Ethical issues in health care rationing.
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Ethics, Medical↗
Biomedical subjects
M Goodman
Publications and source records attributed to M Goodman.
The effect of surface modification of mechanical aortic valves on thrombogenicity.
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Aortic Valve↗
Sequences of the primate epsilon-globin gene: implications for systematics of the marmosets and other New World primates.
Sequences of the epsilon-globin gene were determined for five species of marmosets, along with approximately 2 kb of 5' flanking sequence. An analysis of these data, compared with those of other primates strongly supports the classification of Callithrix jacchus and C. geoffroyi into the jacchus group, and C. argentata and C. mauesi into the argentata group. The pygmy marmoset, formerly identified as Cebuella pygmaea joined strongly to the argentata group, indicating that without the pygmy marmoset the genus Callithrix would be paraphyletic. Our data support recent studies which indicate that C. pygmaea should be included in the genus Callithrix. Relationships among other primates were as indicated by previous studies of epsilon-globin sequences. Divergence times were estimated according to a local molecular clock. These calculations indicated the divergence of C. mauesi and C. argentata to be approximately 1.6-1.9 Myr (million years ago), and the most recent common ancestor of the marmosets to be between 4.5 and 4.7 Myr. The latter estimate corresponds well to the date of 4.6 Myr calculated from an independent data set.
Animals↗
Locus control regions of mammalian beta-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights.
Locus control regions (LCRs) are cis-acting DNA segments needed for activation of an entire locus or gene cluster. They are operationally defined as DNA sequences needed to achieve a high level of gene expression regardless of the position of integration in transgenic mice or stably transfected cells. This review brings together the large amount of DNA sequence data from the beta-globin LCR with the vast amount of functional data obtained through the use of biochemical, cellular and transgenic experimental systems. Alignment of orthologous LCR sequences from five mammalian species locates numerous conserved regions, including previously identified cis-acting elements within the cores of nuclease hypersensitive sites (HSs) as well as conserved regions located between the HS cores. The distribution of these conserved sequences, combined with the effects of LCR fragments utilized in expression studies, shows that important sites are more widely distributed in the LCR than previously anticipated, especially in and around HS2 and HS3. We propose that the HS cores plus HS flanking DNAs comprise a 'unit' to which proteins bind and form an optimally functional structure. Multiple HS units (at least three: HS2, HS3 and HS4 cores plus flanking DNAs) together establish a chromatin structure that allows the proper developmental regulation of genes within the cluster.
Animals↗
Dynamics of regulatory evolution in primate beta-globin gene clusters: cis-mediated acquisition of simian gamma fetal expression patterns.
Phylogenetic reconstructions by parsimony were carried out on an enlarged body of primate gamma1 and gamma2-globin sequences. The results confirm that gamma1 and gamma2 arose from a tandem duplication in an ancient simian lineage ancestral to both platyrrhines (New World monkeys) and catarrhines (Old World monkeys and hominoids). Gene conversions between the two gamma homologs were frequent over the gamma gene proper but less frequent over the 5' flanking and very infrequent over the 3' flanking regions. The ancient platyrrhine conversion in the most distal 5' flanking region had the polarity of gamma2-->gamma1. Recent platyrrhine conversions between 5' regulatory sequences were very infrequent, in striking contrast to catarrhines which have large, uninterrupted stretches of converted 5' regulatory sequences. Comparisons of reconstructed ancestral primate and simian gamma promoter sequences revealed an accumulation of 21 nucleotide substitutions concentrated in or near cis-elements that may have mediated the change from embryonic to fetal gamma expression. Almost all 21 substitutions were retained in the lineages leading to functional gamma genes of extant catarrhines (both gamma1 and gamma2) and platyrrhines (most often gamma2). Fewer of these simian specific substitutions were retained in the platyrrhine gamma1 genes and new mutations occurred more often in the platyrrhine gamma1 than gamma2 promoters.
Animals↗
Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): synthesis and biophysical studies of Gly-Nleu-Pro sequences by circular dichroism and optical rotation.
Single-chain peptide-peptoid structures, Ac-(Gly-Nleu-Pro)n-NH2 (n = 3, 6, and 10) and (Gly-Nleu-Pro)n-NH2 (n = 1 and 9), and template-assembled collagen analogs, KTA-[Gly-(Gly-Nleu-Pro)n-NH2]3 (n = 3 and 6; KTA represents cis,cis-1,3,5-trimethylcyclohexane-1,3, 5-tricarboxylic acid, also known as the Kemp triacid; Nleu denotes N-isobutylglycine), were prepared by solid-phase peptide synthesis methods. Biophysical studies using circular dichroism (CD) and optical rotation measurements show that these collagen analogs form triple-helical conformations when the chain is longer than a critical length. Unlike collagen-based structures composed of Gly-Pro-Hyp and Gly-Pro-Nleu sequences, results reveal that the presence of a positive CD peak between 220 and 225 nm is indicative of triple-helical conformations for these collagen-based structures composed of Gly-Nleu-Pro sequences. Results also indicate that the Gly-Nleu-Pro sequence possesses a higher triple-helical propensity than the Gly-Pro-Nleu sequence as demonstrated by the higher melting temperatures, the faster triple-helix folding, and the lower minimum concentration necessary to detect triple-helicity for the single-chain structures. Therefore, we conclude that the Nleu residue in the second position of the trimeric repeat is more effective in inducing triple-helix formation than Pro in the same position.
Amino Acid Sequence↗
Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): conformational analysis of Gly-Nleu-Pro sequences by 1H-NMR and molecular modeling.
Molecular modeling and 1H-NMR were employed to study the structure and stability of collagen-like triple helices composed of Gly-Nleu-Pro repeats. The compounds studied include the acetyl analogs Ac-(Gly-Nleu-Pro)n-NH2 (where n = 1, 3, 6, and 10) and the KTA conjugates KTA-[Gly-(Gly-Nleu-Pro)n-NH2]3 (where n = 3 and 6 and KTA denotes the Kemp triacid). The presence of collagen-like assembled structures is supported by a consistent set of experimental observations, which include the appearance of a distinct set of resonances, low hydrogen-exchange rates for Gly NH, cooperative melting transition, and observation of several interchain NOEs. Using 1H-NMR, the triple helicity was monitored as a function of chain length, template, and temperature. These studies show that (Gly-Nleu-Pro)n sequences have a somewhat higher triple-helical propensity than (Gly-Pro-Nleu)n sequences. In addition, our investigations have shown that unlike the triple helices composed of Gly-Pro-Nleu repeats those composed of Gly-Nleu-Pro repeats can access conformations in which the Nleu side chains are arrayed between Pro residues belonging to different triple-helix cross sections. These structural features may serve as a basis for free energy computations and for the study of higher-order structures such as collagen-like fibrils containing peptoid moities.
Amino Acid Sequence↗
Lanthionine-somatostatin analogs: synthesis, characterization, biological activity, and enzymatic stability studies.
A series of cyclic somatostatin analogs containing a lanthionine bridge have been subjected to studies of structure-activity relationships. A direct synthesis of the thioether bridged analog (1) of sandostatin (SMS 201,995) and several lanthionine hexa-, hepta-, and octapeptides was carried out by using the method of cyclization on an oxime resin (PCOR) followed by condensation reactions in solution. The structures of the target peptides were analyzed by liquid secondary ion mass spectrometry (LSIMS) and subjected to high-energy collision-induced dissociation (CID) studies after opening of the peptide ring by proteolytic cleavage. The biological activities of these compounds have been evaluated by assaying their inhibitory potencies for the release of growth hormone (GH) from primary cultures of rat anterior pituitary cells, as well as by their binding affinities to cloned somatostatin receptors (SSTR1-5). The structural modification of sandostatin by introducing a lanthionine bridge resulted in a significantly increased receptor binding selectivity. The lanthionine octapeptide with C-terminal Thr-ol (1) showed similar high affinity for rat SSTR5 compared to somatostatin[1-14] and sandostatin. However, it exhibits about 50 times weaker binding affinity for mSSTR2b than sandostatin. Similarly, the lanthionine octapeptide with the C-terminal Thr-NH2 residue (2) has higher affinity for rSSTR5 than for mSSTR2B. Both peptides (compounds 1 and 2) have much lower potencies for inhibition of growth hormone secretion than sandostatin. This is consistent with their affinities to SSTR2, the receptor which is believed to be linked to the inhibition of growth hormone release by somatostatin and its analogs. The metabolic stability of lanthionine-sandostatin and sandostatin have been studied in rat brain homogenates. Although both compounds have a high stability toward enzymatic degradation, the lanthionine analog has a 2.4 times longer half-life than sandostatin. The main metabolites of both compounds have been isolated and identified by using an in vivo technique (cerebral microdialysis) and mass spectrometry.
Alanine↗
A refined model for the somatostatin pharmacophore: conformational analysis of lanthionine-sandostatin analogs.
We report the conformational analysis of a series of analogs of sandostatin (octreotide, D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys 7]-Thr8-ol) using 1H NMR spectroscopy and molecular modeling. Two active compounds in which the disulfide group is replaced by a monosulfide (lanthionine) bridge (D-Phe1-c[AlaL2-Phe3-D-Trp4-Lys5-Thr6-A laL7]-Thr8-ol and D-Phe1-c[AlaL2-Phe3-D-Trp4-Lys5-Thr6-Al aL7]-Thr8-NH2, where AlaL denotes each of the lanthionine amino acid ends linked by the monosulfide bridge) show different mSSTR2b/rSSTR5 receptor selectivities as compared to sandostatin. These new results have enabled us to reveal features of the somatostatin pharmacophore common to the model previously proposed in our laboratory on the basis of main chain and side chain chiral methylation studies. In addition, our studies provide new insight into the role of the disulfide bridge and of Thr8 in binding potency. We also show that the lanthionine group is a good mimetic of beta-VI turns and can be incorporated in sandostatin analogs maintaining the essential secondary structural features of sandostatin. These results facilitate the design of new sandostatin peptidomimetics.
Alanine↗
Evolution of a fetal expression pattern via cis changes near the gamma globin gene.
One basis for the evolution of organisms is the acquisition of new temporal and spatial domains of gene expression. Such novel expression domains could be generated either by cis sequence changes that alter the complement of trans-acting regulators binding to control elements or by changes in the expression patterns of one or more of the regulatory (trans) factors themselves. The gamma globin gene is a prime example of a gene that has undergone a distinct change in temporal expression at a defined time in evolution. Approximately 35-55 million years ago, the previously embryonic gamma gene acquired a fetal expression pattern. This change occurred in a simian primate ancestor after the separation of simian and prosimian primates but before the further separation of the major simian lineages; thus, the (prosimian) galago gamma gene retains the ancestral embryonic expression pattern, whereas the (simian) human gamma gene is fetal. This analysis of galago and human gamma genes in transgenic mice demonstrates that cis changes in sequences within a 4.0-kilobase region surrounding the gamma gene were responsible for the evolution of a novel fetal expression pattern in the gamma globin genes of simian primates.
Animals↗
Phylogenetic footprinting of hypersensitive site 3 of the beta-globin locus control region.
Hypersensitive site 3 (HS3) of the beta-like globin locus control region has been implicated as an important regulator of the beta-like globin genes, but the trans factors that bind HS3 have only been partially characterized. Using a five-species alignment (human, galago, rabbit, goat, and mouse) that represents 370 million years of evolution, we have identified 24 phylogenetic footprints in the HS3 core and surrounding regions. Probes corresponding to the human sequence at each footprint have been used in binding studies to identify the nuclear factors that bind within and near these conserved sequence elements. Among the high-affinity interactions observed were several binding sites for proteins with repressor activity, including YY1, CCAAT displacement protein, and G1/G2 complexes (uncharacterized putative repressors) and several binding sites for the stage selector protein. To complement this analysis, orthologous galago sequences were also used to derive probes and the pattern of proteins binding to human and galago probes was compared. Binding interactions differing between these two species could be responsible for the different expression patterns shown by the two gamma genes (galago gamma is embryonic; human gamma is fetal). Alternatively, binding interactions that are conserved in the two species may be important in the regulation of common expression patterns (eg, repression of gamma in adult life).
Animals↗
Post-hospitalization treatment adherence of schizophrenic patients: gender differences in skill acquisition.
A cohort of acutely ill, hospitalized patients with chronic psychotic disorders participated in a study of a manualized community reintegration skills training program. Initial data analyses revealed that skill levels improved significantly over the course of treatment, and that higher post-training skill levels were associated with better post-discharge functioning for the group as a whole. Post-discharge treatment adherence rates were dramatically better in females, and analyses were conducted to determine the role of gender. Males and females had different predictors of post-training skill level and post-discharge treatment adherence. In males, who as a group were at higher risk for poor post-discharge outcome, there was a positive association between post-training skill level and post-discharge treatment adherence. Females, on the other hand, showed good post-discharge treatment adherence regardless of post-training skill or symptom levels. This report is consistent with prior studies suggesting that male and female individuals with schizophrenia show differential patterns of social skill, skill improvement, and social adjustment.
Female↗
Multiconformational NMR analysis of sandostatin (octreotide): equilibrium between beta-sheet and partially helical structures.
This paper reports a detailed conformational analysis by 1H NMR (DMSO-d6, 300 K) and molecular modeling of the octapeptide D-Phe1-Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys7+ ++-Thr8-ol (disulfide bridged) known as sandostatin (or SMS 201-995 or octreotide) with both somatostatin-like and opioid-like bioactivities. This is the initial report on sandostatin showing that attempts to explain all NMR data using a single average conformation reveal several important inconsistencies including severe violations of mutually exclusive backbone-to-backbone NOEs. The inconsistencies are solved by assuming an equilibrium between antiparallel beta-sheet structures and conformations in which the C-terminal residues form a 3(10) helix-like fold (helical ensemble). This conformational equilibrium is consistent with previous X-ray diffraction investigations which show that sandostatin can adopt both the beta-sheet and the 3(10) helix-like secondary structure folds. In addition, indications of a conformational equilibrium between beta-sheet and helical structures are also found in solvent systems different from DMSO-d6 and for other highly bioactive analogs of sandostatin. In these cases a proper multiconformational NMR refinement is important in order to avoid conformational averaging artifacts. Finally, using the known models for somatostatin-like and opioid-like bioactivities of sandostatin analogs, the present investigation shows the potentials of the proposed structures for the design of novel sandostatin-based conformationally restricted peptidomimetics. These analogs are expected to refine the pharmacophore models for sandostatin bioactivities.
Hormones↗
The complete sequences of the galago and rabbit beta-globin locus control regions: extended sequence and functional conservation outside the cores of DNase hypersensitive sites.
The locus control region (LCR) of mammalian beta-globin genes covers at least 17 kb at the 5' end of the gene cluster and has been implicated in chromatin domain opening, enhancement, and insulation from neighboring sequences. Functional dissection of the LCR has defined the minimal cores for four of the five major DNase hypersensitive sites (HSs) that mark this regulatory region. To examine fully the patterns of conserved sequences in the mammalian homologs to the beta-globin LCR, we determined the complete DNA sequence of the galago beta-globin LCR and completed previously unsequenced regions of the rabbit LCR. Simultaneous alignment of these sequences with the human, goat, and mouse LCRs revealed conserved sequences (phylogenetic footprints) detected using three largely independent methods. The most highly conserved segments are found both within the HS cores and in some but not all regions flanking the cores. These results argue for an extended pattern of well-conserved sequences, many of which lie outside the minimal cores, and we show that a key sequence required for domain opening by the region including HS3 maps about 1 kb 5' to the minimal core. Differential phylogenetic footprints, containing sequences conserved in nonhuman mammals but not in humans, are found primarily around HS3, consistent with some species-specific differences in function that may be important for differences in hemoglobin switching during development.
Animals↗
Activation signals regulate heat shock transcription factor 1 in human B lymphocytes.
We previously showed that the ability of human B lymphocytes to elicit a cytoprotective heat shock response when confronted by heat or other stresses was dependent upon the state of cell activation. This was unexpected, considering the highly conserved nature of the heat shock response and the widely held belief that all nonmutated mature cells were capable of eliciting a heat shock response when stressed. To elucidate the mechanism by which activation primes B cells to respond to stresses, we examined heat shock transcription factor 1 (hHSF1) in B cells since this factor appears to be solely responsible for stress-induced transcription of heat shock genes in human cells. In the current report, we show that hHSF1-DNA binding complexes are undetectable in extracts of unactivated B cells. In fact, hHSF1 protein is not constitutively expressed in unactivated B cells, nor is its synthesis stress-inducible. However, following activation, hHSF1 can be found in either a transcriptionally active or an inactive state, depending upon whether the cell has been stressed or not. Thus, activation pathways play an important role in enabling B cells to survive and function properly in the context of physiologic stresses by regulating hHSF1.
B-Lymphocytes↗
Assessment of the Massachusetts Medicaid managed Behavioral Health Program: year three.
This evaluation of the third year of the Massachusetts Medicaid managed Mental Health/Substance Abuse Program showed that overall utilization increased slightly and expenditures were nearly the same in FY1994 compared to FY1993; however, they were lower for disabled members. Providers believed that access to care, utilization, and quality of care were the same or better than a year earlier and that the clinical review process was improved. Client severity was higher. Aftercare planning improved but gaps in services persisted. Integration of care improved. Administrative and management problems continued. Lessons for similar, more recent initiatives are discussed.
Adult↗
Molecular evolution of cytochrome c oxidase subunit IV: evidence for positive selection in simian primates.
Cytochrome c oxidase (COX) is a multi-subunit enzyme complex that catalyzes the final step of electron transfer through the respiratory chain on the mitochondrial inner membrane. Up to 13 subunits encoded by both the mitochondrial (subunits I, II, and III) and nuclear genomes occur in eukaryotic organisms ranging from yeast to human. Previously, we observed a high number of amino acid replacements in the human COX IV subunit compared to mouse, rat, and cow orthologues. Here we examined COX IV evolution in the two groups of anthropoid primates, the catarrhines (hominoids, cercopithecoids) and platyrrhines (ceboids), as well as one prosimian primate (lorisiform), by sequencing PCR-amplified portions of functional COX4 genes from genomic DNAs. Phylogenetic analysis of the COX4 sequence data revealed that accelerated nonsynonymous substitution rates were evident in the early evolution of both catarrhines and, to a lesser extent, platyrrhines. These accelerated rates were followed later by decelerated rates, suggesting that positive selection for adaptive amino acid replacement became purifying selection, preserving replacements that had occurred. The evidence for positive selection was especially pronounced along the catarrhine lineage to hominoids in which the nonsynonymous rate was first faster than the synonymous rate, then later much slower. The rates of three types of "neutral DNA" nucleotide substitutions (synonymous substitutions, pseudogene nucleotide substitutions, and intron nucleotide substitutions) are similar and are consistent with previous observations of a slower rate of such substitutions in the nuclear genomes of hominoids than in the nuclear genomes of other primate and mammalian lineages.
Amino Acid Sequence↗