Use caution when managing paclitaxel and taxotere infiltrations.
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Antineoplastic Agents, Phytogenic↗
Biomedical subjects
M Goodman
Publications and source records attributed to M Goodman.
High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster.
PCR-assisted binding site selection was used to define the sequence characteristics of high affinity YY1 binding sites. Compilation of the sequences of 189 selected oligonucleotides containing high affinity YY1 binding sites revealed two types of core sequence: ACAT and CCAT. ACAT cores were surrounded by other invariant nucleotides, forming the consensus GACATNTT. A search of the 73 kb human beta-like globin cluster with this consensus revealed eight matching motifs, six of which were located within 1-3 kb upstream of the gamma and beta genes. CCAT-type cores were more variable in surrounding sequence context; the consensus VDCCATNWY was found to fit 89% of the selected CCAT-containing oligonucleotides. A search of the human beta globin cluster with CCAT consensus sequences revealed 171 potential YY1 binding sites. Several of these were tested directly in gel shift assays and confirmed as high affinity YY1 binding sites. Finally, a strategy called motif-based phylogenetic analysis was employed to determine which of the 179 total sites are evolutionarily conserved. This analysis permits the detection of functionally conserved binding sites despite sequence differences present between the two species. The 21 conserved sites identified will serve as important starting points in further dissection of the possible role of YY1 in globin gene regulation.
Animals↗
Fate of a redundant gamma-globin gene in the atelid clade of New World monkeys: implications concerning fetal globin gene expression.
Conclusive evidence was provided that gamma 1, the upstream of the two linked simian gamma-globin loci (5'-gamma 1-gamma 2-3'), is a pseudogene in a major group of New World monkeys. Sequence analysis of PCR-amplified genomic fragments of predicted sizes revealed that all extant genera of the platyrrhine family Atelidae [Lagothrix (woolly monkeys), Brachyteles (woolly spider monkeys), Ateles (spider monkeys), and Alouatta (howler monkeys)] share a large deletion that removed most of exon 2, all of intron 2 and exon 3, and much of the 3' flanking sequence of gamma 1. The fact that two functional gamma-globin genes were not present in early ancestors of the Atelidae (and that gamma 1 was the dispensible gene) suggests that for much or even all of their evolution, platyrrhines have had gamma 2 as the primary fetally expressed gamma-globin gene, in contrast to catarrhines (e.g., humans and chimpanzees) that have gamma 1 as the primary fetally expressed gamma-globin gene. Results from promoter sequences further suggest that all three platyrrhine families (Atelidae, Cebidae, and Pitheciidae) have gamma 2 rather than gamma 1 as their primary fetally expressed gamma-globin gene. The implications of this suggestion were explored in terms of how gene redundancy, regulatory mutations, and distance of each gamma-globin gene from the locus control region were possibly involved in the acquisition and maintenance of fetal, rather than embryonic, expression.
Alouatta↗
Conformational studies of retro-inverso peptides: the crystal and molecular structure of the hydantoin from H-Ala-g-Ala-mGly-OBzl.
The crystal structure of the hydantoin 1-[(S)-1'-aminoethylmalonyl benzyl ester]-(S)-4-methylimidazolidin-2,5-dione (1) derived from the peptide H-Ala-gAla-mGly-OBzl, having the retro-inverso modification of the Ala-Gly bond, has been determined by x-ray diffraction analysis. The crystals are orthorhombic, space group P2(1)2(1)2(1) with a = 6.539, b = 14.721, c = 17.101 A, z = 4. The structure was solved by direct methods and refined with anisotropic thermal factors to a final R value of 0.067 for the 947 observed reflections. Reversal of the Ala-Gly amide bond perturbs the folding tendency of the backbone shown by the parent peptide t-BuCO-Ala-Gly-NHiPr. The gem-diamino residue, gAla, and the malonyl moieties are found in the helical and the extended conformations, respectively. Intramolecular hydrogen bonding is not observed. The molecules in the crystal are held together by the formation of two intermolecular hydrogen bonds of the N-H ... O=C type with N ... O distances of 2.86 and 3.17 A, respectively.
Amides↗
Peptide science.
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Biochemical Phenomena↗
IPT: a novel iodinated ligand for the CNS dopamine transporter.
An iodinated cocaine derivative, N-(3'-iodopropen-2'-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl) tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters in Sprague-Dawley rat brain. Saturation analysis of [125I]IPT in rat striatal homogenates, in two different buffer solutions, Tris-HCl and phosphate, demonstrated a one-site binding with affinities (Kd) of 0.25 +/- 0.02 and 0.16 +/- 0.02 nM and densities (Bmax) of 939 +/- 161 and 1,982 +/- 137 fmol/mg protein, respectively. Competition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (-)cocaine. Binding to 5-HT transporter sites was evaluated in rat cortical homogenates. Saturation experiment results showed a single site with a Kd value of 1.2 +/- 0.2 nM and a Bmax value of 100 +/- 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazindol > R-nisoxetine > GBR12909) suggests that [125I] IPT labels 5-HT transporters in rat cortical homogenates. Both ex vivo and in vitro autoradiographic studies revealed high densities of [125I]IPT binding sites in the caudate nucleus, putamen, olfactory tubercle and nucleus accumbens, areas known to be rich in dopaminergic innervation. Moderate accumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was labeled using in vitro autoradiography with [125I]IPT, but the labeling using ex vivo autoradiography was less prominent at 30 min postinjection and not noticeable at 60 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hominoid phylogeny estimated by model selection using goodness of fit significance tests.
Phylogeny estimation from nucleotide sequence data may be thought of as a problem of choosing between different evolutionary models that vary with the branching pattern of the phylogeny and with the stochastic process of nucleotide sequence change occurring on the branches of the phylogenetic tree. Thus, each evolutionary model consists of both a particular stochastic process and a particular phylogeny. Such models produce multinomial distributions of nucleotide character patterns. As first suggested by Cavalli-Sforza and Edwards [Evolution 21: 550-570 (1967)] the distribution of patterns expected under each model can be compared to the actual observed distribution of patterns by a goodness of fit statistic such as the loglikelihood ratio G2 or Pearson's X2 after the numerical parameters for the model have been chosen to minimize the respective statistic. For each evolutionary model, the probability P of getting a value of the goodness of fit statistic greater than the observed value is computed. A very small P value means that either a rare event has occurred or that the model is false. Employing for each of 16 models a stochastic process which has 12 parameters to describe the mode of nucleotide change on each branch of each putative phylogenetic tree, we examined all 15 unrooted dichotomously branching arrangements of orthologous noncoding sequences from the gamma hemoglobin genomic region of the five hominoids (gibbon, orangutan, gorilla, chimpanzee, and human) plus the branching arrangement with a trichotomous separation of gorilla, chimpanzee, and human. Of these 16 models, all had P values less than 0.01, except for the arrangement of human joined by chimpanzee, in turn joined by gorilla, and then orangutan and gibbon. This analysis allows convincing claims to be made about hominoid phylogenetic relationships by testing the applicability of the assumed stochastic process for nucleotide sequence evolution at the same time as testing the inferred phylogenetic branching arrangement.
Animals↗
DNA evidence on the phylogenetic systematics of New World monkeys: support for the sister-grouping of Cebus and Saimiri from two unlinked nuclear genes.
Previous inferences from epsilon-globin gene sequences on cladistic relationships among the 16 extant genera of Ceboidea (the New World monkeys) were tested by strength of grouping and bootstrap values for the clades in the most parsimonious trees found: for this epsilon data set enlarged with additional Cebus and Saimiri orthologues; for another nuclear DNA sequence data set consisting of IRBP (interstitial retinol-binding protein gene) intron 1 orthologues; and for tandemly combined epsilon and IRBP sequences. Different ceboid species of the same genus always grouped strongly together as demonstrated by results on Cebus (capuchin monkeys), Saimiri (squirrel monkeys), Callicebus (titi monkeys), Aotus (night monkeys), Ateles (spider monkeys), and Alouatta (howler monkeys). Other strong groupings that could be represented as monophyletic taxa in a cladistic classification were: Cebuella (pygmy marmoset) and Callithrix (marmoset) into subtribe Callitrichina; Callitrichina, Callimico (Goeldi's monkey), Leontopithecus (lion tamarin), and Saguinus (tamarin) into subfamily Callitrichinae; Callitrichinae, Aotus, Cebus, and Saimiri into family Cebidae; Cacajao (uakari monkey) and Chiropotes (saki) into subtribe Chiropotina; Chiropotina and Pithecia (bearded saki) into tribe Pitheciini; Pitheciini and Callicebus into subfamily Pitheciinae; Brachyteles (woolly spider monkey), Lagothrix (woolly monkey), and Ateles into tribe Atelini; and Atelini and Alouatta into subfamily Atelinae. In addition the epsilon and IRBP results congruently grouped (but at lesser strengths) Brachyteles and Lagothrix into subtribe Brachytelina within Atelini, and also Cebus and Saimiri into subfamily Cebinae within Cebidae. Because the IRBP results weakly grouped Pitheciinae with Cebidae, whereas the epsilon results weakly grouped Pitheciinae with Atelinae, the present evidence is best represented in an interim cladistic classification of ceboids by dividing the superfamily Ceboidea into three families: Atelidae, Pitheciidae, and Cebidae.
Alouatta↗
Evidence on primate phylogeny from epsilon-globin gene sequences and flanking regions.
Phylogenetic relationships among various primate groups were examined based on sequences of epsilon-globin genes. epsilon-globin genes were sequenced from five species of strepsirhine primates. These sequences were aligned and compared with other known primate epsilon-globin sequences, including data from two additional strepsirhine species, one species of tarsier, 19 species of New World monkeys (representing all extant genera), and five species of catarrhines. In addition, a 2-kb segment upstream of the epsilon-globin gene was sequenced in two of the five strepsirhines examined. This upstream sequence was aligned with five other species of primates for which data are available in this segment. Domestic rabbit and goat were used as outgroups. This analysis supports the monophyly of order Primates but does not support the traditional prosimian grouping of tarsiers, lorisoids, and lemuroids; rather it supports the sister grouping of tarsiers and anthropoids into Haplorhini and the sister grouping of lorisoids and lemuroids into Strepsirhini. The mouse lemur (Microcebus murinus) and dwarf lemur (Cheirogaleus medius) appear to be most closely related to each other, forming a clade with the lemuroids, and are probably not closely related to the lorisoids, as suggested by some morphological studies. Analysis of the epsilon-globin data supports the hypothesis that the aye-aye (Daubentonia madagascariensis) shares a sister-group relationship with other Malagasy strepsirhines (all being classified as lemuroids). Relationships among ceboids agree with findings from a previous epsilon-globin study in which fewer outgroup taxa were employed. Rates of molecular evolution were higher in lorisoids than in lemuroids.
Animals↗
The relationship between the pressor response to involuntary isometric exercise and the contractile protein profile of the active muscle in man.
The present investigation examined the relationship between the pressor response during electrically evoked isometric ankle plantar flexion and the contractile protein profile of the active muscle in seven young men [mean (SD) age, 26 (6) years] and five older men [70 (4) years]. Muscle biopsy samples were taken from lateral gastrocnemius (LG) and soleus (SOL) of each subject. These were analysed for isomyosin composition using non-denaturing pyrophosphate polyacrylamide gel electrophoresis. The degree of association was examined between the cardiovascular changes and the fast isomyosin content of LG and SOL individually and in combination (SOL/LG). In the total subject group there was no association between the heart rate response or the change in systolic blood pressure (BP) and the fast isomyosin composition. However, the change in diastolic BP was significantly associated with the fast isomyosin composition of SOL/LG (delta diastolicBP = 0.31 + 0.045% FM SOL/LG, r = 0.65, P = 0.029). These findings suggest that the magnitude of the peripheral reflex mediated pressor response to isometric exercise and the fast isomyosin content of the active muscle are related.
Adult↗
In vivo effects of lamprey GnRH-I and cyclized analogs: a structure-activity study.
Lamprey GnRH-I and lamprey GnRH-III are the only two members of the GnRH family to have substitutions in the sixth position, Glu6 and Asp6, respectively; all other GnRH peptides have Gly in the sixth position suggesting a different conformational structure. Thus, a structure-activity study of lamprey GnRH-I or analogs that were cyclized or with sixth position substitutions were determined in vivo in adult female sea lamprey, Petromyzon marinus. The following analogs which were tested, ([D-Glu6]-GnRH-I; cyclo-[D-Glu6-Trp7-Lys8]-GnRH-I; or cyclo-[Glu6-Trp7-Lys8]-GnRH-I), significantly elevated plasma estradiol compared to controls. However, [D-Glu6]-lamprey GnRH-I was the only analog to significantly stimulate ovulation while another analog [Gly6]-lamprey GnRH-I significantly delayed ovulation. These data suggest that the sixth position of lamprey GnRH is critical for function.
Amino Acid Sequence↗
Recent developments in retro peptides and proteins--an ongoing topochemical exploration.
Main-chain peptidomimetics based on peptide-bond reversal and inversion of chirality represent important structural alterations for peptides and proteins, and are highly significant for biotechnology; these modifications have been widely applied: the D-HIV-protease dimer cleaves only all-D substrate; an all-D-hexapeptide opioid is able to produce analgesia following intraperitoneal administration. Antigenicity and immunogenicity can be achieved by metabolically stable antigens such as all-D- and retro-inverso-isomers of natural antigenic peptides. Isomers, including the retro- and retro-inverso- forms, of hybrid peptides derived from cercropin A and melittin, maintain antimicrobial activity. Therefore, an insight is provided into structure-activity relationships and the rational design of biologically important isomeric peptides.
Amino Acid Sequence↗
Electrically evoked torque-velocity characteristics and isomyosin composition of the triceps surae in young and elderly men.
The electrically evoked isokinetic torque-velocity relationship of the triceps surae of eight elderly and four non-trained young men was examined in relation to the isomyosin composition of the soleus and the gastrocnemius muscles, determined under non-denaturing conditions using pyrophosphate gel electrophoresis. The angle specific torque-velocity properties of the triceps surae were measured using maximal percutaneous electrical stimulation at 50 Hz and a release technique. The elderly subjects generated significantly (P < 0.05) less absolute torque at all angular velocities when compared with the young subjects. When the isokinetic data were normalized to the isometric torque, the lower normalized torques generated by the elderly subjects were not statistically different from the young. The total fast isomyosin (FM) content of the soleus and gastrocnemius in the elderly subjects was 22 +/- 13 and 35+/- 18%, respectively. This compared with 29 +/- 8 (n.s) and 44 +/- 8% (n.s.) in the young subjects. When the gastrocnemius and soleus muscles were given an equal weighting and considered together to represent the whole triceps surae, the normalized torque at the fixed angular velocity of 5 rads s-1 was significantly associated with %FM (r = 0.90, P < 0.01), and the isomyosin bands %FM1 (r = 0.90, P < 0.01) and %FM2 (r = 0.93, P < 0.001) when only the elderly subjects were considered. No relationships were observed between contractile characteristics and contractile protein profile when only the young subjects were considered. This was despite the inclusion of a further two sprint and three endurance trained athletes to increase the range of contractile characteristics and differences in muscle composition.
Adult↗
Characterization of the spinal antinociceptive activity of constrained peptidomimetic opioids.
We examined the in vitro and in vivo bioactivities of several families of peptidomimetic opioids including: constrained linear enkephalin (n = 12 analogs), dermorphin (n = 9 analogs) and morphiceptin (n = 17 analogs). The biological activities were assessed in vitro by examining the inhibitory effects of these agents on the electrically evoked contractions of the guinea pig ileum (GPI) and the mouse vas deferens (MVD) preparations. The in vivo bioactivities were determined from the antinociceptive activity of these agents on the 52.5 degrees C hot-plate test after spinal administration of rats with chronically placed spinal catheters. Examination of the effect of cyclization, incorporation of retro-inverso bonds and substitutions of D- or constrained amino acids reveals systematic changes in the activity of these agents. There was a significant correlation between the potency of these agents in the hot-plate bioassay and their activity in the GPI and, to a lesser extent, in the MVD tests. Examination of the ability of naltrindole (a delta selective antagonist) to reverse the drug action and the respective potency on the GPI and MVD, showed that a correlation exists with actions on the MVD, but not on the GPI, consistent with the likelihood that agents with high MVD/GPI ratios in vitro act at the mu sites, whereas those with low MVD/GPI ratios act at the delta receptor in the spinal cord. The close correlations between activity in the GPI and spinal cord suggest that the structural requirements for potency in the smooth muscle and in the spinal cord are essentially the same as those mu receptors that mediate nociceptive transmission.
Amino Acid Sequence↗
Illness as lifestyle.
To appreciate what illness means to an individual, physicians must understand that person's attitudes, views, and style of life. People react uniquely and creatively to illness and disability. Some incorporate the illness into their lives and use it to help them achieve goals that might not be obvious to the doctor. A case study presents diagnostic and therapeutic problems familiar to family physicians.
Adult↗
Mapping studies of two G protein-coupled receptor genes: an amino acid difference may confer a functional variation between a human and rodent receptor.
We recently isolated two orphan human G protein-coupled receptor genes designated GPR1 and GPR6. The gene GPR1 was shown to be transcribed abundantly but only in the hippocampus. Here we report the cloning of the rat GPR1 gene and report the absence of expression in hippocampus, demonstrating a functional variation for this receptor in these two species. The evolutionary history of an important sequence difference in the gene GPR1 in primate and rodent species has been examined. In contrast extensive mapping of gene GPR6 mRNA in rat brain was in keeping with the described distribution in human brain.
Amino Acid Sequence↗
A simple method for N-15 labelling of exocyclic amino groups in synthetic oligodeoxynucleotides.
The use of the ammonia deprotection step to introduce (15)N labels at specific exocyclic amino positions of adenine, cytosine, guanine or 2-aminopurine of oligodeoxynucleotides is described.
2-Aminopurine↗
Differential phylogenetic footprinting as a means to identify base changes responsible for recruitment of the anthropoid gamma gene to a fetal expression pattern.
Expression of the anthropoid (simian) gamma gene in fetal life contrasts with the exclusively embryonic expression pattern of the gamma-like genes of other eutherian mammals. To elucidate the factors responsible for this change in expression pattern, we utilized a strategy called differential phylogenetic footprinting (DPF). This strategy entails the following: (a) identification, within regulatory regions, of the gamma promoter, of individual nucleotides that differ between human (fetal expression), and galago (embryonic expression) gamma genes, (b) analysis of the effect of these nucleotide differences on the binding of nuclear proteins to human and galago sequences, and (c) assessment of the functional consequences of these binding changes in expression assays. The DPF analysis revealed several proteins that bind upstream from the CCAAT motif in the galago gamma promoter but do not bind to the corresponding region of the human gamma promoter. In transfection assays, binding of these proteins is associated with erythroid-specific repression of promoter strength. Binding sites for these proteins also occur near the CCAAT box of other embryonically expressed genes, including rabbit, mouse, and dwarf lemur gamma genes and the human epsilon globin gene. These data are consistent with the hypothesis that sequence changes near the proximal CCAAT box in the ancestral simian gamma gene may have facilitated a novel expression pattern by reducing the binding of repressors that act in the fetal stage.
Animals↗