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PubMed2004

Diversification of ftsZ during early land plant evolution.

The plastid division proteins FtsZ are encoded by a small nuclear gene family in land plants. Although it has been shown for some of the gene products that they are imported into plastids and function in plastid division, the evolution and function of this gene family and their products remain to be unraveled. Here we present two new ftsZ genes from the moss Physcomitrella patens and compare the genomic structure of members of the two plant ftsZ gene families. Comparison of sequence features and phylogenetic analyses confirm the presence of two clusters of paralogues in land plants and demonstrate that these genes were duplicated before the divergence of mosses, ferns and seed plants.

Amino Acid Sequence↗

PubMed2003

Distinct expression patterns of the two T-box homologues Brachyury and Tbx2/3 in the placozoan Trichoplax adhaerens.

Trichoplax adhaerens is the only species known from the phylum Placozoa with one of the simplest metazoan body plans. In the small disc-like organism an upper and a lower epithelium can be distinguished with a less compact third cell layer in between. When Trichoplax was first described in 1883, the relation of these three cell layers with ectoderm, endoderm and mesoderm of higher animals was discussed. Still, little is known about embryonic development of Trichoplax, however, genes thought to be specific for mesoderm in bilaterian animals turned out to be already present in non-bilaterians. Searching for a Brachyury homologue, two members of the T-box gene family were isolated from Trichoplax, Brachyury and a Tbx2/3 homologue. The T-box genes encode a transcription factor family characterized by the DNA-binding T-box domain. T-box genes have been found in all metazoans so far investigated, but in contrast to other transcription factors such as the homeobox family, T-box genes are not present in plants or fungi. The distinct expression patterns of two T-box genes in Trichoplax point to non-redundant functions already present at the beginning of animal evolution. Since the expression patterns derived by in situ hybridization do not overlap with anatomical structures, it can be concluded that this simple animal has more than the four cell types described in the literature. This hidden complexity and the unresolved position in relation to Porifera, Cnidaria, Ctenophora and Bilateria highlight the necessity of the inclusion of Trichoplax in studies of comparative evolutionary and developmental biology.

Amino Acid Sequence↗

PubMed2005

Neural systems responding to degrees of uncertainty in human decision-making.

Much is known about how people make decisions under varying levels of probability (risk). Less is known about the neural basis of decision-making when probabilities are uncertain because of missing information (ambiguity). In decision theory, ambiguity about probabilities should not affect choices. Using functional brain imaging, we show that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with a striatal system. Moreover, striatal activity correlates positively with expected reward. Neurological subjects with orbitofrontal lesions were insensitive to the level of ambiguity and risk in behavioral choices. These data suggest a general neural circuit responding to degrees of uncertainty, contrary to decision theory.

Adult↗

PubMed1993

Nursing home queues and home health users.

Home health market growth suggests the need for models explaining home health utilization. We have previously explained state-level Medicare home health visits with reference to nursing home markets. Here we introduce a model whereby state-level Medicare home health use is a function of nursing home queues and other demand and supply factors. Medicare home health users per state population is negatively related to nursing home bed stock, positively to Medicaid eligibility levels and to Medicaid nursing home recipients per population, as well as to various other demand and supply measures. This explanation of home health users explains previously-reported findings for home health visits. The findings support the argument that home health use is explained by factors affecting lengths of nursing home queues.

Health Services Needs and Demand↗

PubMed2002

Deterministic rather than stochastic factors explain most of the variation in the expression of skin telangiectasia after radiotherapy.

BACKGROUND: The large patient-to-patient variability in the grade of normal tissue injury after a standard course of radiotherapy is well established clinically. A better understanding of this individual variation may provide valuable insights into the pathogenesis of radiation damage and the prospects of predicting the outcome. PURPOSE: To estimate the relative importance of the stochastic vs. patient-related components of variability in the expression of radiation-induced normal tissue damage. METHODS AND MATERIALS: The study data were selected from the dose fractionation studies of Turesson in Gothenburg. Patients treated with bilateral internal mammary fields, who completed at least 10 years of follow-up, were included. The material included 22 different fractionation schedules (11 on each side). Telangiectasia was graded on an arbitrary 6-point scale using clinical photographs of the irradiated fields. For each field, in each patient, a curve showing the grade of telangiectasia as a function of time was constructed. A measure of radioresponsiveness was obtained from the difference between the area under the curve (AUC) for a specific field in an individual patient minus the mean AUC of fields receiving the same dose fractionation schedule. As a confirmatory procedure, the same analysis was repeated with a weighted area under the curve (WAUC) approach, in which the time spent at or above each of the 5 nonzero grades was calculated for each field in each patient. These times were used as explanatory variables in a linear regression analysis of biological equivalent dose to establish statistically the weight of each grade providing the optimal relationship between dose and effect. Using these regression coefficients, the weighted area under the grade-time curve (WAUC) was estimated. RESULTS: The AUC was significantly correlated with the isoeffective dose in 2-Gy fractions (ID2). An analysis of variance components, using the maximum likelihood method, showed that 90% (with 95% confidence limits 65% and 100%) of the variance in radioresponsiveness in the right-sided field was explained by the radioresponsiveness on the left-sided field. Through the linear regression analysis between the AUC and the ID2, it was estimated that patients with a reaction that is 1 SD from the population mean would require a dose modification of approximately 23 Gy (from the group mean of 56 Gy) to give them a level of reaction similar to the group average. Similarly, the WAUC was significantly correlated with the ID2, and 81% (with 95% confidence limits 49% and 100%) of the variance in radioresponsiveness in the right-sided field was explained by the radioresponsiveness on the left-sided field. Patients with a reaction that is 1 SD from the population mean would require a dose modification of approximately 21 Gy (from the group mean of 56 Gy) to give them a level of reaction similar to the group average. CONCLUSION: For a given fractionation schedule, patient-related factors explain 81-90% of the patient-to-patient variation in telangiectasia level seen after radiotherapy. The remaining 10-19% are explained by stochastic effects. This observation encourages further research into genetic or phenotypic assays of normal tissue radioresponsiveness.

Analysis of Variance↗

PubMed2006

Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings.

The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within-family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components.

Body Height↗

PubMed1991

Calculating centile curves using kernel density estimation methods with application to infant kidney lengths.

Observing a clinical measurement for an individual is of little value, unless it can be compared with measurements obtained from a healthy population, thought of as standard. The range of measurements observed will, in general, vary with age or some function of time. The usual approach is to assume a distributional form for the population density, but this is inappropriate for variables which do not follow a simple distribution. A method of estimating the centiles of a conditional distribution using multi-dimensional kernel density estimation, to allow conditioning on the value of one or more covariates, is proposed. By careful choice of the kernel used, the percentiles may easily be calculated using a Newton-Raphson procedure. The method is illustrated using kidney lengths and birthweights of a sample of newborn infants.

Anthropometry↗

PubMed1997

Analysis of the posture control system under fixed and sway-referenced support conditions.

To delineate the relative roles of each of the feedback sensors in the posture control system such as the visual, vestibular, and proprioceptive sensors, an identification technique was applied to measurements of antero-posterior sway angeles of the body and ankle moments under the following conditions: standing on a fixed support with eyes open (ox), standing on a fixed support with eyes closed (cx), standing on a sway-referenced support with eyes open (os), and standing on a sway-referenced support with eyes closed (cs). Frequency response functions from the sway angle to the ankle moment were calculated. Gain and phase characteristics for conditions (os) and (cs) were similar to those of Nashner's vestibular model in the high-frequency range, which shows that the vestibular system may be dominant. The gain was higher under condition (cx) than under (ox). Judging from the phase characteristics, this was probably due to increased weighting of the proprioceptive sensor over the vestibular sensor. There was a tendency for gain to increase as balance tasks became more demanding.

Adult↗

PubMed2004

Quantitative risk assessment for developmental neurotoxic effects.

Developmental neurotoxicity concerns the adverse health effects of exogenous agents acting on neurodevelopment. Because human brain development is a delicate process involving many cellular events, the developing fetus is rather susceptible to compounds that can alter the structure and function of the brain. Today, there is clear evidence that early exposure to many neurotoxicants can severely damage the developing nervous system. Although in recent years, there has been much attention given to model development and risk assessment procedures for developmental toxicants, the area of developmental neurotoxicity has been largely ignored. Here, we consider the problem of risk estimation for developmental neurotoxicants from animal bioassay data. Since most responses from developmental neurotoxicity experiments are nonquantal in nature, an adverse health effect will be defined as a response that occurs with very small probability in unexposed animals. Using a two-stage hierarchical normal dose-response model, upper confidence limits on the excess risk due to a given level of added exposure are derived. Equivalently, the model is used to obtain lower confidence limits on dose for a small negligible level of risk. Our method is based on the asymptotic distribution of the likelihood ratio statistic (cf. Crump, 1995). An example is used to provide further illustration.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2004

Carotenoid-based bill colour as an indicator of immunocompetence and sperm performance in male mallards.

Female mate choice is often based on exaggerated sexual traits, signals of male qualities that females cannot assess directly. Two such key qualities are male immune and/or sexual competence, whereby honesty in signalling could be maintained by physiological trade-offs. Carotenoid-based ornaments likely constitute such honest signals, as there is direct competition for (limited) carotenoids between ornament deposition and anti-oxidant support of immune or sperm functioning. Using spectrometry, we assessed the potential signalling function of the yellow, carotenoid-based colour of the bill of male mallards, a target of female mate choice. Here we demonstrate that bill reflectance varied with plasma carotenoid level, indicating antioxidant reserves. Moreover, lower relative UV reflectance during autumn pairing predicted immune responsiveness and correlated positively with sperm velocity during breeding, a trait that affects fertility. Our data provide support for current theories that females could use carotenoid-based sexual signals to detect immune vigour and fertilizing ability of prospective mates.

Animals↗

PubMed1999

Some properties of an estimator for the basic reproduction number of the general epidemic model.

In this paper some properties of a convenient estimator, derived from a martingale estimating function, for the basic reproduction number of the general epidemic model are given for both finite and large samples. These properties give some guidelines for using this convenient estimator. It is shown that it underestimates the parameter and that the bias tends to zero when the population size and the initial number of infectives are increased simultaneously. The bias cannot be removed for a fixed number of introductory infectives. However, the estimator is asymptotically unbiased, conditional on a major outbreak. A simulation study shows that the central limit theorem applies for moderate population sizes.

Bias↗

PubMed1999

Medicare spending by beneficiaries with various types of supplemental insurance.

The authors analyzed Medicare spending by elderly noninstitutionalized Medicare beneficiaries with and without supplemental insurance such as Medigap, employer-sponsored plans, and Medicaid. Use of a detailed survey of Medicare beneficiaries and their Medicare health insurance claims enabled the authors to control for health status, chronic conditions, functional limitations, and other factors that explain spending variations across supplemental insurance categories. The authors found that supplemental insurance was associated with a higher probability and level of Medicare spending, particularly for Part B services. Beneficiaries with both Medigap and employer plans had the highest levels of spending ceteris paribus, suggesting a possible moral hazard effect of insurance. Findings from this study are discussed in the context of the overall financing of health care for the elderly.

Aged↗

PubMed2001

Nonlinear dynamical law governs magnetic field induced changes in lymphoid phenotype.

The results of many different types of animal and human studies dealing with the biological effects of exposure to low frequency electromagnetic fields (EMFs) have consistently been both positive and negative. We addressed the question of why this pattern had occurred so commonly in biological studies involving exposure to EMFs and hypothesized that it stemmed from the prevalent use of a linear model to characterize what are inherently nonlinear input-output relationships. The hypothesis was tested by analyzing biological data using a novel statistical procedure that could be adjusted to detect either nonlinear or linear effects. The reliability of the procedure was established using positive and negative controls and by comparison with the results obtained from sampling a known nonlinear system. In four independent experiments, male and female mice were exposed continuously to 0.1 or 0.5 mT, 60 Hz, for 175 days, and the effect on 20 immune parameters was measured using flow cytometry and functional assays. In each experiment, EMF exposure resulted in statistically significant changes in lymphoid phenotype when and only when the response of the animals to the fields was analyzed as if it were governed by nonlinear laws. Our results suggest that the pattern of inconsistency in the EMF bioeffects studies is an artifact resulting from an incorrect choice of the conceptual model for the relation between the field and the biological effect it causally determines.

Animals↗

PubMed2004

Molecular evolution in large genetic networks: does connectivity equal constraint?

Genetic networks show a broad-tailed distribution of the number of interaction partners per protein, which is consistent with a power-law. It has been proposed that such broad-tailed distributions are observed because they confer robustness against mutations to the network. We evaluate this hypothesis for two genetic networks, that of the E. coli core intermediary metabolism and that of the yeast protein-interaction network. Specifically, we test the hypothesis through one of its key predictions: highly connected proteins should be more important to the cell and, thus, subject to more severe selective and evolutionary constraints. We find, however, that no correlation between highly connected proteins and evolutionary rate exists in the E. coli metabolic network and that there is only a weak correlation in the yeast protein-interaction network. Furthermore, we show that the observed correlation is function-specific within the protein-interaction network: only genes involved in the cell cycle and transcription show significant correlations. Our work sheds light on conflicting results by previous researchers by comparing data from multiple types of protein-interaction datasets and by using a closely related species as a reference taxon. The finding that highly connected proteins can tolerate just as many amino acid substitutions as other proteins leads us to conclude that power-laws in cellular networks do not reflect selection for mutational robustness.

Energy Metabolism↗

PubMed2002

Detecting positively selected amino acid sites using posterior predictive P-values.

Identifying positively selected amino acid sites is an important approach for making inference about the function of proteins; an amino acid site that is undergoing positive selection is likely to play a key role in the function of the protein. We present a new Bayesian method for identifying positively selected amino acid sites and apply the method to a data set of hemagglutinin sequences from the Influenza virus. We show that the results of the new methods are in accordance with results obtained using previous methods. More importantly, we also demonstrate how the method can be used for making further inferences about the evolutionary history of the sequences. For example, we demonstrate that sites that are positively selected tend to have a preponderance of conservative amino acid substitutions.

Amino Acid Sequence↗

PubMed2002

Effective connectivity and intersubject variability: using a multisubject network to test differences and commonalities.

This article is about intersubject variability in the functional integration of activity in different brain regions. Previous studies of functional and effective connectivity have dealt with intersubject variability by analyzing data from different subjects separately or pretending the data came from the same subject. These approaches do not allow one to test for differences among subjects. The aim of this work was to illustrate how differences in connectivity among subjects can be addressed explicitly using structural equation modeling. This is enabled by constructing a multisubject network that comprises m regions of interest for each of the n subjects studied, resulting in a total of m x n nodes. Constructing a network of regions from different subjects may seem counterintuitive but embodies two key advantages. First, it allows one to test directly for differences among subjects by comparing models that do and do not allow a particular connectivity parameter to vary over subjects. Second, a multisubject network provides additional degrees of freedom to estimate the model's free parameters. Any neurobiological hypothesis normally addressed by single-subject or group analyses can still be tested, but with greater sensitivity. The common influence of experimental variables is modeled by connecting a virtual node, whose time course reflects stimulus onsets, to the sensory or "input" region in all subjects. Further experimental changes in task or cognitive set enter through modulation of the connections. This approach allows one to model both endogenous (or intrinsic) variance and exogenous effects induced by experimental design. We present a functional magnetic resonance imaging study that uses a multisubject network to investigate intersubject variability in functional integration in the context of single word and pseudoword reading. We tested whether the effect of word type on the reading-related coupling differed significantly among subjects. Our results showed that a number of forward and backward connections were stronger for reading pseudowords than words, and, in one case, connectivity showed significant intersubject variability. The discussion focuses on the implications of our findings and on further applications of the multisubject network analysis.

Adult↗

PubMed2005

Integrating QTL mapping and genome scans towards the characterization of candidate loci under parallel selection in the lake whitefish (Coregonus clupeaformis).

As natural selection must act on underlying genetic variation, discovering the number and location of loci under the influence of selection is imperative towards understanding adaptive divergence in evolving populations. Studies employing genome scans have hypothesized that the action of divergent selection should reduce gene flow at the genomic locations implicated in adaptation and speciation among natural populations, yet once 'outlier' patterns of variation have been identified the function and role of such loci needs to be confirmed. We integrated adaptive QTL mapping and genomic scans among diverging sympatric pairs of the lake whitefish (Coregonus clupeaformis) species complex in order to test the hypothesis that differentiation between dwarf and normal ecotypes at growth-associated QTL was maintained by directional selection. We found evidence of significantly high levels of molecular divergence among eight growth QTL where two of the strongest candidate loci under the influence of directional selection exhibited parallel reductions of gene flow over multiple populations.

Adaptation, Biological↗

PubMed2002

Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability.

OBJECTIVES: To establish the prevalence of sarcopenia in older Americans and to test the hypothesis that sarcopenia is related to functional impairment and physical disability in older persons. DESIGN: Cross-sectional survey. SETTING: Nationally representative cross-sectional survey using data from the Third National Health and Nutrition Examination Survey (NHANES III). PARTICIPANTS: Fourteen thousand eight hundred eighteen adult NHANES III participants aged 18 and older. MEASUREMENTS: The presence of sarcopenia and the relationship between sarcopenia and functional impairment and disability were examined in 4,504 adults aged 60 and older. Skeletal muscle mass was estimated from bioimpedance analysis measurements and expressed as skeletal muscle mass index (SMI = skeletal muscle mass/body mass x 100). Subjects were considered to have a normal SMI if their SMI was greater than -one standard deviation above the sex-specific mean for young adults (aged 18-39). Class I sarcopenia was considered present in subjects whose SMI was within -one to -two standard deviations of young adult values, and class II sarcopenia was present in subjects whose SMI was below -two standard deviations of young adult values. RESULTS: The prevalence of class I and class II sarcopenia increased from the third to sixth decades but remained relatively constant thereafter. The prevalence of class I (59% vs 45%) and class II (10% vs 7%) sarcopenia was greater in the older (> or = 60 years) women than in the older men (P <.001). The likelihood of functional impairment and disability was approximately two times greater in the older men and three times greater in the older women with class II sarcopenia than in the older men and women with a normal SMI, respectively. Some of the associations between class II sarcopenia and functional impairment remained significant after adjustment for age, race, body mass index, health behaviors, and comorbidity. CONCLUSIONS: Reduced relative skeletal muscle mass in older Americans is a common occurrence that is significantly and independently associated with functional impairment and disability, particularly in older women. These observations provide strong support for the prevailing view that sarcopenia may be an important and potentially reversible cause of morbidity and mortality in older persons.

Activities of Daily Living↗