideally suited to survival of a parasite in a complex host. Analysis of these molecular details may offer solutions for eradicating the pathogen by hitherto unknown methods.

Animals↗
PubMed2004

Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells.

Viral infection generally results in the activation of inducible nitric oxide synthase (iNOS or NOS2) in respiratory epithelial cells by inflammatory cytokines. Activated NOS2 catalyzes synthesis of nitric oxide (NO), which in excess can cause cellular injury. On the other hand, lysophosphatidic acid (LPA), a lipid mediator released from epithelial cells, platelets, and fibroblasts in injured tissue, functions in repair of cell injury. However, details of the mechanism for repair by LPA remain unknown. We demonstrated one effect of LPA favoring repair, specifically inhibition by LPA of cytokine-induced NOS2 protein and mRNA expression by human respiratory epithelial cells in vitro. NO production by LPA-treated, cytokine-stimulated cells was also reduced. These decreases were prevented by Rho kinase inhibition with Y-27632. Thus, down-regulation by LPA of cytokine-induced increases in NOS2 activity is likely to involve a Rho-dependent signaling pathway. Harmful biologic effects of NO in viral respiratory infection might be modified by therapeutic manipulations involving LPA or Rho.

Cell Line↗
PubMed1998

Heme packing motifs revealed by the crystal structure of the tetra-heme cytochrome c554 from Nitrosomonas europaea.

Cytochrome c554 (cyt c554), a tetra-heme cytochrome from Nitrosomonas europaea, is an essential component in the biological nitrification pathway. In N. europaea, ammonia is converted to hydroxylamine, which is then oxidized to nitrite by hydroxylamine oxidoreductase (HAO). Cyt c554 functions in the latter process by accepting pairs of electrons from HAO and transferring them to a cytochrome acceptor. The crystal structure of cyt c554 at 2.6 A resolution shows a predominantly alpha-helical protein with four covalently attached hemes. The four hemes are arranged in two pairs such that the planes of the porphyrin rings are almost parallel and overlapping at the edge; corresponding heme arrangements are observed in other multi-heme proteins. Striking structural similarities are evident between the tetra-heme core of cyt c554 and hemes 3-6 of HAO, which suggests an evolutionary relationship between these redox partners.

Amino Acid Sequence↗
PubMedDate not supplied

Frequency tuning in a frog vestibular organ.

Several distinct mechanisms have evolved in the auditory periphery to extract frequency information from a sound. In the mammalian cochlea, a travelling wave on the basilar membrane enhanced by a physiologically vulnerable neuromechanical interaction performs the primary frequency separation. In lizards, tuning is likely to depend on structures in the papilla other than the basilar membrane, and tuning in the auditory nerve is correlated with the length of the stereocilia. In turtles and possibly some bird species, an electrical resonance in the receptor cells is responsible for frequency selectivity. In addition to those organs obviously specialized to detect acoustic stimuli, afferents of the vestibular system can exhibit tuning to low-frequency airborne sounds, despite the absence of mechanical frequency separation by accessory structures. I report here that in the frog saccule, a vestibular organ apparently constructed for the detection of vibratory accelerations, frequency tuning may arise from an electrical resonance intrinsic to the hair cells. The mechanism is similar to that found in turtle and ensures that a stimulus with frequency corresponding to the membrane resonant frequency will produce the largest signal in the cell. This type of tuning may thus be quite widespread. Oscillatory mechanisms have been reported in sensory cells of other modalities in several lower vertebrates, and may even contribute to their sensitivity, although such mechanisms do imply that the signal-to-noise ratio is degraded near threshold.

Action Potentials↗
PubMed2004

Functional genomic hypothesis generation and experimentation by a robot scientist.

The question of whether it is possible to automate the scientific process is of both great theoretical interest and increasing practical importance because, in many scientific areas, data are being generated much faster than they can be effectively analysed. We describe a physically implemented robotic system that applies techniques from artificial intelligence to carry out cycles of scientific experimentation. The system automatically originates hypotheses to explain observations, devises experiments to test these hypotheses, physically runs the experiments using a laboratory robot, interprets the results to falsify hypotheses inconsistent with the data, and then repeats the cycle. Here we apply the system to the determination of gene function using deletion mutants of yeast (Saccharomyces cerevisiae) and auxotrophic growth experiments. We built and tested a detailed logical model (involving genes, proteins and metabolites) of the aromatic amino acid synthesis pathway. In biological experiments that automatically reconstruct parts of this model, we show that an intelligent experiment selection strategy is competitive with human performance and significantly outperforms, with a cost decrease of 3-fold and 100-fold (respectively), both cheapest and random-experiment selection.

Algorithms↗
PubMed2005

A multiplexed homogeneous fluorescence-based assay for protein kinase activity in cell lysates.

New methods to quantify protein kinase activities directly from complex cellular mixtures are critical for understanding biological regulatory pathways. Herein, a fluorescence-based chemosensor strategy for the direct measurement of kinase activities in crude mammalian cell lysates is described. We first designed a new fluorescent peptide reporter substrate for each target kinase. These kinase chemosensors were readily phosphorylated by recombinant target enzyme and underwent a several-fold fluorescence increase upon phosphorylation. Then, using unfractionated cell lysates, a homogeneous kinase assay was developed that was reproducible, linear and highly preferential for monitoring changes in cellular activity of the target kinase. The general protocol was developed for the kinase Akt and then easily extended to measure protein kinase A (PKA) and mitogen-activated protein kinase-associated protein kinase 2 (MK2) activities. This assay platform is immediately useful for studying protein kinase signaling in crude cellular extracts.

Biosensing Techniques↗
PubMed1998

The SH2-containing adapter protein GRB10 interacts with BCR-ABL.

Bcr-Abl is an oncogenic tyrosine kinase expressed in tumor cells of CML and a subset of ALL which in its unregulated and activated state is thought to cause cell transformation and leukemia. Bcr-Abl contains several autophosphorylation sites which serve as potential docking sites for SH2-containing signaling molecules. Mutational analysis has indicated that these autophosphorylation sites play a critical role in the transforming capability of Bcr-Abl. It has been shown that the SH2-containing adapter protein Grb2 binds to the autophosphorylation site Tyr(p)177 whereby it couples Bcr-Abl to the Ras pathway. The biological consequences of this interaction, however, are presently unclear. A Tyr177-mutated Bcr-Abl which lacks the ability to interact with the Grb2-SH2 domain still transforms myeloid cells and generates tumors in nude mice. We performed a yeast two-hybrid screen to identify signaling proteins which bind to distinct Bcr-Abl autophosphorylation sites. Autophosphorylation of Bcr-Abl in yeast was accomplished by using the DNA binding protein LexA which permits dimerization and crossphosphorylation of the fused bait. Using a LexA-Bcr-Abl full length fusion protein as bait, we identified several SH2-containing proteins. Among them we confirmed molecules already shown by others to interact with Bcr-Abl, in vivo, including Grb2, PI-3-kinase and Crk indicating that dimerization in yeast leads to autophosphorylation of tyrosine residues crucial for Bcr-Abl signaling in vivo. More importantly, we identified the SH2-containing protein Grb10 as a new binding partner for Bcr-Abl. This binding occurs in a phosphotyrosine-dependent manner at Bcr sites of Bcr-Abl. Both Abl and Bcr alone, as well as a kinase-defective Bcr-Abl, failed to interact with Grb10 in yeast. Mutational analysis uncovered a new SH2 binding site in Bcr-Abl located between Bcr aa242-446, which is different from the Grb2 binding site. Binding could be demonstrated in vitro and also in vivo as shown by co-immunoprecipitation analysis in CML cells. Using a temperature sensitive Bcr-Abl stably overexpressed in hematopoetic cells, we demonstrated that complex formation of Grb10 with Bcr-Abl was kinase activation-dependent in vivo. Notably, a Bcr-Abl mutant protein (Bcr/1-242-Abl) which lacks the ability to interact with Grb10 partially alleviated IL-3 dependence of Ba/F3 cells, indicating that the Grb10/Bcr-Abl interaction is important for Bcr-Abl-induced IL-3 independence of Ba/F3 cells. In addition, the Bcr/1-242-Abl mutant has a reduced capacity to induce focus formation in fibroblasts.

Absorption↗
PubMed2004

The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication.

Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are pivotal for vaccinia virus (VV) multiplication [de Magalhães, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353-38360]. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved, is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.

3T3 Cells↗
PubMed1984

Leukotrienes and the lung.

The history, biosynthetic pathways and biological activities of the leukotrienes have been reviewed. These extremely potent substances probably play a major role in the manifestations of reversible obstructive airways disease and possibly in other diseases of the lung. Their relative contribution remains to be determined and awaits the development of an antagonist or 5-lipoxygenase inhibitor which can be safely administered to man. Perhaps in man in vivo, as has been shown in vitro with human airways tissues [100], the combination of an antihistamine and a leukotriene antagonist will prevent antigen-induced and possibly other forms of airways smooth muscle constriction.

Animals↗
PubMed2000

Tone-evoked oscillations in the rat auditory cortex result from interactions between the thalamus and reticular nucleus.

This study investigates the origins of tone-evoked oscillations (5-13 Hz) in the thalamo-cortical auditory system of anaesthetized rats. In three separate experiments, the auditory sector of the reticular nucleus (RE), the auditory cortex and the auditory thalamus were inactivated by local applications of muscimol (1 mg/mL). To assess the efficacy of this procedure, recordings were performed in the inactivated structure in each experiment; and to determine the extent of the drug diffusion autoradiographic experiments were carried out. The evolution of the strength of the oscillations was followed using power spectra during the whole recording session. In the first experiment, muscimol injection in the auditory RE totally suppressed the tone-evoked oscillations in the auditory thalamus and cortex. In the second experiment, inactivation of the auditory cortex did not interfere with the presence of tone-evoked oscillations in the auditory RE. In the third experiment, inactivation of the auditory thalamus impaired the oscillations produced by cortical stimulation in the auditory RE. From these results, it appears that both the auditory thalamus and the auditory sector of the RE, but not the auditory cortex, are involved in the generation of stimulus-evoked oscillations in the thalamo-cortical auditory system.

Acoustic Stimulation↗
PubMed2004

Vitamin C conjugates of genotoxic lipid peroxidation products: structural characterization and detection in human plasma.

alpha,beta-Unsaturated aldehydes such as 4-hydroxy-2-nonenal (HNE) and other electrophilic lipid peroxidation (LPO) products may contribute to the pathogenesis of cancer, cardiovascular diseases, and other age-related diseases by cytotoxic, genotoxic, and proinflammatory mechanisms. The notion that vitamin C (ascorbic acid) acts as a biological antioxidant has been challenged recently by an in vitro study showing that ascorbic acid promotes, rather than inhibits, the formation of genotoxic LPO products from the lipid hydroperoxide, hydroperoxy octadecadienoic acid [Lee, S. H., Oe, T. & Blair, I. A. (2001) Science 292, 2083-2086]. Here, we demonstrate that ascorbic acid acts as a nucleophile and forms Michael-type conjugates with electrophilic LPO products. Several ascorbyl-LPO product conjugates, resulting from the interaction of ascorbic acid with hydroperoxy octadecadienoic acid in vitro, were identified by tandem MS, including ascorbyl conjugates of HNE, 4-oxo-2-nonenal, and presumably, 12-oxo-9-hydroxy-10-dodecenoic acid. The same ascorbyl-LPO product conjugates were detected in human plasma. The concentration of the ascorbyl-HNE conjugate in plasma from 11 healthy subjects was found to be 1.30 +/- 0.74 microM (mean +/- SD). Our data identify ascorbylation (vitamin C conjugation) as a previously unrecognized, biologically relevant pathway for the elimination of electrophilic LPO products, and have implications for the prevention and treatment of chronic inflammatory diseases, as well as the development of novel biomarkers of oxidative stress.

Aldehydes↗
PubMed2000

Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.

Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod = 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome.

Blood Glucose↗