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Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men.

The healthy human male hypothalamo-pituitary-gonadal axis exhibits age-dependent loss of coordinate LH-testosterone secretion. A putative independent defect in Leydig-cell steroidogenesis with aging would confound the attribution of such LH-testosterone asynchrony to a hypothalamo-pituitary locus per se. Accordingly, here we appraise by sampling every 2.5 min overnight the joint synchrony of moment-to-moment LH release with simultaneously monitored pituitary FSH secretion, prolactin release, and nocturnal penile tumescence (NPT) oscillations, as a neurophysiological correlate of sleep regulation) in 10 young (ages 21-34) and 8 older (ages 62-72) healthy men. Joint synchrony for paired LH-FSH, LH-prolactin, and LH-NPT observations in young vs. older individuals was quantified by the cross-approximate entropy (cross-ApEn) statistic, with larger cross-ApEn values indicating greater two-variable asynchrony. Concomitantly, we assessed (possible) univariate changes with age for each of LH, FSH, prolactin, and NPT, as quantified by approximate entropy (ApEn). Hormone assays were performed by random-access direct chemiluminescence analyzer. Overnight mean (+/- SEM) serum LH concentrations (IU/L) were equivalent in older (3.1 +/- 0.31 IU/L) and younger (2.9 +/- 0.29) men, as were their serum total testosterone concentrations; viz., 425 +/- 48 (older) and 523 +/- 40 (younger) ng/dL. However, all three sets of paired time-series were significantly more asynchronous in the older cohort. First, cross-ApEn of paired LH-FSH release was significantly higher (or more asynchronous) in older subjects; viz., 1.902 +/- 0.022 in older men vs. 1.607 +/- 0.058 in younger individuals (P = 0.0005). Second, cross-ApEn of paired LH and prolactin release was 1.744 +/- 0.085 in older volunteers vs. 1.346 +/- 0.084 in younger subjects (P = 0.0046). Third, and most notably, cross-ApEn for the joint LH-NPT observation time-series was significantly greater in older subjects at 1.771 +/- 0.056 vs. 1.223 +/- 0.086 (young) (P = 0.0001), thereby denoting loss of coordination between (neural) signals directing intermittent LH secretion and those governing sleep-associated penile tumescence in older men. Among one-variable results, only ApEn of LH release was significantly higher in older individuals at 1.323 +/- 0.058 vs. 0.897 +/- 0.089 in younger subjects (P = 0.0019), signifying greater disorderliness of the LH secretory process in aged men. Individual ApEn values of FSH and prolactin release and NPT were age-invariant. In ensemble, the present clinical experiments indicate that, within the aging male reproductive axis, bihormonal network disruption is more pronounced than individual signal disruption. We suggest that abrogation of joint synchrony among hypothalamically directed pituitary hormones and a neurogenically organized sexual response (nocturnal penile tumescence) can be unified thematically under an hypothesis of disrupted central nervous system hypothalamo-pituitary network coordination in human aging. Such implicit disarray of multinodal communication is of consequence both scientifically and clinically, especially in proposing aging theories and intervention strategies.

Adult↗

Maximum a posteriori local histogram estimation for image registration.

Image similarity measures for registration can be considered within the general context of joint intensity histograms, which consist of bin count parameters estimated from image intensity samples. Many approaches to estimation are ML (maximum likelihood), which tends to be unstable in the presence sparse data, resulting in registration that is driven by spurious noisy matches instead of valid intensity relationships. We propose instead a method of MAP (maximum a posteriori) estimation, which is well-defined for sparse data, or even in the absence of data. This estimator can incorporate a variety of prior assumptions, such as global histogram characteristics, or use a maximum entropy prior when no such assumptions exist. We apply our estimation method to deformable registration of MR (magnetic resonance) and US (ultrasound) images for an IGNS (image-guided guided neurosurgery) application, where our MAP estimation method results in more stable and accurate registration than a traditional ML approach.

Algorithms↗

Gene functional annotation by statistical analysis of biomedical articles.

BACKGROUND: Functional annotation of genes is an important task in biology since it facilitates the characterization of genes relationships and the understanding of biochemical pathways. The various gene functions can be described by standardized and structured vocabularies, called bio-ontologies. The assignment of bio-ontology terms to genes is carried out by means of applying certain methods to datasets extracted from biomedical articles. These methods originate from data mining and machine learning and include maximum entropy or support vector machines (SVM). PURPOSE: The aim of this paper is to propose an alternative to the existing methods for functionally annotating genes. The methodology involves building of classification models, validation and graphical representations of the results and reduction of the dimensions of the dataset. METHODS: Classification models are constructed by Linear discriminant analysis (LDA). The validation of the models is based on statistical analysis and interpretation of the results involving techniques like hold-out samples, test datasets and metrics like confusion matrix, accuracy, recall, precision and F-measure. Graphical representations, such as boxplots, Andrew's curves and scatterplots of the variables resulting from the classification models are also used for validating and interpreting the results. RESULTS: The proposed methodology was applied to a dataset extracted from biomedical articles for 12 Gene Ontology terms. The validation of the LDA models and the comparison with the SVM show that LDA (mean F-measure 75.4%) outperforms the SVM (mean F-measure 68.7%) for the specific data. CONCLUSION: The application of certain statistical methods can be beneficial for functional gene annotation from biomedical articles. Apart from the good performance the results can be interpreted and give insight of the bio-text data structure.

Abstracting and Indexing↗

Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.

Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.

Activity Cycles↗

Isocratic separation of ginsenosides by high-performance liquid chromatography on a diol column at subambient temperatures.

An improved high-performance liquid chromatographic method for separation of a number of ginsenosides has been developed. The influence of temperature (from 0 to 25 degrees C) on the retention and separation of the ginsenosides was studied by applying a binary mobile phase (acetonitrile/water, 82:18 v/v) and a diol column (LiChrospher 100 Diol). The column temperature is one of the more important parameters for the retention and separation of the components investigated. Selected thermodynamic parameters, including changes of enthalpy (deltaH degrees) and entropy (deltaS degrees), were estimated from linear van't Hoff plots, and possible retention mechanisms were discussed. Moreover, the best separation conditions were selected based on optimization criteria including maximum retention time (t(R max)), minimum resolution (R(s min)), and relative resolution product (r). Temperature regions close to 14 degrees C offered the highest selectivity and almost equal distribution of the ginsenosides peaks across the chromatogram. Under such isocratic conditions, excellent separation of chromatographic standards and selected ginseng samples was achieved in less than 16 min.

Chromatography, High Pressure Liquid↗

Numerical study of the stress response of two-dimensional dense granular packings.

We investigate the Green function of two-dimensional dense random packings of grains in order to discriminate between the different theories of stress transmission in granular materials. Our computer simulations allow for a detailed quantitative investigation of the dynamics which is difficult to obtain experimentally. We show that both hyperbolic and parabolic models of stress transmission fail to predict the correct stress distribution in the studied region of the parameters space. We demonstrate that the compressional and shear components of the stress compare very well with the predictions of isotropic elasticity for a wide range of pressures and porosities and for both frictional and frictionless packings. However, the states used in this study do not include the critical isostatic point for frictional particles, so that our results do not preclude the fact that corrections to elasticity may appear at the critical point of jamming, or for other sample preparation protocols, as discussed in the main text. We show that the agreement holds in the bulk of the packings as well as at the boundaries and we validate the linear dependence of the stress profile width with depth.

Algorithms↗

Measuring polymer surface ordering differences in air and water by sum frequency generation vibrational spectroscopy.

Molecular structures of poly(n-butyl methacrylate) (PBMA) at the PBMA/air and PBMA/water interfaces have been studied by sum frequency generation (SFG) vibrational spectroscopy. PBMA surfaces in both air and water are dominated by the methyl groups of the ester side chains. The average orientation and orientation distribution of these methyl groups at the PBMA/air and PBMA/water interfaces are different, indicating that surface restructuring occurs when the PBMA sample contacts water. Analysis shows that the orientation distribution of side chain methyl groups on the PBMA surface is narrower in water than that in air, indicating that the PBMA surface can be more ordered in water. To our knowledge, this is the first time that quantitative comparisons between molecular surface structures of polymers in air and in water have been made. Two assumptions on the orientation distribution function, including a Gaussian distribution and a formula based on the maximum entropy approach, are used in the analysis. It has been found that the orientation angle distribution function deduced by the Gaussian distribution and the maximum entropy distribution are quite similar, showing that the Gaussian distribution is a good approximation for the angle distribution. The effect of experimental error on the deduced orientational distribution is also discussed.

Journal Article↗

A new method for sleep apnea classification using wavelets and feedforward neural networks.

OBJECTIVES: This paper presents a novel approach for sleep apnea classification. The goal is to classify each apnea in one of three basic types: obstructive, central and mixed. MATERIALS AND METHODS: Three different supervised learning methods using a neural network were tested. The inputs of the neural network are the first level-5-detail coefficients obtained from a discrete wavelet transformation of the samples (previously detected as apnea) in the thoracic effort signal. In order to train and test the systems, 120 events from six different patients were used. The true error rate was estimated using a 10-fold cross validation. The results presented in this work were averaged over 100 different simulations and a multiple comparison procedure was used for model selection. RESULTS: The method finally selected is based on a feedforward neural network trained using the Bayesian framework and a cross-entropy error function. The mean classification accuracy, obtained over the test set was 83.78+/-1.90%. CONCLUSION: The proposed classifier surpasses, up to the author's knowledge, other previous results. Finally, a scheme to maintain and improve this system during its clinical use is also proposed.

Algorithms↗

Self-trapping of magnetic oscillation modes in Landau flux-closure structures.

We investigated the magnetodynamics in rectangular Permalloy platelets by means of time-resolved x-ray photoemission microscopy. 10 nm thick platelets of size 16 x 32 microm were excited by an oscillatory field along the short side of the sample with a fundamental frequency of 500 MHz and considerable contributions of higher harmonics. Under the influence of the oscillatory field, the Néel wall in the initial classical Landau pattern shifts away from the center, corresponding to an induced magnetic moment perpendicular to the exciting field. This phenomenon is explained by a self-trapping effect of the dominating spin-wave mode when the system is excited just below the resonance frequency. The basic driving mechanism is the maximization of entropy.

Journal Article↗

An NQR study of the polymorphism of triphenylchloromethane.

This work is a study of the polymorphic transformations of triphenylchloromethane (TPCM) as well as the structure and dynamics of this molecular solid. Crystalline TPCM has been studied by a variety of techniques and many of its physical properties have been characterized. Previous crystallographic studies have reported the existence of two crystalline phases. Phase II, stable above 372 K, is trigonal with space group P3; and Z = 6. The compound associates pairwise (halogen-to-halogen and triphenylmethyl-to-triphenylmethyl) and linearly with all carbon-halogen bonds aligned with C3 and S6 axes of the lattice. Below 372 K, a triclinic modification (phase III) is found (P1;, Z = 10) where the molecules are also aligned pairwise with close Cl cdots, three dots, centered Cl interactions. However, the C-Cl bonds were no longer parallel. On the other hand, DTA studies have also reported a phase transition at 381 K (to phase I) that can been obtained from slow evaporation of pentane or ether solutions. Crystallographic information about these phases has not been obtained in the literature. Five NQR lines have been observed from liquid nitrogen temperature to 372 K in good agreement with phase III that has Z = 10. Above 372 K, three lines are observed which are related to phase II. Any effort to observe phase I through NQR failed; phase II remains until the sample is melted. Instead, if phase II is cooled down, a second-order phase transition to a new phase at 259 K is observed through NQR studies. The temperature dependence of experimental data in the phase transition region is well explained assuming the transitions occur when molecules in the crystal lattice change their direction uniformly with a change in temperature and the liberational modes, coupled in an anharmonic way with the uniform mode, change their frequencies in such a way that entropy compensates the unfavorable potential energy increase due to the uniform angular tilt.

Journal Article↗

System times and time horizons for biospheric near-matches of primarily non-photic environmental cycles.

System time is defined as the duration (T) and sampling density (deltat) of a given study. A time horizon is obtained by combining analytical results on endpoints of time structures (chronomes), usually on control groups, from accumulating diverse studies carried out with drastically different values of T and deltat. These two design considerations depend upon and are limited by resources. The desideratum of a small At e.g., for studies of chaotic endpoints, limits T, e.g., has thus far precluded a continuous mapping of decadal cycles in endpoints such as the approximate entropy or the correlation dimension. Time horizons are being documented for an increasing number of variables that undergo cycles with infra-annual frequencies - with one cycle in about one, two and/or five decades - in the biosphere as in the environment. These infra-annuals, in and around us, modulate ultra-annuals, including circadians, as well as about 7-day (circaseptan) and about half-yearly (circasemiannual) cycles, all prominent, e.g., in geophysical and biospheric specta. Neglect of infra-annual chronomics can lead to blunders. A statistically highly significant decrease in the excretion of steroidal metabolites (or in heart rate variability) may be misinterpreted as premature aging if it lasts for several years, and may be unnecessarily acted upon, e.g., by drugs. The decrease, however, may only be transient, occurring only during a given stage of a circadecadal cycle, and it may be followed for the next several years by an also spurious "rejuvenation", possibly misinterpreted as a drug effect. When recognized as the alternating stages of decadal cycles and assessed with an affordable deltat, infra-annuals of variables involved in major problems of our day, including homicides and wars, may lead us to manipulable internal or external mechanisms, and thus, eventually, possibly to countermeasures to crime and terror as well as to the optimization of aims such as spirituality.

Circadian Rhythm↗

Sequential projection pursuit using genetic algorithms for data mining of analytical data.

Sequential projection pursuit (SPP) is proposed to detect inhomogeneities (clusters) in high-dimensional analytical data. Such inhomogeneities indicate that there are groups of objects (samples) with different chemical characteristics. The method is compared with principal component analysis (PCA). PCA is generally applied to visually explore structure in high-dimensional data, but is not specifically used to find clustering tendency. Projection pursuit (PP) is specifically designed to find inhomogeneities, but the original method is computationally very intensive. SPP combines the advantages of both methods and overcomes most of their weak points. In this method, latent variables are obtained sequentially according to their importance measured by the entropy index. This involves an optimization step, which is achieved by using a genetic algorithm. The performance of the method is demonstrated and evaluated, first on simulated data sets, and then on near-infrared and gas chromatography data sets. It is shown that SPP indeed reveals more easily information about inhomogeneities than PCA.

Algorithms↗

Differential orderliness of the GH release process in castrate male and female rats.

Male- and female-specific modes of episodic growth hormone (GH) release are presumptively imposed by sex steroid hormones, and, although typically evident visually, are vividly distinguished quantitatively via a regularity statistic, approximate entropy (ApEn), in both the rat and human. GH secretory patterns may determine GH-stimulated growth and specific hepatic and muscle gene expression in the rat. Consequently, it is important to discern mechanisms that underlie their regulation. Here we have examined the impact of prepubertal gonadal suppression (at 4 wk of age) via surgical or pharmacological [gonadotropin-releasing hormone (GnRH) agonist] intervention on the regularity (ApEn) of GH release in male and female rats (at 10-11 wk of age) sampled at 10-min intervals for 10 h (n = 60 points) during a lights-out (dark) period. We observed a graded hierarchy of mean disorderliness of GH release that was quantifiable by ApEn measures, with maximal to minimal disorderliness in the following rank order: intact female, GnRH agonist-treated female, ovariectomized female, orchidectomized male, GnRH agonist-treated male, and intact male. These observations suggest a continuum of sex steroid actions on the regularity of GH secretion and, by inference, on the interplay among GH-releasing hormone, somatostatin, and GH/insulin-like growth factor I negative feedback.

Animals↗

Monomer-dimer equilibrium constants of RNA in the dimer initiation site of human immunodeficiency virus type 1.

The genome of the human immunodeficiency virus (HIV) exists as a dimer of two identical RNA molecules hydrogen bonded to each other near their 5' ends. The dimer, known to be important for viral infectivity, is formed by two monomers interacting through a stem-loop structure called the dimer initiation site (DIS). An initially formed intermediate, the "kissing" dimer, is unstable and rearranges to the stable, duplex form. In this report we use nondenaturing polyacrylamide gel electrophoresis to measure the monomer-dimer equilibrium constant of three RNA sequences, 41-, 27-, and 19-mers, located in the DIS of the MAL isolate of HIV-1. Experiments in which the RNA was equilibrated at various temperatures before electrophoresis revealed that interconversion is rapid for all the sequences, so that they reach equilibrium in the loading well of the gel at 5 degrees C before they enter the gel proper. However, interconversion kinetics in the gel are slow, so autoradiographic spot intensities can be used to measure the amounts of monomer and dimer present when the sample entered the gel. After correction for the amount of RNA added with the radiolabel and dilution of samples in the loading well of the gel, dimerization equilibrium constants were calculated from spot intensities. The calculated values of the dimerization constant K at 5 degrees C were approximately 10(5), approximately 10(6), and approximately 10(8) M(-1) for the 41-, 27-, and 19-mers, respectively, in solutions of ionic strength, I, of about 100 mM. The decrease in K by three orders of magnitude between the 19-mer and 41-mer is due in part to the change in rotational entropy of rodlike molecules on dimerization and in part to the increased conformational entropy of the monomers. As expected, increased ionic strength increases the dimerization constant for all three RNAs. For the 41-mer, however, K has a maximum value at I approximately 140 mM. The origin of the decrease in K for higher I is unknown but it may be due to formation of species (perhaps higher order oligomers) that do not enter the gel. The 41-mer exists in two dimeric forms assigned to the kissing and duplex dimers. The ratio of kissing to duplex form at 5 degrees C is 0.48 +/- 0.22 at I = 113 mM and 0.91 +/- 0.35 at I = 183 mM. The observed decrease in K with RNA length suggests that the dimerization constant of the packaging region of HIV-1 is small, < approximately 10(5) M(-1), implying that the nucleocapsid protein is important in promoting dimerization in the capsid of the virus.

Autoradiography↗

Weak pairwise correlations imply strongly correlated network states in a neural population.

Biological networks have so many possible states that exhaustive sampling is impossible. Successful analysis thus depends on simplifying hypotheses, but experiments on many systems hint that complicated, higher-order interactions among large groups of elements have an important role. Here we show, in the vertebrate retina, that weak correlations between pairs of neurons coexist with strongly collective behaviour in the responses of ten or more neurons. We find that this collective behaviour is described quantitatively by models that capture the observed pairwise correlations but assume no higher-order interactions. These maximum entropy models are equivalent to Ising models, and predict that larger networks are completely dominated by correlation effects. This suggests that the neural code has associative or error-correcting properties, and we provide preliminary evidence for such behaviour. As a first test for the generality of these ideas, we show that similar results are obtained from networks of cultured cortical neurons.

Action Potentials↗

Topological derivation of shape exponents for stretched exponential relaxation.

In homogeneous (ideal) glasses, the important dimensionless stretched-exponential shape parameter beta is described by magic (not adjusted) simple fractions derived from fractal configuration spaces of effective dimension d* determined by different topological axioms (rules) in the presence (absence) of a forcing electric field. The rules are based on a new central principle for defining glassy states: equal a priori distributions of fractal residual configurational entropy. Our approach and its beta estimates are fully supported by the results of relaxation measurements involving many different glassy materials and probe methods. The present unique topological predictions for beta typically agree with observed values to approximately 1% and indicate that for field-forced conditions beta should be constant for appreciable ranges of such exogenous variables as temperature and ionic concentration, as indeed observed using appropriate frequency-domain data analysis. The present approach can also be inverted and used to test sample homogeneity and quality.

Journal Article↗

Thermodynamics of protein-peptide interactions in the ribonuclease-S system studied by molecular dynamics and free energy calculations.

Hydrophobic interactions between the S-peptide and S-protein in the ribonuclease-S complex are probed using molecular dynamics simulations and free energy calculations. Three successive mutations at the buried position Met13 are simulated: Met----Leu, Leu----Ile, and Ile----Val, for which X-ray structures and experimental thermodynamic data are available. The calculations give theoretical estimates of the changes in binding free energies associated with these mutations. The calculated free energy differences are small (0-1.6 kcal/mol), in agreement with experiment. However the simulated structures deviate significantly from the experimental ones (mean deviation approximately 1.5-2 A), and a large uncertainty in the calculated free energies (1-2 kcal/mol) arises from the multiple minimum problem. Indeed, multiple conformations are available to the side chains around the mutation site, and the sampling of dihedral rotamer transitions is limited, despite long simulations. Fluctuations within each local minimum give rise to a small statistical error. However the uncertainty due to multiple conformations is much greater than the uncertainty due to random statistical errors. In our work, an artificial cancellation of errors arose because we studied conformations of the RNase complex and of the S-peptide that were very similar. In general, the criterion for a precise simulation is not merely to reduce the random statistical error, as has been suggested, but rather to sample all the important local minima along the mutation pathway, and to reduce the statistical error for each one. Our calculations suggest that the packing changes associated with the mutations are energetically small and localized, and largely cancel when the complex and the S-peptide are compared. Solvation of the methionine side chain partial charges in the S-peptide and the complex appear to be energetically equivalent, so that removing them (as in Met13----Leu, Ile, Val) does not affect binding. Enthalpy and entropy changes could not be estimated reliably.

Computer Simulation↗

Nuclear and magnetic structures and magnetic properties of the layered cobalt hydroxysulfate Co5(OH)6(SO4)2(H2O)4 and its deuterated analogue, Co5(OD)6(SO4)2(D2O)4.

The structures (nuclear and magnetic), magnetic properties (2-300 K, 1-10(4) bar), and heat capacity of the layered ferromagnet Co5(OH)6(SO4)2(H2O)4 are reported. The crystal structure consists of brucite-like M(II)-OH layers of edge-sharing octahedra, but having two different Co sites, which are pillared by ...O3SO-Co(H2O)4-OSO3.... The absorption spectrum confirms the presence of divalent Co, and by comparison of the two isotopic materials, the assignment of the vibrational spectra is proposed. The magnetic properties are those of a ferromagnet with a Curie temperature of 14 K. Temperature and field dependence magnetization data taken on an aligned sample suggest an easy-plane magnet. The Curie temperature increases linearly with pressure at a rate of +0.12 K/kbar, suggesting small progressive and uniform modifications of the Co-Co exchange interactions. Rietveld refinement of the neutron powder diffraction data and consideration of a group analysis reveal the direction of the moments of the Co within the layer to be along the b-axis, with a maximum moment of 3.33 micro(B) per cobalt. Those of the pillars remain random. Estimation of the entropy from the heat capacity data accounts for the presence of four ordered moments of Co with spin 1/2 at the long-range ordering temperature, while the moment of the pillaring Co contributes only at lower temperature due to the increase of the internal field as the temperature is lowered. The purely 2D-magnetic ordering in an easy-plane magnet, evidenced by neutron diffraction and heat capacity, challenges the existing theories and is a rare example of a single-layer magnet.

Journal Article↗