Biomedical subjects

M Goodman

Publications and source records attributed to M Goodman.

At least 271 records · Page 15Linked to original sources

PubMed1988

The spider monkey psi eta-globin gene and surrounding sequences: recent or ancient insertions of LINEs and SINEs?

A phylogenetic comparison of the psi eta-globin DNA sequence of the spider monkey (Ateles geoffroyi) to orthologous sequences from other primates provides evidence for an evolutionarily recent (less than 17 million years ago (MYA] insertion of a truncated L1 LINE (long interspersed repetitive element). An Alu SINE (short interspersed element), found 3 kb downstream of the poly(A) addition site, arose less than 40 MYA subsequent to the divergence of platyrrhinies (New World monkeys) from catarrhines (humans, apes, and Old World monkeys). Another Alu element, which appears in the catarrhines 588 bp upstream from the psi eta gene, is absent in Ateles, thus placing its possible time of insertion between 20 and 40 MYA. Alignment of the Ateles psi eta sequence with orthologous hominoid sequences (M. M. Miyamoto, J. L. Slightom, and M. Goodman, 1987, Science 238: 369-373) provides unequivocal evidence against the view (J. H. Schwartz, 1987, "The Red Ape: Orang-utans and Human Origins," Houghton Mifflin, Boston, MA) that the orangutan forms a monophyletic group with human. Furthermore, a critical analysis of potential sources of homoplasy (i.e., parallel evolution) reaffirms a Homo-Pan monophyletic clade (Miyamoto et al., 1987). Reconstruction of primate psi eta sequence phylogeny suggests Ateles and Aotus shared a common ancestor only 16 +/- 1.5 MYA. Finally, the results show a mutation rate of 1.7 +/- 0.2 x 10(-9) mutations site-1 year-1 during the evolution of the Ateles psi eta-globin region since the divergence of catarrhines from platyrrhinies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Evolutionary and developmental aspects of two hemoglobin beta-chain genes (epsilon M and beta M) of opossum.

A series of gene duplications that began in a stem species of Mammalia and led to five developmentally regulated hemoglobin beta-chain loci (epsilon, gamma, eta, delta, and beta) in a common ancestor of eutherian orders Artiodactyla, Rodentia, Lagomorpha, and Primates had important consequences in mammalian evolution. Findings reported here indicate that two progenitors of the five linked genes existed by the time of the eutherian (placental mammal)-metatherian (marsupial mammal) split and that these two genes were already differentiated with respect to their promoter regions and developmental expression. Southern blot and sequence analyses of the hemoglobin beta-chain genes of the opossum (Didelphis virginiana) revealed only two genes, one with coding and promoter sequences similar to eutherian prenatally expressed epsilon, gamma, and eta genes and the other coding for adult opossum hemoglobin beta-chains and having eutherian adult beta-type promoters. The most parsimonious arrangement of greater than 80 beta-globin exon sequences depicts the opossum embryonic-type gene as orthologously related to eutherian epsilon, gamma, and eta genes and the opossum adult-type gene as orthologously related to delta and beta genes. These data further indicate that after the initial beta duplication in the stem of Mammalia, the locus that became developmentally delayed in its expression evolved at a faster rate than the locus that became embryonically expressed.

Amino Acid Sequence↗

PubMed1988

Molecular systematics of higher primates: genealogical relations and classification.

We obtained 5' and 3' flanking sequences (5.4 kilobase pairs) from the psi eta-globin gene region of the rhesus macaque (Macaca mulatta) and combined them with available nucleotide data. The completed sequence, representing 10.8 kilobase pairs of contiguous noncoding DNA, was compared to the same orthologous regions available for human (Homo sapiens, as represented by five different alleles), common chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), and orangutan (Pongo pygmaeus). The nucleotide sequence for Macaca mulatta provided the outgroup perspective needed to evaluate better the relationships of humans and great apes. Pairwise comparisons and parsimony analysis of these orthologues clearly demonstrated (i) that humans and great apes share a high degree of genetic similarity and (ii) that humans, chimpanzees, and gorillas form a natural monophyletic group. These conclusions strongly favor a genealogical classification for higher primates consisting of a single family (Hominidae) with two subfamilies (Homininae for Homo, Pan, and Gorilla and Ponginae for Pongo).

Animals↗

PubMed1988

Higher-primate phylogeny--why can't we decide?

At present, no definitive agreement on either the correct branching order or differential rates of evolution among the higher primates exists, despite the accumulated integration of decades of morphological, immunological, protein and nucleic acid sequence data, and numerous reasonable theoretical models for the analysis, interpretation, and understanding of those data. Of the three distinct unrooted phylogenetic trees, that joining human with chimpanzee and the gorilla with the orangutan is currently favored, but the two alternatives that group humans with either gorillas or the orangutan rather than with chimpanzees also have support. This paper is a synthetic and critical review of the methodological literature and isolates some 20 specific reasons why uncertainty in the evolutionary understanding of our closest living relatives persists. Many of the difficulties are eliminated or ameliorated by Lake's new methods of phylogenetic invariants and operator metrics. In the companion paper these new methods are used to analyze both the nuclear and mitochondrial DNA of the higher primates.

Animals↗

PubMed1988

Analysis of higher-primate phylogeny from transversion differences in nuclear and mitochondrial DNA by Lake's methods of evolutionary parsimony and operator metrics.

In the companion paper (Holmquist et al. 1988), we concluded that there is no agreement on either the correct branching order or differential rates of evolution among the higher primates, and we examined in depth why this uncertainty in the evolutionary understanding of our closest living relatives persists. Recently, Lake developed two novel methods, based on group properties of transition and transversion operators, that (a) permit, in principle, objective resolution of problems of the above type and (b) attach a statistical significance level to the conclusions drawn. In the present paper, we develop formulas for using these two methods in tandem and apply them to study transversion differences in (1) nuclear DNA for a 7-kb segment of the psi eta-globin locus and a 3-kb intergenic region between the psi beta- and delta-globin loci and (2) mitochondrial DNA for the 896-bp fragment of Brown et al. Although each of these nucleotide sequence regions has its characteristic tempo and mode of evolution, the nuclear and mitochondrial data together, comprising a total of 10,939 base positions, support a Homo/Pan clade at the 97% confidence level. If we calibrate the divergence point for humans and chimpanzees at 5 Myr, consideration of the transversion branch lengths for the combined nuclear data indicates that the gorilla lineage branched off 600,000-900,000 years prior to that, although the 2 sigma sampling errors do not preclude either a temporal trifurcation for the three species or a considerably more ancient branch point for the gorilla. To resolve the length of this central branch to a relative accuracy of 25% and 30% will require a factor of 16 and nine times more data, respectively--i.e., in excess of 100,000 homologous nucleotides for each of the four primates. For the nuclear genes, heterogeneity in evolutionary rates between different parts of the genome is mostly restricted to the human lineage for these two segments. The lineage leading to chimpanzees has evolved 0.4 (3-kb fragment) to 3.5 (7-kb segment) times as rapidly as the lineage leading to humans, and that leading to the gorilla has evolved approximately one-fifth to one-half as rapidly as that leading to chimpanzees. Thus, even local molecular clocks can "tick" badly. As significant is the fact that virtually contiguous parts of the genome tick at markedly different rates.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique.

We have conducted permeation studies to assess the effectiveness of accelerants Azone, oleic acid (OA), decylmethyl sulfoxide (DCMS) and propylene glycol (PG) in promoting the absorption through human skin of model drugs 5-fluorouracil (5FU) and estradiol (ES). Drug permeation from saturated aqueous solutions was monitored before and after accelerant treatment (applied in aqueous and PG vehicles). With ES, the study was repeated with 50% ethanol/water as donor and receptor phases instead of water. Two percent Azone in PG promoted 5FU absorption by almost 100-fold, but 3% Azone with 0.1% Tween 20 in normal saline demonstrated only an eightfold effect. Five percent OA in PG was moderately successful, but 4% aqueous DCMS enhanced 5FU permeation 35-fold initially, but rapidly fell to fourfold. PG itself was ineffective. The accelerants were much less effective in promoting ES absorption; only 5% OA in PG enhanced steroid permeation by more than tenfold, but this fell with time to threefold due to washout of accelerant (ethanol/water system). The experimental conditions utilized fully hydrated stratum corneum with permeants in saturated solutions; under these already optimized conditions for permeation, accelerants were only marginally effective in enhancing the delivery of the relatively non-polar drug ES. Polar drug delivery, as exemplified by 5FU, could still be increased markedly. Azone was considerably more effective when used in conjunction with PG compared to an aqueous vehicle; thus PG itself may play an accelerating role. The 5FU results indicated that Azone and OA remained in the tissue for a long period, but DCMS was rapidly removed by washout.

Administration, Cutaneous↗

PubMed1988

Synthesis, taste properties, and conformational analysis of four stereoisomeric cyclopropane analogs of aspartame.

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Aspartame↗

PubMed1988

The effect of topical cyclosporin A on the elicitation phase of allergic contact dermatitis.

The effect of cyclosporin A (CSA) on the elicitation phase of allergic contact dermatitis was investigated. Initially, the ability of CSA to penetrate normal human cadaver skin was determined using 3 different vehicles. 10% CSA in Labrafil was found to be the most effective combination at achieving skin penetration (0.33%). Patients with known contact sensitivities to a variety of allergens were selected. After a 48-h pretreatment with 10% CSA in Labrafil, skin sites were exposed to the appropriate contact allergen. 72 h later, the development of an eczematous patch test reaction was evaluated. Only 1 of 10 patients showed unequivocal signs of suppression of allergic contact dermatitis.

Administration, Cutaneous↗

PubMed1988

A comparison of paraganglioma, carcinoid tumor, and small-cell carcinoma of the larynx.

Laryngeal paraganglioma, carcinoid tumor, and small-cell carcinoma are rare. Histologically they are similar to analogous tumors in other locations but may be difficult to identify in small biopsy specimens. We compared the light microscopic, histochemical, immunohistochemical, and electron microscopic features of two laryngeal paragangliomas, one carcinoid tumor, and six small-cell carcinomas. The paraganglioma chief cells stained with Grimelius stain and for chromogranin and neuron-specific enolase. The carcinoid tumor cells stained with Grimelius stain and for chromogranin, serotonin, neuron-specific enolase, and keratin. The small-cell carcinoma cells stained for keratin and neuron-specific enolase. The patients with paragangliomas and carcinoid tumor remain healthy through 20 months of follow-up. Four of the patients with small-cell carcinomas have died. Distinction between these tumors is warranted by differing histologic appearances, staining characteristics, and biologic behavior.

Adult↗

PubMed1987

Phylogenetic relations of humans and African apes from DNA sequences in the psi eta-globin region.

Sequences from the upstream and downstream flanking DNA regions of the psi eta-globin locus in Pan troglodytes (common chimpanzee), Gorilla gorilla (gorilla), and Pongo pygmaeus (orangutan, the closest living relative to Homo, Pan, and Gorilla) provided further data for evaluating the phylogenetic relations of humans and African apes. These newly sequenced orthologs [an additional 4.9 kilobase pairs (kbp) for each species] were combined with published psi eta-gene sequences and then compared to the same orthologous stretch (a continuous 7.1-kbp region) available for humans. Phylogenetic analysis of these nucleotide sequences by the parsimony method indicated (i) that human and chimpanzee are more closely related to each other than either is to gorilla and (ii) that the slowdown in the rate of sequence evolution evident in higher primates is especially pronounced in humans. These results indicate that features (for example, knuckle-walking) unique to African apes (but not to humans) are primitive and that even local molecular clocks should be applied with caution.

Animals↗

PubMed1987

The four stereoisomers of a high potency congener of isoproterenol. Biological activity and the relationship between the native and the chemically inserted asymmetric carbon.

The RR isomer of a para-trifluoromethyl anilide congener of isoproterenol (PTFMA) had an affinity eighty and one hundred times higher than (-)isoproterenol for the beta receptor of turkey erythrocytes and of S49 cells respectively. This affinity was also much higher than that of +/- hydroxybenzyl isoproterenol (HBI) tested in the same experiments. The chemically inserted asymmetric carbon seemed to be as important as the native asymmetric carbon of the catecholamines in determining the binding affinity. Thus the RS and SR isomers demonstrated similar affinities in the turkey erythrocyte membranes as well as in the S49 lysed cells. The RR isomer had the lowest Kact in activation of adenylate cyclase in both beta receptor systems. The three most potent PTFMA isomers showed a Kact/Kd ratio which was higher than that of (-)isoproterenol or (+/-)HBI. It is therefore possible that the large substituent on the amino group in PTFMA, which greatly increases the binding affinity, is not as efficient in receptor activation. Yet the RR isomer had a Kact considerably lower than that of (-)isoproterenol in both of the beta receptor systems. The type of beta receptor of the turkey erythrocyte could be distinguished from that of the S49 cells by comparing the relative order of affinities of the RS and SR isomers and also by comparing (+/-)HBI with (-)isoproterenol. A labeled RR isomer of PTFMA could become most useful as an agonist ligand for beta receptors because of its very high binding affinity for both beta 1 and beta 2 receptors.

Adenylyl Cyclases↗

PubMed1987

In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

Adipose Tissue↗

PubMed1987

Neurodevelopmental predictors of short-term outcome in very-low-birth-weight infants.

Having previously confirmed a lower developmental quotient (DQ) in very-low-birth-weight infants identified by physiotherapists as being at risk, a retrospective analysis was undertaken to ascertain which of the neurodevelopmental tests were of value in predicting subsequent poor outcome. At 3 months corrected age, 9 tests differentiated normal from at-risk infants, and infants with abnormal test results were assessed as having a 56% (mean) risk of subsequent DQ less than 100. At the 6-month assessment, 7 neurodevelopmental tests differentiated normal from at-risk infants; infants with abnormal test results had a 73% (mean) risk of subsequent DQ less than 100. At 12 months, 3 tests differentiated normal from at-risk infants; infants with abnormal test results had a 79% (mean) risk of DQ less than 100. We believe the identification of predictive tests may assist doctors and developmental therapists in assessing need for intervention and response to treatment in high-risk infants. However, it must be noted that the tests studied relate to DQ at 1 year; we are not yet in a position to comment on the relationship between 1 year DQ and subsequent neurodevelopmental outcome.

Age Factors↗

PubMed1987

Orangutan fetal globin genes. Nucleotide sequence reveal multiple gene conversions during hominid phylogeny.

We have determined the nucleotide sequences of the linked gamma 1- and gamma 2- fetal globin genes from a single orangutan (Pongo pygmaeus) chromosome and compared them with the corresponding genes of other simian primates (gamma 1- and gamma 2-genes of human, chimpanzee, gorilla, and the single gamma-gene of the spider monkey). Previous studies have indicated that the two gamma-gene loci in catarrhine primates resulted from a duplication about 25-35 million years ago. However, comparisons of aligned gamma-gene sequences show that these genes contain three regions with distinct histories of which only the 3' third clearly reflects the ancestral nature expected of the gamma-gene duplication. To explain these different evolutionary histories and also hominid relationships we provide evidence for the occurrence of sequence conversions which affect region 1 (120 base pairs 5'-flanking through exon 2) in all hominid species and extend to varying degrees into region 2 (intron 2 through exon 3). Close examinations of the proposed conversions further suggest that 12 of the 13 conversions identified involved gamma 1 converting gamma 2. Polarity of these conversions may be a result of differential survival between these genes because during human fetal development the gamma 1-gene is preferentially expressed over the gamma 2-gene and it may be subjected to greater selection pressure to remain unaltered.

Animals↗

PubMed1987