Upslope migration of snow avalanches in a warming climate.

Snow is highly sensitive to atmospheric warming. However, because of the lack of sufficiently long snow avalanche time series and statistical techniques capable of accounting for the numerous biases inherent to sparse and incomplete avalanche records, the evolution of process activity in a warming climate remains little known. Filling this gap requires innovative approaches that put avalanche activity into a long-term context. Here, we combine extensive historical records and Bayesian techniques to construct a 240-y chronicle of snow avalanching in the Vosges Mountains (France). We show evidence that the transition from the late Little Ice Age to the early twentieth century (i.e., 1850 to 1920 CE) was not only characterized by local winter warming in the order of +1.35 °C but that this warming also resulted in a more than sevenfold reduction in yearly avalanche numbers, a severe shrinkage of avalanche size, and shorter avalanche seasons as well as in a reduction of the extent of avalanche-prone terrain. Using a substantial corpus of snow and climate proxy sources, we explain this abrupt shift with increasingly scarcer snow conditions with the low-to-medium elevations of the Vosges Mountains (600 to 1,200 m above sea level [a.s.l.]). As a result, avalanches migrated upslope, with only a relict activity persisting at the highest elevations (release areas >1,200 m a.s.l.). This abrupt, unambiguous response of snow avalanche activity to warming provides valuable information to anticipate likely changes in avalanche behavior in higher mountain environments under ongoing and future warming.

Intermittent reloading does not prevent reduction in iron availability and hepcidin upregulation caused by hindlimb unloading.

NEW FINDINGS: What is the central question of this study? Could skeletal muscle be involved in microgravity-induced iron misdistribution by modulating expression of hepcidin, the master regulator of iron metabolism? What is the main finding and its importance? We demonstrate, in rats, that hepcidin upregulation is not a transient adaptation associated with early exposure to microgravity and that intermittent reloading does not limit microgravity-induced iron misdistribution despite having a beneficial effect on soleus muscle wasting. ABSTRACT: In humans, exposure to microgravity during spaceflight causes muscle atrophy, changes in iron storage and a reduction in iron availability. We previously observed that during 7 days of simulated microgravity in rats, hepcidin plays a key role in iron misdistribution, and we suggested that a crosstalk between skeletal muscle and liver could regulate hepcidin synthesis in this context. In the present study in rats, we investigated the medium-term effects of simulated microgravity on iron metabolism. We also tested whether intermittent reloading (IR) to target skeletal muscle atrophy limits iron misdistribution efficiently. For this purpose, Wistar rats underwent 14 days of hindlimb unloading (HU) combined or not combined with daily IR. At the end of this period, the serum iron concentration and transferrin saturation were significantly reduced, whereas hepatic hepcidin mRNA was upregulated. However, the main signalling pathways involved in hepcidin synthesis in the liver (BMP-small mothers against decapentaplegic (SMAD), interleukin-6-STAT3 and ERK1/2) were unaffected. Unlike what was observed after 7 days of HU, the iron concentration in the spleen, liver and skeletal muscle was comparable between control animals and those that underwent HU or HU plus IR for 14 days. Despite its beneficial effect on soleus muscle atrophy and slow-to-fast myosin heavy chain distribution, IR did not significantly prevent a reduction in iron availability and hepcidin upregulation. Altogether, these results highlight that iron availability is durably reduced during longer exposure to simulated microgravity and that the related hepcidin upregulation is not a transient adaptation to these conditions. The results also suggest that skeletal muscle does not necessarily play a key role in the iron misdistribution that occurs during simulated microgravity.

Determinants of Therapeutic Alliance With People With Psychotic Disorders: A Systematic Literature Review.

Therapeutic alliance determines medical treatment adherence, the success of psychotherapy, and the effectiveness of care. This systematic review aims at better understanding its determinants. The electronic databases Pubmed, Cochrane Library, and Web of Science were searched, using combinations of terms relating to psychosis and therapeutic alliance. Studies were selected and data were extracted using a PRISMA statement. Forty-one studies were selected, including 20 cross-sectional studies, 10 cohort studies, five randomized controlled trials, four literature reviews, and two retrospective studies. The quality of therapeutic alliance correlates with clinical symptoms, insight, social and family support, the therapist's qualities, the availability of shared therapeutic decision making, and the types of hospitalization. Although current evidence needs to be completed with further studies, it is already clear that group and family psychoeducation, cognitive remediation, community-based psychiatric services, and shared therapeutic decision making are essential approaches in the management of patients with psychosis.

Complex phenotype with social communication disorder caused by mosaic supernumerary ring chromosome 19p.

BACKGROUND: Deletions or duplications of chromosome 19 are rare and there is no previous report in the literature of a ring chromosome derived from proximal 19p. Copy Number Variants (CNVs) responsible for complex phenotypes with Social Communication Disorder (SCD), may contribute to improve knowledge about the distinction between intellectual deficiency and autism spectrum disorders. CASE PRESENTATION: We report the clinical and cytogenetic characterization of a patient (male, 33 years-old, first child of healthy Portuguese non-consanguineous parents) presenting with a complex phenotype including SCD without intellectual deficiency and carrying a mosaic supernumerary ring chromosome 19p. Microarray-Based Comparative Genomic Hybridization and Fluorescence in situ Hybridization were performed. Genetic analysis showed a large mosaic interstitial duplication 19p13.12p12 of the short arm of chromosome 19, spanning 8.35 Mb. Our data suggested a putative association between psychosocial dysfunction and mosaic pure trisomy 19p13.2p12. CONCLUSION: This clinical report demonstrated the need to analyze more discreet trait-based subsets of complex phenotypes to improve the ability to detect genetic effects. To address this question and the broader issue of deciphering the yet unknown genetic contributors to complex phenotype with SCD, we suggest performing systematic psychological and psychiatric assessments in patients with chromosomal abnormalities.

Sex similarities and divergences in systemic and muscle iron metabolism adaptations to extreme physical inactivity in rats.

BACKGROUND: Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI. METHODS: Eight-week-old male and female Wistar rats were assigned to control (CTL) or hindlimb unloading (HU) conditions (n = 12/group). After 7 days of HU, serum, liver, spleen, and soleus muscle were removed. Iron parameters were measured in serum samples, and ICP-MS was used to quantify iron in tissues. Iron metabolism genes and proteins were analysed by RT-qPCR and Western blot. RESULTS: Compared with control males, control females exhibited higher iron concentrations in serum (+43.3%, p < 0.001), liver (LIC; +198%, P < 0.001), spleen (SIC; +76.1%, P < 0.001), and transferrin saturation (TS) in serum (+53.3%, P < 0.001), contrasting with previous observations in humans. HU rat males, but not females, exhibited an increase of LIC (+54% P < 0.001) and SIC (+30.1%, P = 0.023), along with a rise of H-ferritin protein levels (+60.9% and +134%, respectively, in liver and spleen; P < 0.05) and a decrease of TFRC protein levels (-36%; -50%, respectively, P < 0.05). HU males also exhibited an increase of splenic HO-1 and NRF2 mRNA levels, (p < 0.001), as well as HU females (P < 0.001). Concomitantly to muscle atrophy observed in HU animals, the iron concentration increased in soleus in females (+26.7, P = 0.004) while only a trend is observed in males (+17.5%, P = 0.088). In addition, the H-ferritin and myoglobin protein levels in soleus were increased in males (+748%, P < 0.001, +22%, P = 0.011, respectively) and in females (+369%, P < 0.001, +21.9%, P = 0.007, respectively), whereas TFRC and ferroportin (FPN) protein levels were reduced in males (-68.9%, P < 0.001, -76.8%, P < 0.001, respectively) and females (-75.9%, P < 0.001, -62.9%, P < 0.001, respectively). Interestingly, in both sexes, heme exporter FLVCR1 mRNA increased in soleus, while protein levels decreased (-39.9% for males P = 0.010 and -49.1% for females P < 0.001). CONCLUSIONS: Taken together, these data support that, in rats (1) extreme physical inactivity differently impacts the distribution of iron in both sexes, (2) splenic erythrophagocytosis could play a role in this iron misdistribution. The higher iron concentrations in atrophied soleus from both sexes are associated with a decoupling between the increase in iron storage proteins (i.e., ferritin and myoglobin) and the decrease in levels of iron export proteins (i.e., FPN and FLVCR1), thus supporting an iron sequestration in skeletal muscle under extreme physical inactivity.

Combined effects of exercise and immuno-chemotherapy treatments on tumor growth in MC38 colorectal cancer-bearing mice.

Acute exercise induces transient modifications in the tumor microenvironment and has been linked to reduced tumor growth along with increased infiltration of immune cells within the tumor in mouse models. In this study, we aimed to evaluate the impact of acute exercise before treatment administration on tumor growth in a mice model of MC38 colorectal cancer receiving an immune checkpoint inhibitor (ICI) and chemotherapy. Six-week-old mice injected with colorectal cancer cells (MC38) were randomized in 4 groups: control (CTRL), immuno-chemotherapy (TRT), exercise (EXE) and combined intervention (TRT/EXE). Both TRT and TRT-EXE received ICI: anti-PD1-1 (1 injection/week) and capecitabine + oxaliplatin (5 times a week) for 1 week (experimentation 1), 3 weeks (experimentation 2). TRT-EXE and EXE groups were submitted to 50 minutes of treadmill exercise before each treatment administration. Over the protocol duration, tumor size has been monitored daily. Tumor growth and microenvironment parameters were measured after the intervention on Day 7 (D7) and Day 16 (D16). From day 4 to day 7, tumor volumes decreased in the EXE/TRT group while remaining stable in the TRT group (p=0.0213). From day 7 until day 16 tumor volume decreased with no significant difference between TRT and TRT/EXE. At D7 the TRT/EXE group exhibited a higher total infiltrate T cell (p=0.0118) and CD8+ cytotoxic T cell (p=0.0031). At D16, tumor marker of apoptosis, vascular integrity and inflammation were not significantly different between TRT and TRT/EXE. Our main result was that acute exercise before immuno-chemotherapy administration significantly decreased early-phase tumor growth (D0 to D4). Additionally, exercise led to immune cell infiltration changes during the first week after exercise, while no significant molecular alterations in the tumor were observed 3 weeks after exercise.

Strong perceptual consequences of low-level visual predictions: A new illusion.

Predicting information is considered to be an efficient strategy to minimise processing costs by exploiting regularities in the environment, and to allow for adaptation in case of irregularities, i.e. prediction errors. How such errors impact conscious perception is unclear, especially when predictions concern elementary visual features. Here we present results from a novel experimental approach allowing us to investigate the perceptual consequences of violated low-level predictions about moving objects. Observers were presented with two squares moving towards each other with a constant speed, and reported whether they were in contact or not before they disappeared. A compelling illusion of a gap between the squares occurred when the leading edges of those squares contacted briefly. The apparent gap was larger than a physical and stable separation of 2.6 min of arc between the squares. The illusion disappeared only when the contact did not violate extrapolations of the contrast edge between the moving object and the background. The pattern of results is consistent with an early locus of the effect and cannot be explained by decisional biases, guesses, top-down, attentional or masking effects. We suggest that violations of the contrast edge extrapolation in the direction of motion have strong perceptual consequences.

Energy Expenditure Estimation From Respiratory Magnetometer Plethysmography: A Comparison Study.

Physical activity (PA) quantification by estimating energy expenditure (EE) is essential to health. Reference methods for EE estimation often involve expensive and cumbersome systems to wear. To address these problems, light-weighted and cost-effective portable devices are developed. Respiratory magnetometer plethysmography (RMP) is among such devices, based on the measurements of thoraco-abdominal distances. The aim of this study was to conduct a comparative study on EE estimation with low to high PA intensity with portable devices including the RMP. Fifteen healthy subjects aged 23.84±4.36 years were equipped with an accelerometer, a heart rate (HR) monitor, a RMP device and a gas exchange system, while performing 9 sedentary and physical activities: sitting, standing, lying, walking at 4 and 6 km/h, running at 9 and 12 km/h, biking at 90 and 110 W. An artificial neural network (ANN) as well as a support vector regression algorithm were developed using features derived from each sensor separately and jointly. We compared also three validation approaches for the ANN model: leave one out subject, 10 fold cross-validation, and subject-specific. Results showed that 1. for portable devices the RMP provided better EE estimation compared to accelerometer and HR monitor alone; 2. combining the RMP and HR data further improved the EE estimation performances; and 3. the RMP device was also reliable in EE estimation for various PA intensities.

Influence of focused ultrasound on locoregional drug delivery to the brain: Potential implications for brain tumor therapy.

INTRODUCTION: Efficient delivery of therapeutics across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Locoregional drug delivery platforms offer an improved therapeutic index by achieving high drug concentrations in the target tissue with negligible systemic exposure. Intrathecal (intraventricular) [IT] and convection-enhanced delivery [CED] are two clinically relevant methods being employed for various CNS malignancies. Both of these standalone platforms suffer from passive post-administration distribution forces, sometimes limiting the desired distribution for tumor therapy. Focused ultrasound and microbubble-mediated blood-brain barrier opening (FUS-BBBO) is a recent modality used for enhanced drug delivery. It is postulated that coupling of FUS with these alternative delivery routes may provide benefits. Multimodality FUS may provide the desired ability to increase the depth of parenchymal delivery following IT administration and provide a means for contour directionality with CED. Further, the transient enhanced permeability achieved with FUS-BBBO is well established, but drug residence and transit times, important to clinical dose scheduling, have not yet been defined. The present investigation comprises two discrete studies: 1. Conduct a comprehensive quantitative evaluation to elucidate the effect of FUS-BBBO as it relates to varying routes of administration (IT and IV) in its capacity to facilitate drug penetration within the striatal-thalamic region. 2. Investigate the impact of combining FUS-BBBO with CED on drug distribution, with a specific focus on the temporal dynamics of drug retention within the target region. METHODS: Firstly, we quantitatively assessed how FUS-BBBO coupled with IT and IV altered fluorescent dye (Dextran 2000 kDa and 70 kDa) distribution and concentration in a predetermined striatal-thalamic region in naïve mice. Secondly, we analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye. RESULTS: Our results indicate that IV administration coupled with FUS-BBBO successfully enhances delivery of dye into the pre-defined sonication targets. Conversely, measurable dye in the sonication target was consistently less after IT administration. FUS enhances the distribution volume of dye after CED. Furthermore, a shorter time of residence was observed when CED was coupled with FUS-BBBO application when compared to CED alone. CONCLUSION: 1. Based on our findings, IV delivery coupled with FUS-BBBO is a more efficient means for delivery to deep targets (i.e. striatal-thalamic region) within a predefined spatial conformation compared to IT administration. 2. FUS-BBBO increases the volume of distribution (Vd) of dye after CED administration, but results in a shorter time of residence. Whether this finding is reproducible with other classes of agents (e.g., cytotoxic agents, antibodies, viral particles, cellular therapies) needs to be studied.

Leptomeningeal dissemination in pediatric brain tumors.

Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.

Energy Expenditure Estimation in Children, Adolescents and Adults by Using a Respiratory Magnetometer Plethysmography System and a Deep Learning Model.

PURPOSE: Energy expenditure is a key parameter in quantifying physical activity. Traditional methods are limited because they are expensive and cumbersome. Additional portable and cheaper devices are developed to estimate energy expenditure to overcome this problem. It is essential to verify the accuracy of these devices. This study aims to validate the accuracy of energy expenditure estimation by a respiratory magnetometer plethysmography system in children, adolescents and adults using a deep learning model. METHODS: Twenty-three healthy subjects in three groups (nine adults (A), eight post-pubertal (PP) males and six pubertal (P) females) first sat or stood for six minutes and then performed a maximal graded test on a bicycle ergometer until exhaustion. We measured energy expenditure, oxygen uptake, ventilatory thresholds 1 and 2 and maximal oxygen uptake. The respiratory magnetometer plethysmography system measured four chest and abdomen distances using magnetometers sensors. We trained the models to predict energy expenditure based on the temporal convolutional networks model. RESULTS: The respiratory magnetometer plethysmography system provided accurate energy expenditure estimation in groups A (R2 = 0.98), PP (R2 = 0.98) and P (R2 = 0.97). The temporal convolutional networks model efficiently estimates energy expenditure under sitting, standing and high levels of exercise intensities. CONCLUSION: Our results proved the respiratory magnetometer plethysmography system's effectiveness in estimating energy expenditure for different age populations across various intensities of physical activity.

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload.

BACKGROUND: Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes. METHODS: The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 µM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis. RESULTS: In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 µM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 µM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle. CONCLUSIONS: Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

Voluntary Wheel Running Does Not Enhance Radiotherapy Efficiency in a Preclinical Model of Prostate Cancer: The Importance of Physical Activity Modalities?

Physical activity is increasingly recognized as a strategy able to improve cancer patient outcome, and its potential to enhance treatment response is promising, despite being unclear. In our study we used a preclinical model of prostate cancer to investigate whether voluntary wheel running (VWR) could improve tumor perfusion and enhance radiotherapy (RT) efficiency. Nude athymic mice were injected with PC-3 cancer cells and either remained inactive or were housed with running wheels. Apparent microbubble transport was enhanced with VWR, which we hypothesized could improve the RT response. When repeating the experiments and adding RT, however, we observed that VWR did not influence RT efficiency. These findings contrasted with previous results and prompted us to evaluate if the lack of effects observed on tumor growth could be attributable to the physical activity modality used. Using PC-3 and PPC-1 xenografts, we randomized mice to either inactive controls, VWR, or treadmill running (TR). In both models, TR (but not VWR) slowed down tumor growth, suggesting that the anti-cancer effects of physical activity are dependent on its modalities. Providing a better understanding of which activity type should be recommended to cancer patients thus appears essential to improve treatment outcomes.

Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties.

Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions.

Where and when to look: Sequential effects at the millisecond level.

Learning and imitating a complex motor action requires to visually follow complex movements, but conscious perception seems too slow for such tasks. Recent findings suggest that visual perception has a higher temporal resolution at an unconscious than at a conscious level. Here we investigate whether high-temporal resolution in visual perception relies on prediction mechanisms and attention shifts based on recently experienced sequences of visual information. To that aim we explore sequential effects during four different simultaneity/asynchrony discrimination tasks. Two stimuli are displayed on each trial with varying stimulus onset asynchronies (SOA). Subjects decide whether the stimuli are simultaneous or asynchronous and give manual responses. The main finding is an advantage for different-order over same-order trials, when subjects decided that stimuli had been simultaneous on Trial t - 1 , and when Trial t is with an SOA slightly larger than Trial t - 1, or equivalent. The advantage for different-order trials disappears when the stimuli change eccentricity but not direction between trials (Experiment 2), and persists with stimuli displayed in the centre and unlikely to elicit a sense of direction (Experiment 4). It is still observed when asynchronies on Trial t - 1 are small and undetected (Experiment 3). The findings can be explained by an attention shift that is precisely planned in time and space and that incidentally allows subjects to detect an isolated stimulus on the screen, thus helping them to detect an asynchrony.

A reflection upon methods to explore timing in patients with schizophrenia.

Phenomenologists have provided a detailed description of the disorders of the subjective experience associated with minimal-self disorders in patients with schizophrenia. Those patients report a range of distortions of their conscious experiences, including a sense of inner void, confusion between self and others, and, sometimes, a disruption of the sense of time. These reports have been interpreted as distortion of the first-person perspective and a lack of immersion in the world, associated with a breakdown of the temporal structure of consciousness, and especially a disruption of the sense of time continuity. Further, it has been proposed that these disruptions are based on a difficulty to retain past information and to predict future information, that is, the mechanisms that help to relate events with one another and to reach a sense of time continuity. Experimental psychology results seem to converge to similar conclusions, inasmuch as some results in patients with schizophrenia suggest a deficient ability to predict sequences of events at the millisecond level. Several studies have underlined this convergence. Here we reflect on the limits of both the phenomenological and experimental psychology approaches, and of the convergence of their hypotheses. We think that this reflection is necessary to avoid premature conclusions on the mechanisms underlying the impairments in patients, but also to enrich our understanding of schizophrenia.

Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance.

Physical inactivity increases the risk to develop type 2 diabetes, a disease characterized by a state of insulin resistance. By promoting inflammatory state, ceramides are especially recognized to alter insulin sensitivity in skeletal muscle. The present study was designed to analyze, in mice, whether muscle ceramides contribute to physical-inactivity-induced insulin resistance. For this purpose, we used the wheel lock model to induce a sudden reduction of physical activity, in combination with myriocin treatment, an inhibitor of de novo ceramide synthesis. Mice were assigned to 3 experimental groups: voluntary wheel access group (Active), a wheel lock group (Inactive), and wheel lock group treated with myriocin (Inactive-Myr). We observed that 10 days of physical inactivity induces hyperinsulinemia and increases basal insulin resistance (HOMA-IR). The muscle ceramide content was not modified by physical inactivity and myriocin. Thus, muscle ceramides do not play a role in physical-inactivity-induced insulin resistance. In skeletal muscle, insulin-stimulated protein kinase B phosphorylation and inflammatory pathway were not affected by physical inactivity, whereas a reduction of glucose transporter type 4 content was observed. Based on these results, physical-inactivity-induced insulin resistance seems related to a reduction in glucose transporter type 4 content rather than defects in insulin signaling. We observed in inactive mice that myriocin treatment improves glucose tolerance, insulin-stimulated protein kinase B, adenosine-monophosphate-activated protein kinase activation, and glucose transporter type 4 content in skeletal muscle. Such effects occur regardless of changes in muscle ceramide content. These findings open promising research perspectives to identify new mechanisms of action for myriocin on insulin sensitivity and glucose metabolism.

Satisfaction and Needs in Serious Mental Illness and Autism Spectrum Disorder: The REHABase Psychosocial Rehabilitation Project.

OBJECTIVE: The REHABase project is a French observational, prospective, and multicenter cohort study of serious mental illness and autism spectrum disorder (ASD), launched in 2016 for a planned minimum duration of 15 years. The aim is to characterize the care and quality-of-life needs of participants. This article presents initial results from data collection. METHODS: Psychosocial, cognitive, and functional data were collected at baseline, annually, and after rehabilitation care. Data from the baseline evaluation on diagnoses, medications, well-being, insight, life satisfaction, and care needs are presented. The clinical profiles of REHABase participants with serious mental illness or ASD were assessed in relation to their level of satisfaction with life and well-being in nine life dimensions and their needs, according to their stage of recovery in a five-stage model. RESULTS: Baseline data were collected for 1,397 participants between January 2016 and August 2018. Main diagnoses were schizophrenia spectrum disorder (49%); ASD (13%); and personality (12%), bipolar (9%), and major depressive (6%) disorders. More than 50% of participants reported needs for care or interventions in four of nine dimensions: employment, cognitive functioning, symptom management, and interpersonal relationships. Nearly half of participants were not in the active stages of recovery (stages 4 and 5), and even those considered to have reached the final stage continued to require help in several areas. CONCLUSIONS: Most participants had already received psychiatric care for several years, and most remained dissatisfied with their social and emotional life and their psychological well-being.

Exploring Self-Consciousness From Self- and Other-Image Recognition in the Mirror: Concepts and Evaluation.

A historical review of the concepts of self-consciousness is presented, highlighting the important role of the body (particularly, body perception but also body action), and the social other in the construction of self-consciousness. More precisely, body perception, especially intermodal sensory perception including kinesthetic perception, is involved in the construction of a sense of self allowing self-other differentiation. Furthermore, the social other, through very early social and emotional interactions, provides meaning to the infant's perception and contributes to the development of his/her symbolization capacities. This is a necessary condition for body image representation and awareness of a permanent self in a time-space continuum (invariant over time and space). Self-image recognition impairments in the mirror are also discussed regarding a comprehensive developmental theory of self-consciousness. Then, a neuropsychological and neurophysiological approach to self-consciousness reviews the role of complex brain activation/integration pathways and the mirror neuron system in self-consciousness. Finally, this article offers new perspectives on self-consciousness evaluation using a double mirror paradigm to study self- and other- image and body recognition.