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PubMed1986

The 20,000 dalton structural variant of recombinant DNA-derived methionyl human growth hormone has early insulin-like effects in hypophysectomized rats.

The 20,000 dalton variant of recombinant DNA-derived methionyl human growth hormone (20K-Met-hGH) induced decreases in blood glucose and free fatty acid concentrations one hour after intraperitoneal injection into fasted, hypophysectomized rats. Similar results were obtained using the 22,000 dalton form of recombinant DNA-derived methionyl human growth hormone (22K-Met-hGH). The data reported show that 20K-Met-hGH induces early insulin-like effects similar to the responses produced by 22K-Met-hGH in fasted hypophysectomized rats.

Animals↗
PubMed1992

Structural variants of the neural cell adhesion molecule (N-CAM) in developing feathers.

The neural cell adhesion molecule (N-CAM) is expressed in a specific spatiotemporal pattern during feather development, suggesting that adhesion mediated by this molecule is involved in feather morphogenesis. To begin to investigate N-CAM's function in developing feathers, we determined what forms of N-CAM polypeptide are present and the distribution of polysialic acid (PSA), a carbohydrate moiety that decreases N-CAM-mediated cellular adhesion. N-CAM in skin appears as a Mr 145-kDa polypeptide compared to the 140-kDa brain N-CAM polypeptide, and is encoded by a 6.4-kb mRNA, compared to the 6.1-kb mRNA in brain. Polymerase chain reaction analysis of the exon splicing pattern of skin N-CAM shows that the 6.4-kb mRNA band represents two transcripts, with and without a 93-bp insert between exons 12 and 13. Thus, two N-CAM polypeptides are expressed in skin, but the 93-bp insert does not account for the larger size of the skin mRNAs and polypeptides. We show that the size difference of the polypeptides is instead due to N-linked oligosaccharides attached to the skin N-CAM proteins. The larger size of the skin mRNAs may be due to use of a different transcriptional start site. Staining of skin sections and wholemounts confirms previous descriptions of N-CAM in developing feathers, but reveals that N-CAM is also present at low levels on epidermal cells as early as stage 29 (E6). We find that PSA is expressed only on a subset of the cells that express N-CAM, in particular on dermal cells in the feather rudiments from stage 35-36 (E9-10) and on smooth muscle cells at the base of the filaments from stage 37 (E11) until the latest stage examined (stage 44, E18). The known effects on cell-cell adhesion of amount of N-CAM and PSA suggest that the variations we observe in skin may regulate cell-cell interactions that are important in feather development.

Animals↗
PubMed1995

Time-variant structure of auditory cortex of the macaque monkey.

Supra-threshold responses of neurons in the primary auditory cortex of the macaque monkey are so complex that the characteristic frequency cannot be determined. By statistical analyses based on analysis of variance and principal component analysis, we demonstrated that the similarity of neurons from penetration perpendicular to the surface of the cortex decreases to such a level that they cannot be considered as a unit and that correlation among neurons from different cortical positions can be higher than that for neurons from penetration. This means that the frequency map is not evident for stimuli at supra-threshold. Moreover, we found that a single neuron utilizes different time segments to extract different physical aspects of stimuli. Our results indicate that encoding auditory information may involve other structures than the frequency map.

Animals↗
PubMed1982

Purification and identification of two structural variants of porcine tissue plasminogen activator by affinity adsorption on fibrin.

Porcine tissue plasminogen activator has been purified from delipidized heart tissue by affinity adsorption to fibrin. A crude fraction is prepared from an acid tissue extract by precipitation with ammonium sulphate. The tissue activator of this fraction is isolated by adsorption on fibrin and elution with KSCN. The procedure also includes chromatography on arginine-Sepharose and two gel-filtration steps. The final product has a specific activity of 250 000 IU/mg (+/- 16 000) as compared to an international urokinase reference preparation. The yield calculated from the active ammonium sulphate precipitate is about 28%. An approx. 7 000-fold increase of specific activity is obtained, most of which is achieved in the fibrin step. The native tissue plasminogen activator consists of a single chain molecule with a molecular weight of 64 000 as measured by SDS-polyacrylamide gel electrophoresis. In a previous report, it was claimed that the activator is composed of two disulphide-connected polypeptide chains. These results were due to a preparation artefact, caused by proteolytic activity present in the tissue extracts. The introduction of the protease inhibitor aprotinin and 6-amino-hexanoic acid in the purification procedure has abolished the effect of the protease contaminant, leading to the production of a one-chain activator. Treatment with plasmin transforms the native, one-chain tissue activator into a variant composed of two chains of about equal size (Mr 32 000) connected by disulphide bonding. This modified activator is indistinguishable from the one obtained at insufficient protection against proteolytic enzymes. The cleavage by plasmin causes about an 8-fold increase of amidolytic activity as measured on H-D-Val-Gly-Arg-p-nitroanilide. The fibrinolytic activity as measured by clot lysis in only slightly increased. The physiological significance of the cleavage is discussed.

Amino Acids↗
PubMed1988

Structural variants of verapamil and W-7 with combined Ca2+ entry blockade/myosin phosphorylation inhibitory mechanisms.

Arylalkylsulfonamides, identified as Wy-46,622 and Wy-47,324, combine pharmacological properties of the Ca2+ entry blocker verapamil and the calmodulin antagonist W-7. These agents directly inhibit arterial actin-myosin interactions via inhibition of myosin light chain (MLC) phosphorylation in actomyosin. Potencies of both Wy-46,622 (IC50 = 26 microM) and Wy-47,324 (IC50 = 18 microM) are greater than W-7 (IC50 = 35 microM); verapamil is inactive at 100 microM. Both Wy-46,622 and Wy-47,324 are less potent than verapamil, but more potent than W-7, at inhibiting K+-depolarized force development in paced rabbit atria. At higher concentrations (30 microM) which inhibit MLC phosphorylation, Wy-46,622 and Wy-47,324 are either equal to or more efficacious than verapamil in inhibiting receptor-mediated contractions in intact porcine coronary (histamine, serotonin, prostaglandin F2 alpha, carbocyclic thromboxane A2) or guinea pig aortic (leukotriene C4) smooth muscle. Both Wy-47,324 (IC50 = 16 microM) and Wy-46,622 (IC50 = 23 microM) are inhibitors of the second phase of epinephrine-induced human platelet aggregation; Wy-47,324 is more potent than verapamil or W-7 (IC50 for each = 29 microM). These results suggest that these agents possess combined Ca2+ entry blocker/MLC phosphorylation inhibitory mechanisms. Furthermore, they are more vascular specific than verapamil, and are effective inhibitors of intracellular Ca2+-mediated events in vascular smooth muscle and platelets.

Actomyosin↗
PubMed2019

Direct RNA nanopore sequencing of full-length coronavirus genomes provides novel insights into structural variants and enables modification analysis.

Sequence analyses of RNA virus genomes remain challenging owing to the exceptional genetic plasticity of these viruses. Because of high mutation and recombination rates, genome replication by viral RNA-dependent RNA polymerases leads to populations of closely related viruses, so-called "quasispecies." Standard (short-read) sequencing technologies are ill-suited to reconstruct large numbers of full-length haplotypes of (1) RNA virus genomes and (2) subgenome-length (sg) RNAs composed of noncontiguous genome regions. Here, we used a full-length, direct RNA sequencing (DRS) approach based on nanopores to characterize viral RNAs produced in cells infected with a human coronavirus. By using DRS, we were able to map the longest (∼26-kb) contiguous read to the viral reference genome. By combining Illumina and Oxford Nanopore sequencing, we reconstructed a highly accurate consensus sequence of the human coronavirus (HCoV)-229E genome (27.3 kb). Furthermore, by using long reads that did not require an assembly step, we were able to identify, in infected cells, diverse and novel HCoV-229E sg RNAs that remain to be characterized. Also, the DRS approach, which circumvents reverse transcription and amplification of RNA, allowed us to detect methylation sites in viral RNAs. Our work paves the way for haplotype-based analyses of viral quasispecies by showing the feasibility of intra-sample haplotype separation. Even though several technical challenges remain to be addressed to exploit the potential of the nanopore technology fully, our work illustrates that DRS may significantly advance genomic studies of complex virus populations, including predictions on long-range interactions in individual full-length viral RNA haplotypes.

Cell Line↗
PubMed1990

Sparteine metabolism capacity in human liver: structural variants of human P450IID6 as assessed by immunochemistry.

An antibody raised against rat P450dbl was used to examine the heterogeneity of the human enzyme involved in the sparteine/debrisoquine polymorphism. The extent to which the antibody was able to inhibit sparteine metabolism varied in different human livers (10-80%, n = 9) and reflected the amount of sparteine metabolism carried out by the polymorphic P450IID6 in individual liver specimens. The individual sample variation in inhibition by the antibody correlated with the inhibition caused by quinidine, a prototype competitive inhibitor of the P450IID6 enzyme active site. Western immunoblots of the liver microsomes confirmed that the variation in the inhibition of sparteine metabolism by this antibody reflected the amount of P450IID6 protein. In addition, a detailed study of one of the livers (K19) which demonstrated a lack of inhibition by the antibody was performed which confirmed the lack of P450IID6 in this liver specimen and suggested that the nascent sparteine metabolism activity was due to other forms of P450.

Animals↗
PubMed1989

Immunization of cattle with the MSP-1 surface protein complex induces protection against a structurally variant Anaplasma marginale isolate.

The Anaplasma marginale surface protein complex MSP-1 of the Florida isolate is composed of a 105-kilodalton (kDa) polypeptide, which bears a neutralization-sensitive epitope, and a 100-kDa polypeptide. Antigenically similar polypeptides in the Okanogan, Wash. (Washington-O), isolate MSP-1 are 86 and 100 kDa, respectively. Immunization of cattle with Florida isolate MSP-1 induced antibody titers to both MSP-1 polypeptides and protected cattle against homologous and heterologous challenge.

Anaplasma↗
PubMed1995

Structurally variant classes of pilus appendage fibers coexpressed from Burkholderia (Pseudomonas) cepacia.

One or more of five morphologically distinct classes of appendage pili were determined to be peritrichously expressed by Burkholderia (formerly Pseudomonas) cepacia isolated from disparate sources. B. cepacia-encoded cblA pilin gene hybridization-based analysis revealed that one associated class, cable (Cbl) adhesin type IIB. cepacia pili, correlates with epidemically transmitted strains from a single cystic fibrosis (CF) center. When only phenotypic assays were available, correlations between the source and the pilus type were nonetheless observed: filamentous (Fil) type IIIB. cepacia pili correlated with CF-associated nonepidemic isolates, spine (Spn) type IVB. cepacia pili correlated with clinical (non-CF) isolates, and spike (Spk) type VB. cepacia pili correlated with environmental isolates. Further, Cbl, Fil, or Spk pili typically appear as an internal framework for constitutively coexpressed, peritrichously arranged dense mats of fine, curly mesh (Msh) type IB. cepacia pili. Constitutive coexpression of dense mats of Msh type IB. cepacia pili in association with a labyrinth of either Cbl, Fil, or Spk pili suggests possible cooperative pilus interactions mediating adhesion-based colonization in the differing environments from which the strains were isolated. Despite such correlations, phylogenetic analyses indicate that with the exception of the epidemically transmitted clusters of isolates, the remaining B. cepacia strains from the other three sources exhibited an equal degree of genetic relatedness independent of origin. As previously found for Escherichia coli, this discrepancy could be accounted for by selection-driven, in vivo horizontal transfer events between distantly related members of the species B. cepacia, leading to the genetic acquisition of environmentally appropriate adhesion-based colonization pilus operons.

Bacterial Outer Membrane Proteins↗
PubMed1989

Molecular population genetics of structural variants of esterase 6 in Drosophila melanogaster.

Several lines of evidence indicate that natural selection operates between the major EST6-F and EST6-S allozymes of Drosophila melanogaster. In particular, consistent latitudinal clines and seasonal variation in their relative frequencies strongly suggest that they are not selectively equivalent in field populations. Several laboratory studies have found frequency-dependent fitness differences among the Est6-F and Est6-S genotypes. Moreover, the purified EST6-F and EST6-S allozymes differ in biochemical properties and the physiology of the enzyme, as a major component of the seminal fluid, suggests that these differences could affect reproductive aspects of fitness. However, molecular analyses reveal high levels of variation in the EST6 protein both within and between the EST6-F and EST6-S allozymes. Limited thermostability and more sensitive electrophoretic analyses reveal at least 17 variants of the two allozymes and sequence comparisons among 13 isolates of the Est6 gene reveal 16 nucleotide polymorphisms that would lead to amino acid differences. Two closely linked amino acid differences are strongly associated with the major difference between EST6-F and EST6-S; either or both of these are likely to cause the observed biochemical differences between EST6-F and EST6-S and may be the primary targets for the selection between these allozymes. The functional and adaptive significance of the other amino acid polymorphisms is unclear, although the data suggest that the EST6-8 haplotype within EST6-S has both arisen and proliferated relatively recently.

Alleles↗