Characteristic bimodal profiles of RNA polymerase II at thousands of active mammalian promoters.

BACKGROUND: In mammals, ChIP-seq studies of RNA polymerase II (PolII) occupancy have been performed to reveal how recruitment, initiation and pausing of PolII may control transcription rates, but the focus is rarely on obtaining finely resolved profiles that can portray the progression of PolII through sequential promoter states. RESULTS: Here, we analyze PolII binding profiles from high-coverage ChIP-seq on promoters of actively transcribed genes in mouse and humans. We show that the enrichment of PolII near transcription start sites exhibits a stereotypical bimodal structure, with one peak near active transcription start sites and a second peak 110 base pairs downstream from the first. Using an empirical model that reliably quantifies the spatial PolII signal, gene by gene, we show that the first PolII peak allows for refined positioning of transcription start sites, which is corroborated by mRNA sequencing. This bimodal signature is found both in mouse and humans. Analysis of the pausing-related factors NELF and DSIF suggests that the downstream peak reflects widespread pausing at the +1 nucleosome barrier. Several features of the bimodal pattern are correlated with sequence features such as CpG content and TATA boxes, as well as the histone mark H3K4me3. CONCLUSIONS: We thus show how high coverage DNA sequencing experiments can reveal as-yet unnoticed bimodal spatial features of PolII accumulation that are frequent at individual mammalian genes and reminiscent of transcription initiation and pausing. The initiation-pausing hypothesis is corroborated by evidence from run-on sequencing and immunoprecipitation in other cell types and species.

Clara cells drive eosinophil accumulation in allergic asthma.

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the "immunomodulatory barrier" of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 μg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion. Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung. These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.

Dynamic visual information plays a critical role for spatial navigation in water but not on solid ground.

In the Morris water maze (MWM) task, proprioceptive information is likely to have a poor accuracy due to movement inertia. Hence, in this condition, dynamic visual information providing information on linear and angular acceleration would play a critical role in spatial navigation. To investigate this assumption we compared rat's spatial performance in the MWM and in the homing hole board (HB) tasks using a 1.5 Hz stroboscopic illumination. In the MWM, rats trained in the stroboscopic condition needed more time than those trained in a continuous light condition to reach the hidden platform. They expressed also little accuracy during the probe trial. In the HB task, in contrast, place learning remained unaffected by the stroboscopic light condition. The deficit in the MWM was thus complete, affecting both escape latency and discrimination of the reinforced area, and was thus task specific. This dissociation confirms that dynamic visual information is crucial to spatial navigation in the MWM whereas spatial navigation on solid ground is mediated by a multisensory integration, and thus less dependent on visual information.

Performance on a Virtual Reality Angled Laparoscope Task Correlates with Spatial Ability of Trainees

The aim of the present study was to investigate whether trainees' performance on a virtual reality angled laparoscope navigation task correlates with scores obtained on a validated conventional test of spatial ability. 56 participants of a surgery workshop performed an angled laparoscope navigation task on the Xitact LS 500 virtual reality Simulator. Performance parameters were correlated with the score of a validated paper-and-pencil test of spatial ability. Performance at the conventional spatial ability test significantly correlated with performance at the virtual reality task for overall task score (p < 0.001), task completion time (p < 0.001) and economy of movement (p = 0.035), not for endoscope travel speed (p = 0.947). In conclusion, trainees' performance in a standardized virtual reality camera navigation task correlates with their innate spatial ability. This VR session holds potential to serve as an assessment tool for trainees.

Extreme Precipitation Modelling Using Geostatistics and Machine Learning Algorithms

The paper presents an approach for mapping of precipitation data. The main goal is to perform spatial predictions and simulations of precipitation fields using geostatistical methods (ordinary kriging, kriging with external drift) as well as machine learning algorithms (neural networks). More practically, the objective is to reproduce simultaneously both the spatial patterns and the extreme values. This objective is best reached by models integrating geostatistics and machine learning algorithms. To demonstrate how such models work, two case studies have been considered: first, a 2-day accumulation of heavy precipitation and second, a 6-day accumulation of extreme orographic precipitation. The first example is used to compare the performance of two optimization algorithms (conjugate gradients and Levenberg-Marquardt) of a neural network for the reproduction of extreme values. Hybrid models, which combine geostatistical and machine learning algorithms, are also treated in this context. The second dataset is used to analyze the contribution of radar Doppler imagery when used as external drift or as input in the models (kriging with external drift and neural networks). Model assessment is carried out by comparing independent validation errors as well as analyzing data patterns.

Activity in inferior parietal and medial prefrontal cortex signals the accumulation of evidence in a probability learning task.

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.

Development of spatial integration depends on top-down and interhemispheric connections that can be perturbed in migraine: a DCM analysis.

In humans, spatial integration develops slowly, continuing through childhood into adolescence. On the assumption that this protracted course depends on the formation of networks with slowly developing top-down connections, we compared effective connectivity in the visual cortex between 13 children (age 7-13) and 14 adults (age 21-42) using a passive perceptual task. The subjects were scanned while viewing bilateral gratings, which either obeyed Gestalt grouping rules [colinear gratings (CG)] or violated them [non-colinear gratings (NG)]. The regions of interest for dynamic causal modeling were determined from activations in functional MRI contrasts stimuli > background and CG > NG. They were symmetrically located in V1 and V3v areas of both hemispheres. We studied a common model, which contained reciprocal intrinsic and modulatory connections between these regions. An analysis of effective connectivity showed that top-down modulatory effects generated at an extrastriate level and interhemispheric modulatory effects between primary visual areas (all inhibitory) are significantly weaker in children than in adults, suggesting that the formation of feedback and interhemispheric effective connections continues into adolescence. These results are consistent with a model in which spatial integration at an extrastriate level results in top-down messages to the primary visual areas, where they are supplemented by lateral (interhemispheric) messages, making perceptual encoding more efficient and less redundant. Abnormal formation of top-down inhibitory connections can lead to the reduction of habituation observed in migraine patients.

Olfactory and/or visual cues for spatial navigation through ontogeny: olfactory cues enable the use of visual cues

This study analyzed the spatial memory capacities of rats in darkness with visual and/or olfactory cues through ontogeny. Tests were conducted with the homing board, where rats had to find the correct escape hole. Four age groups (24 days, 48 days, 3-6 months, and 12 months) were trained in 3 conditions: (a) 3 identical light cues; (b) 5 different olfactory cues; and (c) both types of cues, followed by removal of the olfactory cues. Results indicate that immature rats first take into account olfactory information but are unable to orient with only the help of discrete visual cues. Olfaction enables the use of visual information by 48-day-old rats. Visual information predominantly supports spatial cognition in adult and 12-month-old rats. Results point out cooperation between vision and olfaction for place navigation during ontogeny in rats.

Visual search in spatial neglect studied with a preview paradigm.

Impaired visual search is a hallmark of spatial neglect. When searching for an unique feature (e.g., color) neglect patients often show only slight visual field asymmetries. In contrast, when the target is defined by a combination of features (e.g., color and form) they exhibit a severe deficit of contralesional search. This finding suggests a selective impairment of the serial deployment of spatial attention. Here, we examined this deficit with a preview paradigm. Neglect patients searched for a target defined by the conjunction of shape and color, presented together with varying numbers of distracters. The presentation time was varied such that on some trials participants previewed the target together with same-shape/different-color distracters, for 300 or 600 ms prior to the appearance of additional different-shape/same-color distracters. On the remaining trials the target and all distracters were shown simultaneously. Healthy participants exhibited a serial search strategy only when all items were presented simultaneously, whereas in both preview conditions a pop-out effect was observed. Neglect patients showed a similar pattern when the target was presented in the right hemifield. In contrast, when searching for a target in the left hemifield they showed serial search in the no-preview condition, as well as with a preview of 300 ms, and partly even at 600 ms. A control experiment suggested that the failure to fully benefit from item preview was probably independent of accurate perception of time. Our results, when viewed in the context of existing literature, lead us to conclude that the visual search deficit in neglect reflects two additive factors: a biased representation of attentional priority in favor of ipsilesional information and exaggerated capture of attention by ipsilesional abrupt onsets.

Optimization of spatial resolution for peripheral magnetic resonance angiography.

RATIONALE AND OBJECTIVES: To determine optimum spatial resolution when imaging peripheral arteries with magnetic resonance angiography (MRA). MATERIALS AND METHODS: Eight vessel diameters ranging from 1.0 to 8.0 mm were simulated in a vascular phantom. A total of 40 three-dimensional flash MRA sequences were acquired with incremental variations of fields of view, matrix size, and slice thickness. The accurately known eight diameters were combined pairwise to generate 22 "exact" degrees of stenosis ranging from 42% to 87%. Then, the diameters were measured in the MRA images by three independent observers and with quantitative angiography (QA) software and used to compute the degrees of stenosis corresponding to the 22 "exact" ones. The accuracy and reproducibility of vessel diameter measurements and stenosis calculations were assessed for vessel size ranging from 6 to 8 mm (iliac artery), 4 to 5 mm (femoro-popliteal arteries), and 1 to 3 mm (infrapopliteal arteries). Maximum pixel dimension and slice thickness to obtain a mean error in stenosis evaluation of less than 10% were determined by linear regression analysis. RESULTS: Mean errors on stenosis quantification were 8.8% +/- 6.3% for 6- to 8-mm vessels, 15.5% +/- 8.2% for 4- to 5-mm vessels, and 18.9% +/- 7.5% for 1- to 3-mm vessels. Mean errors on stenosis calculation were 12.3% +/- 8.2% for observers and 11.4% +/- 15.1% for QA software (P = .0342). To evaluate stenosis with a mean error of less than 10%, maximum pixel surface, the pixel size in the phase direction, and the slice thickness should be less than 1.56 mm2, 1.34 mm, 1.70 mm, respectively (voxel size 2.65 mm3) for 6- to 8-mm vessels; 1.31 mm2, 1.10 mm, 1.34 mm (voxel size 1.76 mm3), for 4- to 5-mm vessels; and 1.17 mm2, 0.90 mm, 0.9 mm (voxel size 1.05 mm3) for 1- to 3-mm vessels. CONCLUSION: Higher spatial resolution than currently used should be selected for imaging peripheral vessels.