Recent thymic emigrants as the bridge between thymoma and autoimmune diseases

Recent thymic emigrants (RTEs) are naïve T cells that egress the thymus following intrathymic development. This continuous process, including self-renewal, is crucial to establish and maintain human immune function. Several biomarkers can identify RTEs, but none of them is specific. Additional methods to detect and study RTEs phenotypically and functionally revealed alterations in RTEs in various adverse health conditions, including autoimmune diseases, systemic disorders and thymic abnormalities such as thymoma. Often associated with autoimmune disease, thymoma is the only tumor that can generate RTEs. However, a causal relationship between RTEs and autoimmune disease remains uncertain. Here, we review current knowledge about the connections between thymoma, RTEs and autoimmune diseases to provide new perspectives for therapeutic strategies.     

Elucidating quantitative stability/flexibility relationships within thioredoxin and its fragments using a distance constraint model

Numerous quantitative stability/flexibility relationships, within Escherichia coli thioredoxin (Trx) and its fragments are determined using a minimal distance constraint model (DCM). A one-dimensional free energy landscape as a function of global flexibility reveals Trx to fold in a low-barrier two-state process, with a voluminous transition state. Near the folding transition temperature, the native free energy basin is markedly skewed to allow partial unfolded forms. Under native conditions the skewed shape is lost, and the protein forms a compact structure with some flexibility. Predictions on ten Trx fragments are generally consistent with experimental observations that they are disordered, and that complementary fragments reconstitute. A hierarchical unfolding pathway is uncovered using an exhaustive computational procedure of breaking interfacial cross-linking hydrogen bonds that span over a series of fragment dissociations. The unfolding pathway leads to a stable core structure (residues 22-90), predicted to act as a kinetic trap. Direct connection between degree of rigidity within molecular structure and non-additivity of free energy is demonstrated using a thermodynamic cycle involving fragments and their hierarchical unfolding pathway. Additionally, the model provides insight about molecular cooperativity within Trx in its native state, and about intermediate states populating the folding/unfolding pathways. Native state cooperativity correlation plots highlight several flexibly correlated regions, giving insight into the catalytic mechanism that facilitates access to the active site disulfide bond. Residual native cooperativity correlations are present in the core substructure, suggesting that Trx can function when it is partly unfolded. This natively disordered kinetic trap, interpreted as a molten globule, has a wide temperature range of metastability, and it is identified as the "slow intermediate state" observed in kinetic experiments. These computational results are found to be in overall agreement with a large array of experimental data.     

Analyses of two-way chronic studies

This paper proposes a method for analyzing tumor data from chronic studies when the experimental design includes combinations of two factors, for example, sex and dose. Both main effects and combined-effect (interaction) hypotheses are considered. A stratified log-rank statistic is presented for tests of no column or row (main) effects. The paper shows that when the numbers of animals in the cells are unequal and disproportional, the null distribution of the unstratified log-rank statistic does not have a chi-square distribution. Two simple models, additive and multiplicative, for representing the combined effect of row and column are considered under the proportional hazards model. A simple conservative statistic is proposed for testing the additivity of the row and column effects. A simulation experiment to examine the behavior of the null distribution of the combined-effect test statistic under the additive model and the power of the test against the multiplicative model is reported. The procedure is illustrated by analyzing mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in yellow and agouti F1 female mice from a laboratory experiment.     

Structure and function of the cassowary's casque and its implications for cassowary history,biology and evolution

Cassowaries (Casuarius) possess a cranial casque, sheathed by keratin and composed of modified cranial bones. We combine data and hypotheses on three areas of cassowary research. First, we present novel observations on casque anatomy. The bony core is fragile, incorporating a mass of trabeculae anteriorly and an empty space posteriorly. Secondly, we use these observations to evaluate hypotheses of casque function. Implications that the casque evolved within the context of activities involving percussive actions are unlikely and observations that might support these hypotheses are absent. It is most likely that the casque serves a sociosexual role and functions in visual and acoustic display. The similarity in casque form between males and females, combined with male parental investment, makes it plausible that the extravagant structures present in cassowaries evolved within the context of mutual sexual selection. Thirdly, we combine morphological, molecular and geological evidence to provide a new phylogenetic history for cassowaries. We suggest that cassowaries invaded New Guinea in at least two waves and provisionally regard crown–cassowaries as a geologically young, post-Pliocene clade. We provide these hypotheses as areas requiring discussion and urge other workers to test our ideas with new data on cassowary anatomy, behaviour and genetics.     

The effects of scale and sample size on the accuracy of spatial predictions of tiger beetle (Cicindelidae) species richness

We apply geostatistical modeling techniques to investigate spatial patterns of species richness. Unlike most other statistical modeling techniques that are valid only when observations are independent, geostatistical methods are designed for applications involving spatially dependent observations. When spatial dependencies, which are sometimes called autocorrelations, exist, geostatistical techniques can be applied to produce optimal predictions in areas (typically proximate to observed data) where no observed data exist. Using tiger beetle species (Cicindelidae) data collected in western North America, we investigate the characteristics of spatial relationships in species numbers data, First, we compare the accuracy of spatial predictions of species richness when data from grid squares of two different sizes (scales) are used to form the predictions. Next we examine how prediction accuracy varies as a function of areal extent of the region under investigation. Then we explore the relationship between the number of observations used to build spatial prediction models and prediction accuracy. Our results indicate that, within the taxon of tiger beetles and for the two scales we investigate, the accuracy of spatial predictions is unrelated to scale and that prediction accuracy is not obviously related lo the areal extent of the region under investigation. We also provide information about the relationship between sample size and prediction accuracy, and, finally, we show that prediction accuracy may be substantially diminished if spatial correlations in the data are ignored.     

Experiments on steady and oscillatory flows at moderate Reynolds numbers in a quasi-two-dimensional channel with a throat.

The study of steady and unsteady oscillatory static fluid pressures acting on the internal wall of a collapsible tube is essential for investigation of the complicated behavior observed when a flow is conveyed inside a tube. To examine the validity of two one-dimensional nonsteady theoretical flow models, this paper presents basic experimental observations of flow separation and reattachment and measured data on the static pressure distributions of the flow in a quasi-two-dimensional channel with a throat, together with information on the corresponding shape of the wall deflection and motion. For combinations of moderate Reynolds numbers and angles of the divergent segment of the channel, a smooth flow is separated from the wall downstream of the minimum cross section and reattached to the wall farther downstream. The measured data are compared with numerical results calculated by the two flow models.     

When can ecological speciation be detected with neutral loci?

It is not yet clear under what conditions empirical studies can reliably detect progress toward ecological speciation through the analysis of allelic variation at neutral loci. We use a simulation approach to investigate the range of parameter space under which such detection is, and is not, likely. We specifically test for the conditions under which divergent natural selection can cause a ‘generalized barrier to gene flow’ that is present across the genome. Our individual‐based numerical simulations focus on how population divergence at neutral loci varies in relation to recombination rate with a selected locus, divergent selection on that locus, migration rate and population size. We specifically test whether genetic differences at neutral markers are greater between populations in different environments than between populations in similar environments. We find that this expected signature of ecological speciation can be detected under part of the parameter space, most consistently when divergent selection is strong and migration is intermediate. By contrast, the expected signature of ecological speciation is not reliably detected when divergent selection is weak or migration is low or high. These findings provide insights into the strengths and weaknesses of using neutral markers to infer ecological speciation in natural systems.     

Prediction of the merits of single crosses

Summary Best linear unbiased prediction of single crosses is described for a model that is somewhat more complete than those previously published. The method applies to unequal subclass numbers with unequal means of the observations. The lines are assumed to be a random sample from some population. Also, methods for unbiased estimation of the variances and covariances from such data are presented.     

Where the Lake Meets the Sea: Strong Reproductive Isolation Is Associated with Adaptive Divergence between Lake Resident and Anadromous Three-Spined Sticklebacks

Contact zones between divergent forms of the same species are often characterised by high levels of phenotypic diversity over small geographic distances. What processes are involved in generating such high phenotypic diversity? One possibility is that introgression and recombination between divergent forms in contact zones results in greater phenotypic and genetic polymorphism. Alternatively, strong reproductive isolation between forms may maintain distinct phenotypes, preventing homogenisation by gene flow. Contact zones between divergent freshwater-resident and anadromous stickleback (Gasterosteus aculeatus L.) forms are numerous and common throughout the species distribution, offering an opportunity to examine these contrasting hypotheses in greater detail. This study reports on an interesting new contact zone located in a tidally influenced lake catchment in western Ireland, characterised by high polymorphism for lateral plate phenotypes. Using neutral and QTL-linked microsatellite markers, we tested whether the high diversity observed in this contact zone arose as a result of introgression or reproductive isolation between divergent forms: we found strong support for the latter hypothesis. Three phenotypic and genetic clusters were identified, consistent with two divergent resident forms and a distinct anadromous completely plated population that migrates in and out of the system. Given the strong neutral differentiation detected between all three morphotypes (mean F_ST = 0.12), we hypothesised that divergent selection between forms maintains reproductive isolation. We found a correlation between neutral genetic and adaptive genetic differentiation that support this. While strong associations between QTL linked markers and phenotypes were also observed in this wild population, our results support the suggestion that such associations may be more complex in some Atlantic populations compared to those in the Pacific. These findings provide an important foundation for future work investigating the dynamics of gene flow and adaptive divergence in this newly discovered stickleback contact zone.     

ARE LYCOPODS WITH HIGH CHROMOSOME NUMBERS ANCIENT POLYPLOIDS?

It has been established that the number of isozymes (different forms of an enzyme encoded by different gene loci) is highly conserved in diploid angiosperms and gymnosperms. In contrast, allopolyploid angiosperms display an increase in isozyme number due to the addition of divergent genomes. Lycopods (Microphyllophyta) are an ancient lineage of vascular plants having very high chromosome numbers. It has been maintained that lycopods acquired these high chromosome numbers through repeated episodes of polyploidy. Despite high chromosome numbers, however, lycopod species having the lowest chromosome numbers within genera possess the number of isozymes typical of diploid seed plants for all enzymes examined except triosephosphate isomerase. There is, therefore, no genetic evidence from enzyme electrophoresis for polyploidy in these plants. These results are comparable to findings for other homosporous pteridophytes including the ferns (Pteridophyta) and horsetails (Arthrophyta). Alternative hypotheses for widespread genetic diploidy in homosporous pteridophytes are 1) repeated cycles of allopolyploidy followed by gene silencing; 2) repeated cycles of autopolyploidy, which would result in duplicated, but not divergent genes for isozymes; 3) initiation of these lineages with relatively high chromosome numbers.     

Extending McNemar's test: estimation and inference when paired binary outcome data are misclassified

McNemar's test is popular for assessing the difference between proportions when two observations are taken on each experimental unit. It is useful under a variety of epidemiological study designs that produce correlated binary outcomes. In studies involving outcome ascertainment, cost or feasibility concerns often lead researchers to employ error-prone surrogate diagnostic tests. Assuming an available gold standard diagnostic method, we address point and confidence interval estimation of the true difference in proportions and the paired-data odds ratio by incorporating external or internal validation data. We distinguish two special cases, depending on whether it is reasonable to assume that the diagnostic test properties remain the same for both assessments (e.g., at baseline and at follow-up). Likelihood-based analysis yields closed-form estimates when validation data are external and requires numeric optimization when they are internal. The latter approach offers important advantages in terms of robustness and efficient odds ratio estimation. We consider internal validation study designs geared toward optimizing efficiency given a fixed cost allocated for measurements. Two motivating examples are presented, using gold standard and surrogate bivariate binary diagnoses of bacterial vaginosis (BV) on women participating in the HIV Epidemiology Research Study (HERS).     

Experimental observation, theoretical models, and biomechanical inference in the study of mandibular form

Experimental studies and mathematical models are disparate approaches for inferring the stress and strain environment in mammalian jaws. Experimental designs offer accurate, although limited, characterization of biomechanical behavior, while mathematical approaches (finite element modeling in particular) offer unparalleled precision in depiction of strain magnitudes, directions, and gradients throughout the mandible. Because the empirical (experimental) and theoretical (mathematical) perspectives differ in their initial assumptions and their proximate goals, the two methods can yield divergent conclusions about how masticatory stresses are distributed in the dentary. These different sources of inference may, therefore, tangibly influence subsequent biological interpretation. In vitro observation of bone strain in primate mandibles under controlled loading conditions offers a test of finite element model predictions. Two issues which have been addressed by both finite element models and experimental approaches are: (1) the distribution of torsional shear strains in anthropoid jaws and (2) the dissipation of bite forces in the human alveolar process. Not surprisingly, the experimental data and mathematical models agree on some issues, but on others exhibit discordance. Achieving congruence between these methods is critical if the nature of the relationship of masticatory stress to mandibular form is to be intelligently assessed. A case study of functional/mechanical significance of gnathic morphology in the hominid genus Paranthropus offers insight into the potential benefit of combining theoretical and experimental approaches. Certain finite element analyses claim to have identified a biomechanical problem unrecognized in previous comparative work, which, in essence, is that the enlarged transverse dimensions of the postcanine corpus may have a less important role in resisting torsional stresses than previously thought. Experimental data have identified subperiosteal cortical thinning as a culprit in diminishing the role of cross-sectional geometry in conditioning the strain environment. These observations raise questions concerning the biomechanical significance of mandibular form in early hominids, fueling persistent arguments over whether gnathic morphology can be related to dietary specialization in the "robust" australopithecines. Nonmechanical explanations (e.g., tooth size or body size) for Paranthropus mandibular dimensions, however, are not compelling as competing hypotheses. Both theoretical and experimental models are in need of refinement before it is possible to conclude that the jaws of the "robust" australopithecines are not functionally linked to elevated masticatory loads.     

A test of fundamental questions in mimicry theory using long‐term datasets

Since the phenomenon of mimicry was first described by Bates in 1862 it has become one of the foundational examples of adaptive evolution. Numerous subcategories of mimicry and dozens of hypotheses pertaining to its evolution and maintenance have been proposed. Many of these hypotheses, however, are difficult to test in experimental settings, and data from natural observations are often inadequate. Here we use data from a long‐term survey of butterfly presence and abundance to test several hypotheses pertaining to Batesian and female‐limited polymorphic mimicry (FPM; a special case of Batesian mimicry). We found strong evidence that models outnumber mimics in both mimicry systems, but no evidence for an increase in relative abundance of FPM mimics to their Batesian counterparts. Tests of the early‐emergence/model first hypothesis showed strong evidence that the Batesian mimic routinely emerges after the model, while emergence timing in the FPM system was site specific, suggesting that other ecological factors are at play. These results demonstrate the importance of long‐term field observations for testing evolutionary and ecological hypotheses.     

Chromosomal fission accounts for small‐scale radiations in Zamia (Zamiaceae; Cycadales)

Zamia is unique among Cycadales in its diversity of morphology, ecology and chromosome numbers. The chromosome numbers in Zamia range from 16 to 28, excluding 20, manifest as both interspecific and intraspecific series. It has long been recognized that Robertsonian transformations (chromosomal fission or fusion) probably dominate karyotype evolution in Zamiaceae, although it has been debated whether chromosome numbers are increasing or decreasing. We re‐analyse published karyotypes of Zamia spp., relating both chromosome forms and sizes to recent phylogenetic data. We show that karyotype evolution is most probably moving towards increased asymmetry, with higher numbers of smaller chromosomes, thus supporting chromosomal fission. We also address additional hypotheses for increasing chromosome numbers, namely pericentric inversions and unequal translocations. Finally, we discuss the role of these chromosomal changes in evolutionary radiations. © 2011 The Linnean Society of London, Botanical Journal of the Linnean Society, 2011, 165 , 168–185.     

Ribosomal DNA Evolution at the Population Level: Nucleotide Variation in Intergenic Spacer Arrays of Daphnia Pulex

Nucleotide variation was surveyed in 21 subrepeat arrays from the ribosomal DNA intergenic spacer of three Daphnia pulex populations. Eighteen of these arrays contained four subrepeats. Contrary to expectations, each of the four positions within the array had a different consensus sequence. However, gene conversion, involving sequences less than the length of a subrepeat, had occurred between subrepeats in different positions. Three arrays had more than four subrepeats and were undoubtedly generated by unequal crossing over between standard-length arrays. The data strongly suggested that most unequal exchanges between arrays are intrachromosomal and that they occur much less frequently than unequal exchanges at the level of the entire rDNA repeat. Strong associations among variants at different positions allowed the recognition of five groups of arrays, two of which were found in more than one population. Five of the seven individuals surveyed had arrays from more than one group. Analysis of the distribution of nucleotide variation suggested that the populations were quite divergent, a result that is concordant with previous surveys of allozyme and mitochondrial DNA variation. It was suggested that some of the subrepeat array types are quite old, at least predating the recolonization of pond habitats in the midwestern United States after the last glaciation.     

Quantitative Analysis of Mechanisms That Govern Red Blood Cell Age Structure and Dynamics during Anaemia

Mathematical modelling has proven an important tool in elucidating and quantifying mechanisms that govern the age structure and population dynamics of red blood cells (RBCs). Here we synthesise ideas from previous experimental data and the mathematical modelling literature with new data in order to test hypotheses and generate new predictions about these mechanisms. The result is a set of competing hypotheses about three intrinsic mechanisms: the feedback from circulating RBC concentration to production rate of immature RBCs (reticulocytes) in bone marrow, the release of reticulocytes from bone marrow into the circulation, and their subsequent ageing and clearance. In addition we examine two mechanisms specific to our experimental system: the effect of phenylhydrazine (PHZ) and blood sampling on RBC dynamics. We performed a set of experiments to quantify the dynamics of reticulocyte proportion, RBC concentration, and erythropoietin concentration in PHZ-induced anaemic mice. By quantifying experimental error we are able to fit and assess each hypothesis against our data and recover parameter estimates using Markov chain Monte Carlo based Bayesian inference. We find that, under normal conditions, about 3% of reticulocytes are released early from bone marrow and upon maturation all cells are released immediately. In the circulation, RBCs undergo random clearance but have a maximum lifespan of about 50 days. Under anaemic conditions reticulocyte production rate is linearly correlated with the difference between normal and anaemic RBC concentrations, and their release rate is exponentially correlated with the same. PHZ appears to age rather than kill RBCs, and younger RBCs are affected more than older RBCs. Blood sampling caused short aperiodic spikes in the proportion of reticulocytes which appear to have a different developmental pathway than normal reticulocytes. We also provide evidence of large diurnal oscillations in serum erythropoietin levels during anaemia.     

How to make methodological decisions when inferring social networks

Social network analyses allow studying the processes underlying the associations between individuals and the consequences of those associations. Constructing and analyzing social networks can be challenging, especially when designing new studies as researchers are confronted with decisions about how to collect data and construct networks, and the answers are not always straightforward. The current lack of guidance on building a social network for a new study system might lead researchers to try several different methods and risk generating false results arising from multiple hypotheses testing. Here, we suggest an approach for making decisions when starting social network research in a new study system that avoids the pitfall of multiple hypotheses testing. We argue that best edge definition for a network is a decision that can be made using a priori knowledge about the species and that is independent from the hypotheses that the network will ultimately be used to evaluate. We illustrate this approach with a study conducted on a colonial cooperatively breeding bird, the sociable weaver. We first identified two ways of collecting data using different numbers of feeders and three ways to define associations among birds. We then evaluated which combination of data collection and association definition maximized (a) the assortment of individuals into previously known “breeding groups” (birds that contribute toward the same nest and maintain cohesion when foraging) and (b) socially differentiated relationships (more strong and weak relationships than expected by chance). This evaluation of different methods based on a priori knowledge of the study species can be implemented in a diverse array of study systems and makes the case for using existing, biologically meaningful knowledge about a system to help navigate the myriad of methodological decisions about data collection and network inference.     

Hydraulic conditions in isothermal lakes

SUMMARY. The paper considers the forms of water movement that occur in unstratified lakes. Although not dealing directly with ecological implications, it is hoped that it will encourage the inclusion of observations of underwater weather as part of normal limnological routine. It is particularly concerned to show what observations are most effective in revealing hydraulic conditions.
Relations between wind, lake geometry and wave characteristics are examined. Factors determining the steady, wind-driven circulation are reviewed and examined in sequence: the action of wind on a water surface and the current directly generated by the wind drag; the effect of the earth's rotation; the need to balance the flow in and out of any part of the lake; the influence of lake morphometry. A simple model of lake circulation is developed that may help in the interpretation of on-lake observations. Some other features of isothermal motion are discussed including the horizontal currents associated with unsteady wind conditions (seiches).
The possible interaction between waves and currents are discussed. A tentative classification of hydraulic conditions in terms of wind speed, lake depth and fetch is suggested as a basis for forming hypotheses about the motion prior to on-lake observations and as a possible starting point for a comparative approach.     

Statistical analysis of microarray data: a Bayesian approach

The potential of microarray data is enormous. It allows us to monitor the expression of thousands of genes simultaneously. A common task with microarray is to determine which genes are differentially expressed between two samples obtained under two different conditions. Recently, several statistical methods have been proposed to perform such a task when there are replicate samples under each condition. Two major problems arise with microarray data. The first one is that the number of replicates is very small (usually 2-10), leading to noisy point estimates. As a consequence, traditional statistics that are based on the means and standard deviations, e.g. t-statistic, are not suitable. The second problem is that the number of genes is usually very large (approximately 10,000), and one is faced with an extreme multiple testing problem. Most multiple testing adjustments are relatively conservative, especially when the number of replicates is small. In this paper we present an empirical Bayes analysis that handles both problems very well. Using different parametrizations, we develop four statistics that can be used to test hypotheses about the means and/or variances of the gene expression levels in both one- and two-sample problems. The methods are illustrated using experimental data with prior knowledge. In addition, we present the result of a simulation comparing our methods to well-known statistics and multiple testing adjustments.