PubMed Health⌕ Search

Biomedical subjects

A Butler

Publications and source records attributed to A Butler.

At least 55 records · Page 3Linked to original sources
PubMed1999

Normal growth and development in the absence of hepatic insulin-like growth factor I.

The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I.

Animals↗
PubMed1999

Genomic organization of nematode 4TM K+ channels.

As many as 50 genes in the C. elegans genome may encode K+ channels belonging to the novel structural class of two-pore (4TM) channels. Many 4TM channels can be grouped into channel subfamilies. We analyzed 4TM channels in C. elegans using methods made possible by having complete genomic sequence. Two genes were chosen for comprehensive analysis, n2P16 and n2P17. By comparing the pattern of conservation in genomic DNA sequences between C. elegans and a closely related species, C. briggsae, we were able to identify all coding regions and predict the gene structure for these two genes. Given the extent of the 4TM channel family, we were surprised to discover that n2P17 produced at least six alternative transcripts encoding a constant central region and variable amino- and carboxyl-termini. Blocks of highly conserved DNA sequences in noncoding regions were also apparent and most likely confer important regulatory functions. The interspecies comparison of the deduced channel proteins revealed that the extracellular loop between M1 and P1 is an apparent hot spot for evolutionary change in both channels. This contrasts with the membrane-spanning domains that are highly conserved. Analysis of intron positions for 36 channels revealed that introns are frequently present at an identical position within the pore region, but very few are located in membrane-spanning domains.

Alternative Splicing↗
PubMed1999

Cytotoxic potential of the phytochemical genistein isoflavone (4',5',7-trihydroxyisoflavone) and certain environmental chemical compounds on testicular cells.

The effects of genistein (Gn), sodium azide (naz), and dexamethasone (dxm) on testicular cells TM3, TM4 and GC-1 spg were studied in vitro. First, a series of experiments were performed to assess the response of the cells to the exposure of Gn, naz, dxm, a combination of Gn with naz and Gn with dxm. Trypan blue exclusion assay was used to determine the percentage of viability, and LDH-cytotoxicity test was used to assess the degree of treatment-induced cytotoxicity on each cell type. A second series of experiments were performed to study cytomorphology and determine the type and percentage of treatment-induced cell death (apoptosis and necrosis) on each cell line, using fluorescent dye technique to detect apoptotic and necrotic cells, and tunnel assay to confirm apoptosis. The results from the data obtained demonstrated: i) that incubation of testis cells with each of the agents (Gn, dxm, naz) alone and in two combinations (Gn-dxm, and Gn-naz) induced significant testicular cell death; ii) that both genistein and dexamethasone mostly and significantly induced apoptotic cell death while sodium azide induced necrotic cell death; iii) that addition of dexamethasone to genistein demonstrated synergism in apoptosis on testis cells; and iv) that combination of naz with Gn demonstrated synergism in necrosis on testis cells even though Gn alone did not induce significant necrosis. It is concluded that the synergistic actions of genistein and dxm, and of genistein + sodium azide in induction of apoptosis and/or necrosis may be of clinical and pathophysiological research interest considering the chemopreventive and chemotherapeutic potential of genistein; and the clinico-pharmacological application of dexamethasone and sodium azide.

Animals↗
PubMed1999

Autosomal dominant distal myopathy not linked to the known distal myopathy loci.

The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected individuals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.

Adult↗
PubMed1999

The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat.

The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.

Adrenergic alpha-Agonists↗
PubMed1998

Localization of HuC (ELAVL3) to chromosome 19p13.2 by fluorescence in situ hybridization utilizing a novel tyramide labeling technique.

HuC is a neural-specific member of the Elav family of RNA-binding proteins. This highly conserved gene family plays a crucial role in neurogenesis, and HuC (HGMW-approved symbol ELAVL3) is expressed at an early stage of neural development. Using a novel tyramide fluorescence in situ hybridization (T-FISH) technique, we localized HuC to chromosome 19p13.2. This localization was confirmed by radiation hybrid mapping and coincides with that of HuR (HGMW-approved symbol ELAVL1), another elav family member. Dual T-FISH analysis with HuC and HuR probes, however, indicated distinct loci, with HuC being centromeric to HuR. This study demonstrates the utility of T-FISH in colocalizing two genes on the same chromosomal preparation using only biotinylated probes.

Antigens, Surface↗
PubMed1998

A physical map of 30,000 human genes.

A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.

Animals↗
PubMed1998

Acquisition and utilization of transition metal ions by marine organisms.

Recent research has revealed that trace metals, particularly transition metals, play important roles in marine productivity. Most of the work has been on iron, which shows a nutrient-depleted profile in the upper ocean. Marine organisms have a variety of means for acquiring iron and other transition metal ions that differ from those of terrestrial organisms.

Animals↗
PubMed1998

Isosteric analogues of nicotinamide adenine dinucleotide derived from furanfurin, thiophenfurin, and selenophenfurin as mammalian inosine monophosphate dehydrogenase (type I and II) inhibitors.

Dinucleotides TFAD (6), FFAD (7), and SFAD (8), isosteric NAD analogues derived, respectively, from C-nucleosides 5-beta-d-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 1), 5-beta-d-ribofuranosylfuran-3-carboxamide (furanfurin, 2), and 5-beta-d-ribofuranosylselenophene-3-carboxamide (selenophenfurin, 5), were synthesized as human inosine monophosphate dehydrogenase (IMPDH) type I and II inhibitors. The synthesis was carried out by imidazole-catalyzed coupling of the 5'-monophosphate of 1, 2, and 5 with AMP. These dinucleotides, which are also analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD), the active metabolites of the oncolytic C-nucleosides 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) and 2-beta-D-ribofuranosylselenazole-4-carboxamide (selenazofurin), were evaluated for their inhibitory potency against recombinant human IMPDH type I and II. The order of inhibitory potency found was SAD > SFAD = TFAD = TAD >> FFAD for both enzyme isoforms. No significant difference was found in inhibition of IMPDH type I and II.

Enzyme Inhibitors↗
PubMed1998

Vanadium haloperoxidases.

The nature of the oxidized halogen intermediate in vanadium bromoperoxidase has recently been shown to depend on the nature of the organic substrate. For example, in the presence of indoles, vanadium bromoperoxidase does not release a freely diffusible oxidized halogen intermediate (such as HOBr+/-BR2+/-Br3-). Regioselective investigations are, therefore, now feasible.

Binding Sites↗
PubMed1997

Thyroid hormone-mediated enhancement of heterodimer formation between thyroid hormone receptor beta and retinoid X receptor.

A subset of nuclear receptors, including those for thyroid hormone (TR), retinoic acid, vitamin D3, and eicosanoids, can form heterodimers with the retinoid X receptor (RXR) on DNA regulatory elements in the absence of their cognate ligands. In a mammalian two-hybrid assay, we have found that recruitment of a VP16-RXR chimera by a Gal4-TRbeta ligand-binding domain fusion is enhanced up to 50-fold by thyroid hormone (T3). This was also observed with a mutant fusion, Gal4-TR(L454A), lacking ligand-inducible activation function (AF-2) and unable to interact with putative coactivators, suggesting that the AF-2 activity of TR or intermediary cofactors is not involved in this effect. The wild-type and mutant Gal4-TR fusions also exhibited hormone-dependent recruitment of RXR in yeast. Hormone-dependent recruitment of RXR was also evident with another Gal4-TR mutant, AHTm, which does not interact with the nuclear receptor corepressor N-CoR, suggesting that ligand-enhanced dimerization is not a result of T3-induced corepressor release. Finally, we have shown that the interaction between RXR and TR is augmented by T3 in vitro, arguing against altered expression of either partner in vivo mediating this effect. We propose that ligand-dependent heterodimerization of TR and RXR in solution may provide a further level of control in nuclear receptor signaling.

Cell Nucleus↗
PubMed1997

Behavioral defects in C. elegans egl-36 mutants result from potassium channels shifted in voltage-dependence of activation.

Mutations in the C. elegans egl-36 gene result in defective excitation of egg-laying and enteric muscles. Dominant gain-of-function alleles inhibit enteric and egg-laying muscle contraction, whereas a putative null mutation has no observed phenotype. egl-36 encodes a Shaw-type (Kv3) voltage-dependent potassium channel subunit. In Xenopus oocytes, wild-type egl-36 expresses noninactivating channels with slow activation kinetics. One gain-of-function mutation causes a single amino acid substitution in S6, and the other causes a substitution in the cytoplasmic amino terminal domain. Both mutant alleles produce channels dramatically shifted in their midpoints of activation toward hyperpolarized voltages. An egl-36::gfp fusion is expressed in egg-laying muscles and in a pair of enteric muscle motor neurons. The mutant egl-36 phenotypes can thus be explained by expression in these cells of potassium channels that are inappropriately opened at hyperpolarized potentials, causing decreased excitability due to increased potassium conductance.

Animals↗
PubMed1997

Structure of the mouse serum amyloid A 5 (Saa5) gene: relationship to other members of the serum amyloid A family.

The mouse and human genes which encode the serum amyloid A (SAA) proteins have been extensively characterized. In the present study, the authors report the sequencing of the constitutively expressed mouse Saa5 gene, including approximately 2 kilobases of promoter sequence which extends into the sequence of the adjacent Saa4 pseudogene. The Saa5 gene was thus determined to have a 4 exon/3 intron structure, with a B2 repeat located approximately 450 base pairs upstream, and a microsatellite contained within intron 2. Analyses of Saa5 intronic and promoter sequences, by comparison with representative members of the mouse Saa and human SAA families, provided evidence which strongly suggests that mouse Saa5 and the constitutively expressed human SAA4 gene are evolutionary and functional homologues. Furthermore, putative transcription motifs were identified within the Saa5 and SAA4 promoters which may account, in part, for the constitutive expression and unique induction profiles of these genes.

Animals↗
PubMed1997

Novel strategies for liver support in acute liver failure.

At present, the treatment of a patient in acute liver failure is based upon scrupulous intensive care. In those patients whose condition deteriorates, emergency liver transplantation must be considered. There would be great benefit if it were possible to provide treatment which would stabilise the condition of a patient in acute liver failure. Thus, there is great incentive to develop a means of artificial liver support. Over many years, a considerable array of therapeutic strategies has been investigated. These can be considered in four main categories: plasma exchange, haemofiltration, extra-corporeal liver assist devices (ELAD), extra-corporeal liver perfusion (ECLP). Finally, the role of xenotransplantation is considered.

Animals↗
PubMed1997

Sequence-specific epigenetic effects of the maternal somatic genome on developmental rearrangements of the zygotic genome in Paramecium primaurelia.

In ciliates, the germ line genome is extensively rearranged during the development of the somatic macronucleus from a mitotic product of the zygotic nucleus. Germ line chromosomes are fragmented in specific regions, and a large number of internal sequence elements are eliminated. It was previously shown that transformation of the vegetative macronucleus of Paramecium primaurelia with a plasmid containing a subtelomeric surface antigen gene can affect the processing of the homologous germ line genomic region during development of a new macronucleus in sexual progeny of transformed clones. The gene and telomere-proximal flanking sequences are deleted from the new macronuclear genome, although the germ line genome remains wild type. Here we show that plasmids containing nonoverlapping segments of the same genomic region are able to induce similar terminal deletions; the locations of deletion end points depend on the particular sequence used. Transformation of the maternal macronucleus with a sequence internal to a macronuclear chromosome also causes the occurrence of internal deletions between short direct repeats composed of alternating thymines and adenines. The epigenetic influence of maternal macronuclear sequences on developmental rearrangements of the zygotic genome thus appears to be both sequence specific and general, suggesting that this trans-nucleus effect is mediated by pairing of homologous sequences.

Animals↗
PubMed1996

Mapping genes within a YAC by computer-assisted interpretation of partial restriction digestions.

Partial restriction digestion is used to map restriction sites and the location of genes within yeast artificial chromosomes (YACs). Locus-specific probes are hybridised to the partially digested YAC DNA and the fragments to which they hybridise are compared with the pattern of partial digestion products that include each map region. A least squares criterion is presented which allows for error in fragment length determination. This rapidly defines the most likely location of a marker within the restriction map and permits the combination of results from digestions with different restriction enzymes. Approximate confidence intervals may be assigned to gene locations, and tests of goodness-of-fit of the data may be performed. Since the number of erroneously matched fragments increases in proportion to the square of the number of sites, denser maps are not necessarily more informative. Simulations indicate that the optimal number of internal restriction sites given typical experimental error (1% of YAC length) is about five sites; the associated broad support interval (on average one third of YAC length) may be reduced by combining results from different enzyme digestions. Application of a computer implementation of this model to experimental data showed that the model fitted well, and estimates of location were found to be consistent with other evidence.

Animals↗
PubMed1996

A gene map of the human genome.

The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.

Amino Acid Sequence↗