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PubMed2002

Laurasian migration explains Gondwanan disjunctions: evidence from Malpighiaceae.

Explanations for biogeographic disjunctions involving South America and Africa typically invoke vicariance of western Gondwanan biotas or long distance dispersal. These hypotheses are problematical because many groups originated and diversified well after the last known connection between Africa and South America (approximately 105 million years ago), and it is unlikely that "sweepstakes" dispersal accounts for many of these disjunctions. Phylogenetic analyses of the angiosperm clade Malpighiaceae, combined with fossil evidence and molecular divergence-time estimates, suggest an alternative hypothesis to account for such distributions. We propose that Malpighiaceae originated in northern South America, and that members of several clades repeatedly migrated into North America and subsequently moved via North Atlantic land connections into the Old World during episodes starting in the Eocene, when climates supported tropical forests. This Laurasian migration route may explain many other extant lineages that exhibit western Gondwanan distributions.

Arabidopsis Proteins↗

PubMed2000

Changes in brain cell shape create residual extracellular space volume and explain tortuosity behavior during osmotic challenge.

Diffusion of molecules in brain extracellular space is constrained by two macroscopic parameters, tortuosity factor lambda and volume fraction alpha. Recent studies in brain slices show that when osmolarity is reduced, lambda increases while alpha decreases. In contrast, with increased osmolarity, alpha increases, but lambda attains a plateau. Using homogenization theory and a variety of lattice models, we found that the plateau behavior of lambda can be explained if the shape of brain cells changes nonuniformly during the shrinking or swelling induced by osmotic challenge. The nonuniform cellular shrinkage creates residual extracellular space that temporarily traps diffusing molecules, thus impeding the macroscopic diffusion. The paper also discusses the definition of tortuosity and its independence of the measurement frame of reference.

Animals↗

PubMed2002

Can patient self-management help explain the SES health gradient?

There are large differences in health outcomes by socioeconomic status (SES) that cannot be explained fully by traditional arguments, such as access to care or poor health behaviors. We consider a different explanation-better self-management of disease by the more educated. We examine differences by education in treatment adherence among patients with two illnesses, diabetes and HIV, and then assess the subsequent impact of differential adherence on health status. One unique component of this research is that for diabetes we combine two different surveys-one cohort study and one randomized clinical trial-that are usually used exclusively by either biomedical or/and social scientists separately. For both illnesses, we find significant effects of adherence that are much stronger among patients with high SES. After controlling for other factors, more educated HIV+ patients are more likely to adhere to therapy, and this adherence made them experience improvements in their self-reported general health. Similarly, among diabetics, the less educated were much more likely to switch treatment, which led to worsening general health. In the randomized trial setting, intensive treatment regimens that compensated for poor adherence led to better improvements in glycemic control for the less educated. Among two distinct chronic illnesses, the ability to maintain a better health regimen is an important independent determinant of subsequent health outcomes. This finding is robust across clinical trial and population-based settings. Because this ability varies by schooling, self-maintenance is an important reason for the steep SES gradient in health outcomes.

Adolescent↗

PubMed2002

Range image statistics can explain the anomalous perception of length.

A long-standing puzzle in visual perception is that the apparent extent of a spatial interval (e.g., the distance between two points or the length of a line) does not simply accord with the length of the stimulus but varies as a function of orientation in the retinal image. Here, we show that this anomaly can be explained by the statistical relationship between the length of retinal projections and the length of their real-world sources. Using a laser range scanner, we acquired a database of natural images that included the three-dimensional location of every point in the scenes. An analysis of these range images showed that the average length of a physical interval in three-dimensional space changes systematically as a function of the orientation of the corresponding interval in the projected image, the variation being in good agreement with perceived length. This evidence implies that the perception of visual space is determined by the probability distribution of the possible real-world sources of retinal images.

Humans↗

PubMed1970

Contemporaneous disequilibrium, a new hypothesis to explain the "paradox of the plankton".

The diversity of lake phytoplankton is unexpectedly high, since the epilimnion of a lake is continuously mixing and might be expected to have only one or at most a few niches for primary producers. However, a carefully replicated series of samples from Castle Lake, Calif., showed a high degree of patchiness for many phytoplankton species, indicating that the rate of mixing is slow enough relative to the reproductive rate of the algae for many different niches to exist simultaneously. Productivity per unit biomass ratios, measured at Lake Tahoe, California-Nevada, shows that the turnover times for carbon in even this ultraoligotrophic lake are often less than 1 day. High diversity is associated with high productivity per unit biomass and high zooplankton populations in this lake.A contemporaneous disequilibrium model to explain the diversity of the lake phytoplankton is therefore highly plausible. At any one time, many patches of water exist in which one species is at a competitive advantage relative to the others. These water masses are stable enough to permit a considerable degree of patchiness to occur in phytoplankton, but are obliterated frequently enough to prevent the exclusive occupation of each niche by a single species.

California↗

PubMed1976

The opiate receptor: a model explaining structure-activity relationships of opiate agonists and antagonists.

A model of the opiate receptor is proposed which explains structure-activity relationships of opiate drugs, including (i) the unique potency of certain opiates such as etonitazene, fentanyl, phenazocine, and oripavines; (ii) the role of N-allyl substituents in conferring antagonist properties; and (iii) chemical features that afford "pure" antagonists. The model indicates mlecular mechanisms for interconversion of the opiate receptor between respective states that bind agonists or antagonists with high affinity.

Allosteric Regulation↗

PubMed1983

Oligomeric structure of muscarinic receptors is shown by photoaffinity labeling: subunit assembly may explain high- and low-affinity agonist states.

The potent muscarinic photoaffinity reagent N-methyl-4-piperidyl p-azidobenzilate (azido-4NMPB) was used to covalently label specific muscarinic binding sites in various brain regions and in the heart. In the cortex and hippocampus, a single specifically labeled protein with an apparent molecular mass of 86,000 daltons was detected by gel electrophoresis. In the medulla pons, cerebellum, and cardiac atria, there was a 160,000-dalton band in addition to the 86,000-dalton polypeptide. Under certain conditions, alkali or hydroxylamine treatment dissociated both macromolecules into a single 40,000-dalton polypeptide. These results suggest that the muscarinic receptor exists in oligomeric forms and that a dimer and tetramer of a basic 40,000-dalton peptide may exist as interconvertible species. We propose a model to explain the biological architecture of the muscarinic receptors and suggest a possible correlation between the azido-4NMPB-labeled polypeptides and the two states of the receptor observed in agonist binding experiments.

Affinity Labels↗

PubMed1984

Human liver alcohol dehydrogenase: amino acid substitution in the beta 2 beta 2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme.

The homodimeric Oriental beta 2 beta 2 isozyme of human liver alcohol dehydrogenase, corresponding to an allelic variant at the ADH2 gene locus, was studied in order to define the amino acid exchange in relation to the beta 1 beta 1 isozyme, the predominant allelic form among Caucasians. Sequence analysis reveals that the amino acid substitution occurs at position 7 of the largest CNBr fragment, corresponding to position 47 of the whole protein chain. Here, the beta 2 form has a histidine residue, while, in common with other characterized mammalian liver alcohol dehydrogenases, the beta 1 form has an arginine residue. This exchange does not affect the adjacent cysteine-46 residue, which is a protein ligand to the active-site zinc atom, thus clarifying previously inconsistent results. The histidine/arginine-47 mutational replacement corresponds to a position that binds the pyrophosphate group of the coenzyme NAD(H); this explains the functional differences between the beta 1 beta 1 and beta 2 beta 2 isozymes, including both a lower pH optimum and higher turnover number of beta 2 beta 2, which is likely to be the mutant form. The exchange demonstrates the existence of parallel but separate mutations in the evolution of alcohol dehydrogenases because these mammalian enzymes differ at exactly the same position by the same type of substitution as is found between a mutant and the wild-type constitutive forms of the corresponding yeast enzyme.

Alcohol Dehydrogenase↗

PubMed1985

Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity.

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuropathological and clinical abnormalities in humans, monkeys, and mice that closely resemble idiopathic parkinsonism. N-Methyl-4-phenylpyridine (MPP+), a metabolite of MPTP formed by monoamine oxidase B, is accumulated into striatal and cerebral cortical synaptosomes by the dopamine and norepinephrine uptake systems, respectively, whereas MPTP itself is not accumulated. The potencies of drugs in inhibiting [3H]MPP+ or [3H]dopamine uptake into striatal synaptosomes are very similar, as are potencies in inhibiting [3H]MPP+ or [3H]norepinephrine uptake into cortical synaptosomes. The Km values for [3H]MPP+ uptake are 170 and 65 nM and the Vmax values are 2 and 0.1 nmol/g of tissue per min in rat striatum and cortex, respectively, similar to values for [3H]dopamine uptake, Autoradiography of accumulated [3H]MPP+ in slices of rat brain shows high densities in the caudate-putamen and nucleus accumbens. Furthermore, blockade of dopamine uptake by mazindol prevents MPTP-induced damage to nigrostriatal dopamine neurons, indicating that MPP+ concentration into dopamine neurons explains their selective destruction by MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Structural differences in a single gene encoding the V kappa Ser group of light chains explain the existence of two mouse light-chain genetic markers.

Two phenotypic markers of mouse immunoglobulin kappa light chains, the IB-peptide marker and the Ef1a isoelectric focusing marker, are expressed by the C58/J, AKR/J, RF/J, and PL/J strains (called expressor strains) but not by BALB/c and most inbred strains. Expression is linked to the kappa light-chain locus and the Lyt-2/Lyt-3 genes on chromosome 6. Light chains bearing these markers belong to a group of variable region kappa chain (V kappa) regions called V kappa Ser, which has a serine amino terminus and a framework 1 region not observed to date among BALB/c light chains. Southern hybridization of genomic DNA with a V kappa Ser-specific cDNA probe has demonstrated a single strongly hybridizing DNA fragment in all strains of mice tested. Characteristic restriction enzyme polymorphisms define the V kappa Ser alleles of expressor (Igk-VSera) and nonexpressor (Igk-VSerb) strains. In the present study, the unrearranged V kappa Ser gene and its flanking regions from an expressor (C.C58) and nonexpressor (BALB/c) strain have been cloned and their nucleotide sequences determined. The C.C58 V kappa Ser gene isolated (the Igk-VSera allele) was shown to code for the two phenotypic markers described. While the nucleotide sequence of the BALB/c coding region (the Igk-VSerb allele) shows 97% identity with the C.C58 gene, single nucleotide substitutions lead to structural changes in the encoded protein which render it IB-negative and Ef1a-negative. These differences alone can explain the failure of strains containing the BALB/c allele to express these kappa-chain phenotypic markers. Also, the BALB/c gene contains a single substitution in a conserved octamer sequence approximately equal to 100 nucleotides upstream of the coding region, which could affect its expression. Finally, the C.C58 allele contains a BAM5/R repetitive DNA element approximately equal to 1200 nucleotides upstream of the coding regions that is not present in BALB/c. This element gives rise to the EcoRI and BamHI restriction enzyme polymorphisms, which distinguish the Igk-VSera and Igk-VSerb alleles.

Amino Acid Sequence↗

PubMed1994

How can the low levels of DNA sequence variation in regions of the drosophila genome with low recombination rates be explained?

Different regions of the Drosophila genome have very different rates of recombination. For example, near centromeres and near the tips of chromosomes, the rates of recombination are much lower than in other regions. Several surveys of polymorphisms in Drosophila have now documented that levels of DNA polymorphism are positively correlated with rates of recombination; i.e., regions with low rates of recombination tend to have low levels of DNA polymorphism within populations of Drosophila. Three hypotheses are reviewed that might account for these observations. The first hypothesis is that regions of low recombination have low neutral mutation rates. Under this hypothesis between-species divergences should also be low in regions of low recombination. In fact, regions of low recombination have diverged at the same rate as other regions of the genome. On this basis, this strictly neutral hypothesis is rejected. The second hypothesis is that the process of fixation of favorable mutations leads to the observed correlation between polymorphism and recombination. This occurs via genetic hitchhiking, in which linked regions of the genome are swept along with the selectively favored mutant as it increases in frequency and eventually fixes in the population. This hitchhiking model with fixation of favorable mutations is compatible with major features of the data. By assuming this model is correct, one can estimate the rate of fixation of favorable mutations. The third hypothesis is that selection against continually arising deleterious mutations results in reduced levels of polymorphism at linked loci. Analysis of this background selection model shows that it can produce some reduction in levels of polymorphism but cannot explain some extreme cases that have been observed. Thus, it appears that hitchhiking of favorable mutations and background selection against deleterious mutations must be considered together to correctly account for the patterns of polymorphism that are observed in Drosophila.

Animals↗

PubMed1996

Recombinational repair of gaps in DNA is asymmetric in Ustilago maydis and can be explained by a migrating D-loop model.

Recombinational repair of double-stranded DNA gaps was investigated in Ustilago maydis. The experimental system was designed for analysis of repair of an autonomously replicating plasmid containing a cloned gene disabled by an internal deletion. It was discovered that crossing over rarely accompanied gap repair. The strong bias against crossing over was observed in three different genes regardless of gap size. These results indicate that gap repair in U. maydis is unlikely to proceed by the mechanism envisioned in the double-stranded break repair model of recombination, which was developed to account for recombination in Saccharomyces cerevisiae. Experiments aimed at exploring processing of DNA ends were performed to gain understanding of the mechanism responsible for the observed bias. A heterologous insert placed within a gap in the coding sequence of two different marker genes strongly inhibited repair if the DNA was cleaved at the promoter-proximal junction joining the insert and coding sequence but had little effect on repair if the DNA was cleaved at the promoter-distal junction. Gene conversion of plasmid restriction fragment length polymorphism markers engineered in sequences flanking both sides of a gap accompanied repair but was directionally biased. These results are interpreted to mean that the DNA ends flanking a gap are subject to different types of processing. A model featuring a single migrating D-loop is proposed to explain the bias in gap repair outcome based on the observed asymmetry in processing the DNA ends.

Base Sequence↗

PubMed1996

Tuning of activation thresholds explains flexibility in the selection and development of T cells in the thymus.

Immature CD4+ CD8+ thymocytes expressing T-cell antigen receptors (TCR) are selected by TCR-mediated recognition of peptides associated with major histocompatibility complex molecules on thymic stromal cells. Selection ensures reactivity of the mature cells to foreign antigens and tolerance to self. Although much has been learned about the factors that determine whether a thymocyte with a given specificity will be positively or negatively selected, selection as an aspect of the developmental process as a whole is less well-understood. Here we invoke a model in which thymocytes tune their response characteristics individually and dynamically in the course of development. Cellular development and selection are driven by receptor-mediated metabolic perturbations. Perturbation is a measure of the net intracellular change induced by external stimulation. It results from the integration of several signals and countersignals over time and therefore depends on the environment and the maturation stage of the cell. Individual cell adaptation limits the range of perturbations. Such adaptation renders thymocytes less sensitive to the level of stimulation per se, but responsive to environmental changes in that level. This formulation begins to explain the mechanisms that link developmental and selection events to each other.

Animals↗

PubMed1999

Habitat, world geographic range, and embryonic development of hosts explain the prevalence of avian hematozoa at small spatial and phylogenetic scales.

The factors explaining interspecific differences in prevalences of blood parasites in birds are poorly known. We simultaneously assessed 20 social, ecological, life history, and sampling-related variables that could influence hemoparasite prevalences among diurnal birds of prey in Spain. Our results show that multiple factors are responsible for the studied host-parasite association. We confirmed for the first time that prevalence is inversely correlated to the embryonic development period, and thus probably to immune performance, even among closely related birds. Macrohabitat features related to vector availability are also important, prevalences being higher in species breeding in forested habitats. Finally, prevalence is positively correlated with the host's world geographic range. We hypothesize that larger geographic ranges offered more opportunities for host-vector-hemoparasite associations to become established. The results from our multivariate analyses differ from those obtained through univariate ones, showing that all potential factors should be assessed jointly when testing any ecological or evolutionary hypothesis dealing with parasites.

Animals↗

PubMed1999

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection.

Interactions between alphabeta T cell receptors and peptides bound to molecules encoded by the MHC genes underly T cell activation. More than 1% of T cells are activated by foreign (allogenic) MHC molecules, a phenomenon called alloreactivity. Reconciling the high frequency of alloreactivity with the fact that only 1 T cell in 10(4)-10(6) responds to a given foreign antigen presented on self MHC has been a long-standing puzzle. We show, by using a quantitative model, that this difference follows from the affinity model of T cell selection. Further, we demonstrate that highly alloreactive pre- and post-selection repertoires can be obtained without assuming germline bias of T cell receptors toward recognition of allele-specific MHC residues. It has been proposed that alloreactivity occurs because self and foreign MHCs bind different subsets of self peptides or alter their conformation differently. We find that such effects decrease rather than increase alloreactivity. Overall, our results show that the affinity model of T cell selection can quantitatively explain both self MHC restriction and high alloreactivity.

Animals↗

PubMed1995

Model of human chorionic gonadotropin and lutropin receptor interaction that explains signal transduction of the glycoprotein hormones.

The goal of these studies was to devise a model that explains how human chorionic gonadotropin (hCG) interacts with lutropin (LH) receptors to elicit a hormone signal. Here we show that alpha-subunit residues near the N terminus, the exposed surface of the cysteine knot, and portions of the first and third loops most distant from the beta-subunit interface were recognized by antibodies that bound to hCG-receptor complexes. These observations were combined with similar data obtained for the beta-subunit (Cosowsky, L., Rao, S.N.V., Macdonald, G.J., Papkoff, H., Campbell, R.K., and Moyle, W.R. (1995) J. Biol. Chem. 270, 20011-20019), information on residues of hCG that can be changed without disrupting hormone function, the crystal structure of deglycosylated hCG, and the crystal structure of a leucine-repeat protein to devise a model of hCG-receptor interaction. This model suggest that the extracellular domain of the LH receptor is "U-" or "J"-shaped and makes several contacts with the transmembrane domain. High affinity hormone binding results from interactions between residues in the curved portion of the extracellular domain of the receptor and the groove in the hormone formed by the apposition of the second alpha-subunit loop and the first and third beta-subunit loops. Most of the remainder of the hormone is found in the large space between the arms of the extracellular domain and makes few, if any, additional specific contacts with the receptor needed for high affinity binding. Signal transduction is caused by steric or other influences of the hormone on the distance between the arms of the extracellular domain, an effect augmented by the oligosaccharides. Because the extracellular domain is coupled at multiple sites to the transmembrane domain, the change in conformation of the extracellular domain is relayed to the transmembrane domain and subsequently to the cytoplasmic surface of the plasma membrane. While the model does not require the hormone to contact the transmembrane domain to initiate signal transduction, small portions of both subunits may be near the transmembrane domain and assist in initiating the hormonal signal. This is the first model that is consistent with all known information on the activity of the gonadotropins including the amounts of the hormone that are exposed in the hormone-receptor complex, the apparent lack of specific contacts between much of the hormone and the receptor, and the roles of the oligosaccharides in signal transduction.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1995

Expression and kinetic characterization of recombinant human stomach alcohol dehydrogenase. Active-site amino acid sequence explains substrate specificity compared with liver isozymes.

A full-length 1966-base pair clone of the human class IV alcohol dehydrogenase (sigma-ADH) was isolated from a human stomach cDNA library. The 373-amino acid sigma-ADH encoded by this cDNA was expressed in Escherichia coli. The specific activity of the recombinant enzyme for ethanol oxidation at pH 7.5 and 25 degrees C, calculated from active-site titration of NADH binding, was 92 +/- 9 units/mg. Kinetic analysis of the catalytic efficiency (kcat/KM) of recombinant sigma-ADH for oxidation of primary alcohols indicated broad substrate specificity. Recombinant human sigma-ADH exhibited high catalytic efficiency for oxidation of all-trans-retinol to all-trans-retinal. This pathway is important in the synthesis of the transcriptional regulator all-trans-retinoic acid. Secondary alcohols and 3 beta-hydroxysteroids were inactive with sigma-ADH or were oxidized with very low efficiency. The KM of sigma-ADH for ethanol was 25 mM, and the KM for primary straight chain alcohols decreased substantially as chain length increased. There are important amino acid differences in the alcohol-binding site between the human class IV (sigma) and human class I (beta) alcohol dehydrogenases that appear to explain the high catalytic efficiency for all-trans-retinol, the high kcat for ethanol, and the low catalytic efficiency for secondary alcohols of sigma-ADH relative to beta 1-ADH. For example, modeling the binding of all-trans-retinol in the human beta 1-ADH structure suggested that coordination of retinol to the active-site zinc is hindered by a loop from residues 114 to 120 that is at the entrance to the alcohol-binding site. The deletion of Gly-117 in human sigma-ADH and a substitution of Leu for the bulky Tyr-110 appear to facilitate retinol access to the active-site zinc.

Alcohol Dehydrogenase↗

PubMed1996

Changes in membrane and surface potential explain the opposite effects of low ionic strength on the two lysine transporters of human erythrocytes.

The sucrose-induced stimulation of lysine influx in human erythrocytes has been attributed to the removal of a competitive inhibition exerted by Na+ on system y+ (Young, J. D., Fincham, D. A., and Harvey, C. M. (1991) Biochim. Biophys. Acta 1070, 111-118). We have reexamined this phenomenon separating the contribution of the two cationic amino acid transporters present in these cells (system y+ and system y+L). NaCl replacement with sucrose increased influx through system y+L, but decreased influx through system y+. We conclude that 1) the inhibition of system y+ is a response to the membrane depolarization that results from chloride removal, and 2) the stimulation of system y+L is due to the enhancement of the negative surface potential. Consistently, lysine influx through system y+L (in sucrose medium) was reduced by Na+, K+, Li+, and choline (K0.5 = 25-34 mM), the effect reaching a maximum at 35-40% of the original flux. Divalent cations (Ca2+ and Mg2+) were also inhibitory, but lower concentrations were required (K0.5 1.1-1.8 mM). The finding that sucrose stimulates uptake through changes in the surface potential explains similar effects observed in other cells with various cationic substrates.

Arginine↗