Bayesian Markov models improve the prediction of binding motifs beyond first order

Transcription factors (TFs) regulate gene expression by binding to specific DNA motifs. Accurate models for predicting binding affinities are crucial for quantitatively understanding of transcriptional regulation. Motifs are commonly described by position weight matrices, which assume that each position contributes independently to the binding energy. Models that can learn dependencies between positions, for instance, induced by DNA structure preferences, have yielded markedly improved predictions for most TFs on in vivo data. However, they are more prone to overfit the data and to learn patterns merely correlated with rather than directly involved in TF binding. We present an improved, faster version of our Bayesian Markov model software, BaMMmotif2. We tested it with state-of-the-art motif discovery tools on a large collection of ChIP-seq and HT-SELEX datasets. BaMMmotif2 models of fifth-order achieved a median false-discovery-rate-averaged recall 13.6% and 12.2% higher than the next best tool on 427 ChIP-seq datasets and 164 HT-SELEX datasets, respectively, while being 8 to 1000 times faster. BaMMmotif2 models showed no signs of overtraining in cross-cell line and cross-platform tests, with similar improvements on the next-best tool. These results demonstrate that dependencies beyond first order clearly improve binding models for most TFs

Fine-structure diagnostics of neutral carbon toward HE 0515-4414

New high-resolution high signal-to-noise spectra of the $z=1.15$ damped Lyman $\alpha$ (DLA) system toward the quasi-stellar object HE 0515-4414 reveal absorption lines of the multiplets 2 and 3 in \ion{C}{i}. The resonance lines are seen in two components with total column densities of $\log N=13.79\pm0.01$ and $\log N=13.36\pm0.01$, respectively. The comparision of theoretical calculations of the relative fine-structure population with the ratios of the observed column densities suggests that the \ion{C}{i} absorbing medium is either very dense or exposed to very intense UV radiation. The upper limit on the local UV energy density is 100 times the galactic UV energy density, while the upper limit on the \ion{H}{i} number density is 110 cm$^{-3}$. The excitation temperatures of the ground state fine-structure levels of $T=15.7$ and $T=11.1$ K, respectively, are consistent with the temperature-redshift relation predicted by the standard Friedmann cosmology. The cosmic microwave background radiation (CMBR) is only a minor source of the observed fine-structure excitation.Comment: 5 pages, 5 figures, uses A&A macro package, gzipped tar archive, accepted by A&

Glutathione deficiency in HIV infection

The tripeptide glutathione (GSH) is the quantitatively most important cysteine derivative of low molecular weight and has numerous important cellular functions. Decreased plasma cysteine and cystine concentrations, decreased intracellular GSH levels, and increased plasma glutamate levels have been found in HIV-infected persons at all stages of the disease and in rhesus macaques within 2 weeks after infection with the closely related simian immunodeficiency virus (SIVmac2). Elevated glutamate levels inhibit the membrane transport of cystine and aggravate thereby the consequences of the cysteine deficiency. Complementary experiments In laboratory animals have shown that glutathione potentiates T cell functions in vivo and in vitro. And studies with healthy human subjects have shown that persons with a combination of a higher than median plasma cystine and lower than median glutamate level have significantly more CD4 T cells than persons with low cystine and high glutamate levels. On the basis of these findings we have proposed that the immunopathology of HIV infection may be largely the consequence of a virus-induced dysregulation of plasma amino acid concentrations. Studies on the mechanistic details revealed that the cysteine and intracellular glutathione deficiency may have several immunologically relevant consequences that affect the antigen presenting cells as well as the responding T lymphocytes. The redox regulation of the transcription factor NFκB accounts at least for some of the consequences.Biomedical Reviews 1993; 2: 9-13

The cosmic microwave background radiation temperature at z = 3.025 toward QSO 0347--3819

From the analysis of the CII fine-structure population ratio in the damped Ly_alpha system at z = 3.025 toward the quasar Q0347--3819 we derive an upper bound of 14.6 (+/- 0.2) K on the cosmic microwave background temperature regardless the presence of other different excitation mechanisms. The analysis of the ground state rotational level populations of H_2 detected in the system reveals a Galactic-type UV radiation field ruling out UV pumping as an important excitation mechanism for CII. The low dust content estimated from the Cr/Zn ratio indicates that the IR dust emission can also be neglected. When the collisional excitation is considered, we measure a temperature for the cosmic background radiation of T = 12.1 (+1.7, -3.2) K. The results are in agreement with the T = 10.968 (+/-) 0.004 K predicted by the hot Big Bang cosmology at z = 3.025.Comment: Accepte

Two-phase equilibrium and molecular hydrogen formation in damped Lyman-alpha systems

Molecular hydrogen is quite underabundant in damped Lyman-alpha systems at high redshift, when compared to the interstellar medium near the Sun. This has been interpreted as implying that the gas in damped Lyman-alpha systems is warm. like the nearby neutral intercloud medium, rather than cool, as in the clouds which give rise to most H I absorption in the Milky Way. Other lines of evidence suggest that the gas in damped Lyman-alpha systems -- in whole or part -- is actually cool; spectroscopy of neutral and ionized carbon, discussed here, shows that the damped Lyman-alpha systems observed at lower redshift z $$ 2.8 are warm (though not devoid of H2). To interpret the observations of carbon and hydrogen we constructed detailed numerical models of H2 formation under the conditions of two-phase thermal equilibrium, like those which account for conditions near the Sun, but with varying metallicity, dust-gas ratio, $etc$. We find that the low metallicity of damped Lyman-alpha systems is enough to suppress H2 formation by many orders of magnitude even in cool diffuse clouds, as long as the ambient optical/uv radiation field is not too small. For very low metallicity and under the most diffuse conditions, H2 formation will be dominated by slow gas-phase processes not involving grains, and a minimum molecular fraction in the range $10^{-8}-10^{-7}$ is expected.Comment: 13 pages, 7 figures; accepted 2002-04-30 by Astronomy and Astrophysic

Constructing coarse-grained skyrmion potentials from experimental data with Iterative Boltzmann Inversion

In an effort to understand skyrmion behavior on a coarse-grained level, skyrmions are often described as 2D quasiparticles evolving according to the Thiele equation. Interaction potentials are the key missing parameters for predictive modeling of experiments. Here, the Iterative Boltzmann Inversion technique commonly used in soft matter simulations is applied to construct potentials for skyrmion-skyrmion and skyrmion-magnetic material boundary interactions from a single experimental measurement without any prior assumptions of the potential form. It is found that the two interactions are purely repulsive and can be described by an exponential function for micrometer-sized skyrmions in a ferromagnetic thin film multilayer stack. This captures the physics on experimental length and time scales that are of interest for most skyrmion applications and typically inaccessible to atomistic or micromagnetic simulations

Constructing coarse-grained skyrmion potentials from experimental data with Iterative Boltzmann Inversion

In an effort to understand skyrmion behavior on a coarse-grained level, skyrmions are often described as 2D quasiparticles evolving according to the Thiele equation. Interaction potentials are the key missing parameters for predictive modeling of experiments. Here, the Iterative Boltzmann Inversion technique commonly used in soft matter simulations is applied to construct potentials for skyrmion-skyrmion and skyrmion-magnetic material boundary interactions from a single experimental measurement without any prior assumptions of the potential form. It is found that the two interactions are purely repulsive and can be described by an exponential function for micrometer-sized skyrmions in a ferromagnetic thin film multilayer stack. This captures the physics on experimental length and time scales that are of interest for most skyrmion applications and typically inaccessible to atomistic or micromagnetic simulations

Mental States Are Like Diseases

While Quine’s linguistic behaviorism is well-known, his Kant Lectures contain one of his most detailed discussions of behaviorism in psychology and the philosophy of mind. Quine clarifies the nature of his psychological commitments by arguing for a modest view that is against ‘excessively restrictive’ variants of behaviorism while maintaining ‘a good measure of behaviorist discipline…to keep [our mental] terms under control’. In this paper, I use Quine’s Kant Lectures to reconstruct his position. I distinguish three types of behaviorism in psychology and the philosophy of mind: ontological behaviorism, logical behaviorism, and epistemological behaviorism. I then consider Quine’s perspective on each of these views and argue that he does not fully accept any of them. By combining these perspectives we arrive at Quine’s surprisingly subtle view about behaviorism in psychology

Dipole source analysis of auditory P300 response in depressive and anxiety disorders

This paper is to study auditory event-related potential P300 in patients with anxiety and depressive disorders using dipole source analysis. Auditory P300 using 2-stimulus oddball paradigm was collected from 35 patients with anxiety disorder, 32 patients with depressive disorder, and 30 healthy controls. P300 dipole sources and peak amplitude of dipole activities were analyzed. The source analysis resulted in a 4-dipole configuration, where temporal dipoles displayed greater P300 amplitude than that of frontal dipoles. In addition, a right-greater-than-left hemispheric asymmetry of dipole magnitude was found in patients with anxiety disorder, whereas a left-greater-than-right hemispheric asymmetry of dipole magnitude was observed in depressed patients. Results indicated that the asymmetry was more prominent over the temporal dipole than that of frontal dipoles in patients. Patients with anxiety disorder may increase their efforts to enhance temporal dipole activity to compensate for a deficit in frontal cortex processing, while depressed patients show dominating reduction of right temporal activity. The opposite nature of results observed with hemispheric asymmetry in depressive and anxiety disorders could serve to be valuable information for psychiatric studies

The microwave background temperature at the redshift of 2.33771

The Cosmic Microwave Background radiation is a fundamental prediction of Hot Big Bang cosmology. The temperature of its black-body spectrum has been measured at the present time, $T_{\rm CMBR,0}$ = 2.726$\pm$ 0.010 K, and is predicted to have been higher in the past. At earlier time, the temperature can be measured, in principle, using the excitation of atomic fine structure levels by the radiation field. All previous measurements however give only upper limits as they assume that no other significant source of excitation is present. Here we report the detection of absorption from the first {\sl and} second fine-structure levels of neutral carbon atoms in an isolated remote cloud at a redshift of 2.33771. In addition, the unusual detection of molecular hydrogen in several rotational levels and the presence of ionized carbon in its excited fine structure level make the absorption system unique to constrain, directly from observation, the different excitation processes at play. It is shown for the first time that the cosmic radiation was warmer in the past. We find 6.0 < T_{\rm CMBR} < 14 K at z = 2.33771 when 9.1 K is expected in the Hot Big Bang cosmology.Comment: 20 pages, 5 figures, accepted for publication in Nature, Press embargo until 1900 hrs London time (GMT) on 20 Dec 200