The recordable cerebral activity (readiness-potential, RP) that precedes a freely voluntary, fully endogenous motor act was directly compared with the reportable time (W) for appearance of the subjective experience of 'wanting' or intending to act. The onset of cerebral activity clearly preceded by at least several hundred milliseconds the reported time of conscious intention to act. This relationship held even for those series (with 'type II' RPs) in which subjects reported that all of the 40 self-initiated movements in the series appeared 'spontaneously' and capriciously. Data were obtained in at least 6 different experimental sessions with each of 5 subjects. In series with type II RPs, onset of the main negative shift in each RP preceded the corresponding mean W value by an average of about 350 ms, and by a minimum of about 150 ms. In series with type I RPs, in which an experience of preplanning occurred in some of the 40 self-initiated acts, onset of RP preceded W by an average of about 800 ms (or by 500 ms, taking onset of RP at 90 per cent of its area). Reports of W time depended upon the subject's recall of the spatial 'clock-position' of a revolving spot at the time of his initial awareness of wanting or intending to move. Two different modes of recall produced similar values. Subjects distinguished awareness of wanting to move (W) from awareness of actually moving (M). W times were consistently and substantially negative to, in advance of, mean times reported for M and also those for S, the sensation elicited by a task-related skin stimulus delivered at irregular times that were unknown to the subject. It is concluded that cerebral initiation of a spontaneous, freely voluntary act can begin unconsciously, that is, before there is any (at least recallable) subjective awareness that a 'decision' to act has already been initiated cerebrally. This introduces certain constraints on the potentiality for conscious initiation and control of voluntary acts.

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex–related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both.

No abstract

The vast majority of phylogenetic models focus on resolution of gene trees, despite the fact that phylogenies of species in which gene trees are embedded are of primary interest. We analyze a Bayesian model for estimating species trees that accounts for the stochastic variation expected for gene trees from multiple unlinked loci sampled from a single species history after a coalescent process. Application of the model to a 106-gene data set from yeast shows that the set of gene trees recovered by statistically acknowledging the shared but unknown species tree from which gene trees are sampled is much reduced compared with treating the history of each locus independently of an overarching species tree. The analysis also yields a concentrated posterior distribution of the yeast species tree whose mode is congruent with the concatenated gene tree but can do so with less than half the loci required by the concatenation method. Using simulations, we show that, with large numbers of loci, highly resolved species trees can be estimated under conditions in which concatenation of sequence data will positively mislead phylogeny, and when the proportion of gene trees matching the species tree is <10%. However, when gene tree/species tree congruence is high, species trees can be resolved with just two or three loci. These results make accessible an alternative paradigm for combining data in phylogenomics that focuses attention on the singularity of species histories and away from the idiosyncrasies and multiplicities of individual gene histories.coalescent theory ͉ importance sampling ͉ molecular clock ͉ yeast M any biological disciplines have as their focus the phylogenetic relationships of species-species trees. With the advent of large-scale comparative genomic data sets and enhanced computational power, statistical methods such as maximum likelihood and Bayesian phylogenetic inference have provided sophisticated approaches to incorporation of heterogeneous models of sequence evolution in combined multilocus data sets (1-3). These methods have vastly increased the efficiency and statistical power that can be gleaned from DNA sequences and will greatly contribute to the ultimate goal of comprehending the full scope of Darwin's Tree of Life (4). The taxonomic units of the Tree of Life are species composed of large numbers of genes distributed across multiple independently segregating chromosomes and linkage groups. Thus, most phylogenetic studies in fact use methodologies that focus not on estimation of species trees per se but on estimation of gene trees, with the usual assumption being that the gene tree resolved by combining many genes is congruent with the species tree. This assumption will hold widely, except in cases when (i) horizontal gene transfer and other reticulate processes, such as interspecific gene flow, are common; (ii) gene duplication has caused gene lineage splits in the absence of splits in the history of species; and (iii) gene lineages fail to coalesce before divergence of species (looking backward i...

The estimation of species trees (phylogenies) is one of the most important problems in evolutionary biology, and recently, there has been greater appreciation of the need to estimate species trees directly rather than using gene trees as a surrogate. A Bayesian method constructed under the multispecies coalescent model can consistently estimate species trees but involves intensive computation, which can hinder its application to the phylogenetic analysis of large-scale genomic data. Many summary statistics-based approaches, such as shallowest coalescences (SC) and Global LAteSt Split (GLASS), have been developed to infer species phylogenies for multilocus data sets. In this paper, we propose 2 methods, species tree estimation using average ranks of coalescences (STAR) and species tree estimation using average coalescence times (STEAC), based on the summary statistics of coalescence times. It can be shown that the 2 methods are statistically consistent under the multispecies coalescent model. STAR uses the ranks of coalescences and is thus resistant to variable substitution rates along the branches in gene trees. A simulation study suggests that STAR consistently outperforms STEAC, SC, and GLASS when the substitution rates among lineages are highly variable. Two real genomic data sets were analyzed by the 2 methods and produced species trees that are consistent with previous results.

The desire to infer the evolutionary history of a group of species should be more viable now that a considerable amount of multilocus molecular data is available. However, the current molecular phylogenetic paradigm still reconstructs gene trees to represent the species tree. Further, commonly used methods of combining data, such as the concatenation method, are known to be inconsistent in some circumstances. In this paper, we propose a Bayesian hierarchical model to estimate the phylogeny of a group of species using multiple estimated gene tree distributions, such as those that arise in a Bayesian analysis of DNA sequence data. Our model employs substitution models used in traditional phylogenetics but also uses coalescent theory to explain genealogical signals from species trees to gene trees and from gene trees to sequence data, thereby forming a complete stochastic model to estimate gene trees, species trees, ancestral population sizes, and species divergence times simultaneously. Our model is founded on the assumption that gene trees, even of unlinked loci, are correlated due to being derived from a single species tree and therefore should be estimated jointly. We apply the method to two multilocus data sets of DNA sequences. The estimates of the species tree topology and divergence times appear to be robust to the prior of the population size, whereas the estimates of effective population sizes are sensitive to the prior used in the analysis. These analyses also suggest that the model is superior to the concatenation method in fitting these data sets and thus provides a more realistic assessment of the variability in the distribution of the species tree that may have produced the molecular information at hand. Future improvements of our model and algorithm should include consideration of other factors that can cause discordance of gene trees and species trees, such as horizontal transfer or gene duplication.

Sphingosine-1-phosphate is a bioactive lipid that is mitogenic for human glioma cell lines by signaling through its G protein-coupled receptors. We investigated the role of sphingosine-1-phosphate receptors and the enzymes that form sphingosine-1-phosphate, sphingosine kinase (SphK)-1, and -2 in human astrocytomas. Astrocytomas of various histologic grades expressed three types of sphingosine-1-phosphate receptors, S1P1, S1P2, and S1P3; however, no significant correlation with histologic grade or patient survival was detected. Expression of SphK1, but not SphK2, in human astrocytoma grade 4 (glioblastoma multiforme) tissue correlated with short patient survival. Patients whose tumors had low SphK1 expression survived a median 357 days, whereas those with high levels of SphK1 survived a median 102 days. Decreasing SphK1 expression using RNA interference or pharmacologic inhibition of SphK significantly decreased the rate of proliferation of U-1242 MG and U-87 MG glioblastoma cell lines. Surprisingly, RNA interference to knockdown SphK2 expression inhibited glioblastoma cell proliferation more potently than did SphK1 knockdown. SphK knockdown also prevented cells from exiting G1 phase of the cell cycle and marginally increased apoptosis. Thus, SphK isoforms may be major contributors to growth of glioblastoma cells in vitro and to aggressive behavior of glioblastoma multiforme.

reviewed independently by 4 neuropathologists to determine interobserver diagnostic concordance rates. Cases wherein diagnostic disagreements arose were re-1 Division of Neuropathology, Barrow Neurologviewed jointly to identify and refine the histologic criteria that were adversely ical Institute, St. Joseph's Hospital and Medical affecting diagnostic reproducibility. Using the criteria developed in the study, a Center, Phoenix, Arizona.set of 315 gliomas with known survival data was evaluated in order to validate the 2 Department of Pathology and Laboratory Medusefulness of the criteria. icine, Mayo Clinic and Mayo Foundation, Roch- RESULTS.There was significant improvement in diagnostic concordance with each ester, Minnesota.session (P Å 0.02). For the first session, the concordance rates were as follows: all 3 Department of Neuropathology, The Ohio 4 reviewers, 52%; any 3 reviewers, 60%; 2 reviewers, 70%. For the fourth session, State University, Columbus, Ohio.the respective rates were 69%, 75%, and 80%. Although features important in grading, particularly microvascular proliferation, were sometimes problematic, 4 Department of Statistics, The Ohio State University, Columbus, Ohio.most disagreements related to the classification of tumors. Much of the improvement related to the refinement of criteria distinguishing diffuse astrocytomas from oligodendrogliomas/oligoastrocytomas and pilocytic astrocytomas. It was concluded that the presence of any typical oligodendroglioma was sufficient to remove a tumor from the astrocytoma category. CONCLUSIONS.The authors' data indicate that oligodendroglial tumors comprise up to 25% of gliomas, a significantly higher proportion than was previously recognized. The data also suggest that the wide range of survival times reported for patients with anaplastic astrocytoma may reflect ''contamination'' resulting from misdiagnosis, particularly of oligodendroglial tumors and pilocytic astrocytomas.