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Detailed characterization of the spatially and temporally varying inherent optical properties (IOPs) of sea ice is necessary to better predict energy and mass balances, as well as ice-associated primary production. Here we present the development of an active optical probe to measure IOPs of a small volume of sea ice (dm3) in situ and non-destructively. The probe is derived from the diffuse reflectance method used to measure the IOPs of human tissues. The instrument emits light into the ice by the use of an optical fibre. Backscattered light is measured at multiple distances away from the source using several receiving fibres. Comparison to a Monte Carlo simulated lookup table allows, in theory, retrieval of the absorption coefficient, the reduced scattering coefficient and a phase function similarity parameter γ, introduced by Bevilacqua and Depeursinge (1999). γ depends on the two first moments of the Legendre polynomials, allowing the analysis of the backscattered light not satisfying the diffusion regime. The depth reached into the medium by detected photons was estimated using Monte Carlo simulations: the maximum depth reached by 95 % of the detected photons was between 40±2 and 270±20 mm depending on the source–detector distance and on the ice scattering properties. The magnitude of the instrument validation error on the reduced scattering coefficient ranged from 0.07 % for the most scattering medium to 35 % for the less scattering medium over the 2 orders of magnitude we validated. Fixing the absorption coefficient and γ, which proved difficult to measure, vertical profiles of the reduced scattering coefficient were obtained with decimetre resolution on first-year Arctic interior sea ice on Baffin Island in early spring 2019. We measured values of up to 7.1 m−1 for the uppermost layer of interior ice and down to 0.15±0.05 m−1 for the bottommost layer. These values are in the range of polar interior sea ice measurements published by other authors. The inversion of the reduced scattering coefficient at this scale was strongly dependent on the value of γ, highlighting the need to define the higher moments of the phase function. This newly developed probe provides a fast and reliable means for measurement of scattering in sea ice.

Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300

Virtual reality platforms producing interactive and highly realistic characters are being used more and more as a research tool in social and affective neuroscience to better capture both the dynamics of emotion communication and the unintentional and automatic nature of emotional processes. While idle motion (i.e., non-communicative movements) is commonly used to create behavioural realism, its use to enhance the perception of emotion expressed by a virtual character is critically lacking. This study examined the influence of naturalistic (i.e., based on human motion capture) idle motion on two aspects (the perception of other’s pain and affective reaction) of an empathic response towards pain expressed by a virtual character. In two experiments, 32 and 34 healthy young adults were presented video clips of a virtual character displaying a facial expression of pain while its body was either static (still condition) or animated with natural postural oscillations (idle condition). The participants in Experiment 1 rated the facial pain expression of the virtual human as more intense, and those in Experiment 2 reported being more touched by its pain expression in the idle condition compared to the still condition, indicating a greater empathic response towards the virtual human’s pain in the presence of natural postural oscillations. These findings are discussed in relation to the models of empathy and biological motion processing. Future investigations will help determine to what extent such naturalistic idle motion could be a key ingredient in enhancing the anthropomorphism of a virtual human and making its emotion appear more genuine.

International audience; Congenital amusia is a neurodevelopmental disorder of music processing, which includes impaired pitch memory, associated to abnormalities in the right fronto-temporal network. Previous research has shown that tonal structures (as defined by the Western musical system) improve short-term memory performance for short tone sequences (in comparison to atonal versions) in non-musician listeners, but the tonal structures only benefited response times in amusic individuals. We here tested the potential benefit of tonal structures for short-term memory with more complex musical material. Congenital amusics and their matched nonmusician controls were required to indicate whether two excerpts were the same or different. Results confirmed impaired performance of amusic individuals in this short-term memory task. However, most importantly, both groups of participants showed better memory performance for tonal material than for atonal material. These results revealed that even amusics' impaired short-term memory for pitch shows classical characteristics of short-term memory, that is the mnemonic benefit of structure in the to-be-memorized material. The findings show that amusic individuals have acquired some implicit knowledge of regularities of their culture, allowing for implicit processing of tonal structures, which benefits to memory even for complex material.

Background Since the beginning of the COVID-19 pandemic, many countries, including Canada, have adopted unprecedented physical distancing measures such as closure of schools and non-essential businesses, and restrictions on gatherings and household visits. We described time trends in social contacts for the pre-pandemic and pandemic periods in Quebec, Canada. Methods CONNECT is a population-based study of social contacts conducted shortly before (2018/2019) and during the COVID-19 pandemic (April 2020 - February 2021), using the same methodology for both periods. We recruited participants by random digit dialing and collected data by self-administered web-based questionnaires. Questionnaires documented socio-demographic characteristics and social contacts for two assigned days. A contact was defined as a two-way conversation at a distance

Background and Purpose Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. Experimental Approach Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. Key results In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal. Conclusion and Implications Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects., This work was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (SAF2017-87349-R, SAF2017-87199-R and CTQ2017-89222-R), ISCIII (PIE14/00034), and the Catalan government (2017 SGR 1604 and 2017 SGR 465). We thank Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya for IDIBELL institutional support. We thank Esther Castaño and Benjamín Torrejón from the Scientific and Technical Services (SCT) group at the Bellvitge Campus of the University of Barcelona for their technical assistance. We thank Lourdes Muñoz, Carme Serra and Juanlo Catena (SimChem, IQAC-CSIC, Barcelona) for support in the synthesis of compounds. Xavier Gasull and Aida Castellanos (Facultat de Medicina, Universitat de Barcelona) are acknowledged by their help with the obtention of DRG neurons from mouse. Also, we thank María Pilar Pérez Villamor (Laboratorios Dr. Esteve, Barcelona) for the kind gift of the HEK293 cell line permanently expressing μ receptors.

International audience; Real-time monitoring of the spinal cord was achieved on pig model with custom devices operating in both reflection and transmission modes. Although the reflective system was generally preferred, the obtained data wasn’t as rich as in transmission and could conduct to erroneous conclusions.

ObjectivesSleep is important for human health and well-being. No previous study has assessed whether the COVID-19 pandemic impacts sleep and daytime function across the globe.MethodsThis large-scale international survey used a harmonised questionnaire. Fourteen countries participated during the period of May–August 2020. Sleep and daytime problems (poor sleep quality, sleep onset and maintenance problems, nightmares, hypnotic use, fatigue and excessive sleepiness) occurring ‘before’ and ‘during’ the pandemic were investigated. In total, 25 484 people participated and 22 151 (86.9%) responded to the key parameters and were included. Effects of COVID-19, confinement and financial suffering were considered. In the fully adjusted logistic regression models, results (weighted and stratified by country) were adjusted for gender, age, marital status, educational level, ethnicity, presence of sleep problems before COVID-19 and severity of the COVID-19 pandemic in each country at the time of the survey.ResultsThe responders were mostly women (64%) with a mean age 41.8 (SD 15.9) years (median 39, range 18–95). Altogether, 3.0% reported having had COVID-19; 42.2% reported having been in confinement; and 55.9% had suffered financially. All sleep and daytime problems worsened during the pandemic by about 10% or more. Also, some participants reported improvements in sleep and daytime function. For example, sleep quality worsened in about 20% of subjects and improved in about 5%. COVID-19 was particularly associated with poor sleep quality, early morning awakening and daytime sleepiness. Confinement was associated with poor sleep quality, problems falling asleep and decreased use of hypnotics. Financial suffering was associated with all sleep and daytime problems, including nightmares and fatigue, even in the fully adjusted logistic regression models.ConclusionsSleep problems, fatigue and excessive sleepiness increased significantly worldwide during the first phase of the COVID-19 pandemic. Problems were associated with confinement and especially with financial suffering.

Objective Many have reported odd dreams during the pandemic. Given that dreams are associated with mental health, understanding these changes could provide crucial information about wellbeing during the pandemic. This study explored associations between COVID-19 and dream recall frequency (DRF), and related social, health, and mental health factors. Methods We conducted a cross-sectional web survey of 19,355 individuals in 14 countries from May to July 2020. We collected data on COVID-19, mental health, sleep and DRF during the pandemic. We performed McNemar Tests to compare low (, Video abstract Point your SmartPhone at the code above. If you have a QR code reader, the video abstract will appear. Or use: https://youtu.be/Qerns3HLO7o

Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) – ie, the difference between sleep timing on working vs free days – and 2) symptoms of insomnia. Patients and Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example. Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23– 54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL. Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms – even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity. publishedVersion

International audience; Oxygen concentration quantification in the blood (SpO 2) has been used as a mean to diagnose and prevent critical medical conditions thanks to pulse oximetry. In spite of its theoretical precision, this method suffers from intrinsic deviations from the components used in such monitoring devices (PVT) that can lead to SpO 2 measurement errors. In this paper, we propose a multi-domain modeling of a NIRS-based blood oxygen saturation monitoring system and its biological environment using SystemC(-AMS) for virtual prototyping, to analyze the impact of PVT variations of opto-electrical components, thanks to Monte-Carlo simulation correlated with transient analysis. We simulated the blood flow of the finger tissue and the dynamic attenuation of the red and infrared light passing through the tissue. The Monte-Carlo simulation method was used to analyze different PVT parameters that may cause measurement deviations separately. Finally, we found that the red/IR LED peak wavelength deviation and the temperature of the system have an important impact on the SpO 2 quantification, especially red LED peak wavelength deviation. This result shows that the choice of the red light source is of prime importance for accurate SpO 2 quantification. a

International audience; In immersive and interactive audio-visual content, there is very significant scope for spatial misalignment between the two main modalities. So, in productions that have both 3D video and spatial audio, the positioning of sound sources relative to the visual display requires careful attention. This may be achieved in the form of object-based audio, moreover allowing the producer to maintain control over individual elements within the mix. Yet each object?s metadata is needed to define its position over time. In the present study, audio-visual studio recordings were made of short scenes representing three genres: drama, sport and music. Foreground video was captured by a light-field camera array, which incorporated a microphone array, alongside more conventional sound recording by spot microphones and a first-order ambisonic room microphone. In the music scenes, a direct feed from the guitar pickup was also recorded. Video data was analysed to form a 3D reconstruction of the scenes, and human figure detection was applied to the 2D frames of the central camera. Visual estimates of the sound source positions were used to provide ground truth. Position metadata were encoded within audio definition model (ADM) format audio files, suitable for standard object-based rendering. The steered response power of the acoustical signals at the microphone array were used, with the phase transform (SRP-PHAT), to determine the dominant source position(s) at any time, and given as input to a Sequential Monte Carlo Probability Hypothesis Density (SMC-PHD) tracker. The output of this was evaluated in relation to the ground truth. Results indicate a hierarchy of accuracy in azimuth, elevation and range, in accordance with human spatial auditory perception. Azimuth errors were within the tolerance bounds reported by studies of the Ventriloquism Effect, giving an initial promising indication that such an approach may open the door to object-based production for live events.

The use of computer-generated characters (avatars) is increasingly being used to study emotion and social cognition in humans, as it offers a highly controllable, yet potentially interactive experimental set-up. However, avatars often fall short at conveying credible emotions. This study explored the interaction between body motion and facial expression on the perceived intensity and believability of an avatar's pain expression. Adults were shown videos of an agematched avatar displaying facial expressions of pain while the body was static or while the trunk was oscillating at varied amplitudes, which represented human dynamic equilibrium (idle motion) or trunk rocking expressing a sustained pain (pain behavior). Pupil size was recorded during the task as an objective marker of emotional reaction. Results showed that the avatar's pain was perceived to be more intense and more believable in the presence of both idle motion and trunk rocking than in the static condition. Pupil dilated more when facial pain expression was combined with trunk rocking than in the static and idle conditions. This work demonstrated the critical role of idle motion when creating dynamical pain-expressing avatars, as well as the potentiating effect of body motion when combined with facial expression on the perception of avatar's pain.

Background Experts in the field of medical education emphasized the need for curricula that improve students’ attitudes toward the underserved. However, some studies have shown that medical education tends to worsen these attitudes in students. We aimed at systematically reviewing the literature assessing the change in medical students’ attitudes toward the underserved and intention to work with the underserved throughout medical education, the sociodemographic and educational factors associated with favorable medical student attitudes toward and/or intention to work with the underserved and the effectiveness of educational interventions to improve medical student attitudes toward and/or intention to work with the underserved. Method We conducted a systematic review on MEDLINE, Scopus, and Web of Science databases. Three investigators independently conducted the electronic search. We assessed the change in medical students attitudes toward the underserved by computing a weighted mean effect size of studies reporting scores from validated scales. The research team performed a meta-analysis for the sociodemographic and educational factors associated with medical students attitudes toward and/or intention to work with the underserved. Results Fifty-five articles met the inclusion criteria, including a total of 109,647 medical students. The average response rate was 73.2%. Most of the studies were performed in the USA (n = 45). We observed a significant decline of medical students attitudes toward the underserved throughout medical education, in both US and non-US studies. A moderate effect size was observed between the first and fourth years (d = 0.51). Higher favorable medical students attitudes toward or intention to work with the underserved were significantly associated with female gender, being from an underserved community or ethnic minority, exposure to the underserved during medical education and intent to practice in primary care. Regarding educational interventions, the effectiveness of experiential community-based learning and curricula dedicated to social accountability showed the most positive outcome. Conclusions Medical students attitudes toward the underserved decline throughout medical education. Educational interventions dedicated to improving the attitudes or intentions of medical students show encouraging but mixed results. The generalizability of our results is impeded by the high number of studies from the global-North included in the review. Supplementary Information The online version contains supplementary material available at 10.1186/s12909-021-02517-x.

Background Targeted radionuclide therapy (TRT) is gaining importance. For TRT to be also used as adjuvant therapy or for treating minimal residual disease, there is a need to increase the radiation dose to small tumours. The aim of this in silico study was to compare the performances of 161Tb (a medium-energy β− emitter with additional Auger and conversion electron emissions) and 177Lu for irradiating single tumour cells and micrometastases, with various distributions of the radionuclide. Methods We used the Monte Carlo track-structure (MCTS) code CELLDOSE to compute the radiation doses delivered by 161Tb and 177Lu to single cells (14 μm cell diameter with 10 μm nucleus diameter) and to a tumour cluster consisting of a central cell surrounded by two layers of cells (18 neighbours). We focused the analysis on the absorbed dose to the nucleus of the single tumoral cell and to the nuclei of the cells in the cluster. For both radionuclides, the simulations were run assuming that 1 MeV was released per μm3 (1436 MeV/cell). We considered various distributions of the radionuclides: either at the cell surface, intracytoplasmic or intranuclear. Results For the single cell, the dose to the nucleus was substantially higher with 161Tb compared to 177Lu, regardless of the radionuclide distribution: 5.0 Gy vs. 1.9 Gy in the case of cell surface distribution; 8.3 Gy vs. 3.0 Gy for intracytoplasmic distribution; and 38.6 Gy vs. 10.7 Gy for intranuclear location. With the addition of the neighbouring cells, the radiation doses increased, but remained consistently higher for 161Tb compared to 177Lu. For example, the dose to the nucleus of the central cell of the cluster was 15.1 Gy for 161Tb and 7.2 Gy for 177Lu in the case of cell surface distribution of the radionuclide, 17.9 Gy for 161Tb and 8.3 Gy for 177Lu for intracytoplasmic distribution and 47.8 Gy for 161Tb and 15.7 Gy for 177Lu in the case of intranuclear location. Conclusion 161Tb should be a better candidate than 177Lu for irradiating single tumour cells and micrometastases, regardless of the radionuclide distribution.

This study investigated the impact of repeated-sprint (RS) training with voluntary hypoventilation at low lung volume (VHL) on RS ability (RSA) and on performance in a 30-15 intermittent fitness test (30-15IFT). Over 4 weeks, 17 basketball players included eight sessions of straight-line running RS and RS with changes of direction into their usual training, performed either with normal breathing (CTL, n = 8) or with VHL (n = 9). Before and after the training, athletes completed a RSA test (12 × 30-m, 25-s rest) and a 30-15IFT. During the RSA test, the fastest sprint (RSAbest), time-based percentage decrement score (RSASdec), total electromyographic intensity (RMS), and spectrum frequency (MPF) of the biceps femoris and gastrocnemius muscles, and biceps femoris NIRS-derived oxygenation were assessed for every sprint. A capillary blood sample was also taken after the last sprint to analyse metabolic and ionic markers. Cohen's effect sizes (ES) were used to compare group differences. Compared with CTL, VHL did not clearly modify RSAbest, but likely lowered RSASdec (VHL: −24.5% vs. CTL: −5.9%, group difference: −19.8%, ES −0.44). VHL also lowered the maximal deoxygenation induced by sprints ([HHb]max; group difference: −2.9%, ES −0.72) and enhanced the reoxygenation during recovery periods ([HHb]min; group difference: −3.6%, ES −1.00). VHL increased RMS (group difference: 18.2%, ES 1.28) and maintained MPF toward higher frequencies (group difference: 9.8 ± 5.0%, ES 1.40). These changes were concomitant with a lower potassium (K+) concentration (group difference: −17.5%, ES −0.67), and the lowering in [K+] was largely correlated with RSASdec post-training in VHL only (r = 0.66, p < 0.05). However, VHL did not clearly alter PO2, hemoglobin, lactate and bicarbonate concentration and base excess. There was no difference between group velocity gains for the 30-15IFT (CTL: 6.9% vs. VHL: 7.5%, ES 0.07). These results indicate that RS training combined with VHL may improve RSA, which could be relevant to basketball player success. This gain may be attributed to greater muscle reoxygenation, enhanced muscle recruitment strategies, and improved K+ regulation to attenuate the development of muscle fatigue, especially in type-II muscle fibers.

International audience; A sound source?s apparent distance provides information about spatial relations that can have primary salience relative to other dimensions, including azimuth and elevation in the scene of a story told in 3D. Having methods to create a sense of presence and to control this attribute in immersive content are therefore valuable capabilities in sound design, particularly in object-based audio. This paper examines the ability of the reverberant spatial audio object (RSAO) to cue apparent source distance, using acoustic parameters extracted from publicly-available spatial room impulse responses (RIRs) of real environments measured at a range of source-receiver distances. The RSAO?s spatio-temporal reverb representation derived from the directional B-format RIRs encoded the timing, direction and timbre of early reflections, as well as the onset, colouration and decay times of the late reverberation, which were rendered over a 42.1 setup in an acoustically- treated listening room to provide a quasi-transparent pipeline for the reproduced room impression, from recording to listening. An objective analysis of re-synthesised RIRs and re-estimated parameters demonstrated the pipeline?s transparency for most parameters. However spectral leakage of bandpass filters in the late tail encouraged reverb time convergence across bands. Formal listening tests evaluated the apparent source distance that participants perceived via a multi-stimulus rating method. Statistical analysis indicates participants perceived reproduced distance changes, with logarithmic distance resolution inside the rooms? critical distance. Beyond this, ratings tended to saturate. These effects were clearer in the large hall than in the classroom, and for the voice source than the percussion. The results suggest that the RSAO can provide appropriate cues for source distance perception with resolution comparable to natural sound fields. Further work will investigate how distance perception performs across reproduction setups and develop methods to extrapolate source distance by adapting the RSAO parameters.

International audience; Periodic paralyses (PP) are characterized by episodic muscle weakness and are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Nav1.4 — the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4 or Cav1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysis who was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Nav1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4 activation was strengthened in low concentration of extracellular K+. Our data prove the existence of a phenotype combining signs of hyperPP and hypoPP due to dominant Nav1.4 mutations. The hyperPP component would result from gain-of-function effects on Nav1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non-negligible role of Nav1.4 loss-of-function in familial hypoPP.

Mutations in NaV1.4, the skeletal muscle voltage-gated Na+ channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L.

Simultaneous profiling of biospecimens using different technological platforms enables the study of many data types, encompassing microbial communities, omics and meta-omics as well as clinical or chemistry variables. Reduction in costs now enables longitudinal or time course studies on the same biological material or system. The overall aim of such studies is to investigate relationships between these longitudinal measures in a holistic manner to further decipher the link between molecular mechanisms and microbial community structures, or host-microbiota interactions. However, analytical frameworks enabling an integrated analysis between microbial communities and other types of biological, clinical or phenotypic data are still in their infancy. The challenges include few time points that may be unevenly spaced and unmatched between different data types, a small number of unique individual biospecimens and high individual variability. Those challenges are further exacerbated by the inherent characteristics of microbial communities-derived data (e.g. sparsity, compositional).We propose a generic data-driven framework to integrate different types of longitudinal data measured on the same biological specimens with microbial communities data, and select key temporal features with strong associations within the same sample group. The framework ranges from filtering and modelling, to integration using smoothing splines and multivariate dimension reduction methods to address some of the analytical challenges of microbiome-derived data. We illustrate our framework on different types of multi-omics case studies in bioreactor experiments as well as human studies.

In the last decade, research has shown that word processing is influenced by the lexical and semantic features of words. However, norms for a crucial semantic variable—that is, conceptual familiarity—have not been available for a sizeable French database. We thus developed French Canadian conceptual familiarity norms for 3,596 nouns. This enriches Desrochers and Thompson’s (2009) database, in which subjective frequency and imageability values are already available for the same words. We collected online data from 313 Canadian French speakers. The full database of conceptual familiarity ratings is freely available at http://lingualab.ca/fr/projets/normes-de-familiarite-conceptuelle . We then demonstrated the utility of these new conceptual familiarity norms by assessing their contribution to lexical decision times. We conducted a stepwise regression model with conceptual familiarity in the last step. This allowed us to assess the independent contribution of conceptual familiarity beyond the contributions of other well-known psycholinguistic variables, such as frequency, imageability, and age of acquisition. The results showed that conceptual familiarity facilitated lexical decision latencies. In sum, these ratings will help researchers select French stimuli for experiments in which conceptual familiarity must be taken into account.

Single-molecule photoswitchable emitters are demonstrated in the near-infrared based on single-wall carbon nanotube hybrids., The design of single-molecule photoswitchable emitters was the first milestone toward the advent of single-molecule localization microscopy, setting a new paradigm in the field of optical imaging. Several photoswitchable emitters have been developed, but they all fluoresce in the visible or far-red ranges, missing the desirable near-infrared window where biological tissues are most transparent. Moreover, photocontrol of individual emitters in the near-infrared would be highly desirable for elementary optical molecular switches or information storage elements since most communication data transfer protocols are established in this spectral range. Here, we introduce a type of hybrid nanomaterials consisting of single-wall carbon nanotubes covalently functionalized with photoswitching molecules that are used to control the intrinsic luminescence of the single nanotubes in the near-infrared (beyond 1 μm). Through the control of photoswitching, we demonstrate super-localization imaging of nanotubes unresolved by diffraction-limited microscopy.

Objectives The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Methods Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Results Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids. Conclusions Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism., Graphical abstract Image 1, Highlights • Loss of the translational regulator FMRP impacts glucose and lipid homeostasis in mouse and human. • FMR1-deficiency modifies blood metabolic markers. • Loss of FMRP enhances the insulin response and lipolysis. • Loss of FMRP exaggerates hepatic protein synthesis. • FMRP controls the translation of key hepatic proteins involved in lipid metabolism.

International audience; Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

International audience; Bilaterian voltage-gated Na(+) channels (NaV) evolved from voltage-gated Ca(2+) channels (CaV). The Drosophila melanogaster Na(+) channel 1 (DSC1), which features a D-E-E-A selectivity filter sequence that is intermediate between CaV and NaV channels, is evidence of this evolution. Phylogenetic analysis has classified DSC1 as a Ca(2+)-permeable Na(+) channel belonging to the NaV2 family because of its sequence similarity with NaV channels. This is despite insect NaV2 channels (DSC1 and its orthologue in Blatella germanica, BSC1) being more permeable to Ca(2+) than Na(+) In this study, we report the cloning and molecular characterization of the honeybee (Apis mellifera) DSC1 orthologue. We reveal several sequence variations caused by alternative splicing, RNA editing, and genomic variations. Using the Xenopus oocyte heterologous expression system and the two-microelectrode voltage-clamp technique, we find that the channel exhibits slow activation and inactivation kinetics, insensitivity to tetrodotoxin, and block by Cd(2+) and Zn(2+) These characteristics are reminiscent of CaV channels. We also show a strong selectivity for Ca(2+) and Ba(2+) ions, marginal permeability to Li(+), and impermeability to Mg(2+) and Na(+) ions. Based on current ion channel nomenclature, the D-E-E-A selectivity filter, and the properties we have uncovered, we propose that DSC1 homologues should be classified as CaV4 rather than NaV2. Indeed, channels that contain the D-E-E-A selectivity sequence are likely to feature the same properties as the honeybee's channel, namely slow activation and inactivation kinetics and strong selectivity for Ca(2+) ions.

Empathy refers to our capacity to share and understand the emotional states of others. It relies on two main processes according to existing models: an effortless affective sharing process based on neural resonance and a more effortful cognitive perspective-taking process enabling the ability to imagine and understand how others feel in specific situations. Until now, studies have focused on factors influencing the affective sharing process but little is known about those influencing the cognitive perspective-taking process and the related brain activations during vicarious pain. In the present fMRI study, we used the well-known physical pain observation task to examine whether the visual perspective can influence, in a bottom-up way, the brain regions involved in taking others' cognitive perspective to attribute their level of pain. We used a pseudo-dynamic version of this classic task which features hands in painful or neutral daily life situations while orthogonally manipulating: (1) the visual perspective with which hands were presented (first-person versus third-person conditions) and (2) the explicit instructions to imagine oneself or an unknown person in those situations (Self versus Other conditions). The cognitive perspective-taking process was investigated by comparing Other and Self conditions. When examined across both visual perspectives, this comparison showed no supra-threshold activation. Instead, the Other versus Self comparison led to a specific recruitment of the bilateral temporo-parietal junction when hands were presented according to a first-person (but not third-person) visual perspective. The present findings identify the visual perspective as a factor that modulates the neural activations related to cognitive perspective-taking during vicarious pain and show that this complex cognitive process can be influenced by perceptual stages of information processing.

Background The “Age of Blood in Children in Pediatric Intensive Care Unit” (ABC PICU) study is a randomized controlled trial (RCT) that aims to determine if red blood cell (RBC) unit storage age affects outcomes in critically ill children. While RBCs can be stored for up to 42 days in additive solutions, their efficacy and safety after long-term storage have been challenged. Preclinical and clinical observational evidence suggests loss of efficacy and lack of safety of older RBC units, especially in more vulnerable populations such as critically ill children. Because there is a belief that shorter storage will improve outcomes, some physicians and institutions systematically transfuse fresh RBCs to children. Conversely, the standard practice of blood banks is to deliver the oldest available RBC unit (first-in, first-out policy) in order to decrease wastage. Methods/design The ABC PICU study, is a double-blind superiority trial comparing the development of “New or Progressive Multiple Organ Dysfunction Syndrome” (NPMODS) in 1538 critically ill children randomized to either transfusion with RBCs stored for ≤ 7 days or to standard-issue RBCs (oldest in inventory). Patients are being recruited from 52 centers in the US, Canada, France, Italy, and Israel. Discussion The ABC PICU study should have significant implications for blood procurement services. A relative risk reduction of 33% is postulated in the short-storage arm. If a difference is found, this will indicate that fresher RBCs do improve outcomes in the pediatric intensive care unit population and would justify that use in critically ill children. If no difference is found, this will reassure clinicians and transfusion medicine specialists regarding the safety of the current system of allocating the oldest RBC unit in inventory and will discourage clinicians from preferentially requesting fresher blood for critically ill children. Trial registration ClinicalTrials.gov, ID: NCT01977547. Registered on 6 November 2013. Electronic supplementary material The online version of this article (10.1186/s13063-018-2809-y) contains supplementary material, which is available to authorized users.

International audience; In this paper, the luminescence properties of self-trapped excitons (STEs) of undoped and Eu2+-doped perovskite-type materials CsMgX3 (X=Cl, Br, I) are presented. The three compounds crystallize isostructurally in a hexagonal crystal system that exhibits an intrinsic pseudo-one-dimensionality. This feature has a highly stabilizing effect on the localization of excitons. The similarities to the properties of STEs in alkali halides are drawn that are justified by the band-structure and density-of-states calculations. The luminescence spectra of all three halides are characterized and interpreted despite their high complexity with many emissive transitions. It is illustrated that both STEs and impurity-localized self-trapped excitons (IL STEs) are responsible for the features in the spectra. The impurity localization of the STEs is proven by doping the hosts with Sr2+ ions instead of Eu2+ ions. The decay times in the microsecond range indicate that emission predominantly occurs from a triplet state of the STEs with a prominent afterglow component for the IL STEs that ideally suits a trapping model along the one-dimensional chains of the halides. Moreover, by thermal activation, the excitons tend to annihilate at the Eu2+ traps, thereby inducing an energy transfer to the Eu2+ ions. Because of this action, an extreme increase of the intensity of the Eu2+-based 4f65d−4f7 emission at room temperature is observed, which might be a general explanation for unusual temperature-dependent emission intensities of Eu2+ ions. In general, an understanding of the basic optical properties of the STEs may give some insights into the mechanism of currently used x-ray storage phosphors as well as scintillators.

International audience; Genome-wide studies have associated several genetic variants upstream of PITX2 on chromosome 4q25 with atrial fibrillation (AF), suggesting a potential role of PITX2 in AF. Our study aimed at identifying rare coding variants in PITX2 predisposing to AF. The Polymerase chain reaction sequencing of PITX2c was performed in 60 unrelated patients with idiopathic AF. The p.Met207Val variant was identified in 1 of 60 French patients with early onset AF and in none of 389 French referents. This variant, located in the inhibitory domain 1 distal to the homeodomain, was evaluated by the software MutationTaster as a disease-causing mutation with a probability of 0.999. Reporter gene assays demonstrated that p.Met207Val caused a 3.1-fold increase in transactivation activity of PITX2c in HeLa cells in comparison with its wild-type counterpart. When the variant was coexpressed with wild-type PITX2c in the HL-1 immortalized mouse atrial cell line, this gain-of-function caused an increase in the mRNA level of KCNH2 (2.6-fold), SCN1B (1.9-fold), GJA5 (3.1-fold), GJA1 (2.1-fold), and KCNQ1 in the homozygous form (1.8-fold). These genes encode for the IKr channel α subunit, the β-1 Na+ channel subunit, connexin 40, connexin 43 and the IKs channel α subunit, respectively. These conditions may contribute to the propensity to AF found in patients carrying the p.Met207Val variant. In conclusion, the present report is the first to associate a gain-of-function mutation of PITX2c with increased vulnerability to AF, therefore, restoration of normal PITX2c function may be a potential therapeutic target in AF patients.

Musculoskeletal simulations are useful in biomechanics to investigate the causes of movement disorder, to estimate non-measurable physiological quantities or to study the optimality of human movement. We introduce Bioptim, an easy-to-use Python framework for biomechanical optimal control, handling musculoskeletal models. Relying on algorithmic differentiation and the multiple shooting formulation, Bioptim interfaces nonlinear solvers to quickly provide dynamically consistent optimal solutions. The software is both computationally efficient (C++ core) and easily customizable, thanks to its Python interface. It allows to quickly define a variety of biomechanical problems such as motion tracking/prediction, muscle-driven simulations, parameters optimization, multiphase problems, etc. It is also intended for real-time applications such as moving horizon estimation and model predictive control. Six contrasting examples are presented, comprising various models, dynamics, objective functions and constraints. They include data-driven simulations (i.e., a multiphase muscle driven gait cycle and an upper-limb real-time moving horizon estimation of muscle forces) and predictive simulations (i.e., a muscle-driven pointing task, a twisting somersault with a quaternion-based model, a position controller using external forces, and a multiphase torque-driven maximum-height jump motion).

OBJECTIVE: Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse. METHOD: Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type-specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy. RESULTS: A history of child abuse was associated with cell type-specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse. CONCLUSIONS: The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

International audience; Background: Schizophrenia is associated with important disturbances in empathy that are related to everyday functioning. Empathy isclassically defined as including affective (sharing others’ emotions) and cognitive (taking others’ cognitive perspectives) processes. Inhealthy individuals, studies on empathy for pain revealed specific brain systems associated with these sets of processes, notably the anteriormiddle cingulate (aMCC) and anterior insula (AI) for affective sharing and the bilateral temporoparietal junction (TPJ) for the cognitiveprocesses, but the integrity of these systems in patients with schizophrenia remains uncertain. Methods: Patients with schizophreniaand healthy controls performed a pain empathy task while undergoing fMRI scanning. Participants observed pictures of hands ineither painful or nonpainful situations and rated the level of pain while imagining either themselves (self) or an unknown person (other) inthese situations. Results: We included 27 patients with schizophrenia and 21 healthy controls in our analyses. For the pain versus nopain contrast, patients showed overall typical activation patterns in the aMCC and AI, with only a small part of the aMCC showing reducedactivation compared with controls. For the other versus self contrast, patients showed an abnormal modulation of activation in theTPJ bilaterally (extending to the posterior superior temporal sulcus, referred to as the TPJ/pSTS). Limitations: The design included anunnecessary manipulation of the visual perspective that reduced the number of trials for analysis. The sample size may not account forthe heterogeneity of schizophrenia. Conclusion: People with schizophrenia showed relatively intact brain activation when observingothers’pain, but showed abnormalities when asked to take the cognitive perspectives of others.

International audience; OBJECTIVE: To evaluate the association between maternal physical activity and infant's birth weight or risk of inappropriate weight for gestational age (GA), and whether this association differs by infant's sex, maternal body mass index (BMI) or pregnancy complications in a prospective cohort study.METHODS: 1913 pregnant women from the 3D Birth Cohort (Québec, Canada) completed the Pregnancy Physical Activity Questionnaire at each trimester. Energy expenditure (metabolic equivalent of task (MET)*hours/week) for total activity, sports and exercise and vigorous intensity activities was calculated. The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling. Interactions were tested with infant's sex, maternal prepregnancy BMI, gestational diabetes, hypertensive disorders and prematurity.RESULTS: Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant's birth weight (95% CI -4.8 to -0.3) but was not associated with the risk of small weight for GA. In contrast, although not significant, a 17% reduction in the risk of large weight for GA was observed with increasing sports and exercise. Furthermore, in women with subsequent pre-eclampsia (but not normotensive or hypertensive women), each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant's birth weight by 19.8 g (95% CI -35.2 to -4.3).CONCLUSIONS: Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight. The risk of reducing infant's birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation.

Metaflumizone is the latest addition to the armamentarium of the Na+ channel inhibitor insecticide family. We used the Xenopus oocyte expression system and a Markovian model to assess the effect of metaflumizone on Apis mellifera Na+ channels (AmNaV 1). Our results reveal that metaflumizone inhibits AmNaV 1 channels by targeting the kinetics of recovery from slow inactivation. Multistate modeling of fast and slow inactivation of the AmNaV 1 channel made it possible to study the effects of metaflumizone on a set of rate constants underlying the transition between the open and inactivated conformations and provided insights into their specificity. We conclude that the methods we used could be extended to assessing the toxicity of other Na+ channel inhibitor insecticides.

Voltage-gated Ca(2+) channels are key transducers of cellular excitability and participate in several crucial physiological responses. In vertebrates, 10 Ca(2+) channel genes, grouped in 3 families (CaV1, CaV2 and CaV3), have been described and characterized. Insects possess only one member of each family. These genes have been isolated in a limited number of species and very few have been characterized although, in addition to their crucial role, they may represent a collateral target for neurotoxic insecticides. We have isolated the 3 genes coding for the 3 Ca(2+) channels expressed in Apis mellifera. This work provides the first detailed characterization of the honeybee T-type CaV3 Ca(2+) channel and demonstrates the low toxicity of inhibiting this channel. Comparing Ca(2+) currents recorded in bee neurons and myocytes with Ca(2+) currents recorded in Xenopus oocytes expressing the honeybee CaV3 gene suggests native expression in bee muscle cells only. High-voltage activated Ca(2+) channels could be recorded in the somata of different cultured bee neurons. These functional data were confirmed by in situ hybridization, immunolocalization and in vivo analysis of the effects of a CaV3 inhibitor. The biophysical and pharmacological characterization and the tissue distribution of CaV3 suggest a role in honeybee muscle function.

Granule cells (GCs) in the olfactory bulb (OB) play an important role in odor information processing. Although they have been classified into various neurochemical subtypes, the functional roles of these subtypes remain unknown. We used in vivo two-photon Ca2+ imaging combined with cell-type-specific identification of GCs in the mouse OB to examine whether functionally distinct GC subtypes exist in the bulbar network. We showed that half of GCs express Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα+) and that these neurons are preferentially activated by olfactory stimulation. The higher activity of CaMKIIα+ neurons is due to the weaker inhibitory input that they receive compared to their CaMKIIα-immunonegative (CaMKIIα-) counterparts. In line with these functional data, immunohistochemical analyses showed that 75%-90% of GCs expressing the immediate early gene cFos are CaMKIIα+ in naive animals and in mice that have been exposed to a novel odor and go/no-go operant conditioning, or that have been subjected to long-term associative memory and spontaneous habituation/dishabituation odor discrimination tasks. On the other hand, a perceptual learning task resulted in increased activation of CaMKIIα- cells. Pharmacogenetic inhibition of CaMKIIα+ GCs revealed that this subtype is involved in habituation/dishabituation and go/no-go odor discrimination, but not in perceptual learning. In contrast, pharmacogenetic inhibition of GCs in a subtype-independent manner affected perceptual learning. Our results indicate that functionally distinct populations of GCs exist in the OB and that they play distinct roles during different odor tasks.

Maternal stress is associated with an altered mother-infant relationship that endangers offspring development, leading to emotional/behavioral problems. However, little research has investigated the stress-induced alterations of the maternal brain that could underlie such a disruption of mother-infant bonding. Olfactory cues play an extensive role in the coordination of mother-infant interactions, suggesting that motherhood may be associated to enhanced olfactory performances, and that this effect may be abolished by maternal stress. To test this hypothesis, we analyzed the impact of motherhood under normal conditions or after gestational stress on olfactory functions in C57BL/6 J mice. We report that gestational stress alters maternal behavior and prevents both mothers’ ability to discriminate pup odors and motherhood-induced enhancement in odor memory. We investigated adult bulbar neurogenesis as a potential mechanism of the enhanced olfactory function in mothers and found that motherhood was associated with an increased complexity of the dendritic tree of newborn neurons. This motherhood-evoked remodeling was totally prevented by gestational stress. Altogether, our results may thus provide insight into the neural changes that could contribute to altered maternal behavior in stressed mothers.

Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains.SIGNIFICANCE STATEMENTThis study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.

International audience; Although neurobiological models of language argue for a left lateralization of the audio-motor dorsal pathway during speech perception [1], the question of the role of the right and left premotor ventral (PMv) areas in multisensory speech integration processes remains largely unknown. What is the contribution of the hemispheric differentiation in the integration processing and what role do premotor areas play in these mechanisms? Further, given the known differences in speech perception accuracy for young and older adults and decreasing sensorial acuities with age, it is possible that the lateralization of multimodal integration processes evolves over time. In the present study, we explored the impact of inhibitory transcranial magnetic stimulation (rTMS) on the right and left PMv during auditory (A), visual (V) and tactile (T) unimodal conditions as well as during audio-visual (AV) and audio-tactile (AT) bimodal conditions across age.The experiment consisted of 2 rTMS sessions (related to the left and right PMv) conducted for each of the 24 healthy right-handed participants (16 females; mean 46±19 [19-78] years). Following completion of each session, participants performed a force-choice identification task. They were told that they would be presented with /pa/, /ta/ or /ka/ syllables in 5 different sensory modalities (A, V, AV, T, AT) and had to identify, as quickly as possible, the perceived syllable by pressing on one of three keys on a response pad. To increase task-difficulty, half the trials were presented in quiet, while the other half was presented in noise. Mixed-model ANOVAs were conducted on the mean accuracy and median reaction time (RT) data with the target region (left PMv/right PMv), the acoustic environment (noise/no noise), and the modality (A/AV/AT/V/T for the accuracy analysis and A/AV/AT for the RT analysis) as the within-subjects factors, the order of the stimulation (left PMv first, right PMv first) as a between-subjects factor, and age as a continuous quantitative between-subjects co-variable.Our results demonstrate that multimodal integration is relatively preserved in aging, becoming slower but not less accurate. Importantly, we found a significant linear negative relationship between hemispheric difference and age in the auditory modality, i.e., with increasing age, hemispheric differences declined. Interestingly, no such difference occurred in the bimodal modalities. This suggests a larger recruitment of the right PMv to support auditory speech processes in elderly adults, possibly as a consequence of a reduced auditory acuity with age, or a de-differentiation of the phonemic categories. In contrast, the absence of an age effect in the bimodal conditions suggests that multisensory processing remains stable throughout adulthood. Together, these results demonstrate that multisensory integration mechanisms are, at least in part, maintained with age despite a decline in auditory acuity, and demonstrate the feasibility of using rTMS in healthy elderly adults to study speech and language processes.

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Background GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. Methods We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88 −/− mice using extensive behavioral testing. Results We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88 −/− mice. Conclusions We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.

International audience; Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca(2+) concentration. However the mechanism by which a short-lasting rise in Ca(2+) concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca(2+) elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that αCaMKII, but not βCaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and αCaMKII. We then show that interfering with GluN2B/αCaMKII interaction prevents synaptic activity from inducing ERK-dependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and αCaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.

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International audience; This chapter introduces the principles of digital holography, as well as the associated reconstruction methods. It presents the basic properties related to a digital hologram. In order to discuss the digital reconstruction of the object wave at the object plane, the chapter presents the basics of the scalar diffraction of light. Algorithms used to back-propagate the object field estimated at the sensor plane are based on this approach. The chapter discusses the use of the theoretical basics of wave propagation to numerically reconstruct the object wave at the object plane. It also discusses the different experimental configurations to record a digital hologram. The chapter provides basic experimental arrangements and gives few explications on how it works. Digital holographic interferometry exploits not only the amplitude of the object, but also its phase. Finally, the chapter describes the basic principle of digital holographic interferometry, and quantitative phase tomography.

Pollination is important for both agriculture and biodiversity. For a significant number of plants, this process is highly and sometimes exclusively, dependent on the pollination activity of honeybees. The large numbers of honeybee colony losses reported in recent years have been attributed to colony collapse disorder. Various hypotheses, including pesticide overuse, have been suggested to explain the disorder. Using the Xenopus oocytes expression system and two microelectrode voltage-clamp, we report the functional expression and the molecular, biophysical and pharmacological characterization of the western honeybee’s sodium channel (Apis Mellifera NaV1). The NaV1 channel is the primary target for pyrethroid insecticides in insect pests. We further report that the honeybee’s channel is also sensitive to permethrin and fenvalerate, respectively type I and type II pyrethroid insecticides. Molecular docking of these insecticides revealed a binding site that is similar to sites previously identified in other insects. We describe in vitro and in silico tools that can be used to test chemical compounds. Our findings could be used to assess the risks that current and next generation pesticides pose to honeybee populations.

International audience; The aim of this study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochon- dria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were mea- sured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindopri- late. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial per- meability transition pores. This opening is mainly due to oxidative stress and cal- cium overload and seems to be the pivotal event in cell death after I/R. No drug treatment changed haemodynamic and electrophysiological parameters, but amlod- ipine and perindoprilate, either alone or combined, prevented mitochondrial altera- tions but only partially. The preservation of mitochondrial structure and functions reported in our study probably plays an important role in preventing calcium over- load and mPTP opening during myocardial I/R by a specially increased CRC, which can explain their cardioprotective effects.

International audience; Voltage-gated Ca(2+) channels allow the influx of Ca(2+) ions from the extracellular space upon membrane depolarization and thus serve as a transducer between membrane potential and cellular events initiated by Ca(2+) transients. Most insects are predicted to possess three genes encoding Cavα, the main subunit of Ca(2+) channels, and several genes encoding the two auxiliary subunits, Cavβ and Cavα2δ; however very few of these genes have been cloned so far. Here, we cloned three full-length cDNAs encoding the three Cavα subunits (AmelCav1a, AmelCav2a and AmelCav3a), a cDNA encoding a novel variant of the Cavβ subunit (AmelCavβc), and three full-length cDNAs encoding three Cavα2δ subunits (AmelCavα2δ1 to 3) of the honeybee Apis mellifera. We identified several alternative or mutually exclusive exons in the sequence of the AmelCav2 and AmelCav3 genes. Moreover, we detected a stretch of glutamine residues in the C-terminus of the AmelCav1 subunit that is reminiscent of the motif found in the human Cav2.1 subunit of patients with Spinocerebellar Ataxia type 6. All these subunits contain structural domains that have been identified as functionally important in their mammalian homologues. For the first time, we could express three insect Cavα subunits in Xenopus oocytes and we show that AmelCav1a, 2a and 3a form Ca(2+) channels with distinctive properties. Notably, the co-expression of AmelCav1a or AmelCav2a with AmelCavβc and AmCavα2δ1 produces High Voltage-Activated Ca(2+) channels. On the other hand, expression of AmelCav3a alone leads to Low Voltage-Activated Ca(2+) channels

International audience; The honeybee is a model system to study learning and memory, and Ca2+ signals play a key role in these processes. We have cloned, expressed, and characterized the first honeybee Ca2+ channel subunit. We identified two splice variants of the Apis CaVβ Ca2+ channel subunit (Am-CaVβ) and demonstrated expression in muscle and neurons. Although AmCaVβ shares with vertebrate CaVβ subunits the SH3 and GK domains, it beholds a unique N terminus that is alternatively spliced in the first exon to produce a long (a) and short (b) variant. When expressed with the CaV2 channels both, AmCaVβa and AmCaVβb, increase current amplitude, shift the voltage-sensitivity of the channel, and slow channel inactivation as the vertebrate CaVβ2a subunit does. However, as opposed to CaVβ2a, slow inactivation induced by Am-CaVβa was insensitive to palmitoylation but displayed a unique PI3K sensitivity. Inactivation produced by the b variant was PI3K-insensitive but staurosporine/H89-sensitive. Deletion of the first exon suppressed the sensitivity to PI3K inhibitors, staurosporine, or H89. Recording of Ba2+ currents in Apis neurons or muscle cells evidenced a sensitivity to PI3K inhibitors and H89, suggesting that both AmCaVβ variants may be important to couple cell signaling to Ca2+ entry in vivo. Functional interactions with phospho-inositide and identification of phosphorylation sites in AmCaVβa and AmCaVβb N termini,respectively, suggest that AmCaVβ splicing promoted two novel and alternative modes of regulation of channel activity with specific signaling pathways. This is the first description of a splicing-dependent kinase switch in the regulation of Ca2+ channel activity by CaVβ subunit.

The aims of this study were to i) evaluate proximal-to-distal sequencing (PDS) in pianists’ attack and release movements during pressed-staccato keystrokes, and ii) investigate if trunk motion facilitates PDS of upper-limb movements. Nine expert pianists performed a series of loud pressed-staccato keystrokes. Kinematic data was recorded with a 3 D motion capture system. PDS was assessed by comparing temporal organization of peak velocities from the pelvis to the wrist. Evidence of PDS was found across the kinematic chain. Pianists’ use of PDS differed mainly between scapula and shoulder movements. Trunk motion facilitated PDS by increasing anticipatory shoulder movements and by preceding shoulder-girdle attack and release movements. Implications might relate to research on performance optimization and injury prevention strategies.

International audience; The primary mode of action of pyrethroids in insects is to interfere with the normal function of voltage-gated sodium channels (VGSC). We have shown that deactivation kinetics were more deeply affected in VGSC from the sensory neurons of the honey bee, Apis mellifera , than from its brain neurons (Kadala et al 2011 Neurotoxicology, 2014 PLoS one) and suggested from studies using the cloned AmNa V 1 sodium channel, that Na V accessory subunits could partly un- derlie this differential sensitivity (Gosselin-Badaroudine et al 2015, Sci Rep). On the other hand, the side effects of neonicotinoids towards non-target organ- isms (including pollinators), has recently focused the attention and led the European Union to restrict the use of three members of this compounds family. This restriction may mechanically lead to an increase in pyrethroids usage (e.g. deltamethrin, cypermethrin, l -cyalothrin, permethrin). Whereas our past work was focused on domestic honey bee VGSC susceptibility, the impact of pyre- throids on wild bee channels remained largely unknown. Here, the effect of veratridine and two pyrethroids are compared on neuronal VGSCs from the honey bee and Bombus terrestris , a common bumble bee. Modeling the sodium channel as a multi-state channel with fast and slow inactivation mechanisms al- lows a more precise analysis of gating kinetics modifications induced by pyre- throids. Together with molecular modeling, these results give some clues to understand how such compounds could selectively target different species.