Preclinical to clinical translation of cenerimod, a novel S1P receptor modulator, in systemic lupus erythematosus.

Objectives:: SLE is an autoimmune disease characterised by aberrant lymphocyte activation and autoantibody production. This study provides an in-depth preclinical and clinical characterisation of the treatment effect of cenerimod, a sphingosine-1-phosphate receptor type 1 (S1P) modulator, in SLE.

Methods:: Cenerimod effect on lymphocyte numbers, organ pathology, inflammation, and survival was evaluated in the MRL/lpr lupus mouse model.

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1.

Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/TAZ. We were interested whether fibroblasts can be sensitized to TGFβ1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands.

The Antifibrotic Activity of Prostacyclin Receptor Agonism Is Mediated through Inhibition of YAP/TAZ.

Idiopathic pulmonary fibrosis is a life-threatening progressive disease characterized by loss of alveolar epithelial cells, inflammation, and aberrant fibroblast activation. The two currently approved therapies do not halt or reverse tissue remodeling, and therefore novel disease-modifying mechanisms are needed. Our results describe YAP/TAZ inhibition through prostacyclin (IP) receptor activation as a novel mechanism that suppresses profibrotic (myo)fibroblast activity.

Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.

Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling.

Methods And Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling.

A novel genomic signature with translational significance for human idiopathic pulmonary fibrosis.

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7.

Sphingosine 1-phosphate (S1P) receptor agonists mediate pro-fibrotic responses in normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent signaling.

Synthetic sphingosine 1-phosphate receptor 1 modulators constitute a new class of drugs for the treatment of autoimmune diseases. Sphingosine 1-phosphate (S1P) signaling, however, is also involved in the development of fibrosis. Using normal human lung fibroblasts, we investigated the induction of fibrotic responses by the S1P receptor (S1PR) agonists S1P, FTY720-P, ponesimod, and SEW2871 and compared them with the responses induced by the known fibrotic mediator TGF-β1.

Identification of cathepsin L as a potential sex-specific biomarker for renal damage.

The renin-angiotensin system is a well-known regulator of blood pressure and plays an important role in the pathogenesis of cardiovascular disease and renal damage. Genetic factors, including single nucleotide polymorphisms and sex, are increasingly recognized as potential risk factors for the development of cardiovascular disease. Double transgenic rats (dTGRs), harboring human renin and angiotensinogen genes, were used in this study to investigate potential sex differences influencing renal function and renal gene expression.

Shifting visual attention away from fixation is specifically associated with alpha band activity over ipsilateral parietal regions.

We studied brain activity during the displacement of attention in a modified visuo-spatial orienting paradigm. Using a behaviorally relevant no-shift condition as a control, we asked whether ipsi- or contralateral parietal alpha band activity is specifically related to covert shifts of attention. Cue-related event-related potentials revealed an attention directing anterior negativity (ADAN) contralateral to the shift of attention and P3 and contingent negative variation waveforms that were enhanced in both shift conditions as compared to the no-shift task.

Somatosensory cortical remodelling after rehabilitation and clinical benefit of in writer's cramp.

In order to explore the pathophysiological basis of a new rehabilitation therapy in writer's cramp (WC), healthy controls, untreated WC patients and WC patients who recovered a legible handwriting after rehabilitation were explored using magnetoencephalography, and the somatosensory evoked fields of fingers I, II, III and V in the sensory cortex were studied. In the cortex controlling the dystonic limb, the size of the hand representation in the trained patients was similar to that of healthy controls, and significantly different from that of untrained patients. Trained patients exhibited 'super-normal' reorganisation of the finger maps.

Enter feelings: somatosensory responses following early stages of visual induction of emotion.

In a MEG experiment, we imaged the early dynamics of the human cerebral cortex during the induction of emotion by visual stimuli. We tested the hypothesis that early cortical responses would correlate with the emotional competence of visual stimuli and subsequent subjective ratings of feeling in a set of specific target regions important for somatosensory, attentional, and motivational functions, just after initial visual and appraisal related cortical responses to picture presentation. Relative to the neutral condition, cortical responses, during the 350-500 ms phase of the MEG evoked response, were stronger for both pleasant and unpleasant stimuli in the orbitofrontal cortex, ventromedial prefrontal cortex, anterior cingulate and somatosensory cortices.

A combined spectroscopic and theoretical study of dibutyltin diacetate and dilaurate in supercritical CO2.

Two organotin catalysts, namely, dibutyltin dilaurate (DBTDL) and dibutyltin diacetate (DBTDA), commonly used in the synthesis of polyurethanes, have been investigated combining vibrational spectroscopic measurements with molecular modeling. The structure and vibrational spectra of the DBTDA molecule have been simulated using density functional theory. Thus, because of the Sn.

Cortical dynamics of anticipatory mechanisms in interception: a neuromagnetic study.

Humans demonstrate an amazing ability for intercepting and catching moving targets, most noticeably in fast-speed ball games. However, the few studies exploring the neural bases of interception in humans and the classical studies on visual motion processing and visuomotor interactions have reported rather long latencies of cortical activations that cannot explain the performances observed in most natural interceptive actions. The aim of our experiment was twofold: (1) describe the spatio-temporal unfolding of cortical activations involved in catching a moving target and (2) provide evidence that fast cortical responses can be elicited by a visuomotor task with high temporal constraints and decide if these responses are task or stimulus dependent.

Rapid interactions between the ventral visual stream and emotion-related structures rely on a two-pathway architecture.

Visual attention can be driven by the affective significance of visual stimuli before full-fledged processing of the stimuli. Two kinds of models have been proposed to explain this phenomenon: models involving sequential processing along the ventral visual stream, with secondary feedback from emotion-related structures ("two-stage models"); and models including additional short-cut pathways directly reaching the emotion-related structures ("two-pathway models"). We tested which type of model would best predict real magnetoencephalographic responses in subjects presented with arousing visual stimuli, using realistic models of large-scale cerebral architecture and neural biophysics.

A dynamic network involving M1-S1, SII-insular, medial insular, and cingulate cortices controls muscular activity during an isometric contraction reaction time task.

Magnetoencephalographic, electromyographic (EMG), work, and reaction time (RT) were recorded from nine subjects during visually triggered intermittent isometric contractions of the middle finger under two conditions: unloaded and loaded (30% of maximal voluntary contraction). The effect of muscle fatigue was studied over three consecutive periods under both conditions. In the loaded condition, the motor evoked field triggered by the EMG onset decreased with fatigue, whereas movement-evoked fields (MEFs) increased (P < 0.

On the perturbation of the intramolecular H-bond in diols by supercritical CO2: a theoretical and spectroscopic study.

The role played by supercritical carbon dioxide used as a dispersant medium in the synthesis of polyurethane particles has been investigated. High-temperature-high-pressure in situ infrared spectroscopic measurements combined with ab initio calculations were performed to investigate the hydroxyl stretching vibrations of ethylene glycol (EG) and 1,4-butanediol (BD), two monomers commonly used in the field of step growth polymerization. Specific interactions between the diols and CO2 have been put in evidence.

Frequency flows and the time-frequency dynamics of multivariate phase synchronization in brain signals.

The quantification of phase synchrony between brain signals is of crucial importance for the study of large-scale interactions in the brain. Current methods are based on the estimation of the stability of the phase difference between pairs of signals over a time window, within successive frequency bands. This paper introduces a new approach to study the dynamics of brain synchronies, Frequency Flows Analysis (FFA).

Electrophysiological correlates of facial decision: insights from upright and upside-down Mooney-face perception.

We investigated the ERP correlates of the subjective perception of upright and upside-down ambiguous pictures as faces using two-tone Mooney stimuli in an explicit facial decision task (deciding whether a face is perceived or not in the display). The difficulty in perceiving upside-down Mooneys as faces was reflected by both lower rates of "Face" responses and delayed "Face" reaction times for upside-down relative to upright stimuli. The N170 was larger for the stimuli reported as "faces".

Neural network involved in time perception: an fMRI study comparing long and short interval estimation.

In this study, long ( approximately 1,300 ms) and short duration ( approximately 450 ms) estimation trials in an event-related functional MRI (fMRI) study were contrasted in order to reveal the regions within a time estimation network yielding increased activation with the increase of the duration to be estimated. In accordance with numerous imaging studies, our results showed that the presupplementary motor area (preSMA), the anterior cingulate, the prefrontal and parietal cortices, and the basal ganglia were involved in the estimation trials whatever the duration to be estimated. Moreover, only a subset of the regions within this distributed cortical and subcortical network yielded increased activation with increasing time, namely, the preSMA, the anterior cingulate cortex, the right inferior frontal gyrus (homolog to Broca's area), the bilateral premotor cortex, and the right caudate nucleus.

The many faces of the gamma band response to complex visual stimuli.

While much is known about the functional architecture of the visual system, little is known about its large-scale dynamics during perception. This study describes this dynamics with a high spatial, temporal and spectral resolution. We recorded depth EEG of epileptic patients performing a face detection task and found that the stimuli induced strong modulations in the gamma band (40 Hz to 200 Hz) in selective occipital, parietal and temporal sites, in particular the fusiform gyrus, the lateral occipital gyrus and the intra-parietal sulcus.

Waves of consciousness: ongoing cortical patterns during binocular rivalry.

We present here ongoing patterns of distributed brain synchronous activity that correlate with the spontaneous flow of perceptual dominance during binocular rivalry. Specific modulation of the magnetoencephalographic (MEG) response evoked during conscious perception of a frequency-tagged stimulus was evidenced throughout rivalry. Estimation of the underlying cortical sources revealed, in addition to strong bilateral striate and extrastriate visual cortex activation, parietal, temporal pole and frontal contributions.

Age-related changes in brain responses to personally known faces: an event-related potential (ERP) study in humans.

Midlife period has not been investigated so far regarding associations between brain responses and spared abilities for face processing. This study examines the effects of midlife aging on behavioural performance and event-related potentials (ERPs) during the perception of personally known faces. Ten middle-aged adults (aged 45-60) and 12 young adults (aged 20-30) performed a visual discrimination task based on the detection of modified eye colours.

Face versus non-face object perception and the 'other-race' effect: a spatio-temporal event-related potential study.

Objective: To investigate a modulation of the N170 face-sensitive component related to the perception of other-race (OR) and same-race (SR) faces, as well as differences in face and non-face object processing, by combining different methods of event-related potential (ERP) signal analysis.

Methods: Sixty-two channel ERPs were recorded in 12 Caucasian subjects presented with Caucasian and Asian faces along with non-face objects. Surface data were submitted to classical waveforms and ERP map topography analysis.