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R A Feldman

Publications and source records attributed to R A Feldman.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cospeciation of chemoautotrophic bacteria and deep sea clams.

Vesicomyid clams depend entirely on sulfur-oxidizing endosymbiotic bacteria for their nutriment. Endosymbionts that are transmitted cytoplasmically through eggs, such as these, should exhibit a phylogenetic pattern that closely parallels the phylogeny of host mitochondrial genes. Such parallel patterns are rarely observed, however, because they are obscured easily by small amounts of horizontal symbiont transmission or occasional host switching. The present symbiont genealogy, based on bacterial small subunit (16S) rDNA sequences, was closely congruent with the host genealogy, based on clam mitochondrial cytochrome oxidase subunit I and large subunit (16S) rDNA sequences. This phylogenetic evidence supports the hypothesis of cospeciation and a long term association between the participants in this symbiosis.

Animals↗
PubMed1998

c-Fes tyrosine kinase binds to and activates STAT3 after granulocyte-macrophage colony-stimulating factor stimulation.

Granulocyte-macrophage colony stimulating factor (GM-CSF) induces proliferation and maturation of myeloid progenitor cells and also activates neutrophils. In order to investigate the pleiotropic effects of GM-CSF stimulation, we examined the signaling pathways of protein tyrosine kinases (PTKs) and signal transducers and activators of transcription (STATs) in GM-CSF-dependent proliferation of leukemia cells. Using TF-1, a GM-CSF-dependent human erythroleukemia cell line, we found that GM-CSF enhanced DNA-binding and tyrosine phosphorylation of STAT3. GM-CSF receptor (GM-CSFR) and c-Fes tyrosine kinase were also activated upon GM-CSF stimulation. Furthermore, c-Fes formed a complex with STAT3. Experiments using a c-Fes mutant that lacked tyrosine kinase activity revealed that the activation of STAT3 is kinase-dependent, but that the c-Fes-STAT3 interaction is not affected by c-Fes tyrosine kinase activity. The results suggest that STAT3 is activated by c-Fes tyrosine kinase through direct interaction during hematopoietic cell proliferation induced by GM-CSF.

Base Sequence↗
PubMed1998

The complete genome of the hyperthermophilic bacterium Aquifex aeolicus.

Aquifex aeolicus was one of the earliest diverging, and is one of the most thermophilic, bacteria known. It can grow on hydrogen, oxygen, carbon dioxide, and mineral salts. The complex metabolic machinery needed for A. aeolicus to function as a chemolithoautotroph (an organism which uses an inorganic carbon source for biosynthesis and an inorganic chemical energy source) is encoded within a genome that is only one-third the size of the E. coli genome. Metabolic flexibility seems to be reduced as a result of the limited genome size. The use of oxygen (albeit at very low concentrations) as an electron acceptor is allowed by the presence of a complex respiratory apparatus. Although this organism grows at 95 degrees C, the extreme thermal limit of the Bacteria, only a few specific indications of thermophily are apparent from the genome. Here we describe the complete genome sequence of 1,551,335 base pairs of this evolutionarily and physiologically interesting organism.

Chromosome Mapping↗
PubMed1998

Genomic analysis reveals chromosomal variation in natural populations of the uncultured psychrophilic archaeon Cenarchaeum symbiosum.

Molecular phylogenetic surveys have recently revealed an ecologically widespread crenarchaeal group that inhabits cold and temperate terrestrial and marine environments. To date these organisms have resisted isolation in pure culture, and so their phenotypic and genotypic characteristics remain largely unknown. To characterize these archaea, and to extend methodological approaches for characterizing uncultivated microorganisms, we initiated genomic analyses of the nonthermophilic crenarchaeote Cenarchaeum symbiosum found living in association with a marine sponge, Axinella mexicana. Complex DNA libraries derived from the host-symbiont population yielded several large clones containing the ribosomal operon from C. symbiosum. Unexpectedly, cloning and sequence analysis revealed the presence of two closely related variants that were consistently found in the majority of host individuals analyzed. Homologous regions from the two variants were sequenced and compared in detail. The variants exhibit >99.2% sequence identity in both small- and large-subunit rRNA genes and they contain homologous protein-encoding genes in identical order and orientation over a 28-kbp overlapping region. Our study not only indicates the potential for characterizing uncultivated prokaryotes by genome sequencing but also identifies the primary complication inherent in the approach: the widespread genomic microheterogeneity in naturally occurring prokaryotic populations.

Animals↗
PubMed1998

Vestimentiferan on a whale fall.

Discovery of chemosynthetic communities associated with whale bones led to the hypothesis that whale falls may serve as stepping-stones for faunal dispersal between disjunct hydrothermal vents and cold seeps on the ocean floor (1). The initial observation was followed by a faunal inventory that revealed a diverse assemblage of microbes and invertebrates, supported by chemoautotrophic production, living in close proximity to whale remains (2, 3). To date, the conspicuous absence from whale falls of vestimentiferan tubeworms (a predominant constituent of eastern Pacific vent and seep habitats) has been a major objection to the stepping-stone hypothesis (4-5). We report the first evidence of a vestimentiferan tubeworm associated with a whale fall (Fig. 1). The tubeworm, Escarpia spicata, was identified by morphological criteria and DNA sequence data from a portion of the mitochondrial cytochrome oxidase C subunit I (COI) gene. Additionally, the bacterial endosymbiont in the tubeworm possessed a 16S rRNA gene that was similar to that of endosymbionts from vestimentiferans in sedimented cold-seep environments.

Animals↗
PubMed1998

Confounding factors in observational and intervention studies.

In studying the association of Helicobacter pylori with any particular illness, it is essential to consider the effects of confounding. The methods of dealing with confounding, a situation in which there is a true association of a risk factor and a disease, and the association is not causal, include matching during the design and carrying out of the study, or stratification and adjustment during the analysis. Adjustment during analysis of data collected in observational studies can reduce the effects of confounding. However, multivariate models are seriously limited in their ability to control for confounding, especially when covariates are imprecisely measured.

Adult↗
PubMed1997

A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells.

The Shc gene encodes three proteins that have been implicated as mediators of signal transduction from growth factor receptors and nonreceptor tyrosine kinases to Ras. Overexpression of Shc in established murine fibroblasts results in oncogenic transformation, indicating that Shc has oncogenic potential. Shc proteins contain a carboxy terminal SH2 domain and a novel non-SH2 phosphotyrosine-binding (PTB) domain that specifically recognizes a phosphorylated NPXpY motif in target proteins such as the epidermal growth factor receptor. We show here that Shc is constitutively tyrosine-phosphorylated in all primary acute myeloid leukemias analyzed and that, in some of these leukemias, Shc is associated through its PTB domain with a tyrosine-phosphorylated protein of 140 kD (p140) in vivo. In factor-dependent cells, this 140-kD protein can be tyrosine-phosphorylated in vitro in response to cytokines involved in myeloid proliferation and differentiation, ie, granulocyte-macrophage colony-stimulating factor and colony-stimulating factor-1. A similar or identical protein of 140 kD is constitutively bound to the C-terminal SH3 domain of Grb2 in the same acute myeloid leukemias. In addition to p140, other tyrosine-phosphorylated proteins of 61 and 200 kD are constitutively associated with Shc in some of the leukemias analyzed. Our results implicate Shc, Grb2, p140, and additional tyrosine-phosphorylated proteins of 61 and 200 kD in signalling of acute myeloid leukemia cells.

Acute Disease↗
PubMed1997

The Fes protein-tyrosine kinase phosphorylates a subset of macrophage proteins that are involved in cell adhesion and cell-cell signaling.

The c-fps/fes proto-oncogene encodes a 92-kDa protein-tyrosine kinase that is expressed at high levels in macrophages. We have previously shown that overexpression of c-fps/fes in a CSF-1-dependent macrophage cell line (BAC1.2F5) partially released these cells from their factor dependence and that this correlated with the tyrosine phosphorylation of a subset of proteins in a tissue-specific manner. We have now identified one of the macrophage substrates of Fes as the crk-associated substrate (Cas) and a second substrate as a 130-kDa protein that has been previously described as a T cell activation-dependent substrate and is unrelated to Cas. Both of these proteins, which have optimal consensus sequences for phosphorylation by Fes, were tightly associated with this kinase through its SH2 domain, suggesting that they were direct substrates of Fes. Remarkably, when the Fes SH2 domain was used as an affinity reagent to identify potential substrates of endogenous Fes in control BAC1.2F5 cells, the phosphotyrosyl proteins that were recognized were the same as those that were specifically phosphorylated when Fes was overexpressed in the same cells. We conclude that the substrates we identified may be structurally related or identical to the physiological targets of this kinase in macrophages. The known functions of Cas and p130 suggest that Fes kinase may play a role in signaling triggered by cell adhesion and cell-cell interactions during immune responses of macrophages.

Animals↗
PubMed1997

Cryptosporidiosis in adults in Lusaka, Zambia, and its relationship to oocyst contamination of drinking water.

In Lusaka, where human immunodeficiency virus seroprevalence in young adults is approximately 25%, four townships were studied to establish the prevalence of persistent diarrhea in adults and the etiologic importance of cryptosporidiosis in adults with persistent diarrhea. Cryptosporidium parvum oocyst contamination of urban water supplies was measured and the results used to categorize these populations into high or low exposure. In total, 506 adults were reported as having had diarrhea in the 2 weeks prior to the survey; 101 of these episodes were persistent. Adults with persistent diarrhea in the high-exposure areas were more likely to have cryptosporidiosis (odds ratio, 5.14; 95% confidence interval, 1.57-17.2; risk ratio, 1.83; 95% confidence interval, 1.04-3.21; P = .003) although overall prevalence of persistent diarrhea was not greater in these areas. This association was not confounded by animal exposure, travel, or boiling water. Within these urban populations, water contamination with C. parvum was a major influence on the prevalence of infection.

Adult↗
PubMed1997

Molecular phylogenetics of bacterial endosymbionts and their vestimentiferan hosts.

Vestimentiferan tube worms from deep-sea hydrothermal vents and cold-water seeps rely entirely on sulfur-oxidizing bacterial endosymbionts for nutriment. We examined host-symbiont co-evolution by comparing phylogenetic trees from symbiont 16S ribosomal DNA and host mitochondrial COI genes. The endosymbionts comprised two distinct clades, one associated with tube worms from basaltic vent habitats and the other associated with tube worms from sedimented seep-like environments. Within each symbiont clade, 16S rDNA sequences were nearly identical, suggesting that vent vestimentiferans share a single endosymbiont species that is distinct from the seep endosymbiont species. A third endosymbiont type, related to the seep species, was found in a tube worm collected from a whale carcass. Our results are consistent with a horizontal model of symbiont transmission.

Animals↗
PubMed1996

Interleukin-4 induces association of the c-fes proto-oncogene product with phosphatidylinositol-3 kinase.

We have previously demonstrated that interleukin-4 (IL-4) induces tyrosine phosphorylation of a protein closely related or identical to the c-fes proto-oncogene product (FES) and association of this protein with the IL-4 receptor alpha chain (IL-4R alpha). IL-4 is known to induce association of phosphatidylinositol-3 (PI3) kinase with the IL-4R alpha. Since FES contains the consensus motifs for PI3 kinase binding, we tested the possibility that FES may associate with PI3 kinase upon IL-4 stimulation. We demonstrate herein that IL-4 stimulation induced rapid association of FES or a related protein with PI3 kinase in mouse T-cell lines. We also show an association of human FES (hFES) with the src homology 2 (SH2) domain of PI3 kinase in a COS7 cell expression system. The in vitro PI3 kinase assay using COS7 cells suggested that hFES partly contributes to the association between the hIL-4R alpha and PI3 kinase. We have further identified the important region in the cytoplasmic domain of the hIL-4R alpha for association of tyrosine-phosphorylated hFES with the hIL-4R alpha and SH2 domain of PI3 kinase using a COS7 cell expression system. These results suggest that FES or a related protein/PI3 kinase pathway may play a role in the pleiotropic effects of IL-4.

Animals↗
PubMed1996

Novel adapter proteins that link the human GM-CSF receptor to the phosphatidylino-sitol 3-kinase and Shc/Grb2/ras signaling pathways.

We have used a human GM-CSF-dependent hematopoietic cell line that responds to physiological concentrations of hGM-CSF to analyze a set of signaling events that occur in normal myelopoiesis and whose deregulation may lead to leukemogenesis. Stimulation of these cells with hGM-CSF induced the assembly of multimeric complexes that contained known and novel phosphotyrosyl proteins. One of the new proteins was a major phosphotyrosyl substrate of 76-85 kDa (p80) that was directly associated with the p85 subunit of phosphatidylinositol (PI) 3-kinase through the SH2 domains of p85. p80 also associated with the beta subunit of the activated hGM-CSF receptor, and assembly of this complex correlated with activation of PI 3-kinase. A second phosphotyrosyl protein we identified, p140, associated with the Shc and Grb2 adapter proteins by direct binding to a novel phosphotyrosine-interacting domain located at the N-terminus of Shc. and to the SH3 domains of Grb2, respectively. The Shc/p140/Grb2 complex was found to be constitutively activated in acute myeloid leukemia cells, indicating that activation of this pathway may be a necessary step in the development of some leukemias. The p80/p85/PI 3-kinase and the Shc/Grb2/p140 complexes were tightly associated with Src family kinases, which were prime candidates for phosphorylation of Shc, p80, p140 and other phosphotyrosyl substrates present in these complexes. Our studies suggest that p80 and p140 may link the hGM-CSF receptor to the PI 3-kinase and Shc/Grb2/ras signaling pathways, respectively, and that abnormal activation of hGM-CSF-dependent targets may play a role in leukemogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Pneumococcal meningitis in the North East Thames Region UK: epidemiology and molecular analysis of isolates.

One hundred and fourteen cases of pneumococcal meningitis were identified by prospective laboratory based surveillance during 1990-3 in the North East Thames Region. Higher rates of disease were seen in Asians (2.1/100000) than Caucasians (0.8/100000) (P = 0.002). The incidence of meningitis was higher in children than adults, while mortality rates were highest in adults over the age of 60 (48%). In 72 cases, both blood and CSF were culture positive. Serotyping of 65 isolates collected identified 22 serotypes (and one non-typable) causing disease, the most common being serotype 6 (13 cases) and serotype 14 (11 cases). Overall, 90% of serotype antigens identified were represented in the 23 valent vaccine. Ribotyping of 62 isolates identified 35 different patterns, of which 26 were single types. Different ribotypes were found among isolates of the same serotypes, with the exception of serotype 14, where 9 of 11 isolates had the same ribotype pattern. Four percent of isolates had reduced susceptibility to penicillin, but no high level penicillin resistance was found.

Adolescent↗
PubMed1995

Identification of a new adapter protein that may link the common beta subunit of the receptor for granulocyte/macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 to phosphatidylinositol 3-kinase.

Binding of human granulocyte/macrophage colony-stimulating factor (hGM-CSF) to its receptor induces the rapid activation of phosphatidylinositol-3 kinase (PI 3-kinase). As hGM-CSF receptor (hGMR) does not contain a consensus sequence for binding of PI 3-kinase, hGMR must use a distinct mechanism for its association with and activation of PI 3-kinase. Here, we describe the identification of a tyrosine-phosphorylated protein of 76-85 kDa (p80) that associates with the common beta subunit of hGMR and with the SH2 domains of the p85 subunit of PI 3-kinase in hGM-CSF-stimulated cells. Src/Yes and Lyn were tightly associated with the p80.PI 3-kinase complex, suggesting that p80 and other phosphotyrosyl proteins present in the complex were phosphorylated by Src family kinases. Tyrosine phosphorylation of p80 was only detected in hGM-CSF or human interleukin-3-stimulated cells, suggesting that activation of p80 might be specific for signaling via the common beta subunit. We postulate that p80 functions as an adapter protein that may participate in linking the hGM-CSF receptor to the PI 3-kinase signaling pathway.

Binding Sites↗
PubMed1995

Catalytic specificity of protein-tyrosine kinases is critical for selective signalling.

How do distinct protein-tyrosine kinases activate specific down-stream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.

Amino Acid Sequence↗