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PubMed2001

A Bayesian method for finding regulatory segments in DNA.

A goal of the human genome project is to determine the entire sequence of DNA (3 x 10(9) base pairs) found in chromosomes. The massive amounts of data produced by this project require interpretation. A Bayesian model is developed for locating regulatory regions in a DNA sequence. Regulatory regions are areas of DNA to which specific proteins bind and control whether or not a gene is transcribed to produce templates for protein synthesis. Each human cell contains the same DNA sequence. Thus the particular function of different cells is determined by the genes that are transcribed in that cell. A Hidden Markov chain is used to model whether a small interval of the DNA is in a regulatory region or not. This can be regarded as a changepoint problem where the changepoints are the start of a regulatory or nonregulatory region. The data consists of protein-binding elements, which are short subsequences, or "words," in the DNA sequence. Although these words can occur anywhere in the sequence, a larger number are expected in regulatory regions. Therefore, regulatory regions are detected by locating clusters of words. For a particular DNA sequence, the model automatically selects those words that best predict regions of interest. Markov chain Monte Carlo methods are used to explore the posterior distribution of the Hidden Markov chain. The model is tested by means of simulations, and applied to several DNA sequences.

Bayes Theorem↗

PubMedDate not supplied

Geometric morphometric study of population variation in indigenous southern African crania.

Much of our understanding of population variation in southern Africa is derived from traditional morphometric research. In the search for new perspectives, this paper reports on new geometric morphometric data examining cranial variation in 12 modern human populations from southern Africa. In total, 298 male Bantu-speaking individuals were studied. In addition, a small Khoisan (Khoikhoi and San) series was also examined. The purpose of this study was to investigate Khoisan-Bantu morphological similarities and differences, and to examine variation within both the Bantu-speaking and Khoisan populations. The three-dimensional coordinates of 96 landmarks were analyzed, using the shape-analysis software morphologika. Interpopulation variation was examined by calculating Procrustes distances between groups; a cluster analysis was then used to summarize phenetic relationships. A principal components analysis explored the relationships between populations; shape differences were visualized and explored using three-dimensional rendered models, and further interpreted using thin-plate splines. Morphological differences are present within and between the crania of Bantu-speaking and Khoisan individuals. The Khoisan demonstrate features (e.g., a pentagonoid vault, more rounded forehead contour, and a small and less prognathic face) that clearly distinguish them from Bantu-speaking populations. Although southern African Bantu-speaking populations are clearly closely related, they show population-specific features (e.g., the crania of more southerly populations (Xhosa, Southern Sotho, and Zulu) are characteristically more brachycephalic and less prognathic). This study suggests that differential admixture with adjacent Khoisan peoples has contributed to diversity within southern African Bantu-speaking populations.

Africa, Southern↗

PubMed2006

Orangutan positional behavior and the nature of arboreal locomotion in Hominoidea.

The Asian apes, more than any other, are restricted to an arboreal habitat. They are consequently an important model in the interpretation of the morphological commonalities of the apes, which are locomotor features associated with arboreal living. This paper presents a detailed analysis of orangutan positional behavior for all age-sex categories and during a complete range of behavioral contexts, following standardized positional mode descriptions proposed by Hunt et al. ([1996] Primates 37:363-387). This paper shows that orangutan positional behavior is highly complex, representing a diverse spectrum of positional modes. Overall, all orthograde and pronograde suspensory postures are exhibited less frequently in the present study than previously reported. Orthograde suspensory locomotion is also exhibited less often, whereas pronograde and orthograde compressive locomotor modes are observed more frequently. Given the complexity of orangutan positional behavior demonstrated by this study, it is likely that differences in positional behavior between studies reflect differences in the interplay between the complex array of variables, which were shown to influence orangutan positional behavior (Thorpe and Crompton 2005 Am. J. Phys. Anthropol. 127:58-78). With the exception of pronograde suspensory posture and locomotion, orangutan positional behavior is similar to that of the African apes, and in particular, lowland gorillas. This study suggests that it is orthogrady in general, rather than forelimb suspend specifically, that characterizes the positional behavior of hominoids.

Animals↗

PubMed2004

Influence of interhemispheric interactions on motor function in chronic stroke.

In patients with chronic stroke, the primary motor cortex of the intact hemisphere (M1(intact hemisphere)) may influence functional recovery, possibly through transcallosal effects exerted over M1 in the lesioned hemisphere (M1(lesioned hemisphere)). Here, we studied interhemispheric inhibition (IHI) between M1(intact hemisphere) and M1(lesioned hemisphere) in the process of generation of a voluntary movement by the paretic hand in patients with chronic subcortical stroke and in healthy volunteers. IHI was evaluated in both hands preceding the onset of unilateral voluntary index finger movements (paretic hand in patients, right hand in controls) in a simple reaction time paradigm. IHI at rest and shortly after the Go signal were comparable in patients and controls. Closer to movement onset, IHI targeting the moving index finger turned into facilitation in controls but remained deep in patients, a finding that correlated with poor motor performance. These results document an abnormally high interhemispheric inhibitory drive from M1(intact hemisphere) to M1(lesioned hemisphere) in the process of generation of a voluntary movement by the paretic hand. It is conceivable that this abnormality could adversely influence motor recovery in some patients with subcortical stroke, an interpretation consistent with models of interhemispheric competition in motor and sensory systems.

Adult↗

PubMed2007

Stereoselective biocatalytic synthesis of (S)-2-hydroxy-2-methylbutyric acid via substrate engineering by using "thio-disguised" precursors and oxynitrilase catalysis.

3-Tetrahydrothiophenone (4) and 4-phenylthiobutan-2-one (7) were used as masked 2-butanone equivalents to give the corresponding cyanohydrins 5 (79 % yield, 91 % ee) and 8 (95 % yield, 96 % ee) in an enzymatic cyanohydrin reaction applying the hydroxynitrile lyase (HNL) from Hevea brasiliensis. After hydrolysis and desulphurisation the desired intermediate (S)-2-hydroxy-2-methylbutyric acid (10) was obtained with 99 % ee. Interestingly, when applying (R)-selective HNL from Prunus amygdalus again the (S)-cyanohydrin 5 was formed (62 % ee). The absolute configuration of 5 was verified by crystal structure determination of the corresponding hydrolysis derived carboxylate. The fact that both enzymes yield the same enantiomer was analysed and interpreted by molecular modelling calculations.

Aldehyde-Lyases↗

PubMed1976

"Early T cells" and "late T cells"; suggestive evidence for two T cell lineages with separate developmental pathways.

Peripheral lymphocytes from mice have been analyzed by a combination of cell electrophoresis and size distribution analysis and the data have been processed with a computer into two-dimensional distribution patterns (fingerprints). The fingerprints of lymph node cells revealed the existence of at least three major classes of small lymphocytes. Cells with similar physical properties were found in the spleen and thoracic duct lymph. The data also allowed calculation of the quantitative ratios of the three cell types. In the normal mouse, the two electrophoretically faster cell classes represent essentially two subclasses of T cells. The quantitative ratios are here always in agreement with the known percentages of B and T cells. Lethally irradiated mice that have been reconstituted with syngeneic bone marrow or fetal liver cells often lack one of the T cell subclasses. This has two important implications. 1) It indicates that the widely used syngeneic or allogeneic bone marrow chimeras may be incomplete in respect to their T cell repertoire and that experiments with these models should be interpreted with caution. 2) The deficiency was found to correlate strictly with a deficiency in a physically defined subset of small cortical thymocytes that has been described previously. This correlation suggests strongly that the fast peripheral T cells and the "early small cortical thymocytes" represent two developmental stages of a distinct cell lineage ("early T cell lineage"), while the thymic pool of "late small cortical thymocytes" gives rise to electrophoretically slow peripheral T cells, which may be called "late T cells). The possibility that both T cell lineages are derived from different classes of prethymic stem cells in the reconstitlting stem cell preparation is discussed. The proportion of "early T cells" in the lymph nodes decreases with age. The ratio of "late" and "early T cells" is similar in the spleen and in the lymph nodes, and both cell classes contain a significant proportion of cells that are not affected by the early effects of adult thymectomy. Thus, they do not correspond to T1 and T2 cells.

Age Factors↗

PubMedDate not supplied

Temperature differentially affects encounter and docking thermodynamics of antibody--antigen association.

Using BIACORE SPR, we have examined the mechanism of temperature effects on the binding kinetics of two closely related antibody Fabs (H10 and H26) which recognize coincident epitopes on hen egg-white lysozyme (HEL), and whose association and dissociation kinetics are best described by the two-step conformational change model which we interpret as molecular encounter and docking. Time-course series data obtained at a series of six temperatures (6, 10, 15, 25, 30 and 37 degrees C) showed that temperature differentially affects the rate constants of the encounter and docking steps. Docking is more temperature-sensitive than the encounter step, and energetically less favorable at higher temperatures. At elevated temperatures, the time required for docking is longer and the apparent increase in off-rate reflects the greater proportion of the molecules failing to dock and remaining in the less stable encounter state. As a consequence, distribution of free energy change between the encounter and docking steps is altered. At physiological temperature (37 degrees C) the docking step of the H26 complex is energetically unfavorable and most complexes essentially do not dock. There is a significant decrease in total free energy change of the H26 complex at higher temperatures. Elevated temperature changes the rate-limiting step of H26--HEL association from the encounter to the docking step, but not that of H10--HEL. Our results indicate that the mechanism by which elevated temperature reduces the affinities of antigen--antibody complexes is to decrease the net docking rate, and/or stability of the docked complex; at higher temperatures, a smaller proportion of the complexes actually anneal to a more stable docked state. This mechanism may have broad applicability to other receptor--ligand complexes.

Antigen-Antibody Complex↗

PubMed1990

Interpretation of the hindered settling of calcium carbonate suspensions in terms of permeability.

Many pharmaceutical formulations are produced in the form of concentrated suspensions. Calcium carbonate suspensions are used in this study and interpreted as the "model" for the behavior of such suspensions. The behavior of concentrated suspensions of powders in a liquid medium cannot be treated by the simple application of the normal principles of free fall and the use of Stokes Law pertaining to the viscous resistance offered by the surrounding fluid to fall. A single particle operating by the Stokes principle obeys this relationship. This law applies to the behavior of particles at low concentration in a liquid medium and is the basis for particle size distribution methods. At higher concentrations, however, the particles do not enjoy the freedom of unhindered fall. The system subsides "en bloc," and it is common practice to offer a modification to the Stokes equation which takes into consideration some function of the porosity of the system. There have been a considerable number of equations developed and modified based on this principle. However, an alternative method is to approach the problem by dealing with the permeability of a bed of powders in a liquid in which the bed is slowly altering with time. This is best achieved by the use of the permeability equation developed and presented by Kozeny-Carmen. This equation, as well as the Richardson-Zaki expression, are related to show that the Kozeny parameter K varies with the suspension porosity under sedimentation conditions. The values of K are often larger than the value normally reported (i.e., approximately 5). The data and treatment outlined here are extended to include not only the calcium carbonate suspensions, but other systems previously mentioned in the literature.

Calcium Carbonate↗

PubMed2005

Input parameter sensitivity analysis and comparison of quantification models for continuous arterial spin labeling.

The regional cerebral blood flow (rCBF) values determined using continuous arterial spin labeling (CASL) are subject to several sources of variability, including natural physiologic variations, sensitivity to the input parameters, and the use of different quantification models. To date, a thorough analysis of the impact of input parameters and the choice of quantification model has not been performed. These sources of variability were investigated through computer simulations using bootstrap techniques on actual CASL data. Coefficients of variation for representative single voxels were 6.7% for gray matter and 29% for white matter, and for eight-voxel regions of interest they were 4.5% for gray matter and 23% for white matter. Comparison of nine CASL quantification models showed differences in gray matter rCBF values of up to 42%. An analysis of the sensitivity of the rCBF to input parameters for each of the nine quantification models demonstrated that accurate quantification of the inversion efficiency, tissue and arterial blood longitudinal relaxation times, and transit times were critical in calculating precise rCBF values. The large potential variations in rCBF and the effect of the choice of quantification model suggest that interpreting absolute rCBF values in CASL studies can be challenging and requires great care.

Adult↗

PubMed1998

Dissociable coordinate frames of unilateral spatial neglect: "viewer-centered" neglect.

Detailed analyses of reading and nonlexical tasks by three patients with unilateral spatial neglect (USN) secondary to stroke indicate that the USN in each of these patients affects the left side (contralateral to brain damage) of the viewer, with respect to the viewer's head, mid-sagittal plane of the body, or line of sight. In one case, the neglect was further specified as concerning the left side of the viewer's line of sight (the left half of her residual visual field). Thus, the frame of reference of USN in these three cases appears to have viewer-centered (in at least one case, specifically retinotopic) coordinates. The performance of these patients is contrasted to that of other patients in the literature whose USN appears to have a frame of reference with stimulus-centered or object-centered coordinates. These results are interpreted within a model of visual processing (adapted from Marr, 1980 and others) with at least three coordinate frames. It is argued that USN can affect one or more of these coordinate frames independently.

Aged↗

PubMed2000

Visuographemic alexia: a new form of a peripheral acquired dyslexia.

We report a single-case study of peripherally acquired dyslexia that meets the clinical criteria of "alexia without agraphia." The patient, AA, has a large infarct involving the left posterior cerebral artery. The most striking feature is a severe impairment in recognizing single visually presented letters that precludes explicit or implicit access to reading, even in a letter-by-letter fashion. AA can, however, differentiate letters from similar nonsense characters and digits, and he is also able to identify alphanumeric signs when the visual channel is bypassed (through somesthesic or kinesthesic presentation). Spelling tasks are also well performed. Since there is a breakdown in mapping a visually presented letter to its abstract graphemic representation, we propose the term "visuographemic alexia" for this kind of reading disorder. The pattern of deficits is interpreted following theoretical models previously developed in cognitive neuropsychology. An alexia for arabic numerals with preserved comprehension lends additional support for the crucial processing of different notational systems (e.g., phonographic vs logographic). More general perceptive disorders do not seem to account for these patterns; they are material-specific. Finally, we attempt to specify functional correlations with the implied neural networks.

Dominance, Cerebral↗

PubMed1997

Adsorption Kinetics of Alkylphosphine Oxides at Water/Hexane Interface

A theoretical model is presented to describe the adsorption of surfactant molecules at the water/oil interface for the case when transport across the interface must be considered due to the solubility of the surfactant in both liquid phases (aqueous solution drop in an oil phase). The theory is based on a diffusion-controlled adsorption model and a numerical difference scheme is used to solve the problem for closed finite systems. By simulating adsorption-desorption processes, the influence of the geometrical and thermodynamic parameters on the dynamic adsorption behavior is studied. In particular, the effects of the volume ratio, surfactant concentration, diffusion coefficients, and distribution coefficient on the process are analyzed. The model allows quantitative interpretation of the experimental data obtained for an alkyldimethylphosphine oxide at the water/hexane interface. The interfacial tension signals, presenting a minimum under some conditions, are fitted by the theoretical curves.

Journal Article↗

PubMed2001

Probing proteins in solution by (129)Xe NMR spectroscopy.

The interaction of xenon with different proteins in aqueous solution is investigated by (129)Xe NMR spectroscopy. Chemical shifts are measured in horse metmyoglobin, hen egg white lysozyme, and horse cytochrome c solutions as a function of xenon concentration. In these systems, xenon is in fast exchange between all possible environments. The results suggest that nonspecific interactions exist between xenon and the protein exteriors and the data are analyzed in term of parameters which characterize the protein surfaces. The experimental data for horse metmyoglobin are interpreted using a model in which xenon forms a 1:1 complex with the protein and the chemical shift of the complexed xenon is reported (Locci et al., Keystone Symposia "Frontiers of NMR in Molecular Biology VI", Jan. 9--15, 1999, Breckenridge, CO, Abstract E216, p. 53; Locci et al., XeMAT 2000 "Optical Polarization and Xenon NMR of Materials", June 28--30, 2000, Sestri Levante, Italy, p. 46).

Animals↗

PubMed1994

Tracer-kinetic analysis for measuring regional cerebral blood flow by dynamic nuclear magnetic resonance imaging.

Measurement of regional cerebral blood flow in vivo has proved useful in the study of normal and diseased states in the brain. This circumstance has led to a variety of techniques for its quantitative determination and has continued to motivate the search for ever safer and more accurate methods of measurement. Recently, the use of nuclear magnetic resonance (NMR) in medical imaging has stimulated efforts to make it the basis for a non-invasive method of measuring flow in the brain. New advances in fast NMR imaging (MRI) provide data potentially amenable to analysis by tracer-kinetic methods. Such an analysis has not previously been available. In this paper we present theoretical results that may permit measurement of brain blood flow by NMR. The data interpreted by our model are those generated by a novel MRI protocol developed by Perman et al. (1992, Magn. Reson. Med. 28, 74-83; Radiology 185(P), Abstr. 154, 127) that is entirely compatible with existing routine MRI procedures. These data are fast dynamic NMR signals that reflect passage of an intravenously administered paramagnetic contrast agent serving as a plasma tracer. Our equations show how to use such data sequences to determine plasma mean transit time, plasma volume, and plasma and whole-blood flow in arbitrarily selected regions of interest in the brain. The theory accounts rigorously for recirculation of tracer to the imaged regions. Our analysis provides an explanation for the linear relationship observed experimentally by others between regional vascular volumes and time integrals of vascular-tracer residue curves, and shows that this relationship remains valid in the presence of tracer recirculation.

Brain↗

PubMed1998

Spatial structure, environmental heterogeneity, and population dynamics: analysis of the coupled logistic map.

Spatial extent can have two important consequences for population dynamics: It can generate spatial structure, in which individuals interact more intensely with neighbors than with more distant conspecifics, and it allows for environmental heterogeneity, in which habitat quality varies spatially. Studies of these features are difficult to interpret because the models are complex and sometimes idiosyncratic. Here we analyze one of the simplest possible spatial population models, to understand the mathematical basis for the observed patterns: two patches coupled by dispersal, with dynamics in each patch governed by the logistic map. With suitable choices of parameters, this model can represent spatial structure, environmental heterogeneity, or both in combination. We synthesize previous work and new analyses on this model, with two goals: to provide a comprehensive baseline to aid our understanding of more complex spatial models, and to generate predictions about the effects of spatial structure and environmental heterogeneity on population dynamics. Spatial structure alone can generate positive, negative, or zero spatial correlations between patches when dispersal rates are high, medium, or low relative to the complexity of the local dynamics. It can also lead to quasiperiodicity and hyperchaos, which are not present in the nonspatial model. With density-independent dispersal, spatial structure cannot destabilize equilibria or periodic orbits that would be stable in the absence of space. When densities in the two patches are uncorrelated, the probability that the population in a patch reaches extreme low densities is reduced relative to the same patch in isolation; this "rescue effect" would reduce the probability of metapopulation extinction beyond the simple effect of spreading of risk. Pure environmental heterogeneity always produces positive spatial correlations. The dynamics of the entire population is approximated by a nonspatial model with mean patch characteristics. This approximation worsens as the difference between the patches increases and the dispersal rate decreases: Under extreme conditions, destabilization of equilibria and periodic orbits occurs at mean parameter values lower than those predicted by the mean parameters. Apparent within-patch dynamics are distorted: The local population appears to have the wrong growth parameter and a constant number of immigrants (or emigrants) per generation. Adding environmental heterogeneity to spatial structure increases the occurrence of spatially correlated population dynamics, but the resulting temporal dynamics are more complex than would be predicted by the mean parameter values. The three classes of spatial pattern (positive, negative, and zero correlation), while still mathematically distinct, become increasingly similar phenomenologically.

Animals↗

PubMed1991

HINT: a new method of empirical hydrophobic field calculation for CoMFA.

An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydrophobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An example is given using the steroid model reported by Cramer et al. (J. Am. Chem. Soc., 110 (1988) 5959). While addition of the HINT field did not improve statistical parameters in this model, the CoMFA coefficient contours from the hydrophobic field unambiguously define the most active steroid molecules in the chemical terms of hydrophobic and polar substituents.

Aldosterone↗

PubMed1990

The third birth in Sweden.

"This paper considers the formulation, estimation and interpretation of microdynamic models of fertility. Our model explains parity choices, sterility, childlessness, interbirth intervals and initiation of pregnancy within a unified framework. We develop a general methodology for estimating the determinants of transition times to births of different orders. Our procedure incorporates time-varying explanatory variables and unobservables. We present conditions that justify conventional formulae relating hazards to survivor functions when time-varying variables enter hazards. We also consider the validity of widely-used piecemeal estimation strategies that focus on one birth at a time. We consider methods for selecting a best model among a class of non-nested models. Two criteria are set forth and used to evaluate the determinants of third births in Sweden."

Birth Order↗

PubMed1994

New insights into receptor theory, as provided by an artificial partial agonist made-to-measure.

In the present study a mixture of a full agonist (noradrenaline) and a full antagonist (yohimbine) was used to mimic the effects of a partial agonist (clonidine) on alpha 2-autoreceptor-mediated regulation of noradrenaline release in order to learn more about the shape of concentration-response curves in the absence and presence of spare receptors. The sigmoidal shape of the cloud of single experimental data points may be reflected by different curve fits based on either descriptive or mechanistic mathematical models. Only mechanistic models allow the interpretation of the relationship between occupancy of receptors and induced response. The experiments were performed in rat neocortex and in rabbit hippocampus tissue where electrical field stimulation with 4 pulses/100 Hz of slices prelabelled with [3H]noradrenaline elicited the release of noradrenaline. A receptor reserve was found in the rabbit hippocampus and quantified from the concentration-response curve of noradrenaline in this tissue using a mechanistic general response function, developed to reflect the condition of spare receptors. The mixture of noradrenaline and yohimbine, NA-Yoh, (three parts to one part), corrected by the different affinities to the alpha 2-autoreceptors, was designed to mirror the quantified proportion of 75% non-spare and 25% spare alpha 2-autoreceptors. In the spare receptor-free rat cortex NA-Yoh acted like a typical partial agonist, as clonidine, with nearly the same EC50 (= Kd in this case) as the full agonist noradrenaline, but with a maximum effect significantly lower than that of noradrenaline. In the rabbit hippocampus, however, the same maximum effect was obtained with NA-Yoh, noradrenaline and clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗