Judging Time-to-Passage of looming sounds: evidence for the use of distance-based information

Perceptual judgments are an essential mechanism for our everyday interaction with other moving agents or events. For instance, estimation of the time remaining before an object contacts or passes us is essential to act upon or to avoid that object. Previous studies have demonstrated that participants use different cues to estimate the time to contact or the time to passage of approaching visual stimuli. Despite the considerable number of studies on the judgment of approaching auditory stimuli, not much is known about the cues that guide listeners’ performance in an auditory Time-to-Passage (TTP) task. The present study evaluates how accurately participants judge approaching white-noise stimuli in a TTP task that included variable occlusion periods (portion of the presentation time where the stimulus is not audible). Results showed that participants were able to accurately estimate TTP and their performance, in general, was weakly affected by occlusion periods. Moreover, we looked into the psychoacoustic variables provided by the stimuli and analysed how binaural cues related with the performance obtained in the psychophysical task. The binaural temporal difference seems to be the psychoacoustic cue guiding participants’ performance for lower amounts of occlusion, while the binaural loudness difference seems to be the cue guiding performance for higher amounts of occlusion. These results allowed us to explain the perceptual strategies used by participants in a TTP task (maintaining accuracy by shifting the informative cue for TTP estimation), and to demonstrate that the psychoacoustic cue guiding listeners’ performance changes according to the occlusion period.This study was supported by: Bial FoundationGrant 143/14 (https://www.bial.com/en/bial_foundation.11/11th_symposium.219/ fellows_preliminary_results.235/fellows_ preliminary_results.a569.html); FCT PTDC/EEAELC/112137/2009 (https://www.fct.pt/apoios/projectos/consulta/vglobal_projecto?idProjecto=112137&idElemConcurso=3628); and COMPETE: POCI-01-0145-FEDER-007043 and FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2013.info:eu-repo/semantics/publishedVersio

Improving gene-set enrichment analysis of RNA-Seq data with small replicates

Deregulated pathways identified from transcriptome data of two sample groups have played a key role in many genomic studies. Gene-set enrichment analysis (GSEA) has been commonly used for pathway or functional analysis of microarray data, and it is also being applied to RNA-seq data. However, most RNA-seq data so far have only small replicates. This enforces to apply the gene-permuting GSEA method (or preranked GSEA) which results in a great number of false positives due to the inter-gene correlation in each gene-set. We demonstrate that incorporating the absolute gene statistic in one-tailed GSEA considerably improves the false-positive control and the overall discriminatory ability of the gene-permuting GSEA methods for RNA-seq data. To test the performance, a simulation method to generate correlated read counts within a gene-set was newly developed, and a dozen of currently available RNA-seq enrichment analysis methods were compared, where the proposed methods outperformed others that do not account for the inter-gene correlation. Analysis of real RNA-seq data also supported the proposed methods in terms of false positive control, ranks of true positives and biological relevance. An efficient R package (AbsFilterG- SEA) coded with C++ (Rcpp) is available from CRAN.open

The Invasion and Metastasis Promotion Role of CD97 Small Isoform in Gastric Carcinoma

CD97 is over-expressed in the majority of gastric adenocarcinomas and is associated with its dedifferentiation and aggressiveness. Our previous results demonstrated that out of three CD97 isoforms tested, only the small one was able to promote increased invasiveness in vitro. Based on these data we further aimed to investigate the role of CD97 small isoform in gastric cancer progression in vivo by employing the cells with a stable CD97 small isoform knock-down and an orthotopic gastric cancer mouse model. We could demonstrate that the knock down of CD97/EGF1,2,5, led to a significant decrease in the number of cells penetrating the gelatin coated membrane as compared with control cells. In the gastric cancer mouse model, both the hypodermic and the orthotopic yielded tumor masses of the CD97/EGF1,2,5kd group and were significantly smaller than the control. Metastatic tumor cell number in early metastatic regional lymph nodes on post-operative day 42 was distinctly decreased in the CD97/EGF1,2,5kd group as compared with the SGC-NS group, and was accompanied with the downregulation of CD44, VEGFR, CD31 and CD97. We concluded in this study that CD97 small isoform not only supported gastric cancer local growth, but also promoted metastatic spread in orthotopically implanted mouse model suggesting involvement of the CD97 small isoform in the preparation of (pre)metastatic niche

Human physiologically based pharmacokinetic model for propofol

BACKGROUND: Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol. METHODS: PKQuest, a freely distributed software routine , was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. RESULTS: The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. CONCLUSION: A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed

A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense

Background: In addition to its complement-regulating activity, CD55 is a ligand of the adhesion class G protein-coupled receptor CD97; however, the relevance of this interaction has remained elusive. We previously showed that mice lacking a functional CD97 gene have increased numbers of granulocytes. Methodology/Results: Here,wedemonstratethatCD55-deficientmicedisplay a comparable phenotype with about two-fold more circulating granulocytes in the blood stream, the marginated pool, and the spleen. This granulocytosis was independent of increased complement activity. Augmented numbers of Gr-1-positive cells in cell cycle in the bone marrow indicated a higher granulopoietic activity in mice lacking either CD55 or CD97. Concomitant with the increase in blood granulocyte numbers, Cd55-/mice challenged with the respiratory pathogen Streptococcus pneumoniae developed less bacteremia and died later after infection. Conclusions: Collectively, these data suggest that complement-independent interaction of CD55 with CD97 is functionall

Reph, a Regulator of Eph Receptor Expression in the Drosophila melanogaster Optic Lobe

Receptors of the Eph family of tyrosine kinases and their Ephrin ligands are involved in developmental processes as diverse as angiogenesis, axon guidance and cell migration. However, our understanding of the Eph signaling pathway is incomplete, and could benefit from an analysis by genetic methods. To this end, we performed a genetic modifier screen for mutations that affect Eph signaling in Drosophila melanogaster. Several dozen loci were identified on the basis of their suppression or enhancement of an eye defect induced by the ectopic expression of Ephrin during development; many of these mutant loci were found to disrupt visual system development. One modifier locus, reph (regulator of eph expression), was characterized in molecular detail and found to encode a putative nuclear protein that interacts genetically with Eph signaling pathway mutations. Reph is an autonomous regulator of Eph receptor expression, required for the graded expression of Eph protein and the establishment of an optic lobe axonal topographic map. These results reveal a novel component of the regulatory pathway controlling expression of eph and identify reph as a novel factor in the developing visual system

Scroll-Wave Dynamics in Human Cardiac Tissue: Lessons from a Mathematical Model with Inhomogeneities and Fiber Architecture

Cardiac arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), are among the leading causes of death in the industrialized world. These are associated with the formation of spiral and scroll waves of electrical activation in cardiac tissue; single spiral and scroll waves are believed to be associated with VT whereas their turbulent analogs are associated with VF. Thus, the study of these waves is an important biophysical problem. We present a systematic study of the combined effects of muscle-fiber rotation and inhomogeneities on scroll-wave dynamics in the TNNP (ten Tusscher Noble Noble Panfilov) model for human cardiac tissue. In particular, we use the three-dimensional TNNP model with fiber rotation and consider both conduction and ionic inhomogeneities. We find that, in addition to displaying a sensitive dependence on the positions, sizes, and types of inhomogeneities, scroll-wave dynamics also depends delicately upon the degree of fiber rotation. We find that the tendency of scroll waves to anchor to cylindrical conduction inhomogeneities increases with the radius of the inhomogeneity. Furthermore, the filament of the scroll wave can exhibit drift or meandering, transmural bending, twisting, and break-up. If the scroll-wave filament exhibits weak meandering, then there is a fine balance between the anchoring of this wave at the inhomogeneity and a disruption of wave-pinning by fiber rotation. If this filament displays strong meandering, then again the anchoring is suppressed by fiber rotation; also, the scroll wave can be eliminated from most of the layers only to be regenerated by a seed wave. Ionic inhomogeneities can also lead to an anchoring of the scroll wave; scroll waves can now enter the region inside an ionic inhomogeneity and can display a coexistence of spatiotemporal chaos and quasi-periodic behavior in different parts of the simulation domain. We discuss the experimental implications of our study

Identification of Candidate Growth Promoting Genes in Ovarian Cancer through Integrated Copy Number and Expression Analysis

Ovarian cancer is a disease characterised by complex genomic rearrangements but the majority of the genes that are the target of these alterations remain unidentified. Cataloguing these target genes will provide useful insights into the disease etiology and may provide an opportunity to develop novel diagnostic and therapeutic interventions. High resolution genome wide copy number and matching expression data from 68 primary epithelial ovarian carcinomas of various histotypes was integrated to identify genes in regions of most frequent amplification with the strongest correlation with expression and copy number. Regions on chromosomes 3, 7, 8, and 20 were most frequently increased in copy number (>40% of samples). Within these regions, 703/1370 (51%) unique gene expression probesets were differentially expressed when samples with gain were compared to samples without gain. 30% of these differentially expressed probesets also showed a strong positive correlation (r≥0.6) between expression and copy number. We also identified 21 regions of high amplitude copy number gain, in which 32 known protein coding genes showed a strong positive correlation between expression and copy number. Overall, our data validates previously known ovarian cancer genes, such as ERBB2, and also identified novel potential drivers such as MYNN, PUF60 and TPX2

Identification and Characterization of NF-Y Transcription Factor Families in the Monocot Model Plant Brachypodium distachyon

BACKGROUND: Nuclear Factor Y (NF-Y) is a heterotrimeric transcription factor composed of NF-YA, NF-YB and NF-YC proteins. Using the dicot plant model system Arabidopsis thaliana (Arabidopsis), NF-Y were previously shown to control a variety of agronomically important traits, including drought tolerance, flowering time, and seed development. The aim of the current research was to identify and characterize NF-Y families in the emerging monocot model plant Brachypodium distachyon (Brachypodium) with the long term goal of assisting in the translation of known dicot NF-Y functions to the grasses. METHODOLOGY/PRINCIPAL FINDINGS: We identified, annotated, and further characterized 7 NF-YA, 17 NF-YB, and 12 NF-YC proteins in Brachypodium (BdNF-Y). By examining phylogenetic relationships, orthology predictions, and tissue-specific expression patterns for all 36 BdNF-Y, we proposed numerous examples of likely functional conservation between dicots and monocots. To test one of these orthology predictions, we demonstrated that a BdNF-YB with predicted orthology to Arabidopsis floral-promoting NF-Y proteins can rescue a late flowering Arabidopsis mutant. CONCLUSIONS/SIGNIFICANCE: The Brachypodium genome encodes a similar complement of NF-Y to other sequenced angiosperms. Information regarding NF-Y phylogenetic relationships, predicted orthologies, and expression patterns can facilitate their study in the grasses. The current data serves as an entry point for translating many NF-Y functions from dicots to the genetically tractable monocot model system Brachypodium. In turn, studies of NF-Y function in Brachypodium promise to be more readily translatable to the agriculturally important grasses