Automatic filtering and substantiation of drug safety signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

Bump time-frequency toolbox: a toolbox for time-frequency oscillatory bursts extraction in electrophysiological signals

Background: oscillatory activity, which can be separated in background and oscillatory burst pattern activities, is supposed to be representative of local synchronies of neural assemblies. Oscillatory burst events should consequently play a specific functional role, distinct from background EEG activity – especially for cognitive tasks (e.g. working memory tasks), binding mechanisms and perceptual dynamics (e.g. visual binding), or in clinical contexts (e.g. effects of brain disorders). However extracting oscillatory events in single trials, with a reliable and consistent method, is not a simple task. Results: in this work we propose a user-friendly stand-alone toolbox, which models in a reasonable time a bump time-frequency model from the wavelet representations of a set of signals. The software is provided with a Matlab toolbox which can compute wavelet representations before calling automatically the stand-alone application. Conclusion: The tool is publicly available as a freeware at the address: http:// www.bsp.brain.riken.jp/bumptoolbox/toolbox_home.html

Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival.

Intrathymic T-cell maturation critically depends on the selective expansion of thymocytes expressing a functionally rearranged T-cell receptor (TCR) beta chain. In addition, TCR-independent signals also contribute to normal T-cell development. It is unclear whether and how signals from the 2 types of pathways are integrated. Here, we show that T-cell factor-1 (TCF-1), a nuclear effector of the canonical wingless/int (wnt)/catenin signaling pathway, ensures the survival of proliferating, pre-TCR(+) thymocytes. The survival of pre-TCR(+) thymocytes requires the presence of the N-terminal catenin-binding domain in TCF-1. This domain can bind the transcriptional coactivator beta-catenin and may also bind gamma-catenin (plakoglobin). However, in the absence of gamma-catenin, T-cell development is normal, supporting a role for beta-catenin. Signaling competent beta-catenin is present prior to and thus arises independently from pre-TCR signaling and does not substantially increase on pre-TCR signaling. In contrast, pre-TCR signaling significantly induces TCF-1 expression. This coincides with the activation of a wnt/catenin/TCF reporter transgene in vivo. Collectively, these data suggest that efficient TCF-dependent transcription requires that pre-TCR signaling induces TCF-1 expression, whereas wnt signals may provide the coactivator such as beta-catenin. The 2 pathways thus have to cooperate to ensure thymocyte survival at the pre-TCR stage.

Blind channel deconvolution of real world signals using source separation techniques

In this paper we present a method for blind deconvolution of linear channels based on source separation techniques, for real word signals. This technique applied to blind deconvolution problems is based in exploiting not the spatial independence between signals but the temporal independence between samples of the signal. Our objective is to minimize the mutual information between samples of the output in order to retrieve the original signal. In order to make use of use this idea the input signal must be a non-Gaussian i.i.d. signal. Because most real world signals do not have this i.i.d. nature, we will need to preprocess the original signal before the transmission into the channel. Likewise we should assure that the transmitted signal has non-Gaussian statistics in order to achieve the correct function of the algorithm. The strategy used for this preprocessing will be presented in this paper. If the receiver has the inverse of the preprocess, the original signal can be reconstructed without the convolutive distortion.

Investigation of ICA algorithms for feature extraction of EEG signals in discrimination of Alzheimer disease

In this paper we present a quantitative comparisons of different independent component analysis (ICA) algorithms in order to investigate their potential use in preprocessing (such as noise reduction and feature extraction) the electroencephalogram (EEG) data for early detection of Alzhemier disease (AD) or discrimination between AD (or mild cognitive impairment, MCI) and age-match control subjects.

Orchestration signals in the classroom: managing the jigsaw collaborative learning flow

The orchestration of collaborative learning processes in face-to-facephysical settings, such as classrooms, requires teachers to coordinate students indicating them who belong to each group, which collaboration areas areassigned to each group, and how they should distribute the resources or roles within the group. In this paper we present an Orchestration Signal system,composed of wearable Personal Signal devices and an Orchestration Signal manager. Teachers can configure color signals in the manager so that they are transmitted to the wearable devices to indicate different orchestration aspects.In particular, the paper describes how the system has been used to carry out a Jigsaw collaborative learning flow in a classroom where students received signals indicating which documents they should read, in which group they were and in which area of the classroom they were expected to collaborate. The evaluation results show that the proposed system facilitates a dynamic, visual and flexible orchestration.

In vivo brain macromolecule signals in healthy and glioblastoma mouse models: (1) H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T.

In (1) H magnetic resonance spectroscopy, macromolecule signals underlay metabolite signals, and knowing their contribution is necessary for reliable metabolite quantification. When macromolecule signals are measured using an inversion-recovery pulse sequence, special care needs to be taken to correctly remove residual metabolite signals to obtain a pure macromolecule spectrum. Furthermore, since a single spectrum is commonly used for quantification in multiple experiments, the impact of potential macromolecule signal variability, because of regional differences or pathologies, on metabolite quantification has to be assessed. In this study, we introduced a novel method to post-process measured macromolecule signals that offers a flexible and robust way of removing residual metabolite signals. This method was applied to investigate regional differences in the mouse brain macromolecule signals that may affect metabolite quantification when not taken into account. However, since no significant differences in metabolite quantification were detected, it was concluded that a single macromolecule spectrum can be generally used for the quantification of healthy mouse brain spectra. Alternatively, the study of a mouse model of human glioma showed several alterations of the macromolecule spectrum, including, but not limited to, increased mobile lipid signals, which had to be taken into account to avoid significant metabolite quantification errors.

Inhibition of fas death signals by FLIPs.

The death receptor Fas is a member of the tumor necrosis factor receptor family; upon interaction with its ligand it efficiently activates caspases and induces apoptosis. Despite abundant Fas surface expression, however, Fas death-signals are frequently interrupted. Many viruses express antiapoptotic proteins, including caspase inhibitors, Bcl-2 homologues and death-effector-domain-containing proteins that are termed FLIPs (FLICE [Fas-associated death-domain-like IL-1beta-converting enzyme]-inhibitory proteins). Cellular homologues of these inhibitors have been identified. Cellular FLIPs structurally resemble caspase-8 except that they lack proteolytic activity. FLIPs are highly expressed in tumor cells, T lymphocytes and healthy, but not injured, myocytes; this suggests a critical role of FLIPs as endogenous modulators of apoptosis.

Oligogalacturonide defense signals in plants: large fragments interact with the plasma membrane in vitro.

Oligogalacturonides are plant cell wall-derived regulatory molecules which stimulate defense gene expression during pathogenesis. In vitro, these compounds enhance the phosphorylation of an approximately 34-kDa protein (pp34) in purified plasma membranes from potato and tomato leaves. We now show that polygalacturonate-enhanced phosphorylation of pp34 occurs in plasma membranes purified from tomato roots, hypocotyls, and stems and from undifferentiated potato cells. Furthermore, a similar phosphorylation is detected in leaf plasma membranes from soybean, a plant distantly related to tomato. Purified oligogalacturonides 13 to at least 26 residues long stimulate pp34 thiophosphorylation in vitro. This stimulation pattern differs from the induction of many known defense responses in vivo, where a narrower range of smaller fragments, between approximately 10 and 15 residues long, are active. On the basis of these differences we suggest that observed effects of applied exogenous oligogalacturonides on defense responses may not necessarily reflect the situation during pathogenesis. The cell wall could act as a barrier to many exogenous oligo- and polygalacturonides as well as other large regulatory ligands.

Neural substrates of social emotion regulation: a FMRI study on imitation and expressive suppression to dynamic facial signals.

Emotion regulation is crucial for successfully engaging in social interactions. Yet, little is known about the neural mechanisms controlling behavioral responses to emotional expressions perceived in the face of other people, which constitute a key element of interpersonal communication. Here, we investigated brain systems involved in social emotion perception and regulation, using functional magnetic resonance imaging (fMRI) in 20 healthy participants. The latter saw dynamic facial expressions of either happiness or sadness, and were asked to either imitate the expression or to suppress any expression on their own face (in addition to a gender judgment control task). fMRI results revealed higher activity in regions associated with emotion (e.g., the insula), motor function (e.g., motor cortex), and theory of mind (e.g., [pre]cuneus) during imitation. Activity in dorsal cingulate cortex was also increased during imitation, possibly reflecting greater action monitoring or conflict with own feeling states. In addition, premotor regions were more strongly activated during both imitation and suppression, suggesting a recruitment of motor control for both the production and inhibition of emotion expressions. Expressive suppression (eSUP) produced increases in dorsolateral and lateral prefrontal cortex typically related to cognitive control. These results suggest that voluntary imitation and eSUP modulate brain responses to emotional signals perceived from faces, by up- and down-regulating activity in distributed subcortical and cortical networks that are particularly involved in emotion, action monitoring, and cognitive control.

Identification of neuronal network properties from the spectral analysis of calcium imaging signals in neuronal cultures

Neuronal networks in vitro are prominent systems to study the development of connections in living neuronal networks and the interplay between connectivity, activity and function. These cultured networks show a rich spontaneous activity that evolves concurrently with the connectivity of the underlying network. In this work we monitor the development of neuronal cultures, and record their activity using calcium fluorescence imaging. We use spectral analysis to characterize global dynamical and structural traits of the neuronal cultures. We first observe that the power spectrum can be used as a signature of the state of the network, for instance when inhibition is active or silent, as well as a measure of the network's connectivity strength. Second, the power spectrum identifies prominent developmental changes in the network such as GABAA switch. And third, the analysis of the spatial distribution of the spectral density, in experiments with a controlled disintegration of the network through CNQX, an AMPA-glutamate receptor antagonist in excitatory neurons, reveals the existence of communities of strongly connected, highly active neurons that display synchronous oscillations. Our work illustrates the interest of spectral analysis for the study of in vitro networks, and its potential use as a network-state indicator, for instance to compare healthy and diseased neuronal networks.

How siblings adjust sib-sib communication and begging signals to each other

Parents allocate food resources to their offspring in proportion to the intensity of begging behaviour. Begging encompasses several activities including vocalizations that should honestly signal need and jostling for the position in the nest where parents predictably deliver food items. Although siblings are known to adjust begging level to each other, the underlying mechanism remains unknown. We examined this issue in experimental two-chick broods of the barn owl, Tyto alba, a species in which siblings communicate vocally with each other in the prolonged absence of parents. The function of sib-sib vocal communication, so-called sibling negotiation, is to resolve conflicts over which individual will have priority of access to the next delivered indivisible food item. We found that when a nestling produced longer negotiation calls and stood closer to the nestbox entrance in the absence of parents, its sibling vocally negotiated at a lower rate. Additionally, when an individual produced more negotiation calls in the absence of parents, its sibling begged less intensely at the parent's return, with begging being the key factor that determined which nestling obtained a food item. We conclude that position in the nest and the duration of negotiation calls produced in the absence of parents influence the rate of producing negotiation calls, which in turn influences the rate at which siblings beg for food from their parents. Adjusting begging behaviour could therefore depend on complex sib-sib interactions taking place in the prolonged absence of parents.

Nuclear translocation and DNA recognition signals colocalized within the bZIP domain of cyclic adenosine 3',5'-monophosphate response element-binding protein CREB.

CREB is a cAMP-responsive nuclear DNA-binding protein that binds to cAMP response elements and stimulates gene transcription upon activation of the cAMP signalling pathway. The protein consists of an amino-terminal transcriptional transactivation domain and a carboxyl-terminal DNA-binding domain (bZIP domain) comprised of a basic region and a leucine zipper involved in DNA recognition and dimerization, respectively. Recently, we discovered a testis-specific transcript of CREB that contains an alternatively spliced exon encoding multiple stop codons. CREB encoded by this transcript is a truncated protein lacking the bZIP domain. We postulated that the antigen detected by CREB antiserum in the cytoplasm of germinal cells is the truncated CREB that must also lack its nuclear translocation signal (NTS). To test this hypothesis we prepared multiple expression plasmids encoding carboxyl-terminal deletions of CREB and transiently expressed them in COS-1 cells. By Western immunoblot analysis as well as immunocytochemistry of transfected cells, we show that CREB proteins truncated to amino acid 286 or shorter are sequestered in the cytoplasm, whereas a CREB of 295 amino acids is translocated into the nucleus. Chimeric CREBs containing a heterologous NTS fused to the first 248 or 261 amino acids of CREB are able to drive the translocation of the protein into the nucleus. Thus, the nine amino acids in the basic region involved in DNA recognition between positions 287 and 295 (RRKKKEYVK) of CREB contain the NTS. Further, mutation of the lysine at position 290 in CREB to an asparagine diminishes nuclear translocation of the protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

Melanin-based colour polymorphism signals aggressive personality in nest and territory defence in the tawny owl (Strix aluco)

Nest and territory defence are risky and potentially dangerous behaviours. If the resolution of life history trade-offs differs between individuals, the level of defence may also vary among individuals. Because melanin-based colour traits can be associated with life history strategies, differently coloured individuals may display different nest and territory defence strategies. We investigated this issue in the colour polymorphic tawny owl (Strix aluco) for which plumage varies from dark to light reddish melanic. Accordingly, we found that (1) our presence induced a greater response (flying around) from dark-coloured than light-coloured females and (2) dark reddish males suffered lower nest predation rates than light-coloured males. In experimentally enlarged broods, the probability that females reacted after we played back the hoot calls of a stranger male was higher if these females were lighter reddish; the opposite pattern was found in experimentally reduced broods with dark parents being more reactive than light parents. Finally, darker females alarmed more frequently when paired with a light than with a dark male, suggesting that partners adjust their behaviour to each other. We also tested whether colouration is used as a signal by conspecifics to adjust the level of their defensive behaviour. Accordingly, breeding females responded more vigorously to a dark than a light reddish stuffed tawny owl placed beside their nest. We conclude that melanin-based colouration is a signal of alternative nest and territory defence behaviour that depends on ecological factors.