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Funding Information: Funding: This work was supported by Fundação para Ciência e Tecnologia [PTDC/MED-TOX/30418/2017] and iNOVA4Health [UID/Multi/04462/2013]. M.J.C., F.L.-C., N.R.C., C.G.-D. and J.M. are supported by FCT grants [SFRH/BD/131331/2017, PD/BD/128337/2017, PD/BD/114257/2016, and PD/BD/105892/2014, PTDC/MED-TOX/30418/2017 respectively]. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA. publishersversion published

International audience; The objectives were to explore, among university students, the level of COVID-19 vaccine acceptance, hesitancy, and resistancy and to determine the motivations and barriers, and the reasons that may change student vaccination decision making. An online observational cross-sectional study was conducted among students of a French university in January 2021 with questions about the intention to be vaccinated against COVID-19, the motivations and the barriers. The convenience sample included 3089 students, with a mean of age of 20.3 (SD = 1.9). To the question on the intention to vaccinate against the COVID-19, 58.0% of students reported that they would choose to have a vaccination, 17.0% reported that they would not and 25.0% were not sure. The main motivations for vaccine acceptance were “I don′t want to transmit COVID-19 to others”, the main barriers for vaccine resistance or hesitancy were “I prefer to wait until I have more experience with these new vaccines”. Age, female gender, being in first three years of study, studied sciences courses and neither sciences nor healthcare courses of study were significantly associated with a higher risk of vaccine hesitancy or resistancy. Self-estimated knowledge of conventional vaccines and COVID-19 vaccines, and confidence in efficiency and safety of conventional vaccination were associated with a lower risk of vaccine hesitancy or resistancy. It is relevant to disseminate evidence-based interventions to promote COVID-19 vaccine acceptability for college students, especially for the students in neither sciences nor healthcare courses of study, as college students will soon be eligible to receive a COVID-19 vaccine.

International audience; Background. The objectives of this study were (1) to determine factors associated with impaired sleep and (2) to evaluate the relationship between impaired sleep and the outcome.Methods. Secondary analysis of a prospective observational cohort study in 54 intensive care units in France and Belgium. Sleep quality was quantified by the patients with a semi-quantitative scale.Results. Among the 389 patients included, 40% reported poor sleep during the first night in the ICU and the median (interquartile) total sleep time was 4 h (2–5). Factors independently associated with poor sleep quality were the SOFA score (odds ratio [OR] 0.90, p = 0.037), anxiety (OR 0.43, p = 0.001) and the presence of air leaks (OR 0.52, p = 0.013). Factors independently associated with short-estimated sleep duration (

International audience; Objective: Dietary intakes must cover protein and essential amino acid (EAA) requirements. For this purpose, different methods have been developed such as the nitrogen balance method, factorial method, or AA tracer studies. However, these methods are either invasive or imprecise, and the Food and Agriculture Organization of the United Nations (FAO, 2013) recommends new methods and, in particular, metabolomics. The aim of this study is to determine total protein/EAA requirement in the plasma and urine of growing rats. Methods: 36 weanling rats were fed with diets containing 3, 5, 8, 12, 15, and 20% protein for 3 weeks. During experimentation, urine was collected using metabolic cages, and blood from the portal vein and vena was taken at the end of the experiment. Metabolomics analyses were performed using LC-MS, and the data were analyzed with a multivariate analysis model, partial least Squares (PLS) regression, and independent component-discriminant analysis (ICDA). Each discriminant metabolite identified by PLS or ICDA was tested by one-way ANOVA to evaluate the effect of diet. Results: PLS and ICDA allowed us to identify discriminating metabolites between different diet groups. Protein deficiency led to an increase in the AA catabolism enzyme systems inducing the production of breakdown metabolites in the plasma and urine. Conclusion: These results indicate that metabolites are specific for the state of EAA deficiency and sufficiency. Some types of biomarkers such as AA degradation metabolites appear to be specific candidates for protein/EAA requirement.

International audience; The Western diet, rich in lipids and in n-6 polyunsaturated fatty acids (PUFAs), favors gut dysbiosis observed in Crohn's disease (CD). The aim of this study was to assess the effects of rebalancing the n-6/n-3 PUFA ratio in CEABAC10 transgenic mice that mimic CD. Mice in individual cages with running wheels were randomized in three diet groups for 12 weeks: high-fat diet (HFD), HFD + linseed oil (HFD-LS-O) and HFD + extruded linseed (HFD-LS-E). Then, they were orally challenged once with the Adherent-Invasive Escherichia coli (AIEC) LF82 pathobiont. After 12 weeks of diet, total energy intake, body composition, and intestinal permeability were not different between groups. After the AIEC-induced intestinal inflammation, fecal lipocalin-2 concentration was lower at day 6 in n-3 PUFAs supplementation groups (HFD-LS-O and HFD-LS-E) compared to HFD. Analysis of the mucosa-associated microbiota showed that the abundance of Prevotella, Paraprevotella, Ruminococcus, and Clostridiales was higher in the HFD-LS-E group. Butyrate levels were higher in the HFD-LS-E group and correlated with the Firmicutes/Proteobacteria ratio. This study demonstrates that extruded linseed supplementation had a beneficial health effect in a physically active mouse model of CD susceptibility. Additional studies are required to better decipher the matrix influence in the linseed supplementation effect.

Hypoxia and inflammation play a major role in revascularization following ischemia. Sildenafil inhibits phosphodiesterase-5, increases intracellular cGMP and induces revascularization through a pathway which remains incompletely understood. Thus, we investigated the effect of sildenafil on post-ischemic revascularization. The left femoral artery was ligated in control and sildenafil-treated (25 mg/kg per day) rats. Vascular density was evaluated and expressed as the left/right leg (L/R) ratio. In control rats, L/R ratio was 33 ± 2% and 54 ± 9%, at 7- and 21-days post-ligation, respectively, and was significantly increased in sildenafil-treated rats to 47 ± 4% and 128 ± 11%, respectively. A neutralizing anti-VEGF antibody significantly decreased vascular density (by 0.48-fold) in control without effect in sildenafil-treated animals. Blood flow and arteriolar density followed the same pattern. In the ischemic leg, HIF-1α and VEGF expression levels increased in control, but not in sildenafil–treated rats, suggesting that sildenafil did not induce angiogenesis. PI3-kinase, Akt and eNOS increased after 7 days, with down-regulation after 21 days. Sildenafil induced outward remodeling or arteriogenesis in mesenteric resistance arteries in association with eNOS protein activation. We conclude that sildenafil treatment increased tissue blood flow and arteriogenesis independently of VEGF, but in association with PI3-kinase, Akt and eNOS activation.

International audience; High spinal cord injuries (SCIs) lead to permanent diaphragmatic paralysis. The search for therapeutics to induce functional motor recovery is essential. One promising noninvasive therapeutic tool that could harness plasticity in a spared descending respiratory circuit is repetitive transcranial magnetic stimulation (rTMS). Here, we tested the effect of chronic high-frequency (10 Hz) rTMS above the cortical areas in C2 hemisected rats when applied for 7 days, 1 month, or 2 months. An increase in intact hemidiaphragm electromyogram (EMG) activity and excitability (diaphragm motor evoked potentials) was observed after 1 month of rTMS application. Interestingly, despite no real functional effects of rTMS treatment on the injured hemidiaphragm activity during eupnea, 2 months of rTMS treatment strengthened the existing crossed phrenic pathways, allowing the injured hemidiaphragm to increase its activity during the respiratory challenge (i.e., asphyxia). This effect could be explained by a strengthening of respiratory descending fibers in the ventrolateral funiculi (an increase in GAP-43 positive fibers), sustained by a reduction in inflammation in the C1–C3 spinal cord (reduction in CD68 and Iba1 labeling), and acceleration of intracellular plasticity processes in phrenic motoneurons after chronic rTMS treatment. These results suggest that chronic high-frequency rTMS can ameliorate respiratory dysfunction and elicit neuronal plasticity with a reduction in deleterious post-traumatic inflammatory processes in the cervical spinal cord post-SCI. Thus, this therapeutic tool could be adopted and/or combined with other therapeutic interventions in order to further enhance beneficial outcomes.

International audience; Unhealthy lifestyle choices, such as bad eating behaviors and cigarette smoking, have major detrimental impacts on health. However, the interrelations between obesity and smoking are still not fully understood. We thus developed an experimental model of high-fat diet-fed obese C57BL/6 male mice chronically exposed to cigarette smoke. Our study evaluated for the first time the resulting effects of the combined exposure to unhealthy diet and cigarette smoke on several metabolic, pulmonary, intestinal, and cardiac parameters. We showed that the chronic exposure to cigarette smoke modified the pattern of body fat distribution in favor of the visceral depots in obese mice, impaired the respiratory function, triggered pulmonary inflammation and emphysema, and was associated with gut microbiota dysbiosis, cardiac hypertrophy and myocardial fibrosis.

International audience; Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD) without specific treatment. As macrophages are the key actors in inflammatory responses and the wound healing process, they have been extensively studied in chronic diseases these past decades. By their exceptional ability to integrate diverse stimuli in their surrounding environment, macrophages display a multitude of phenotypes to underpin a broad spectrum of functions, from the initiation to the resolution of inflammation following injury. The hypothesis that distinct macrophage subtypes could be involved in fibrogenesis and wound healing is emerging and could open up new therapeutic perspectives in the treatment of intestinal fibrosis. Gut microbiota and diet are two key factors capable of modifying intestinal macrophage profiles, shaping their specific function. Defects in macrophage polarisation, inadequate dietary habits, and alteration of microbiota composition may contribute to the development of intestinal fibrosis. In this review, we describe the intriguing triangle between intestinal macrophages, diet, and gut microbiota in homeostasis and how the perturbation of this discreet balance may lead to a pro-fibrotic environment and influence fibrogenesis in the gut.

International audience; Proctocolectomy with ileal pouch-anal anastomosis is the intervention of choice for ulcerative colitis and familial adenomatous polyposis requiring surgery. One of the long-term complications is pouch cancer, having a poor prognosis. The risk of high-grade dysplasia and cancer in the anal transitional zone and ileal pouch after 20 years is estimated to be 2 to 4.5% and 3 to 10% in ulcerative colitis and familial polyposis, respectively. The risk factors for ulcerative colitis are the presence of pre-operative dysplasia or cancer, disease duration > 10 years and severe villous atrophy. For familial polyposis, the risk factors are the number of pre-operative polyps > 1000, surgery with stapled anastomosis and the duration of follow-up. In the case of ulcerative colitis, a pouchoscopy should be performed annually if one of the following is present: dysplasia and cancer at surgery, primary sclerosing cholangitis, villous atrophy and active pouchitis (every 5 years without any of these factors). In the case of familial polyposis, endoscopy is recommended every year including chromoendoscopy. Even if anal transitional zone and ileal pouch cancers seldom occur following proctectomy for ulcerative colitis and familial adenomatous polyposis, the high mortality rate associated with this complication warrants endoscopic monitoring.

International audience; Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD.

International audience; Between 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.

International audience; This study aimed to determine the changes in health behaviors among students of a French university during the COVID-19 lockdown. An online retrospective survey was distributed to Rouen-Normandy University students at the end of the COVID-19 lockdown (13th March–11th May 2020). Voluntary university students were included. Data collected were on socio-demographics, academic environment, COVID19 concerns, tobacco smoking, binge drinking, cannabis use, and physical activity in the periods before and during COVID-19 lockdown. The survey was completed by 3671 university students (mean age 20.9 ± 2.47 years, 72.9% female). Significantly favorable changes between the periods before and during COVID-19 were reported for tobacco smoking (18.5% vs. 14.8%), binge drinking (35.9% vs. 9.3%) and cannabis use (5.6% vs. 3.2%) and unfavorable changes for moderate (79.4% vs. 67.9%) and vigorous physical activity (62.5% vs. 59.1%). After logistic regression, factors associated with unfavorable changes in tobacco smoking and with favorable changes in vigorous physical activity were the worry of not validating the academic year and stress related to changes in the mode of teaching, respectively. For each health behavior, unfavorable changes were associated with higher depression levels, and male gender. Then as a decrease, mainly in binge drinking was observed during the COVID-19 lockdown, care must be taken to prevent university students from resuming binge drinking after the end of the lockdown. Health-promotion strategies directed at adopting or maintaining positive mental health and promoting physical activity should be developed for university students to better manage future lockdown periods.

Obesity is characterized by an alteration in body composition (BC), however, it is not known whether this alteration is modified by aging or sex. The aims of this study were to analyze BC in individuals with obesity based on age and sex and to determine the prevalence of sarcopenia. Seven hundred and fifty-five obese individuals were subdivided into four age groups. The hole (WB) and segmental BC were determined using dual-energy X-ray absorptiometry (DXA). In men, the WB lean tissue mass (LTM) and fat mass (FM) adjusted by weight and height were relatively constant with age. In women, the WBLTM was higher and WBFM was lower in the &gt, 65 group compared to the 18&ndash, 34 group. A decrease in the LTM and FM at lower limbs and an increase in the trunk were observed, particularly in women, inducing a lower appendicular lean mass index (ALMI, appendicular LTM/height2) in the &gt, 34 group in both sexes. This study demonstrated that even though the WBLTM and FM are relatively constant with age, individuals with obesity present a localized redistribution of these two components. This body composition change leads to a decrease of the ALMI with age, one of the criteria included in the sarcopenia definition.

Despite considerable appeal, the growing appreciation of biosignals complexity reflects that system complexity needs additional support. A dynamically coordinated network of neurovisceral integration has been described that links prefrontal-subcortical inhibitory circuits to vagally-mediated heart rate variability. Chronic stress is known to alter network interactions by impairing amygdala functional connectivity. HRV-biofeedback training can counteract stress defects. We hypothesized the great value of an entropy-based approach of beat-to-beat biosignals to illustrate how HRVB training restores neurovisceral complexity, which should be reflected in signal complexity. In thirteen moderately-stressed participants, we obtained vagal tone markers and psychological indexes (state anxiety, cognitive workload, and Perceived Stress Scale) before and after five-weeks of daily HRVB training, at rest and during stressful cognitive tasking. Refined Composite Multiscale Entropy (RCMSE) was computed over short time scales as a marker of signal complexity. Heightened vagal tone at rest and during stressful tasking illustrates training benefits in the brain-to-heart circuitry. The entropy index reached the highest significance levels in both variance and ROC curves analyses. Restored vagal activity at rest correlated with gain in entropy. We conclude that HRVB training is efficient in restoring healthy neurovisceral complexity and stress defense, which is reflected in HRV signal complexity. The very mechanisms that are involved in system complexity remain to be elucidated, despite abundant literature existing on the role played by amygdala in brain interconnections.

Background. Minor digestive symptoms are common and dietary approaches such as probiotic administration or fibre and fermentable carbohydrate intake adjustments are often recommended. A Fermented Milk Product (FMP) containing Bifidobacterium animalis subsp. lactis CNCM I-2494 and lactic acid bacteria has been shown to improve digestive symptoms after 4 weeks of consumption, but the speed of onset of this effect and its dependence on fibre intake or physical activity is unknown. To answer these questions, data from two previously published trials on FMP for minor digestive symptoms were combined. Methods. In total, 538 participants provided weekly assessments of bloating, abdominal pain/discomfort, flatulence, borborygmi/rumbling stomach from which a composite score was calculated. At baseline in one study (n = 336), dietary fibre consumption was recorded and physical activity classified as high, moderate or low. The speed of the FMP&rsquo, s effect was assessed by a repeated measure analysis of variance measuring the change from baseline for the composite score of digestive symptoms. Results. FMP consumption resulted in a significant decrease in the composite score of symptoms after only 2 weeks in both studies and the pooled data at week 1 (&minus, 0.35 [&minus, 0.69, 0.00], p = 0.05), week 2 (&minus, 0.66 [&minus, 1.04, &minus, 0.27], p &lt, 0.001), week 3 (&minus, 0.49 [&minus, 0.89, &minus, 0.10], p = 0.01) and week 4 (&minus, 0.46 [&minus, 0.88, &minus, 0.04], p = 0.03). The interactions fibre intake-by-product group, physical activity-by-product group and time-by-product group were not statistically significant. Conclusion. FMP consumption leads to a rapid improvement in symptoms which is likely to encourage adherence to this dietary intervention. This effect is independent of dietary fibre and physical activity.