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Results for “Pathway analysis”

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PubMed1988

Isolation and characterization of Schizosaccharomyces pombe mutants phenotypically similar to ras1-.

We isolated mutants of Schizosaccharomyces pombe which have deformed cell morphology, are deficient in conjugation and poor in sporulation. This phenotype is characteristic of the ras1 defective mutant previously identified. Tests of the mutants for allelism using cell fusion showed that they define five complementation groups, one of which is ras1 itself. The others are named ral1 through ral4 (ras like). Mutants in ral3 or ral4 conjugate at a very low frequency, while the others apparently do not conjugate at all. Plasmid clones complementing ral1, ral2 or ral3, which apparently carry the respective gene, were isolated from S. pombe genomic libraries. Multiple copies of either the ral2 or the ral3 gene could partially restore mating ability in ral1- strains. Multiple copies of the ras1 gene could partially restore mating ability in ral1- and ral2- strains. These results suggest that the ral1, ral2 and ras1 genes may function in a common pathway in that order. The ral3 gene may influence this pathway. Analysis of these gene products will aid identification of factors which interact with Ras proteins.

Alleles↗

PubMed1985

Role of uptake in gamma-aminobutyric acid (GABA)-mediated responses in guinea pig hippocampal neurons.

Intracellular recordings were obtained from hippocampal pyramidal neurons maintained in vitro. Measurements were made of the conductance change induced by iontophoretically applied gamma-aminobutyric acid (GABA) and, using voltage-clamp techniques, of inhibitory postsynaptic currents resulting from activation of inhibitory pathways. Analysis of GABA iontophoretic charge-response curves indicated that there was considerable variation among neurons with respect to the slope of this relation. The placement of the GABA-containing pipette did not appear to be responsible for the observed variation, since vertical repositioning of the pipette did not alter the slope of the charge-response relationship. Steady iontophoresis of GABA from one barrel of a double-barreled pipette markedly affected the charge-response relation obtained when short pulses were applied to the other barrel. The curve was shifted to the left, and the slope was decreased. Concomitantly, the enhanced GABA-induced responses were prolonged. Similar alterations in GABA responsiveness were observed when the uptake blocker, nipecotic acid, was iontophoretically applied. Furthermore, bath application of saline containing a reduced sodium concentration (25% of control) also produced a prolongation of GABA-mediated responses. Under voltage clamp, inhibitory postsynaptic currents were observed to have biphasic decays. The initial, fast decay was prolonged by an average of 18% by nipecotic acid, whereas the later, slow phase was prolonged by 23%. The results of these studies support the hypothesis that a saturable GABA uptake system is responsible for the observed variation in the charge-response curves and, in turn, underlies the apparent sensitizing effect of excess GABA application. The results also suggest that a reduction of transmitter uptake affects the time course of inhibitory postsynaptic currents in the hippocampus.

Animals↗

PubMed2003

The pathogenetic role of oncogenes deregulated by chromosomal translocation in B-cell malignancies.

Chromosomal translocations involving the immunoglobulin (IG) loci play a pivotal role in the pathogenesis of many subtypes of mature B-cell malignancy. Although all the common IG translocations have been cloned, cloning of rare but nonetheless recurrent translocations continues to allow identification of genes of importance to the development of both normal and malignant B-cells. Clustering of breakpoints within the IG gene segments has allowed development of polymerase chain reaction methods that facilitate cloning. IG translocations result in overexpression of a wide variety of genes ranging from cell surface receptors to transcriptional repressors. Genes recently shown to be involved in such translocations include BCL11A and MALT1. As with the acute leukemias, different translocations in B-cell lymphomas may target different proteins that interact directly. A common endpoint for several translocations is activation of the nuclear factor kappaB pathway. Analysis of the mechanisms of transformation may define new therapeutic strategies.

Cell Transformation, Neoplastic↗

PubMed1997

Cadmium leads to stimulated expression of the lipid transfer protein genes in barley: implications for the involvement of lipid transfer proteins in wax assembly.

In order to investigate the nature of genes expressed in leaf epidermal cells of higher plants, we have identified the nucleotide sequence of a cDNA designated ltp 7a2b encoding a novel nonspecific lipid transfer protein of barley (Hordeum vulgare L. cv. Gerbel). The cDNA of 755 basepairs contains an open reading frame of 366 nucleotides coding for a 12.3-kDa polypeptide. The first 29 amino acids constitute the putative signal peptide, characteristic for targeting to the secretory pathway. Analysis of mRNA levels by Northern blotting indicated that ltp 7a2b is preferentially expressed in the leaf epidermis. Levels of mRNA decreased during ageing of leaf tissue. Expression of ltp 7a2b was stimulated by a factor of 2 - 3 when the seedlings were grown in the presence of cadmium (10 - 1600 microM). Concomitantly, the primary leaves of Cd-exposed seedlings contained elevated levels of abscisic acid and thicker was layer of the cuticle. At 100 microM Cd in the hydroponic medium, the was cover was increased by 50%. The increase in abscisic acid content, ltp 7a2b mRNA and was coverage was either not seen, or seen much less, in Ni- and Zn-stressed seedlings. The data add circumstantial evidence to the recently proposed hypothesis that nonspecific lipid transfer proteins function in transfer of cutin and/or wax monomers from the site of synthesis in the cell to the cuticle.

Amino Acid Sequence↗

PubMed1999

Characterisation of an Arabidopsis thaliana cDNA encoding a novel thylakoid lumen protein imported by the delta pH-dependent pathway.

An Arabidopsis thaliana (L.) Heynh. cDNA encoding a novel 16-kDa protein (P16) of the chloroplast thylakoid lumen has been characterised. The function of the protein is unknown but it shares some sequence similarity with alpha allophycocyanins. P16 is synthesised with a bipartite, lumen-targeting presequence, and import experiments demonstrated that this protein follows the delta pH-dependent pathway. Analysis of the thylakoid transfer peptide revealed two unusual features. Firstly, the key targeting determinant is predicted to be a twin-arginine followed by a highly hydrophobic residue two residues later, rather than at the third position as in most transfer peptides. Secondly, the C-terminal domain of the transfer peptide contains multiple charged residues which may help to prevent mistargeting by the Sec-type protein translocase.

Amino Acid Sequence↗

PubMed1998

Synthesis of glutamine, glycine and 10-formyl tetrahydrofolate is coregulated with purine biosynthesis in Saccharomyces cerevisiae.

Glutamine, glycine and 10-formyl tetrahydrofolate are consumed during de novo purine biosynthesis. We have found that, in Saccharomyces cerevisiae, synthesis of these cosubstrates is coregulated with synthesis of enzymes of the purine biosynthetic pathway. Analysis of three genes required for synthesis of glutamine, glycine and 10-formyl tetrahydrofolate (GLN1, SHM2 and MTD1, respectively) shows that their expression is repressed by adenine and requires the transcription factors Baslp and Bas2p. Northern analysis reveals that regulation of SHM2 and MTD1 expression by adenine takes place at the transcriptional level. We also show that Bas1p and Bas2p bind in vitro to the promoters of the SHM2 and MTD1 genes, and that mutations in the consensus Bas1p binding sequences strongly affect expression of these genes in vivo. Finally, we have found that a SHM2-lacZ fusion is expressed at a significantly higher level in a bas2-2 disrupted strain than in bas1-2 or bas1-2 bas2-2 mutant strains. The BAS1-dependent, BAS2-independent expression of SHM2-lacZ suggests that, in the absence of Bas2p, Bas1p can interact with another protein partner to activate SHM2 expression.

Base Sequence↗

PubMed1989

Activity-induced depression of synaptic inhibition during LTP-inducing patterned stimulation.

In the hippocampus, patterns of electrical stimulation that approximate bursting neuronal activity during theta rhythm have been shown to induce a long-term potentiation (LTP) of excitatory synapses. In this study, a single subthreshold stimulus applied to one set of Schaffer/commissural fibers affected the response to a second stimulation delivered 200 ms later to a separate set of Schaffer/commissural fibers in the CA1 field of rat hippocampal slices. The first (priming) stimulus caused a prolongation of the synaptic response elicited by the second (primed) stimulus. In addition, the priming stimulation facilitated the induction of LTP by bursts of stimulation (4 pulses at 100 Hz) of the second afferent pathway. Analysis of the shape of the synaptic responses indicates that the prolongation is due to the removal of an inhibitory component rather than the addition of a novel excitatory component. Blockade of GABAA-ergic transmission with picrotoxin mimicked the priming effect in that it also widened synaptic responses and facilitated burst-induced LTP. We suggest that these patterns of stimulation result in a transient loss of inhibition during the primed stimulation. This, in turn, brings about a prolongation of the synaptic response that allows short bursts of excitatory synaptic activity to depolarize postsynaptic cells sufficiently to trigger LTP.

Animals↗

PubMed1984

Stellate ganglion stimulation with alpha and beta adrenergic blockade: effect on lung lipids and compliance in cats.

Stellate ganglion stimulation (SGS) can alter lung lipids and reduce static lung compliance, although the mechanisms remain unclear. Phentolamine and propranolol were administered to anesthetized cats prior to stimulation in order to investigate SGS effects on lung lipids and compliance mediated via alpha and beta adrenergic pathways. Analysis of lung lavage revealed that SGS alone decreased cholesterol and the cholesterol/DSPC ratio which might be expected to decrease lung compliance. Alpha and beta blockade alone resulted in no changes from control in cholesterol or DSPC. Alpha blockade plus SGS yielded increased rather than decreased cholesterol and DSPC, while beta blockade prevented any change. A reduction in both static and dynamic lung compliance caused by SGS also was blocked by both alpha and beta blockade. Thus both the alpha and beta blockade prevented the SGS-induced decreases in cholesterol, cholesterol/DSPC ratio, and lung compliance. Furthermore, alpha blockade plus SGS resulted in increased TPL as well as cholesterol and DSPC. The data are consistent with the view that DSPC and cholesterol are released into the subphase by beta adrenergic mechanisms, and that their relative amounts may influence surface properties.

Adrenergic alpha-Antagonists↗

PubMed1982

Exposure of man to environmental nickel--an exposure commitment assessment.

Nickel is one of many trace metals that are pervasive in the environment, being released from natural and man-made sources, and to which man is exposed. Representative values of nickel concentrations in the background environment and in man are selected from available data and a pathway analysis is performed to illustrate application of the exposure commitment method to environmental pollutant assessment. Estimated dietary intake of nickel is of the order of 170 micrograms d-1. With fractional absorption of five per cent, retention in the body of 30 per cent of the absorbed amount and an estimated mean body content of nickel of 500 micrograms, an effective mean retention time of 200 days is derived. Contributions to the body burden from drinking water and inhalation of nickel in air are generally less important than dietary intake in normal circumstances. The exposure evaluation is performed for total nickel in the environment and in man. Relationships for specific nickel compounds would be useful and can be derived in a similar fashion as data become available.

Air Pollutants↗

PubMed1983

Exposure of man to environmental selenium - an exposure commitment assessment.

Selenium is an element which occurs naturally in varying concentrations in soil and is released from industrial sources, particularly from fossil fuel combustion. Harmful effects in animals and man may result from both deficient or excessive amounts of intake. Representative values of selenium concentrations in the background environment and in man are selected from available data and a pathway analysis is performed utilizing the exposure commitment method. Dietary intake of selenium is of the order of 70 micrograms d-1. With fractional absorption of 80% and retention in the body of 90% for an effective retention time of 140 days, the estimated mean body content of selenium is 7 mg. The contribution to the body burden from inhalation intake is much less significant. The exposure evaluation is performed for total selenium in the environment and in man. The parameters may be adjusted for specific selenium compounds, if data are available, and for more particular environmental and exposure conditions as required.

Absorption↗

PubMed1985

Exposure of man to environmental copper--an exposure commitment assessment.

Copper, an essential element for man, is widespread in the environment and is released from both natural and anthropogenic sources. A summary of representative values of copper concentrations in environmental media is presented and a pathways analysis performed utilizing the exposure commitment method. The assessment indicates that an average dietary intake rate of 2 mg day-1 contributes 630 micrograms kg-1 of copper to the body, while inhalation of copper in air (0.05 micrograms m-3 in urban air and 0.02 micrograms m-3 in rural air) makes, in comparison, a negligible contribution to the body content.

Air Pollutants↗

PubMed1986

Exposure of man to environmental aluminium--an exposure commitment assessment.

Aluminium is one of the most abundant elements in the environment and is released from both natural and anthropogenic sources. Representative values of aluminium concentrations in the background environment and in man are selected from available data and a pathway analysis is performed utilising the exposure commitment method. Using a derived estimate of the body burden (60 mg), a representative value for dietary intake (20 mg day-1) and fractional absorption of 0.01, a mean retention time of A1 in the body of 300 days is obtained. This corresponds to a biological half-time of 210 days. The assessment indicates that an average dietary intake rate of 20 mg day-1 contributes 660 micrograms kg-1 of aluminium to the body, while inhalation of aluminium in air makes, in comparison, a negligible contribution to the body content.

Aluminum↗

PubMed1991

Abnormal pituitary function during melancholia: reduced alpha-melanocyte-stimulating hormone secretion and increased intact ACTH non-suppression.

In order to investigate pituitary alpha-melanocyte-stimulating hormone (alpha-MSH), intact (1-39 structure) adrenocorticotropic hormone (ACTH), and adrenal cortisol secretion, we measured 8 a.m. plasma levels of those hormones before and after administration of 1 mg dexamethasone in 39 depressed inpatients and 10 healthy controls. We found a significantly lower baseline alpha-MSH secretion in melancholic patients as opposed to healthy controls. There were no significant relations between alpha-MSH secretion on the one hand and ACTH or cortisol secretion on the other. Dexamethasone did not affect the 8 a.m. alpha-MSH circulating levels. The post-dexamethasone intact ACTH and cortisol values were significantly higher in melancholics as compared with healthy, minor and simple major depressed subjects. ACTH non-suppression was defined as post-dexamethasone intact ACTH greater than or equal to 12 pg/ml. ACTH non-suppression was found to be more sensitive (70%) and specific (100%) for melancholia than cortisol non-suppression. By means of pathway analysis we have established that cortisol non-suppression during a severe depression is completely determined by an augmented ACTH escape from suppression by dexamethasone. It is concluded that the assay of post-dexamethasone intact ACTH could, in the future, replace post-dexamethasone cortisol determination.

Adjustment Disorders↗

PubMed1996

Parasite richness/sampling effort/host range: the fancy three-piece jigsaw puzzle.

In this article, Jean-François Guégan and Clive Kennedy propose an alternative explanation for the confounding effects of host geographical range and sampling effort on parasite species richness using pathway analysis procedure. They suggest that much of the species richness revealed by sampling effort is also a reflection of host range. Thus, the total contribution of host range logically incorporates a contribution from sampling effort. The implications of indirect effects of host range on richness estimates have not previously been discussed, and the authors here attempt to redress the balance. The contribution of host range to richness, as derived from control of sampling effort on richness estimates, therefore, is a mathematical expression that does not take into account the cause-and-effect nature of things.

Journal Article↗

PubMedDate not supplied

Effect of D-amino acids on Escherichia coli strains with impaired penicillin-binding proteins.

Escherichia coli cells growing in the presence of some D-amino acids incorporate D-amino acid into the peptidoglycan layer of the cell wall by a mechanism most likely independent of the normal biosynthetic pathway. Analysis of the sensitivity of mutant strains with impaired penicillin-binding proteins (PBP) to D-amino acids indicated that ponB and DD-endopeptidase/DD-carboxypeptidase-I-defective strains are hypersensitive to D-amino acids. D-tryptophan containing peptidoglycan was found to be more susceptible to the action of lytic transglycosilases than native material, which could explain in part the harmful effects of D-amino acids. ponB strains carrying additional mutations suppressing hypersensitivity to D-amino acids have been obtained and the results of their initial characterization are reported.

Amino Acids↗

PubMed2006

Soybean ATP sulfurylase, a homodimeric enzyme involved in sulfur assimilation, is abundantly expressed in roots and induced by cold treatment.

Soybeans are a rich source of protein and a key feed ingredient in livestock production, but lack sufficient levels of cysteine and methionine to meet the nutritional demands of swine or poultry as feed components. Although engineering the sulfur assimilatory pathway could lead to increased sulfur-containing amino acid content, little is known about this pathway in legumes. Here, we describe the cloning and characterization of soybean ATP sulfurylase (ATPS), which acts as the metabolic entry point into the sulfur assimilation pathway. Analysis of the ATPS clone isolated from a soybean seedling cDNA library revealed an open-reading frame, encoding a 52 kDa polypeptide with an N-terminal chloroplast/plastid transit peptide, which was related to the enzymes from Arabidopsis, potato, human, and yeast. Soybean ATP sulfurylase was expressed in Escherichia coli and purified to apparent homogeneity. Based on gel-filtration chromatography, the enzyme functions as a 100 kDa homodimer. Analysis of genomic DNA by Southern blotting revealed that multiple genes encode ATP sulfurylase in soybean. Analysis of the transcript profiles retrieved from a soybean EST database indicated that ATP sulfurylase mRNA was most abundant in root tissue. Cold treatment induced mRNA accumulation and enhanced the specific activity of ATP sulfurylase in root tissue. Northern blot analysis indicated a decline in the ATP sulfurylase transcript levels during seed development. Likewise, ATP sulfurylase specific activity also declined in the later stages of seed development. Increasing the expression levels of this key enzyme during soybean seed development could lead to an increase in the availability of sulfur amino acids, thereby enhancing the nutritional value of the crop.

Chloroplasts↗

PubMed2025

Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction.

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.

Humans↗

PubMed2005

Identification of candidate genes associated with salivary adenoid cystic carcinomas using combined comparative genomic hybridization and oligonucleotide microarray analyses.

Adenoid cystic carcinoma (ACC) of the salivary gland often has a variable clinical course with a poor prognosis. To investigate DNA copy number aberrations associated with ACCs, we compared comparative genome hybridization data from ACCs (n = 6) with other types of salivary gland tumors such as adenocarcinomas (n = 3) and pleomorphic adenomas (n = 6). While 15 gain loci (1q32, 6p25, 6q21-q24, 7q11.2, 7q31, 10q11.2, 11p12-q12, 12q13, 12q14, 13q24, 16p13.3-13.2, 18p11.3, 18q23, 19q13.4, and Xq28) were detected, no DNA loss locus was evident. To examine the expression status of genes on the ACC-associated loci, transcriptional measurements of approximately 38000 human genes then were monitored using Affymetrix U133 Plus 2.0 GeneChips. A total of 4431 genes were found differentially expressed by at least two-fold between ACCs and normal salivary glands. Of them, 3162 genes were up-regulated and 1269 genes were down-regulated in ACCs. After obtaining locus information about the RNA transcripts from the Affymetrix database, we found 262 ACC-associated genes with increased expression on ACC-associated loci. To investigate functional network and gene ontology, the 262 genes were analyzed using Ingenuity Pathway Analysis Tool. The function with the highest P value was a cancer-related function (P = 2.52e-4 to 4.71e-2). In addition, we identified pituitary tumor-transforming gene 1 and transformation related protein 63 genes that were up-regulated by increasing DNA copy number and modulated expression of oncogenes. These results suggested that the combination of copy number and gene expression profiling provides an improved strategy for gene identification in salivary gland ACCs.

Adenocarcinoma↗