Models of DNA sequence evolution

Models of DNA sequence evolution and methods for estimating evolutionary distances are needed for studying the rate and pattern of molecular evolution and for inferring the evolutionary relationships of organisms or genes. In this dissertation, several new models and methods are developed.^ The rate variation among nucleotide sites: To obtain unbiased estimates of evolutionary distances, the rate heterogeneity among nucleotide sites of a gene should be considered. Commonly, it is assumed that the substitution rate varies among sites according to a gamma distribution (gamma model) or, more generally, an invariant+gamma model which includes some invariable sites. A maximum likelihood (ML) approach was developed for estimating the shape parameter of the gamma distribution $(\alpha)$ and/or the proportion of invariable sites $(\theta).$ Computer simulation showed that (1) under the gamma model, $\alpha$ can be well estimated from 3 or 4 sequences if the sequence length is long; and (2) the distance estimate is unbiased and robust against violations of the assumptions of the invariant+gamma model.^ However, this ML method requires a huge amount of computational time and is useful only for less than 6 sequences. Therefore, I developed a fast method for estimating $\alpha,$ which is easy to implement and requires no knowledge of tree. A computer program was developed for estimating $\alpha$ and evolutionary distances, which can handle the number of sequences as large as 30.^ Evolutionary distances under the stationary, time-reversible (SR) model: The SR model is a general model of nucleotide substitution, which assumes (i) stationary nucleotide frequencies and (ii) time-reversibility. It can be extended to SRV model which allows rate variation among sites. I developed a method for estimating the distance under the SR or SRV model, as well as the variance-covariance matrix of distances. Computer simulation showed that the SR method is better than a simpler method when the sequence length $L>1,000$ bp and is robust against deviations from time-reversibility. As expected, when the rate varies among sites, the SRV method is much better than the SR method.^ The evolutionary distances under nonstationary nucleotide frequencies: The statistical properties of the paralinear and LogDet distances under nonstationary nucleotide frequencies were studied. First, I developed formulas for correcting the estimation biases of the paralinear and LogDet distances. The performances of these formulas and the formulas for sampling variances were examined by computer simulation. Second, I developed a method for estimating the variance-covariance matrix of the paralinear distance, so that statistical tests of phylogenies can be conducted when the nucleotide frequencies are nonstationary. Third, a new method for testing the molecular clock hypothesis was developed in the nonstationary case. ^

A comparison of Markov and generalized linear models of hospital mortality

This paper reports a comparison of three modeling strategies for the analysis of hospital mortality in a sample of general medicine inpatients in a Department of Veterans Affairs medical center. Logistic regression, a Markov chain model, and longitudinal logistic regression were evaluated on predictive performance as measured by the c-index and on accuracy of expected numbers of deaths compared to observed. The logistic regression used patient information collected at admission; the Markov model was comprised of two absorbing states for discharge and death and three transient states reflecting increasing severity of illness as measured by laboratory data collected during the hospital stay; longitudinal regression employed Generalized Estimating Equations (GEE) to model covariance structure for the repeated binary outcome. Results showed that the logistic regression predicted hospital mortality as well as the alternative methods but was limited in scope of application. The Markov chain provides insights into how day to day changes of illness severity lead to discharge or death. The longitudinal logistic regression showed that increasing illness trajectory is associated with hospital mortality. The conclusion is reached that for standard applications in modeling hospital mortality, logistic regression is adequate, but for new challenges facing health services research today, alternative methods are equally predictive, practical, and can provide new insights. ^

A nonparametric method of comparing the partial areas under two correlated receiver operating characteristic curves

A non-parametric method was developed and tested to compare the partial areas under two correlated Receiver Operating Characteristic curves. Based on the theory of generalized U-statistics the mathematical formulas have been derived for computing ROC area, and the variance and covariance between the portions of two ROC curves. A practical SAS application also has been developed to facilitate the calculations. The accuracy of the non-parametric method was evaluated by comparing it to other methods. By applying our method to the data from a published ROC analysis of CT image, our results are very close to theirs. A hypothetical example was used to demonstrate the effects of two crossed ROC curves. The two ROC areas are the same. However each portion of the area between two ROC curves were found to be significantly different by the partial ROC curve analysis. For computation of ROC curves with large scales, such as a logistic regression model, we applied our method to the breast cancer study with Medicare claims data. It yielded the same ROC area computation as the SAS Logistic procedure. Our method also provides an alternative to the global summary of ROC area comparison by directly comparing the true-positive rates for two regression models and by determining the range of false-positive values where the models differ. ^

Stable-Isotope Time Series and Precipitation Origin from Firn-Core and Snow Samples, Altai Glaciers, Siberia

In the summers of 2001 and 2002, glacio-climatological research was performed at 4110-4120 m a.s.l. on the Belukha snow/firn plateau, Siberian Altai. Hundreds of samples from snow pits and a 21 m snow/firn core were collected to establish the annual/seasonal/monthly depth-accumulation scale, based on stable-isotope records, stratigraphic analyses and meteorological and synoptic data. The fluctuations of water stable-isotope records show well-preserved seasonal variations. The delta(18)O and delta D relationships in precipitation, snow pits and the snow/firn core have the same slope to the covariance as that of the global meteoric water line. The origins of precipitation nourishing the Belukha plateau were determined based on clustering analysis of delta(18)O and d-excess records and examination of synoptic atmospheric patterns. Calibration and validation of the developed clusters occurred at event and monthly timescales with about 15% uncertainty. Two distinct moisture sources were shown: oceanic sources with d-excess < 12 parts per thousand, and the Aral-Caspian closed drainage basin sources with d-excess > 12 parts per thousand. Two-thirds of the annual accumulation was from oceanic precipitation, of which more than half had isotopic ratios corresponding to moisture evaporated over the Atlantic Ocean. Precipitation from the Arctic/Pacific Ocean had the lowest deuterium excess, contributing one-tenth to annual accumulation.

Significant Contribution of Large Particles to Optical Backscattering in the Open Ocean

The light scattering properties of oceanic particles have been suggested as an alternative index of phytoplankton biomass than chlorophyll-a concentration (chl-a), with the benefit of being less sensitive to physiological forcings (e.g., light and nutrients) that alter the intracellular pigment concentrations. The drawback of particulate scattering is that it is not unique to phytoplankton. Nevertheless, field studies have demonstrated that, to first order, the particulate beam-attenuation coefficient (c(p)) can track phytoplankton biomass. The relationship between c(p) and the particulate backscattering coefficient (b(bp)), a property retrievable from space, has not been fully evaluated, largely due to a lack of open-ocean field observations. Here, we present extensive data on inherent optical properties from the Equatorial Pacific surface waters and demonstrate a remarkable coherence in b(bp) and c(p). Coincident measurements of particle size distributions (PSDs) and optical properties of size-fractionated samples indicate that this covariance is due to both the conserved nature of the PSD and a greater contribution of phytoplankton-sized particles to b(bp) than theoretically predicted. These findings suggest that satellite-derived b(bp)could provide similar information on phytoplankton biomass in the open ocean as c(p).

Plasticity to wind is modular and genetically variable in Arabidopsis thaliana

Thigmomorphogenesis, the characteristic phenotypic changes by which plants react to mechanical stress, is a widespread and probably adaptive type of phenotypic plasticity. However, little is known about its genetic basis and population variation. Here, we examine genetic variation for thigmomorphogenesis within and among natural populations of the model system Arabidopsis thaliana. Offspring from 17 field-collected European populations was subjected to three levels of mechanical stress exerted by wind. Overall, plants were remarkably tolerant to mechanical stress. Even high wind speed did not significantly alter the correlation structure among phenotypic traits. However, wind significantly affected plant growth and phenology, and there was genetic variation for some aspects of plasticity to wind among A. thaliana populations. Our most interesting finding was that phenotypic traits were organized into three distinct and to a large degree statistically independent covariance modules associated with plant size, phenology, and growth form, respectively. These phenotypic modules differed in their responsiveness to wind, in the degree of genetic variability for plasticity, and in the extent to which plasticity affected fitness. It is likely, therefore, that thigmomorphogenesis in this species evolves quasi-independently in different phenotypic modules.

Professional musicians listen differently to music

INTRODUCTION: Experience-based adaptation of emotional responses is an important faculty for cognitive and emotional functioning. Professional musicians represent an ideal model in which to elicit experience-driven changes in the emotional processing domain. The changes of the central representation of emotional arousal due to musical expertise are still largely unknown. The aim of the present study was to investigate the electroencephalogram (EEG) correlates of experience-driven changes in the domain of emotional arousal. Therefore, the differences in perceived (subjective arousal via ratings) and physiologically measured (EEG) arousal between amateur and professional musicians were examined. PROCEDURE: A total of 15 professional and 19 amateur musicians listened to the first movement of Ludwig van Beethoven's 5th symphony (duration=∼7.4min), during which a continuous 76-channel EEG was recorded. In a second session, the participants evaluated their emotional arousal during listening. In a tonic analysis, we examined the average EEG data over the time course of the music piece. For a phasic analysis, a fast Fourier transform was performed and covariance maps of spectral power were computed in association with the subjective arousal ratings. RESULTS: The subjective arousal ratings of the professional musicians were more consistent than those of the amateur musicians. In the tonic EEG analysis, a mid-frontal theta activity was observed in the professionals. In the phasic EEG, the professionals exhibited an increase of posterior alpha, central delta, and beta rhythm during high arousal. DISCUSSION: Professionals exhibited different and/or more intense patterns of emotional activation when they listened to the music. The results of the present study underscore the impact of music experience on emotional reactions.

Evidence from the real world: N-15 natural abundances reveal enhanced nitrogen use at high plant diversity in Central European grasslands

Complementarity that leads to more efficient resource use is presumed to be a key mechanism explaining positive biodiversity–productivity relationships but has been described solely for experimental set-ups with controlled environmental settings or for very short gradients of abiotic conditions, land-use intensity and biodiversity. Therefore, we analysed plant diversity effects on nitrogen dynamics across a broad range of Central European grasslands. The 15N natural abundance in soil and plant biomass reflects the net effect of processes affecting ecosystem N dynamics. This includes the mechanism of complementary resource utilization that causes a decrease in the 15N isotopic signal. We measured plant species richness, natural abundance of 15N in soil and plants, above-ground biomass of the community and three single species (an herb, grass and legume) and a variety of additional environmental variables in 150 grassland plots in three regions of Germany. To explore the drivers of the nitrogen dynamics, we performed several analyses of covariance treating the 15N isotopic signals as a function of plant diversity and a large set of covariates. Increasing plant diversity was consistently linked to decreased δ15N isotopic signals in soil, above-ground community biomass and the three single species. Even after accounting for multiple covariates, plant diversity remained the strongest predictor of δ15N isotopic signals suggesting that higher plant diversity leads to a more closed nitrogen cycle due to more efficient nitrogen use. Factors linked to increased δ15N values included the amount of nitrogen taken up, soil moisture and land-use intensity (particularly fertilization), all indicators of the openness of the nitrogen cycle due to enhanced N-turnover and subsequent losses. Study region was significantly related to the δ15N isotopic signals indicating that regional peculiarities such as former intensive land use could strongly affect nitrogen dynamics. Synthesis. Our results provide strong evidence that the mechanism of complementary resource utilization operates in real-world grasslands where multiple external factors affect nitrogen dynamics. Although single species may differ in effect size, actively increasing total plant diversity in grasslands could be an option to more effectively use nitrogen resources and to reduce the negative environmental impacts of nitrogen losses.

The brain’s default state interacts with working memory processes in a complex and load-dependent manner

Recently, many studies about a network active during rest and deactivated during tasks emerged in the literature: the default mode network (DMN). Spatial and temporal DMN features are important markers for psychiatric diseases. Another prominent indicator of cognitive functioning, yielding information about the mental condition in health and disease, is working memory (WM) processing. In EEG studies, frontal-midline theta power has been shown to increase with load during WM retention in healthy subjects. From these findings, the conclusion can be drawn that an increase in resting state DMN activity may go along with an increase in theta power in high-load WM conditions. We followed this hypothesis in a study on 17 healthy subjects performing a visual Sternberg WM task. The DMN was obtained by a BOLD-ICA approach and its dynamics represented by the percent-strength during pre-stimulus periods. DMN dynamics were temporally correlated with EEG theta spectral power from retention intervals. This so-called covariance mapping yielded the spatial distribution of the theta EEG fluctuations associated with the dynamics of the DMN. In line with previous findings, theta power was increased at frontal-midline electrodes in high- versus low-load conditions during early WM retention. However, load-dependent correlations of DMN with theta power resulted in primarily positive correlations in low-load conditions, while during high-load conditions negative correlations of DMN activity and theta power were observed at frontal-midline electrodes. This DMN-dependent load effect reached significance during later retention. Our results show a complex and load-dependent interaction of pre-stimulus DMN activity and theta power during retention, varying over the course of the retention period. Since both, WM performance and DMN activity, are markers of mental health, our results could be important for further investigations of psychiatric populations.

The brain’s pre-stimulus default state interacts with working memory in a load-dependent manner

Recently, multiple studies showed that spatial and temporal features of a task-negative default mode network (DMN) (Greicius et al., 2003) are important markers for psychiatric diseases (Balsters et al., 2013). Another prominent indicator of cognitive functioning, yielding information about the mental condition in health and disease, is working memory (WM) processing. In EEG and MEG studies, frontal-midline theta power has been shown to increase with load during WM retention in healthy subjects (Brookes et al., 2011). Negative correlations between DMN activity and theta amplitude have been found during resting state (Jann et al., 2010) as well as during WM (Michels et al., 2010). Likewise, WM training resulted in higher resting state theta power as well as increased small-worldness of the resting brain (Langer et al., 2013). Further, increased fMRI connectivity between nodes of the DMN correlated with better WM performance (Hampson et al., 2006). Hence, the brain’s default state might influence it’s functioning during task. We therefore hypothesized correlations between pre-stimulus DMN activity and EEG-theta power during WM maintenance, depending on the WM load. 17 healthy subjects performed a Sternberg WM task while being measured simultaneously with EEG and fMRI. Data was recorded within a multicenter-study: 12 subjects were measured in Zurich with a 64-channels MR-compatible system (Brain Products) in a 3T Philips scanner, 5 subjects with a 96-channel MR-compatible system (Brain Products) in a 3T Siemens Scanner in Bern. The DMN components was obtained by a group BOLD-ICA approach over the full task duration (figure 1). The subject-wise dynamics were obtained by back-reconstructed onto each subject’s fMRI data and normalized to percent signal change values. The single trial pre-stimulus-DMN activation was then temporally correlated with the single trial EEG-theta (3-8 Hz) spectral power during retention intervals. This so-called covariance mapping (Jann et al., 2010) yielded the spatial distribution of the theta EEG fluctuations during retention associated with the dynamics of the pre-stimulus DMN. In line with previous findings, theta power was increased at frontal-midline electrodes in high- versus low-load conditions during early WM retention (figure 2). However, correlations of DMN with theta power resulted in primarily positive correlations in low-load conditions, while during high-load conditions negative correlations of DMN activity and theta power were observed at frontal-midline electrodes. This DMN-dependent load effect reached significance in the middle of the retention period (TANOVA, p<0.05) (figure 3). Our results show a complex and load-dependent interaction of pre-stimulus DMN activity and theta power during retention, varying over time. While at a more global, load-independent view pre-stimulus DMN activity correlated positively with theta power during retention, the correlation was inversed during certain time windows in high-load trials, meaning that in trials with enhanced pre-stimulus DMN activity theta power decreases during retention. Since both WM performance and DMN activity are markers of mental health our results could be important for further investigations of psychiatric populations.

Systemic inflammation is higher in peripheral artery disease than in stable coronary artery disease.

OBJECTIVE The knowledge on the level of systemic inflammation in peripheral artery disease (PAD) is less well established than that in coronary artery disease (CAD). Systemic inflammation frequently coincides with atherosclerosis, but also with various traits of the metabolic syndrome (MetS). The individual contribution of CAD, PAD, and the MetS to inflammation is not known. METHODS We enrolled a total of 1396 patients, 460 patients with PAD Fontaine stages IIa-IV verified by duplex ultrasound (PAD group) and 936 patients free of limb claudication undergoing coronary angiography, of whom 507 had significant CAD with coronary stenoses ≥50% (CAD group), and 429 did not have significant CAD at angiography (control group). RESULTS C-reactive protein (CRP) was significantly higher in the PAD than in the CAD or in the control group (0.86 ± 1.85 mg/dl versus 0.44 ± 0.87 mg/dl and 0.39 ± 0.52 mg/dl, respectively, p < 0.001 for both comparisons). These significant differences were confirmed when patients with and subjects without the MetS were analyzed separately. In particular, within the PAD group, CRP was significantly higher in patients with the MetS than in subjects without the MetS (1.04 ± 2.01 vs. 0.67 ± 1.64 mg/dl; p = 0.001) and both, the presence of PAD and the MetS proved to be independently associated with CRP in analysis of covariance (F = 31.84; p < 0.001 and F = 10.52; p = 0.001, respectively). CONCLUSION Inflammatory activity in PAD patients is higher than in CAD patients and is particularly high in PAD patients affected by the MetS. Low grade systemic inflammation is independently associated with both the MetS and PAD.

Habituation and consolidation of prospective memory over a week: An ERP study

Prospective memory (ProM) is the ability to remember and perform an intention in the future. If a prospective memory task is to be performed only once, it is episodic. If it is repeated, then it becomes habitual. Thus, with repetition, a task changes from episodic to habitual. The goal of this study was to investigate the transition from episodic to habitual prospective memory with event-related potentials (ERP). The ProM task was to respond to a target word which was embedded in an ongoing lexical decision task. 40 ProM trials were administered in each of two sessions that were separated by a week. The results revealed a behavioural consolidation effect with increased ProM performance after one week. The ERP-analyses showed that when the task became more habitual a difference occurred in a time-window between 450-650 ms post-stimulus in an ERP-component. In addition, a covariance analysis revealed that this transition is continued in the second session. These results demonstrate that the transition from episodic to habitual prospective memory is long-lasting and continuous.

M-Functionals of Multivariate Scatter

This survey provides a self-contained account of M-estimation of multivariate scatter. In particular, we present new proofs for existence of the underlying M-functionals and discuss their weak continuity and differentiability. This is done in a rather general framework with matrix-valued random variables. By doing so we reveal a connection between Tyler's (1987) M-functional of scatter and the estimation of proportional covariance matrices. Moreover, this general framework allows us to treat a new class of scatter estimators, based on symmetrizations of arbitrary order. Finally these results are applied to M-estimation of multivariate location and scatter via multivariate t-distributions.

A comment on the article “A collinearity diagnosis of the GNSS geocenter determination” by P. Rebischung, Z. Altamimi, and T. Springer

Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) showed that the geocenter z -component estimated from observations of global navigation satellite systems (GNSS) is strongly correlated to a particular parameter of the solar radiation pressure (SRP) model developed by Beutler et al. (Manuscr Geod 19:367–386, 1994). They analyzed the forces caused by SRP and the impact on the satellites’ orbits. The authors achieved their results using perturbation theory and celestial mechanics. Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) also deal with the geocenter determination with GNSS. The authors carried out a collinearity diagnosis of the associated parameter estimation problem. They conclude “without much exaggerating that current GNSS are insensitive to any component of geocenter motion”. They explain this inability by the high degree of collinearity of the geocenter coordinates mainly with satellite clock corrections. Based on these results and additional experiments, they state that the conclusions drawn by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) are questionable. We do not agree with these conclusions and present our arguments in this article. In the first part, we review and highlight the main characteristics of the studies performed by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) to show that the experiments are quite different from those performed by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026,2013) . In the second part, we show that normal equation (NEQ) systems are regular when estimating geocenter coordinates, implying that the covariance matrices associated with the NEQ systems may be used to assess the sensitivity to geocenter coordinates in a standard way. The sensitivity of GNSS to the components of the geocenter is discussed. Finally, we comment on the arguments raised by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) against the results of Meindl et al. (Adv Space Res 51(7):1047–1064, 2013).

The Influence of Pre-stimulus EEG Activity on Reaction Time During a Verbal Sternberg Task is Related to Musical Expertise

Abstract Previous work highlighted the possibility that musical training has an influence on cognitive functioning. The suggested reason for this influence is the strong recruitment of attention, planning, and working memory functions during playing a musical instrument. The purpose of the present work was twofold, namely to evaluate the general relationship between pre-stimulus electrophysiological activity and cognition, and more specifically the influence of musical expertise on working memory functions. With this purpose in mind, we used covariance mapping analyses to evaluate whether pre-stimulus electroencephalographic activity is predictive for reaction time during a visual working memory task (Sternberg paradigm) in musicians and non-musicians. In line with our hypothesis, we replicated previous findings pointing to a general predictive value of pre-stimulus activity for working memory performance. Most importantly, we also provide first evidence for an influence of musical expertise on working memory performance that could distinctively be predicted by pre-stimulus spectral power. Our results open novel perspectives for better comprehending the vast influences of musical expertise on cognition.