Concordance of hospital cancer registry- and physician-collected data for patients with melanoma.
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California↗
Biomedical subjects
M Goodman
Publications and source records attributed to M Goodman.
Synthesis and conformational properties of the lanthionine-bridged opioid peptide [D-AlaL2,AlaL5]enkephalin as determined by NMR and computer simulations.
We report the synthesis and conformational analysis by means of NMR and computer simulations of a novel opioid peptide with the sequence [formula: see text], which we write as [formula: see text], abbreviated [D-AlaL2,L-AlaL5]EA, where AlaL denotes each of the lanthionine amino acid ends linked by a monosulfide bridge and EA indicates enkephalinamide. Data from 2D NMR (HOHAHA and ROESY) provide short-range NOEs that are used as constraints in molecular modeling; measurement of coupling constants shows that chi 1 (D-AlaL2) is predominantly in either the t or g- conformation, and temperature coefficient data suggest the participation of the AlaL5 amide proton in an intramolecular hydrogen bond. The use of NOE and hydrogen-bond constraints in a distance-geometry program yields a large number of initial conformations compatible with the data. Energy minimization of these structures using CHARMM results in three families of backbone ring conformations, labled A1, A2, and B. The torsion chi 1 in D-AlaL2 remains close to trans for all three conformations. Molecular dynamics in vacuo at 300 K show that these three families of conformers interconvert, with concerted shifts in two of the three torsions psi(Phe), phi(AlaL5), and chi(AlaL5). The [D-AlaL2,L-AlaL5]EA is superactive in the guinea pig ileum (GPI) and mouse vas deferens (MVD) in vitro tests and also in the rat hot plate test in vivo. At the same time, this analog with a constrained 13-membered ring shows virtually no selectivity with a ratio IC50 (MVD)/IC50 (GPI) of 0.882.
Amino Acid Sequence↗
Tandemly duplicated alpha globin genes of gibbon.
The alpha globin gene locus of the common gibbon (Hylobates lar) was isolated, and it contains two closely linked alpha globin genes that share the same arrangement as that found for the homologous genes of other catarrhine primates. The nucleotide sequences of the gibbon alpha globin genes were determined and compared with the alpha globin gene sequences from other primate species (human, chimpanzee, orangutan, baboon, and rhesus); the prosimian primate, galago, alpha A and alpha B globin genes provided the out-group for this analysis. The degree of divergence for both synonymous and nonsynonymous substitutions among the alpha globin genes are generally smaller for intraspecies than interspecies comparisons, which is indicative of concerted evolution between the paired alpha globin genes of each catarrhine species. The pattern of differences is suggestive of gene conversions. This possibility is supported by both site-by-site and branch-swapping parsimony analyses. The site-by-site parsimony analysis was also used to determine the 3' boundary of each catarrhine species-specific conversion. These alpha globin gene conversion events encompass most of the transcriptional region, including the promoter, exons, introns, and about one-half of the 3'-untranslated region. However, the paired gibbon alpha globin genes show the highest degree of divergence, differing by five nucleotides in their coding regions, three of which encode amino acid replacement substitutions. It appears that the last convergence event between the paired gibbon alpha globin genes is relatively ancient, having occurred approximately 11 million years ago. The remaining 3'-untranslated region and flanking DNAs show no evidence of involvement in any recent conversion event as the parsimony analysis of these sequences group all the alpha 1 globin genes of the different catarrhine species into one clade and all the alpha 2 globin gene of these species into a separate clade. The sequence comparison among the alpha globin genes of different primate species also provides interesting implications regarding the evolution and functional domains of the 3'-untranslated regions.
Amino Acid Sequence↗
Fetal recruitment of anthropoid gamma-globin genes. Findings from phylogenetic analyses involving the 5'-flanking sequences of the psi gamma 1 globin gene of spider monkey Ateles geoffroyi.
We determined the nucleotide sequence of a 2.5 kb DNA fragment (1 kb is 10(3) base-pairs) that includes exon 1, intron 1 and about 1.4 kb of 5'-flanking DNA of the spider monkey gamma 1-globin pseudogene locus and compared this sequence to its homologous from other primates and rabbit. This region of the gamma 1 locus of spider monkey still retains conserved regulatory elements, suggesting that it became a pseudogene late in New World monkey phylogeny. In the 250 base-pair region immediately 5' from the transcription start site where many known regulatory elements are located, a higher rate of nucleotide substitutions occurred in the ancestral anthropoid (human, ape and monkey) lineage than in the prosimian (galago) lineage, as was also the case for non-synonymous substitutions in the coding region. The opposite pattern was observed for most other non-coding regions and for synonymous substitutions. These substitution patterns correlate with the embryonic-to-fetal transformation of the gamma-globin genes of the ancestral anthropoids. Analysis of the 5'-flanking sequences suggests that 11 gene conversion events have occurred in the anthropoid gamma-gene lineages. In the parts of the 5'-flanking region where no gene conversions have been detected, gamma 2-gene sequences have accumulated more nucleotide changes than gamma 1, which suggests that the gamma 2 gene was the more redundant duplicate that may have accumulated first the nucleotide changes responsible for the anthropoid fetal pattern of gamma-globin gene expression.
Animals↗
Rejection of the "flying primate" hypothesis by phylogenetic evidence from the epsilon-globin gene.
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Animals↗
Minimum energy conformations of proline-containing helices.
Proline occurs frequently in transmembrane alpha-helices of transport and receptor proteins even though statistical surveys demonstrate the overwhelming preference of this residue for a non-alpha-helical, hydrophilic environment. As a result, membrane-buried proline has been proposed to be functionally important, with function arising from structural discontinuity or destabilization of the helix. Destabilization may occur by Pro-mediated conformational transitions between discrete states, and may be manifested in membrane protein systems through reversible processes such as channel opening and closing or signal transduction. In this study, computer modeling of a model transmembrane alpha-helix, (Ala)8-Leu-Pro-Phe-(Ala)8, in a medium of low polarity (dielectric = 2), is used to examine the occurrence and energetic accessibility of Pro-mediated conformational interconversions. Leu psi and chi 1, Pro psi, and Phe phi and chi 1 torsion angles were assigned random values so that a data base of 200 conformations for each of the cis and trans states was generated. The conformations were minimized and low-energy structures organized into families. This analysis demonstrated that the most populated lowest energy family is the Trans-I conformation, corresponding to proline in a kinked alpha-helix. Two additional trans structures, Trans-II and Trans-III, as well as a cis conformation, Cis-I, are also energetically competitive. Interconversions between the trans states could thus be mediated by changes at a single torsion angle, accompanied by minor local hydrogen-bonding rearrangements. This work substantiates that membrane-buried proline can provide the basis for conformational transitions between discrete alpha-helix-based structures in a nonpolar environment.
Amino Acid Sequence↗
The beta globin gene cluster of the prosimian primate Galago crassicaudatus: nucleotide sequence determination of the 41-kb cluster and comparative sequence analyses.
The nucleotide sequence of the beta globin gene cluster of the prosimian Galago crassicaudatus has been determined. A total sequence spanning 41,101 bp contains and links together previously published sequences of the five galago beta-like globin genes (5'-epsilon-gamma-psi eta-delta-beta-3'). A computer-aided search for middle interspersed repetitive sequences identified 10 LINE (L1) elements, including a 5' truncated repeat that is orthologous to the full-length L1 element found in the human epsilon-gamma intergenic region. SINE elements that were identified included one Alu type I repeat, four Alu type II repeats, and two methionine tRNA-derived Monomer (type III) elements. Alu type II and Monomer sequences are unique to the galago genome. Structural analyses of the cluster sequence reveals that it is relatively A+T rich (about 62%) and regions with high G+C content are associated primarily with globin coding regions. Comparative analyses with the beta globin cluster sequences of human, rabbit, and mouse reveal extensive sequence homologies in their genic regions, but only human, galago, and rabbit sequences share extensive intergenic sequence homologies. Divergence analyses of aligned intergenic and flanking sequences from orthologous human, galago, and rabbit sequences show a gradation in the rate of nucleotide sequence evolution along the cluster where sequences 5' of the epsilon globin gene region show the least sequence divergence and sequences just 5' of the beta globin gene region show the greatest sequence divergence.
Amino Acid Sequence↗
Reexamination of the African hominoid trichotomy with additional sequences from the primate beta-globin gene cluster.
Additional DNA sequence information from a range of primates, including 13.7 kb from pygmy chimpanzee (Pan paniscus), was added to data sets of beta-globin gene cluster sequence alignments that span the gamma 1, gamma 2, and psi eta loci and their flanking and intergenic regions. This enlarged body of data was used to address the issue of whether the ancestral separations of gorilla, chimpanzee, and human lineages resulted from only one trichotomous branching or from two dichotomous branching events. The degree of divergence, corrected for superimposed substitutions, seen in the beta-globin gene cluster between human alleles is about a third to a half that observed between two species of chimpanzee and about a fourth that between human and chimpanzee. The divergence either between chimpanzee and gorilla or between human and gorilla is slightly greater than that between human and chimpanzee, suggesting that the ancestral separations resulted from two closely spaced dichotomous branchings. Maximum parsimony analysis further strengthened the evidence that humans and chimpanzees share the longest common ancestry. Support for this human-chimpanzee clade is statistically significant at P = 0.002 over a human-gorilla clade or a chimpanzee-gorilla clade. An analysis of expected and observed homoplasy revealed that the number of sequence changes uniquely shared by human and chimpanzee lineages is too large to be attributed to homoplasy. Molecular clock calculations that accommodated lineage variations in rates of molecular evolution yielded hominoid branching times that ranged from 17-19 million years ago (MYA) for the separation of gibbon from the other hominoids to 5-7 MYA for the separation of chimpanzees from humans. Based on the relatively late dates and mounting corroborative evidence from unlinked nuclear genes and mitochondrial DNA for the close sister grouping of humans and chimpanzees, a cladistic classification would place all apes and humans in the same family. Within this family, gibbons would be placed in one subfamily and all other extant hominoids in another subfamily. The later subfamily would be divided into a tribe for orangutans and another tribe for gorillas, chimpanzees, and humans. Finally, gorillas would be placed in one subtribe with chimpanzees and humans in another, although this last division is not as strongly supported as the other divisions.
Africa↗
A molecular perspective on mammalian evolution from the gene encoding interphotoreceptor retinoid binding protein, with convincing evidence for bat monophyly.
The evolutionary relationships of the various orders of placental mammals remain an issue of uncertainty and controversy. Molecular studies of mammalian phylogeny at the DNA level that include more than just a few orders are still relatively meager. Here we report results on mammalian phylogeny deduced from the coding sequence of the single-copy nuclear gene for the interphotoreceptor retinoid binding protein (IRBP). Analysis of 13 species representing eight eutherian orders and one marsupial yielded results that falsify the hypothesis that megachiropteran bats are "flying primates," only convergently resembling microchiropteran bats. Instead, in agreement with more traditional views, as well as those from other recent molecular studies, the results strongly support a monophyletic Chiroptera (micro- and megabats grouped together). The IRBP results also offer some rare molecular support for the Glires concept, in which rodents and lagomorphs form a superordinal grouping. Also in congruence with other recent molecular evidence, IRBP sequences do not support the view of a superorder Archonta that includes Chiroptera along with Dermoptera (flying lemur), Scandentia (tree shrew), and Primates. IRBP was not however, without its shortcomings as a molecular phylogenetic system: high levels of homoplasy, evident in the marsupial outgroup, did not allow us to properly root the tree, and several of the higher level eutherian clades were only weakly supported (e.g., a Carnivora/Chiroptera clade and an Artiodactyla/Carnivora/Chiroptera clade). We suggest that these shortcomings may be diminished as the phylogenetic density of the data set is increased.
Amino Acid Sequence↗
A path not taken: a cultural analysis of regrets and childlessness in the lives of older women.
This paper explores regrets about childlessness in 90 older women interviewed using qualitative methods. Regrets were discussed in the context of the changing meaning of childlessness over the life course. We found that issues of regret are situated in a cultural system that renders childless women marginal. We argue that regrets should be understood in a wider cultural context that incorporates the cultural construction of the self over time.
Aged↗
14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. I. Synthesis and biological activity.
As a continuation of our program to study structure-activity relationships of opiate peptides, we report the syntheses and biological activities of a series of 14-membered cyclic dermorphin analogues closely related to enkephalin analogue Tyr-c[D-A2bu-Gly-Phe-Leu] incorporating a phenylalanine at the third position in place of glycine. In addition to two parent dermorphin analogues Tyr-c[D-A2bu-Phe-Phe-(L and D)-Leu], four stereoisomeric retro-inverso modified analogues Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu] with a reversed amide bond between residues four and five, and Tyr-c[D-Glu-Phe-gPhe-(L and D)-rLeu] with two reversed amide bonds between residues four and five, and between residue five and the side chain of residue two have been synthesized. The results from the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays show that all analogues are superactive at either one or both opiate receptors and in general display higher activities as compared to the corresponding enkephalin analogues with a glycine at the third position. Results from the in vitro biological assays and conformational analysis using 1H-NMR spectroscopy (adjoining paper) will provide useful information to understand the role of the Phe3 aromatic side chain in dermorphin, and that of the Phe4 aromatic side chain in enkephalin, on opiate activity since these cyclic dermorphin analogues contain two Phe residues at both the third and fourth positions.
Amino Acid Sequence↗
14-membered cyclic opioids related to dermorphin and their partially retro-inverso modified analogues. II. Preferred conformations in solution as studied by 1H-NMR spectroscopy.
The 1H-NMR studies were extensively carried out to elucidate preferred conformations of a series of 14-membered cyclic dermorphin analogues containing two phenylalanines at both the third and fourth positions, e.g., Tyr-c[D-A2bu-Phe-Phe-(L and D)-Leu], Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu], and Tyr-c[D-Glu-Phe-gPhe-(L and D)-rLeu]. The temperature coefficients of the amide proton chemical shifts, vicinal 1H-1H coupling constants for the NH-CH groupings, and nuclear Overhauser effects provided information regarding the preferred conformations of the backbones. The conformational preferences and flexibility of the side chains were also estimated from the vicinal 1H-1H coupling constants around the C-C beta and C beta-C bonds in the articulated side chains. A comparison of the results obtained was made with the results previously obtained for the corresponding enkephalin analogues containing a glycine at the third position. It was found that the replacement of the glycine with the phenylalanine at the third position increases the conformational flexibility of the molecules with an L-, or S-, residue at the fifth position but reduces the flexibility of the molecules with D-, or R-, residue at the same position. The rotating frame nuclear Overhauser experiments gave direct evidence for compact conformations, with the Tyr side chain folding back over the 14-membered ring in Tyr-c[D-Glu-Phe-gPhe-rLeu], which displays relatively high selectivity for the delta-receptor over the mu-receptor. This observation is in agreement with our model proposed for the cyclic enkephalin analogues: folded forms with close aromatic ring placement are required for the activity at the delta-receptor.
Amino Acid Sequence↗
Phylogenetic footprinting reveals a nuclear protein which binds to silencer sequences in the human gamma and epsilon globin genes.
Tissue- and developmental stage-specific expression of the human beta-like globin genes is regulated by a combination of ubiquitous and erythroid-restricted trans factors that bind to cis elements near each of the five active genes. Additional interactions of these cis and trans factors with sequences located in the far 5' end of the cluster occur by as yet obscure mechanisms. Because of the complexity of this regulatory puzzle, precise identification of the determinants that control hemoglobin switching has proven difficult. Phylogenetic footprinting is an evolutionary approach to this problem which is based on the supposition that the basic mechanisms of switching are conserved throughout mammalian phylogeny. Alignment of the 5' flanking regions of the gamma genes of several species allows the identification of footprints of 100% conserved sequence. We have now tested oligomers spanning 13 such phylogenetic footprints and find that 12 are bound by nuclear proteins. One conserved element located at -1086 from the gamma genes exhibits repressor activity in transient transfection studies. The protein that binds this element, CSBP-1 (conserved sequence-binding protein 1), also binds at three sites within a silencer element upstream from the epsilon globin gene. Further analysis reveals that the CSBP-1 binding activity is identical to that of a recently cloned zinc finger protein that has been shown to act as a repressor in other systems. The binding of CSPB-1 to silencer sequences in the epsilon and gamma globin genes may be important in the stage-specific silencing of these genes.
Animals↗
Topochemical analysis of morphiceptin and dermorphin bioactivities.
To elucidate the topochemical requirements for bioactivities of morphiceptin (Tyr-Pro-Phe-Pro-NH2) and dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), we have designed and synthesized two diastereomers Tyr-(L and D)-(NMe)Ala-Phe-D-Pro-NH2. Both the analogs display high activities in the guinea pig ileum assay. The only difference in the composition of these two diastereomers arises from the chirality at residue 2. The high mu-receptor activities are attributed to structures where the Tyr1-L-(NMe)Ala2 amide bond assumes a cis configuration while the Tyr1-D-(NMe)Ala2 amide bond assumes a trans configuration. Accessible space studied for the second residues of these molecules confirms the fact that the L-(NMe)Ala2 analog belongs to the morphiceptin family of opioids while the D-(NMe)Ala2 analog belongs to the dermorphin class of opioids. The similarity in the spacial array of the analogs explains their high mu-receptor activities and indicates that they are likely recognized at the same opioid receptor.
Amino Acid Sequence↗
Duplication of the gamma-globin gene mediated by L1 long interspersed repetitive elements in an early ancestor of simian primates.
Regions surrounding the single gamma-globin gene of galago and the duplicated gamma 1- and gamma 2-globin genes of gibbon, rhesus monkey, and spider monkey were sequenced and aligned with those from humans. Contrary to previous studies, spider monkey was found to have not one but two gamma-globin genes, only one of which (gamma 2) is functional. The reconstructed evolutionary history of the gamma-globin genes and their flanking sequences traces their origin to a tandem duplication of a DNA segment approximately 5.5 kilobases long that occurred before catarrhine primates (humans, apes, and Old World monkeys) diverged from platyrrhines (New World monkeys), much earlier than previously thought. This reconstructed molecular history also reveals that the duplication resulted from an unequal homologous crossover between two related L1 long interspersed repetitive elements, one upstream and one downstream of the single ancestral gamma-globin gene. Perhaps facilitated by the redundancy resulting from the duplication, the gamma-globin genes escaped the selective constraints of embryonically functioning genes and evolved into fetally functioning genes. This view is supported by the finding that a burst of nonsynonymous substitutions occurred in the gamma-globin genes while they became restructured for fetal expression in the common ancestor of platyrrhines and catarrhines.
Animals↗
Concerted evolution led to high expression of a prosimian primate delta globin gene locus.
The delta globin gene in simian primates is either weakly expressed (in hominoids and New World monkeys) or silent (in Old World monkeys). In prosimian primates, however, an unequal homologous crossover between the psi eta and delta loci of lemurs produced a hybrid psi eta delta pseudogene locus, whereas in tarsier the delta locus encodes a beta-type chain found in 18% of adult tarsier hemoglobin molecules. In the present study, the nucleotide and amino acid sequences of the galago delta and beta globin genes and their encoded peptides were determined, and evidence is provided showing that the galago delta locus encodes a beta-type chain (beta 2) found in 40% of the galago fetal and postnatal hemoglobin molecules, whereas the beta locus encodes the remaining 60% of the beta-type chain (beta 1). Galago beta 1 and beta 2 chains differ from each other by only one amino acid residue. The homology between the galago delta and beta loci extends from 800 base pairs 5' of the proximal CCAAT element to near the end of exon 3 as a result of a recombination event in which beta sequence replaced delta sequence. After this initial recombination event, concerted evolution between the loci continued over their conserved coding, intron 1, and promoter regions but failed to occur between the two loci in their intron 2 and distal 5'-flanking sequences where the two loci have now diverged by 20%. Calculations based on this divergence value and on a rate of noncoding sequence evolution of 4.2 x 10(-9) to 5.5 x 10(-9) substitutions/site/year for the lorisiform lineage to galago yielded a date of 18-24 million years ago for the initial recombination event. The fact that the promoter sequences of the galago delta locus are the same as that of the galago beta locus may account for the high level of expression of the galago delta gene.
Amino Acid Sequence↗
Conformational studies of stereoisomeric 14-membered cyclic enkephalin analogues containing 1-naphthylalanine at the fourth position: chirality effect of leucine at the fifth position on biological activity and receptor selectivity.
In order to study structure-activity relationships of enkephalin-related analogues, we report the biological activity and conformational analysis of four 14-membered cyclic enkephalin analogues with beta-(1-naphthyl) alanine in place of phenylalanine at the fourth position, Tyr-c[D-A2bu-Gly-(L and D)-beta Nal(1)-(L and D)-Leu]. The L-beta Nal(1)-containing analogues display higher activity at both the mu and delta receptors than the corresponding analogues with the L-Phe residue. In contrast to the linear enkephalins, the cyclic analogues with the D-beta Nal(1) residue are also active at the mu receptor since the relative spatial arrangement of functional groups required for biological activity is achieved by the constrained nature of the cyclic molecules. A comparison of the findings from the conformational analysis and biological assays establishes that relatively extended structures, in which the two aromatic side chains are oriented in opposite directions with a approximately 14 A separation, is required for activity at the mu receptor. On the other hand, folded conformations with nearly parallel orientations and a close proximity (less than 10A) of the aromatic rings of the Tyr and beta Nal(1) residues are required for activity at the delta receptor. It should be noted that the overall structures and thus the biological profiles of the 14-membered cyclic enkephalin analogues are strongly dependent on the conformation of the second residue. The folded conformations with parallel orientation of the two aromatic side chains of Tyr-c[D-A2bu-Gly-L-beta Nal(1)-D-Leu] is stabilized by an interaction between the Tyr phenolic OH proton and beta Nal(1) C*O groups. This analogue, which shows the highest activity at both the mu and delta receptors among the four stereoisomers studied, displays an increase of the fraction of the side-chain chi 1 = t conformer for the beta Nal(1) residue. It is concluded that the incorporation of the D-Leu residue at the fifth position increases the relative fraction of the folded conformations with parallel orientation of the aromatic side chains, and hence enhances activity at the delta receptor as compared to the corresponding L-Leu containing analogue.
Alanine↗
Cyclic retro-inverso dipeptides with two aromatic side chains. I. Synthesis.
A series of cyclic retro-inverso dipeptides--2-[(4-hydroxy)benzyl]-5-benzyl-4,6(1H,2H,3H,5H)-pyrimidinedi one (c[mPhe-gTyr]), 2-benzyl-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[mTyr-gPhe]), and 2-benzyl-5-amino-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[(alpha-amino)mTyr-gPhe])--were synthesized in order to define the minimum structural requirements for binding affinity with opiate receptors and biological activity. Although the first two compounds lack a free amine proposed to be necessary for receptor recognition, the c[mPhe-gTyr] and c[mTyr-gPhe] analogues serve as model molecules in conformational studies of the target analogue, c[(alpha-amino)mTyr-gPhe]. The cis- and trans-c[(alpha-amino)mTyr-gPhe] contain all the functional groups such as the amine and phenolic groups in the tyrosine, and the aromatic group in the phenylalanine, necessary for opiate activity. In addition, the c[(alpha-amino)mTyr-gPhe] analogues possess similar geometries to the Tyr-Pro part of morphiceptin (Tyr-Pro-Phe-Pro-NH2) whose high mu-receptor activity is attributed to conformations with the Tyr-Pro amide bond in a cis conformation because the peptide bonds assume a cis conformation. However, both analogues are inactive in the guinea pig ileum and the mouse vas deferens assays. This may result from wrong orientation of the benzyl group of the gPhe residue with respect to the (alpha-amino)mTyr residue. Conformational studies of these molecules using 1H-nmr spectroscopy and molecular mechanics calculations will be reported in the following paper. Results of conformational analysis should provide information about backbone-side-chain interactions in the retro-inverso peptide chains since all the fundamental structural elements of the retro-inverso peptides are included in these model systems even though the peptide bonds must assume a cis conformation.
Amino Acid Sequence↗