Evaluating the neurophysiological evidence for predictive processing as a model of perception

For many years, the dominant theoretical framework guiding research into the neural origins of perceptual experience has been provided by hierarchical feedforward models, in which sensory inputs are passed through a series of increasingly complex feature detectors. However, the long‐standing orthodoxy of these accounts has recently been challenged by a radically different set of theories that contend that perception arises from a purely inferential process supported by two distinct classes of neurons: those that transmit predictions about sensory states and those that signal sensory information that deviates from those predictions. Although these predictive processing (PP) models have become increasingly influential in cognitive neuroscience, they are also criticized for lacking the empirical support to justify their status. This limited evidence base partly reflects the considerable methodological challenges that are presented when trying to test the unique predictions of these models. However, a confluence of technological and theoretical advances has prompted a recent surge in human and nonhuman neurophysiological research seeking to fill this empirical gap. Here, we will review this new research and evaluate the degree to which its findings support the key claims of PP

Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation.

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures

The Look-back Time Evolution of Far-Ultraviolet Flux from the Brightest Cluster Elliptical Galaxies at z < 0.2

We present the GALEX UV photometry of the elliptical galaxies in Abell clusters at moderate redshifts (z < 0.2) for the study of the look-back time evolution of the UV upturn phenomenon. The brightest elliptical galaxies (M_r < -22) in 12 remote clusters are compared with the nearby giant elliptical galaxies of comparable optical luminosity in the Fornax and Virgo clusters. The sample galaxies presented here appear to be quiescent without signs of massive star formation or strong nuclear activity, and show smooth, extended profiles in their UV images indicating that the far-UV (FUV) light is mostly produced by hot stars in the underlying old stellar population. Compared to their counterparts in nearby clusters, the FUV flux of cluster giant elliptical galaxies at moderate redshifts fades rapidly with ~ 2 Gyrs of look-back time, and the observed pace in FUV - V color evolution agrees reasonably well with the prediction from the population synthesis models where the dominant FUV source is hot horizontal-branch stars and their progeny. A similar amount of color spread (~ 1 mag) in FUV - V exists among the brightest cluster elliptical galaxies at z ~ 0.1, as observed among the nearby giant elliptical galaxies of comparable optical luminosity.Comment: Accepted for publication in the Special GALEX ApJ Supplement, December 200

Mid-IR Luminosities and UV/Optical Star Formation Rates at z<1.4

UV continuum and mid-IR emission constitute two widely used star formation indicators at intermediate and high redshifts. We study 2430 galaxies with z<1.4 in the Extended Groth Strip with MIPS 24 mic observations from FIDEL, spectroscopy from DEEP2, and UV, optical, and near-IR photometry from AEGIS. The data are coupled with stellar population models and Bayesian SED fitting to estimate dust-corrected SFRs. In order to probe the dust heating from stellar populations of various ages, the derived SFRs were averaged over various timescales--from 100 Myr for "current" SFR to 1--3 Gyr for long-timescale SFRs. These SED-based UV/optical SFRs are compared to total infrared luminosities extrapolated from 24 mic observations. We find that for the blue, actively star forming galaxies the correlation between the IR luminosity and the UV/optical SFR shows a decrease in scatter when going from shorter to longer SFR-averaging timescales. We interpret this as the greater role of intermediate age stellar populations in heating the dust than what is typically assumed. This holds over the entire redshift range. Many so-called green valley galaxies are simply dust-obscured actively star-forming galaxies. However, there exist 24 mic-detected galaxies, some with L>10^11 L_sun, yet with little current star formation. For them a reasonable amount of dust absorption of stellar light is sufficient to produce the observed levels of IR. In our sample optical and X-ray AGNs do not contribute on average more than ~50% to the mid-IR luminosity, and we see no evidence for a large population of "IR excess" galaxies (Abridged).Comment: Accepted for publication in ApJ. Content identical to arXiv version 1. No color figure

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.Peer reviewe

Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kB.

BACKGROUND: Endothelial MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the oxidant-dependent induction and progress of inflammatory bowel disease (IBD). Melatonin, a relatively safe, potent antioxidant, has shown efficacy in several chronic injury models may limit MAdCAM-1 expression and therefore have a therapeutic use in IBD. METHODS: We examined how different doses of melatonin reduced endothelial MAdCAM-1 induced by TNF-a in an in vitro model of lymphatic endothelium. Endothelial monolayers were pretreated with melatonin prior to, and during an exposure, to TNF-a (1 ng/ml, 24 h), and MAdCAM-1 expression measured by immunoblotting. RESULTS: MAdCAM-1 was induced by TNF-a. Melatonin at concentrations over 100 μm (10(-4) M) significantly attenuated MAdCAM-1 expression and was maximal at 1 mM. CONCLUSIONS: Our data indicate that melatonin may exert therapeutic activity in IBD through its ability to inhibit NF-kB dependent induction of MAdCAM-1

Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation

The diagnosis and management of drug-induced liver injury (DILI) is hindered by the limited utility of traditional clinical chemistries. It has recently been shown that hepatotoxicants can produce compound-specific changes in the peripheral blood (PB) transcriptome in rodents, suggesting the blood transcriptome might provide new biomarkers of DILI. To investigate in humans, we used DNA microarrays as well as serum metabolomic methods to characterize changes in the transcriptome and metabolome in serial PB samples obtained from 6 healthy adults treated with a 4 g bolus dose of acetaminophen (APAP) and from 3 receiving placebo. Treatment did not cause liver injury as assessed by traditional liver chemistries. However, 48 hours after exposure, treated subjects showed marked down-regulation of genes involved in oxidative phosphorylation/mitochondrial function that was not observed in the placebos (p <1.66E-19). The magnitude of down-regulation was positively correlated with the percent of APAP converted to the reactive metabolite NAPQI (r = 0.739; p=0.058). In addition, unbiased analysis of the serum metabolome revealed an increase in serum lactate from 24 to 72 hours post dosing in the treated subjects alone (p<0.005). Similar PB transcriptome changes were observed in human overdose patients and rats receiving toxic doses

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation

Metallicity and Temperature Indicators in M dwarf K band Spectra: Testing New & Updated Calibrations With Observations of 133 Solar Neighborhood M dwarfs

We present K band spectra for 133 nearby (d < 33 parsecs) M dwarfs, including 18 M dwarfs with reliable metallicity estimates (as inferred from an FGK type companion), 11 M dwarf planet hosts, more than 2/3 of the M dwarfs in the Northern 8 pc sample, and several M dwarfs from the LSPM catalog. From these spectra, we measure equivalent widths of the Ca and Na lines, and a spectral index quantifying the absorption due to H2O opacity (the H2O-K2 index). Using empirical spectral types standards and synthetic models, we calibrate the H2O-K2 index as an indicator of an M dwarf's spectral type and effective temperature. We also present a revised relationship that estimates the [Fe/H] and [M/H] metallicities of M dwarfs from their Na I, Ca I, and H2O-K2 measurements. Comparisons to model atmosphere provide a qualitative validation of our approach, but also reveal an overall offset between the atomic line strengths predicted by models as compared to actual observations. Our metallicity estimates also reproduce expected correlations with Galactic space motions and H alpha emission line strengths, and return statistically identical metallicities for M dwarfs within a common multiple system. Finally, we find systematic residuals between our H2O-based spectral types and those derived from optical spectral features with previously known sensitivity to stellar metallicity, such as TiO, and identify the CaH1 index as a promising optical index for diagnosing the metallicities of near-solar M dwarfs.Comment: 132 pages, 48 figures. Paper resubmitted to Ap