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International audience; This paper presents an efficient design for a lateral control synthesis of an off-road vehicle. The considered vehicles have two steering axles and are intended to move on a slippery soil with important lateral and longitudinal slopes. The proposed design relies on an extended bicycle model that accounts for the slopes. The lateral control is designed based on a feedforward/feedback architecture. The feedforward takes advantage of the knowledge of the path characteristics (curvature and slopes), and the feedback ensures robust reference-trajectory tracking. Through an H2 /H∞multi-objective synthesis, the robustness of the lateral controller is ensured with regard to the model uncertainties, path, and soil features. This is important because off-road vehicles’ dynamics are by nature highly variable. To cope with the difficulty caused by uncertain knowledge of key parameters, the proposed robust approach is a practical compromise that maximizes performance under constraints of robustness. The results obtained on a realistic non-linear simulator support this assertion.

A cross-sectional observational study was conducted to describe the lifestyle of people ≥90 years, living in Evdilos or Raches, two municipalities of the Greek island of Ikaria, classified a longevity blue zone. The 71 participants were interviewed and underwent the Mediterranean Islands study food frequency questionnaire (MEDIS-FFQ) and the international physical activity questionnaire (IPAQ). The frequency of social contacts was daily for 77.9% of participants, weekly for 16.1%, and monthly for 5.9%. Most participants (90.0%) believed in God, and 81.4% took part in religious events. A total of 62.0% attended Panigiria festivals. Access to primary health care was considered difficult in the past for 66.2% of participants, while 22.1% felt that it remained difficult at the time of the survey. The level of adherence to the Mediterranean diet was 62.7% (61.6% in women and 64.0% in men). Physical activity levels were moderate or high for 71.8% of participants (59.5% of women and 85.3% of men). In conclusion, the participants had a very high level of family solidarity, social interaction and physical activity. The results concerning the Mediterranean diet are less convincing. It would be interesting to study the impact of these factors on the longevity of the oldest old aged people living in Ikaria.

Human longevity may be found in single individuals as well as in the population as a whole ("population longevity"). Longevity Blue Zones (LBZs), which are areas with an unusually high number of oldest old, have been identified in Sardinia and the Greek island of Ikaria. We compared the lifestyle, health status and some genetic markers of the LBZ populations with those of reference populations from Italy and Greece; the data were extracted from the GEHA database. In the LBZs, the proportion of individuals who never married or were married and still living with their spouse was significantly greater. Nonagenarians males and females with a high self‒perception of optimism and/or a high score for self-rated health were also found in larger proportions in LBZs. Among the variables with lower frequency were the proportion of the widowed, the percentage of subjects who had suffered a stroke and the frequency of Apoe4 and Apoe2 and the TT genotype of FOXO3A gene. Compared to behavioral and health indicators, the impact of genetic factors might be relatively less important in the LBZs. Nevertheless, further research is needed to identify potential epigenetic traits that might play a predominant role due to the interaction between genetics and the human and physical environments.

Eating disorders (EDs) are increasingly frequent. Their pathophysiology involves disturbance of peptide signaling and the microbiota&ndash, gut&ndash, brain axis. This study analyzed peptides and corresponding immunoglobulin (Ig) concentrations in groups of ED. In 120 patients with restrictive (R), bulimic (B), and compulsive (C) ED, the plasma concentrations of leptin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin were analyzed by Milliplex and those of acyl ghrelin (AG), des-acyl ghrelin (DAG), and &alpha, melanocyte-stimulating hormone (&alpha, MSH) by ELISA kits. Immunoglobulin G (in response to an antigen) concentrations were analyzed by ELISA, and their affinity for the respective peptide was measured by surface plasmon resonance. The concentrations of leptin, insulin, GLP-1, and PYY were higher in C patients than in R patients. On the contrary, &alpha, MSH, DAG, and AG concentrations were higher in R than in C patients. After adjustment for body mass index (BMI), differences among peptide concentrations were no longer different. No difference in the concentrations of the IgG was found, but the IgG concentrations were correlated with each other. Although differences of peptide concentrations exist among ED subtypes, they may be due to differences in BMI. Changes in the concentration and/or affinity of several anti-peptide IgG may contribute to the physiopathology of ED or may be related to fat mass.

Background/objectives Based on the recent identification of E.coli heat shock protein ClpB as a mimetic of the anorexigenic α-melanocyte stimulating hormone (α-MSH), the objective of this study was to preclinically validate Hafnia alvei, a ClpB-producing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity. Methods The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient E.coli. A food-grade H. alvei HA4597 strain synthetizing the ClpB protein with an α-MSH-like motif was selected as a candidate probiotic to be tested in ob/ob and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the “MetaHIT” database. Results Chronic per os administration of native but not ClpB-deficient E.coli strain reduced body weight gain (p p ob/ob mice. Oral gavage of H.alvei for 18 and 46 days in ob/ob and HFD-fed obese mice, respectively, was well tolerated, reduced body weight gain and fat mass in both obesity models (p ob/ob mice (p H.alvei -treated ob/ob mice (p Enterobacter, Klebsiella and Hafnia. Conclusions H.alvei HA4597 strain reduces food intake, body weight and fat mass gain in hyperphagic and obese mice. These data combined with low enterobacterial ClpB gene abundance in the microbiota of obese humans provide the rationale for using H.alvei as a probiotic for appetite and body weight management in overweight and obesity.

International audience; Anorexia nervosa is a severe eating disorder often associated with physical hyperactivity and is more frequently observed in female sex. Activity-Based Anorexia (ABA) model combines physical activity (PA) and reduced food intake and thus allows a better understanding of the mechanisms underlying anorexia nervosa. We aimed to assess sex differences in response to ABA model in C57Bl/6 mice. Twenty four male and 16 female C57BL/6 mice were studied. ABA mice were placed in individual cages with a continuously recorded activity wheel. ABA mice had a progressive limited food access from 6 h/day (day 6) to 3 h/day (day 9) until the end of the protocol (day 17). Body weight and food intake were daily measured. We studied physical activity during 24 h, during the dark phase (D-PA) and the light phase (L-PA). We also evaluated the feeding anticipatory physical activity (A-PA), the physical activity during food intake period (FI-PA) and the post-prandial physical activity (PP-PA). We observed 16.7% of mortality in males (4 out of 24 mice) during ABA protocol while no female mice died (p = 0.09). At day 17, food intake was significantly higher in females than in males (p < 0.05) that was associated with a lower body weight loss than in females (p < 0.05). Before limited food access, no gender differences in wheel running activity were observed. From day 9, A-PA significantly increased over time in males (p < 0.05 vs females) while females exhibited higher FI-PA and PP-PA (p < 0.05 vs males). Correlations between wheel running activities and, respectively, food intake and body weight loss showed gender differences, in particularly for L-PA and A-PA. Our results suggest a greater susceptibility of male mice to develop ABA, males and females exhibit different patterns of physical activity after limitation of food access. Underlying mechanisms should be further investigated.

Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC from all subjects were binding and activating MC4R, the receptor binding affinity was decreased in obesity. Additionally, α-MSH/IgG IC had lower MC4R-mediated cAMP activation threshold as compared with α-MSH alone in all but not obese subjects. Furthermore, the cellular internalization rate of α-MSH/IgG IC by MC4R-expressing cells was decreased in obese but increased in patients with anorexia nervosa. Moreover, IgG from obese patients prevented central anorexigenic effect of α-MSH. These findings reveal that MC4R is physiologically activated by IC formed by α-MSH/IgG and that different levels and molecular properties of α-MSH-reactive IgG underlie biological activity of such IC relevant to altered appetite in obesity and eating disorders.

International audience; OBJECTIVE: Activity-based anorexia (ABA) in rodents is a behavioral model of anorexia nervosa, characterized by negative energy balance, hyperactivity, and dysbiosis of gut microbiota. Gut bacteria are known to produce energy substrates including adenosine triphosphate (ATP) and acetate. The aim of this study was to determine whether ABA alters the proteome of gut microbiota relevant to ATP and acetate production. METHODS: The ABA was developed in male mice and compared with food-restricted and ad libitum-fed conditions. Proteomic analysis of feces was performed using the two-dimentional gel electrophoresis and mass spectrometry. The in vitro ATP-producing capacity of proteins extracted from feces was assayed. RESULTS: Increased levels of the phosphoglycerate kinase, an ATP-producing glycolytic enzyme, was detected in feces of food-restricted mice and this enzyme was further increased in the ABA group. Starvation also upregulated several other proteins synthetized by order Clostridiales including Clostridiaceae and Lachnospiraceae families. No significant differences in the in vitro ATP-producing capacity by bacterial proteins from ABA, food-restricted, and ad libitum-fed control mice were found. However, plasma levels of acetate strongly tended to be increased in the activity groups including ABA mice. CONCLUSION: The data revealed that starvation in food-restricted and ABA mice induced proteome modification in gut bacteria favoring ATP production mainly by the order Clostridiales. However, this did not result in increased total ATP-production capacity by gut microbiota. These changes can be interpreted as an adaptation of specific gut bacteria to the host malnutrition beneficial for host survival.

Objective. To describe the demographic characteristics, socio-economic status, functional status (autonomy, strength), and health status (cognitive and thymic functions, cardiovascular risk factors, and nutritional status) of the oldest olds living on the Greek island of Ikaria. We also try to explain the longevity observed in this population. Methods. A cross-sectional observational study of people aged 90 and over living in both municipalities of north-western Ikaria (Evdilos and Raches) was conducted over one year, from October 21, 2012 to October 21, 2013. The participants were interviewed (medical history), had a brief clinical examination, and underwent standardized geriatric assessments including the Geriatric Depression Scale (GDS-15), the Mini-Mental-State Examination (MMSE), the Activities of Daily Living (ADL), the Instrumental ADL (IADL), and an assessment of grip strength. Results. Seventy-one persons (37 females, 34 males), aged 94.1 years on average, were interviewed at their homes. Seven percent were current smokers (females 5.4%, males 8.8%). Hypertension was diagnosed in 70.4% of participants, diabetes in 19.7%, hypercholesterolemia in 12.7%, and obesity in 17.2%; 66.0% of the population had one chronic disease or more. The mean score for the GDS-15 scale was 3.7/15.0, 23.7/30.0 for the MMSE, 4.0/6.0 for the ADL, and 4.2/8.0 in females and 3.6/5.0 in males for the IADL. Grip strength was 17.0 kg in females and 26.5 kg in males. Conclusions. This study provides an overview of the socio-demographic and medical characteristics of the oldest olds living in a longevity Blue Zone.

In the present work we explain the anomalous behavior of the attenuation of the longitudinal acoustic phonon in GaAs as a function of the phonon energy $\ensuremath{\omega}$ in the subterahertz domain. These attenuations along the [100] direction show a plateau between 0.6 and 1 GHz at low temperatures. We found an excellent agreement between measurements performed by some of us, and new ab initio calculations of third-order anharmonic processes. The formation of the plateau is explained by the competition between different phonon-phonon scattering processes such as Herring's mechanism, which dominates at low frequencies, saturates, and disappears. The plateau is shown to be determined by the phononic final-state phase space available at a given temperature. We predict that a change of scattering mechanism should also show up in the attenuation of silicon around 1.2--1.7 THz, and argue that the attenuation plateau is a general feature of cubic semiconductors.

Obese subjects display elevated plasma levels of leptin reflecting the phenomenon of leptin resistance. Here, we aimed to determine whether leptin-reactive immunoglobulins (Ig) are present in obese and type 2 diabetes (T2D) patients and whether their plasma levels and affinity kinetics may correlate with obesity and diabetes markers. We show that leptin levels are increased in obese patients with and without T2D. Although mean plasma levels of leptin-reactive IgG were similar between study groups, IgG in obese non-diabetic patients had increased dissociation rate and lower affinity (increased dissociation equilibrium constant value; KD). In controls and diabetic patients, the association rates of leptin IgG correlated negatively with obesity and diabetes markers, respectively. In contrast, KD values correlated positively with plasma leptin levels and obesity traits in our cohort, and with diabetes markers in both the total cohort and in the obese T2D group. Taken together, our data reveal that leptin-reactive IgG are present in healthy subjects, obese, and diabetic patients but display altered affinity kinetics in obesity. Increased IgG binding to leptin in healthy subjects associated with lower body mass index (BMI) suggests an enhancing role of IgG in leptin signaling. Accordingly, a decreased affinity of IgG for leptin, found in obese patients, can be relevant to leptin resistance.

International audience; Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1 nM) together or not with total IgG (1 nM) from obese ob/ob or lean mice before access to food during 8 days of 3 h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food.

Objective Caseinolytic protease B (ClpB) produced by Enterobacteria, such as Escherichia coli, has been identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic and anxiogenic neuropeptide. In mice, ClpB induces α-MSH cross-reactive antibodies and activates anorexigenic brain neurons. In patients with eating disorders (ED), anti-ClpB and anti-α-MSH antibodies correlate with psychopathological traits. However, it is not known if ClpB is present in human plasma including ED patients. Methods Plasma concentrations of ClpB were measured using a recently developed ClpB immunoassay in female patients with anorexia nervosa, bulimia nervosa, and binge-eating disorder and compared with healthy participants, all characterized by the Eating Disorder Inventory-2 (EDI-2) scale. Results We found that ClpB was readably detectable in plasma of healthy participants and ED patients and that its concentrations were elevated in ED patients, without significant differences in patient's subgroups. Plasma ClpB concentrations correlated with the EDI-2 scores, with α-MSH as well as with plasma levels of anti-ClpB and anti-α-MSH antibodies. Discussion These data revealed that bacterial ClpB is naturally present in human plasma and that its concentrations can be elevated in ED patients and associated with ED-related psychopathological traits. These results support a link between bacterial ClpB and the ED pathophysiology. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:805–808)

Identification of mutations at the origin of various phenotypes in donkeys. From 1990s, many results have described punctual mutations in the genes responsible for different colors of dresses of horses, but to day no study had been achieved for the asinine species, which display very different phenotypes although a close phylogenetic neighboring. Our study was designed to try to establish the genetic basis of two features : the long hair dress found in Baudets du Poitou, and the discoloration observed around the muzzle, eyes and limbs and which is called Light Point. We have so adopted an approach by candidate genes from the existing literature in horses and other mammals. By this approach two mutations have been identified in the gene FGF5 responsible for the phenotype long hair and one mutation in the gene ASIP was associated with the phenotype No Light Point., Publiées depuis le début des années 1990, de nombreuses observations décrivent l’effet de mutations ponctuelles affectant les gènes responsables des différentes couleurs de la robe du cheval. Par contre, à ce jour, aucune étude n’a encore été consacrée à l’espèce asine, bien que celle-ci, en dépit de sa grande proximité phylogénique, présente des phénotypes très différents de ceux du cheval. Notre étude permet d’établir les bases génétiques de deux particularités : la robe à poils longs, caractéristique des Baudets du Poitou, et la décoloration observée autour du museau, des yeux et au niveau des membres et appelée Pangaré. Pour accomplir cette analyse, nous utilisons une approche par gènes candidats basée sur les données de la littérature concernant le cheval et d’autres espèces de mammifères. Par cette approche, nous mettons en évidence deux mutations dans le gène FGF5, toutes les deux responsables du phénotype poils longs, et une mutation dans le gène ASIP, associée au phénotype bouchard ou non pangaré., Legrand Romain, Abitbol Marie. Identification de mutations à l’origine de différents phénotypes chez les ânes. In: Bulletin de l'Académie Vétérinaire de France tome 169 n°2, 2016. pp. 110-116.

In obesity or anorexia, changes in body composition and mostly alterations in fat mass distribution are observed. The lymphatic system, which is implicated in fat absorption, might play a major role in the phenotype and development of these pathologies. In this study, two mice animal models were used: the high-fat diet model used for obesity and the activity-based anorexia model for anorexia. Lymphatic system marker levels were measured by reverse transcriptase quantitative polymerase chain reaction on the different parts of the intestine. Moreover, the effects of these models were evaluated on lymphatic fat absorption using lipidic tracer. Using these two models, lymphatic system alterations were observed. Indeed, whether in the obesity or the anorectic model, lymphatic fat absorption modifications were noticed with an increase of this parameter in the anorectic mice and a decrease in obesity. Expression levels of lymphatic markers also were impaired in these models. Both obesity and anorectic models induced lymphatic system alterations mainly in the jejunum and ileum parts of the intestine. These alterations are associated with lipid absorption modifications.

Use of new generation probiotics may become an integral part of the prevention and treatment strategies of obesity. The aim of the present study was to test the efficacy of a potential probiotic strain of lactic bacteria Hafnia alvei (H. alvei) HA4597&trade, in a mouse model of obesity characterized by both hyperphagia and diet-induced adiposity. For this purpose, 10-week-old high-fat-diet (HFD)-fed hyperphagic ob/ob male mice received a daily treatment with 1.4 &times, 1010 CFU of H. alvei for 38 days. Effects of H. alvei were compared to those of a lipase inhibitor orlistat (80 mg/kg daily) and a vehicle (NaCl 0.9%) in HFD-fed ob/ob mice. A control untreated group of ob/ob mice received the standard diet throughout the experiment. The vehicle-treated HFD group displayed increased food intake, worsening of adiposity, and glycemia. Treatment with H. alvei was accompanied by decreased body weight and fat-mass gain along with reduced food intake to the level of the standard-diet-fed mice. At the end of the experiment, the group treated with H. alvei showed a decrease of glycemia, plasma total cholesterol, and alanine aminotransferase. The orlistat-treated mice showed a lower rate of body weight gain but were hyperphagic and hyperglycemic. These results demonstrate the beneficial anti-obesity and metabolic effects of H. alvei HA4597&trade, in mice with obesity resulting from hyperphagia and diet-induced adiposity.

Significance The number of inmates imprisoned for violent aggression is increasing, as are the penitentiaries, but still our understanding of mechanisms underlying criminality is limited. Our analysis of violent aggressor inmates reveals unique properties of IgG reactive with adrenocorticotropic hormone (ACTH). We show that these IgGs can regulate ACTH-induced cortisol secretion in the adrenal gland, and they exhibit a clear-cut difference in ACTH epitope binding in violent aggressors vs. controls. Additionally, IgG from a subset of aggressive subjects selectively bind to hypothalamic vasopressin neurons. Thus, using several in vitro and in vivo approaches, the study reveals a molecular mechanism involved in the variability of stress response relevant to the neurobiology of aggression and possibly other stress-related conditions., Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11–24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1–13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident–intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors’ sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.

Discipline Clinique. Introduction et but de l’etude Les troubles du comportement alimentaires (TCA) sont des pathologies frequentes, dont la physiopathologie implique l’axe microbiote-intestin-cerveau. Plusieurs neuropeptides et hormones sont impliques dans la regulation du comportement alimentaire et du metabolisme energetique. Des etudes ont mis en evidence au cours des TCA la presence d’autoanticorps (AutoAc) diriges contre les neuropeptides orexigenes et anorexigenes, avec des differences de profil (taux/affinite) qui pourraient participer a la deregulation neurobiologique du comportement alimentaire. Evaluer les principaux neuropeptides impliques dans la regulation du comportement alimentaire et les anticorps correspondants au cours des differents TCA : anorexie mentale (AN), boulimie nerveuse (BN) et hyperphagie boulimique (BED). Materiel et methodes Les analyses plasmatiques ont ete realisees chez 120 patients (34 AN, 12 BN et 74 BED) inclus avant traitement dans la cohorte EDILS (Eating Disorder Inventory Longitudinal Study). Les taux de leptine, GLP-1, PYY et insuline, ont ete analyses par Milliplex et ceux d’acyl ghreline, des-acyl ghreline et α-MSH par Elisa. L’affinite des IgG reconnaissant ces peptides a ete mesuree par resonance plasmonique de surface et le taux des IgG analyses par ELISA. Le test de Kruskal-Wallis et de Spearman a ete utilise. Resultats et analyse statistique La leptinemie etait correlee positivement avec l’IMC et plus elevee dans le groupe BED (AN vs BED et BN vs BED : p Conclusion L’elevation des taux de leptine, PYY et GLP-1 au cours de l’hyperphagie soulignent la resistance aux signaux anorexigenes au cours de ce TCA. Inversement, le taux d’α-MSH est plus eleve au cours de l’AN vs BED et associe a une elevation de la ghreline totale, de l’acyl ghreline et de la des-acyl ghreline qui semble donc etre impliquee dans la ghrelinoresistance au cours de l’AN. Ces analyses seront etendues sur un plus grand nombre de patients, pour preciser les profils de deregulation neuropeptidergique au cours des TCA et identifier des cibles therapeutiques.

Ubiquitin proteasome system contributes to the regulation of intestinal inflammatory response as its inhibition is associated with tissue damage improvement. We aimed to evaluate whether glutamine is able to limit inflammation by targeting ubiquitin proteasome system in experimental colitis. Colitis was induced in male rats by intrarectal instillation of 2-4-6-trinitrobenzen sulfonic acid (TNBS) at day 1. From day 2 to day 6, rats daily received either an intrarectal instillation of PBS (TNBS/PBS group) or glutamine (TNBS/Gln). Rats were euthanized at day 7 and colonic samples were taken to evaluate ubiqutinated proteins by proteomic approach combining 2D electrophoresis and immunoblots directed against ubiquitin. Results were then confirmed by evaluating total expression of proteins and mRNA levels. Survival rate, TNFα, and IL-1β mRNA were improved in TNBS/Gln compared with TNBS/PBS (p < 0.05). Proteasome activities were affected by TNBS but not by glutamine. We identified eight proteins that were less ubiquitinated in TNBS/PBS compared with controls with no effect of glutamine. Four proteins were more ubiquitinated in TNBS/PBS group and restored in TNBS/Gln group. Finally, 12 ubiquitinated proteins were only affected by glutamine. Among proteins affected by glutamine, eight proteins (GFPT1, Gapdh, Pkm2, LDH, Bcat2, ATP5a1, Vdac1, and Vdac2) were involved in metabolic pathways. In conclusion, glutamine may regulate ubiquitination process during intestinal inflammation.

Objectives The biological background of sex-related differences in the development of eating disorders (EDs) is unknown. Recent data showed that gut bacteria Escherichia coli induce autoantibodies against anorexigenic α-melanocyte-stimulating hormone (α-MSH) associated with psychopathology in ED. The aim of this study was to compare the effects of E. coli on feeding and autoantibodies against α-MSH and adrenocorticotropic hormone (ACTH), between female and male rats. Methods Commensal E. coli K12 were given in a culture medium daily to adult Wistar rats by intragastric gavage over a 3-wk period; control rats received culture medium only. Results Before gavage, E. coli K12 DNA was detected in feces of female but not male rats. E. coli provision was accompanied by an increase in body weight gain in females, but a decrease in body weight gain and food intake in males. Independent of E. coli treatment, plasma levels of anti-α-MSH and ACTH immunoglobulin (Ig)G were higher in female than male rats. Females responded to E. coli by increasing α-MSH IgG levels and affinity, but males by increasing α-MSH IgM levels. Affinity of IgG for ACTH was increased in both E. coli -treated females and males, although with different kinetics. IgG from females stimulated more efficiently α-MSH-induced cyclic adenosine monophosphate production by melanocortin 4 receptor-expressing cells compared with IgG from males. Discussion Sex-related response to how E. coli affects feeding and anti-melanocortin hormone antibody production may depend on the presence of these bacteria in the gut before E. coli supplementation. These data suggest that sex-related presence of certain gut bacteria may represent a risk factor for ED development.

International audience

Specific peptide molecules classified as hormones, neuropeptides and cytokines are involved in intercellular signaling regulating various physiological processes in all organs and tissues. This justifies the peptidergic signaling as an attractive pharmacological target. Recently, a protein mimetic of a peptide hormone has been identified in Escherichia coli suggesting the potential use of specific bacterial proteins as a new type of peptide-like drugs. We review the scientific rational and technological approaches leading to the identification of the E. coli caseinolytic protease B (ClpB) homologue protein as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), a melanocortin peptide critically involved in the regulation of energy homeostasis in humans and animals. Theoretical and experimental backgrounds for the validation of bacterial ClpB as a potential drug are discussed based on the known E. coli ClpB amino acid sequence homology with α-MSH. Using in silico analysis, we show that other protein sources containing similar to E. coli ClpB α-MSH-like epitopes with potential biological activity may exist in Enterobacteriaceae and in some Brassicaceae. Thus, the original approach leading to the identification of E. coli ClpB as an α-MSH mimetic protein can be applied for the identification of mimetic proteins of other peptide hormones and development of a new type of peptide-like protein-based drugs.

Part of circulating ghrelin is bound to immunoglobulins (Ig) protecting it from degradation and preserving its functional activity. This review summarizes the data on ghrelin- and desacyl- ghrelin-reactive IgG in conditions of altered appetite and energy balance. Plasma levels and affinity kinetics of such IgG were compared in patients with obesity and anorexia nervosa and in animal models of obesity including ob/ob mice, high-fat diet- induced obese mice and obese Zucker rats as well as in mice after chronic food restriction and activity-based anorexia and in rats with methotrexate-induced anorexia. We show that plasmatic IgG in both obese humans and animals are characterized by increased affinity for ghrelin. In contrast, patients with anorexia nervosa and anorectic rodents all show lower affinity of ghrelin- and desacyl-ghrelin- reactive IgG, respectively, the changes which were not observed in non-anorectic, chronically starved mice. We also show that affinity of ghrelin-reactive IgG correlate with plasma levels of ghrelin. These data point to common mechanisms underlying modifications of affinity kinetics properties of ghrelin-reactive IgG during chronic alterations of energy balance in humans and rodents and support a functional role of such autoantibodies in ghrelin-mediated regulation of appetite.

International audience; We present experimental results on the light-to-sound transduction by a superlattice embedded in an optical microcavity, using picosecond ultrasonics. Experiments on the ability to generate and detect phonons at 0.3 and 0.6 THz were performed at low temperature. Finally, we demonstrate that such a device can detect the acoustic burst that it has generated and which has propagated through the substrate, been reflected on the backside of the substrate and has returned to the device. We study the efficiency of this detection by varying independently the laser wavelength of the pump and probe, by means of asynchronous optical sampling.

The introduction of the Euro in January 1999 consecrated the achievement of a single currency system within most of the European Union. Despite the dramatic change in the macroeconomic dynamics that this event is likely to have caused, the literature has paid little attention to testing for the existence of such a break and establishing its qualitative characteristics. This empirical study, based on the Blanchard and Quah (1989) methodology for seven countries having adopted the Euro currency and three members of the European Union which have preserved their own currencies reveals: i) very significant breaks for the Euro countries around 1992 – the year of adoption of the Maastricht Treaty – and 2000, not shared by the three non-Euro countries. ii) an increase in the influence of supply shocks on the dynamics of output, unemployment and the interest rate after the breaks for the Euro countries, along with an increase of the part played by monetary disturbances within total demand at long horizons. These conclusions do not generally hold for the three non-Euro countries.

Anti-α-melanocyte-stimulating hormone (α-MSH) polyclonal antibodies have been used for α-MSH neutralization in functional studies, but the results are sometime inconsistent with the antibody expected blocking properties. The present study aimed to determine if rabbit (Rb) anti-α-MSH immunoglobulins (Ig) may inhibit or enhance α-MSH signaling on melanocortin receptor type 4 (MC4R) and α-MSH-induced anorexigenic effect if presented as immune complexes with α-MSH. Polyclonal Rb anti-α-MSH IgG were commercially available and their ability to bind α-MSH has been confirmed by the immunohistochemical detection of α-MSH neurons in the rat hypothalamus. In vitro assay of the cyclic-adenosine mono-phosphate (cAMP) secreted by cells transfected with MC4R was performed to analyze effect of Rb IgG on α-MSH-induced cAMP production. We found that adding Rb IgG to α-MSH resulted in stimulation of cAMP detected at lower peptide concentrations as compared to α-MSH alone. To determine effects of Rb IgG on food intake, rats were injected into the arcuate hypothalamic nucleus with either α-MSH, Rb IgG alone or Rb IgG preincubated with α-MSH. During 2 days after injections, food intake was increased in both groups of rats receiving Rb IgG. However, during following 4 days when food was restricted to 1h/day, only the Rb IgG group displayed higher food intake. Furthermore, after the refeeding, 24h food intake was lower in rats receiving Rb IgG - α-MSH immune complexes. This group of rats was also characterized by higher number of immunopositive neurons in the arcuate nucleus expressing α-MSH and agouti-related protein but not tyrosine hydroxylase. Taken together, these results show that Rb anti-α-MSH antisera, although efficient for immunohistochemical detection of α-MSH, does not always display α-MSH blocking properties but, in contrast, may enhance α-MSH binding to MC4R and increase α-MSH anorexigenic effects when presented as immune complexes with the peptide.

Microbiota contributes to the regulation of eating behavior and might be implicated in the pathophysiology of anorexia nervosa. ClpB (Caseinolytic peptidase B) protein produced mainly by the Enterobacteriaceae family has been identified as a conformational mimetic of &alpha, MSH, which could result in similar anorexigenic effects. The aim of this study was to highlight the role of the microbiome and the ClpB protein in deregulation and self-maintenance of anorexia pathology. Male C57Bl/6 mice were undergone to the ABA (Activity-Based Anorexia) protocol: after 5 days of acclimatization, both ABA and LFA (Limited Food Access) mice had progressively limited access to food until D17. At the end of protocol, the plasma ClpB concentration and Enterobacteriaceae DNA in colonic content were measured. As expected, dietary restriction induced lost weight in LFA and ABA mice. At D10, colonic permeability and plasma concentration of the ClpB protein were significantly increased in LFA and ABA mice vs. controls. At D17, plasma concentration of ClpB was increased in LFA and ABA mice and, it was correlated with proportion of Enterobacteriaceae in the faeces. These abnormally high ClpB concentrations and all associated factors, and therefore might contribute to the initiation and/or perpetuation of anorexia nervosa by interfering with satiety signaling.

Elevated levels of corticotropin (ACTH)-reactive immunoglobulins (ACTH IgG) were found in mates with conduct disorder, suggesting their involvement in the biology of antisocial behavior. We first aimed to confirm these findings in a large general population sample of adolescents. Secondly, we studied the association between ACTH IgG levels and hypothalamic-pituitary-adrenal (HPA) axis response to stress.Free and total ACTH IgG levels were measured in sera of 1230 adolescents (15-18 years). HPA axis activity was determined by measuring salivary cortisol before, during, and after a social stress test. Antisocial behavior was assessed using the Antisocial Behavior Questionnaire. ACTH peptide and IgG affinity kinetics for ACTH were assayed in a subsample of 90 adolescents selected for high or low ACTH IgG levels.In boys, higher total ACTH IgG levels were associated with higher antisocial behavior scores (beta = 1.05, p = 0.04), especially at high levels of free ACTH IgG. In girls, antisocial behavior was associated with low free ACTH IgG levels (beta = -0.20, p = 0.04). Stress-induced cortisol release was associated with free ACTH IgG in boys (beta(area under the curve) = -0.67, p These data show that ACTH IgG levels are related to antisocial behavior and HPA axis response to stress in adolescents. The mechanisms behind these associations, including different ACTH binding properties of IgG in subjects with antisocial behavior, deserve further attention. (C) 2013 Elsevier Ltd. All rights reserved.

International audience; Background and aims: Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia–cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig). To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX).Methods: Rats received MTX (2.5 mg/kg, subcutaneously) for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively.Results: In MTX-treated anorectic rats, the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p < 0.001) as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p < 0.05 and 98.3%, p < 0.01, respectively). In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2 and 88.4%, respectively, both p < 0.001), and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior.Conclusion: MTX-induced anorexia, weight loss, and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties. Such changes of ghrelin-reactive IgG may underlie their decreased ghrelin-transporting capacities compromising ghrelin orexigenic and anxiolytic effects and contributing to chemotherapy-induced loss of appetite.

International audience; ObjectivesMechanisms of high-fat diet (HFD)–induced obesity may involve ghrelin, an orexigenic and adipogenic hormone secreted by the stomach. Previous studies showed that obese subjects may display higher numbers of ghrelin-producing cells and increased affinity of plasma immunoglobulins (Ig) for ghrelin, protecting it from degradation. The aim of this study was to determine if a HFD in mice would increase the number of ghrelin-expressing cells and affinity of ghrelin-reactive IgG.MethodsObesity in mice was induced by consumption of a 13-wk HFD. The number of preproghrelin mRNA-expressing cells in the stomach was analyzed by in situ hybridization and compared with chow-fed, nonobese controls and with genetically obese ob/ob mice. Affinity of ghrelin-reactive IgG was analyzed using surface plasmon resonance. Plasma levels of ghrelin and des-acyl ghrelin were measured.ResultsHFD resulted in 30% of body fat content versus only 8% in controls (P < 0.001). The number of preproghrelin mRNA-producing cells was 15% (P < 0.05) higher in HFD-fed mice than in controls, contrasting with ob/ob mice, having a 41% (P < 0.001) decrease. Both models of obesity had normal plasma levels of ghrelin but a decrease of its des-acylated form. Ghrelin-reactive IgG affinity was found in the micromolar range with mean values of the dissociation equilibrium constant 1.5-fold (P < 0.05) lower in HFD-fed versus control mice.ConclusionResults from the present study showed that HFD in mice induces obesogenic changes, including increased numbers of ghrelin precursor-expressing cells and increased affinity of ghrelin-reactive IgG. Such changes may contribute to the mechanisms of HFD-induced obesity.

A role of gut-brain axis emerges in the pathophysiology of anorexia nervosa and maintaining adapted physical activity during refeeding remains discussed. We aimed to assess gastrointestinal protein metabolism and investigate the contribution of physical activity during refeeding in C57BL/6 mice with activity-based anorexia (ABA). ABA mice exhibited lower body weight and food intake with increase of lean mass/fat mass ratio and fat oxidation. Colonic permeability was increased in ABA. Ad libitum food access was then restored and ABA group was divided into two subgroups, with access to running wheel (ABA-PA) or not (ABA-NPA). After refeeding, fat free mass was completely restored only in ABA-PA. Colonic permeability was enhanced in ABA-NPA. Finally, muscle kynurenine conversion into kynurenic acid was lower in ABA-NPA who also exhibited altered behavior. Maintaining physical activity during refeeding may thus limit colonic hyperpermeability and improve behavior in anorectic mice.

International audience; The composition of gut microbiota has been associated with host metabolic phenotypes, but it is not known if gut bacteria may influence host appetite. Here we show that regular nutrient provision stabilizes exponential growth of E. coli, with the stationary phase occurring 20 min after nutrient supply accompanied by bacterial proteome changes, suggesting involvement of bacterial proteins in host satiety. Indeed, intestinal infusions of E. coli stationary phase proteins increased plasma PYY and their intraperitoneal injections suppressed acutely food intake and activated c-Fos in hypothalamic POMC neurons, while their repeated administrations reduced meal size. ClpB, a bacterial protein mimetic of alpha-MSH, was upregulated in the E. coli stationary phase, was detected in plasma proportional to ClpB DNA in feces, and stimulated firing rate of hypothalamic POMC neurons. Thus, these data show that bacterial proteins produced after nutrient-induced E. coli growth may signal meal termination. Furthermore, continuous exposure to E. coli proteins may influence long-term meal pattern.

L’Allemagne occupe en Europe une place singuliere du fait d’avoir connu, sur la periode post-1970, deux changements structurels majeurs : tout d’abord la reunification de la rfa et de la rda en 1990, puis l’entree en vigueur de l’euro en janvier 1999.Cet article propose de dater de maniere endogene la presence d’une ou plusieurs ruptures dans le processus dynamique joint du produit et du taux de chomage, et de tester formellement leur significativite. En suivant la methodologie developpee par Blanchard et Quah [1989], il identifie les contributions respectives des chocs d’offre et de demande agreges, avant et apres la rupture estimee.Cette etude empirique, menee sur des donnees posterieures a 1979, revele : une rupture fortement significative situee a la fin de l’annee 1997, l’annee de l’entree en vigueur du Pacte de stabilite et de croissance ; une predominance de la composante offre dans les fluctuations du produit pour la periode precedant immediatement la mise en place de l’euro ; cette predominance reste verifiee pour les deux variables apres la rupture, a court terme pour le chomage et a moyen terme pour le produit.

Background Seven donkey breeds are recognized by the French studbook and are characterized by a black, bay or grey coat colour including light cream-to-white points (LP). Occasionally, Normand bay donkeys give birth to dark foals that lack LP and display the no light points (NLP) pattern. This pattern is more frequent and officially recognized in American miniature donkeys. The LP (or pangare) phenotype resembles that of the light bellied agouti pattern in mouse, while the NLP pattern resembles that of the mammalian recessive black phenotype; both phenotypes are associated with the agouti signaling protein gene (ASIP). Findings We used a panel of 127 donkeys to identify a recessive missense c.349 T > C variant in ASIP that was shown to be in complete association with the NLP phenotype. This variant results in a cysteine to arginine substitution at position 117 in the ASIP protein. This cysteine is highly-conserved among vertebrate ASIP proteins and was previously shown by mutagenesis experiments to lie within a functional site. Altogether, our results strongly support that the identified mutation is causative of the NLP phenotype. Conclusions Thus, we propose to name the c.[349 T > C] allele in donkeys, the anlp allele, which enlarges the panel of coat colour alleles in donkeys and ASIP recessive loss-of-function alleles in animals. Electronic supplementary material The online version of this article (doi:10.1186/s12711-015-0112-x) contains supplementary material, which is available to authorized users.

Introduction et but de l’etude L’anorexie mentale, trouble du comportement alimentaire restrictif, est souvent associe a des troubles fonctionnels intestinaux a type de constipation severe et de troubles de la vidange gastrique qui peuvent etre un frein a la renutrition. Les mecanismes impliques dans ces troubles sont cependant peu documentes. Le but de ce travail etait donc d’evaluer la vidange gastrique au cours du modele d’anorexie appele Activity-Based Anorexia (ABA) et d’explorer les mecanismes mis en jeu. Materiel et methodes Des souris femelles C57Bl/6 (n = 8/groupe) ont ete placees dans des cages avec une roue d’activite (ABA) ou non (groupe Controle et groupe acces limite a l’alimentation ou LFA). Les souris ABA et LFA ont eu un acces progressivement limite a l’alimentation de 6 h/jour a j6, a 3 h/jour a j9 et ce, jusqu’a la fin des experiences. A j17, apres une nuit de jeune et un acces a l’alimentation d’une heure, une mesure de la vidange gastrique (VG) a ete realisee en utilisant la formule suivante : VG ( %) = (1- poids sec du contenu gastrique/prise alimentaire) x 100. A partir des extraits gastriques (antre), une analyse proteomique comparative basee sur des gels 2D-PAGE a ete realisee, ainsi qu’une mesure de la synthese proteique par injection i.p. de puromycine 20 minutes avant l’euthanasie. Resultats et analyse statistique A j17, les souris ABA avaient une perte de poids plus prononcee que les souris LFA (−13,59 ± 2,05 % vs −8,06 ± 1,08 %) et une prise alimentaire cumulee plus faible (p Conclusion Le ralentissement de la vidange gastrique observe dans le modele ABA semble secondaire a la denutrition. L’implication de la diminution d’expression des proteines KRT19, DESM et KRT8 devra etre evaluee ainsi que le role du stress oxydant.

BACKGROUND Anorexia nervosa, a restrictive eating disorder, is often associated with gastrointestinal disorders, particularly a delayed gastric emptying. However, the mechanisms remained poorly documented. Thus, we aimed to evaluate gastric emptying and antrum protein metabolism in the Activity-Based Anorexia model (ABA). METHODS Females C57Bl/6 mice were randomized into 3 groups: Control, ABA, and Limited Food Access (LFA). Food access has been progressively limited from 6 h/day at day 6 to 3 h/day at day 9 and until day 17. ABA mice had free access to an activity wheel. Gastric emptying was assessed. On gastric extracts, a proteomic analysis was performed, as well as an evaluation of protein synthesis and protein oxidation. KEY RESULTS Both LFA and ABA mice exhibited a delayed gastric emptying compared with Controls (P

Phonon mean free path is generally inferred from the measurement of thermal conductivity and we are still lacking precise information on this quantity. Recent advances in the field of high frequency phonons transduction using semiconductor superlattices give the opportunity to fill this gap. We present experimental results on the attenuation of longitudinal acoustic phonons in GaAs in the frequency and temperature ranges 0.2-1THz and 10-80K respectively. Surprisingly, we observe a plateau, in the frequency dependence of the attenuation, above 0.4THz, that we ascribe to a breakdown of Herring processes., 9 pages, 4 figures

International audience; α-Melanocyte-stimulating hormone (α-MSH), is a hypothalamic neuropeptide signaling satiation, but it is not known if α-MSH may stimulate dopamine release in a feeding control brain region of the lateral hypothalamic area (LHA), during the anticipatory and consummatory phases of feeding behavior. To address these questions, dynamics of dopamine release were measured in 15 min microdialysis samples simultaneously from the LHA and the nucleus accumbens (NAc) during consecutive exposure and provision of food and 1% sucrose in Wistar rats after overnight food deprivation. α-MSH was infused via the microdialysis probe either into the LHA or NAc starting before food exposure. Food, sucrose and water intakes were automatically monitored and analyzed concomitantly with microdialysis samples. We found that LHA-α-MSH-infused rats stopped eating earlier and consumed less food and sucrose as compared to control and NAc-α-MSH-infused rats. Exposure to food produced a peak of LHA dopamine in both LHA-α-MSH and NAc-α-MSH-infused rats but not in the controls. During food provision, LHA dopamine levels were strongly elevated in LHA-α-MSH infused rats, while delivery of α-MSH into the NAc induced a less intense increase of dopamine in both NAc and LHA. In all rats, LHA dopamine levels correlated inversely with sucrose intake. In conclusion, our study showed that α-MSH stimulates dopamine release in the LHA during both the anticipatory and consummatory phases of feeding, decreases food intake and inhibits sucrose intake. These data suggest that LHA dopamine release can be involved in α-MSH anorexigenic effects.

Chronic delivery of neuropeptides in the brain is a useful experimental approach to study their long-term effects on various biological parameters. In this work, we tested albumin-alginate microparticles, as a potential delivery system, to study if continuous release in the hypothalamus of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, may result in a long-term decrease in food intake and body weight. The 2-week release of α-MSH from peptide-loaded particles was confirmed by an in vitro assay. Then, daily food intake and body weight were studied for 18 days in rats injected bilaterally into the paraventricular hypothalamic nucleus with particles loaded or not with α-MSH. A decrease in body weight gain, persisting throughout the study, was found in rats injected with α-MSH-charged particles as compared with rats receiving non-charged particles and with rats injected with the same dose of α-MSH in solution. Food intake was significantly decreased for 3 days in rats receiving α-MSH-loaded particles and it was not followed by the feeding rebound effect which appears after food restriction. The presence of α-MSH-loaded particles in the hypothalamus was confirmed by immunohistochemistry. In conclusion, our study validates albumin-alginate microparticles as a new carrier system for long-term delivery of neuropeptides in the brain and demonstrates that chronic delivery of α-MSH in the hypothalamus results in a prolonged suppression of food intake and a decrease of body weight gain in rats.

International audience; The seven donkey breeds recognised by the French studbook are characterised by few coat colours: black, bay and grey. Normand bay donkeys seldom give birth to red foals, a colour more commonly seen and recognised in American miniature donkeys. Red resembles the equine chestnut colour, previously attributed to a mutation in the melanocortin 1 receptor gene (MC1R). We used a panel of 124 donkeys to identify a recessive missense c.629T>C variant in MC1R that showed a perfect association with the red coat colour. This variant leads to a methionine to threonine substitution at position 210 in the protein. We showed that methionine 210 is highly conserved among vertebrate melanocortin receptors. Previous in silico and in vitro analyses predicted this residue to lie within a functional site. Our in vivo results emphasised the pivotal role played by this residue, the alteration of which yielded a phenotype fully compatible with a loss of function of MC1R. We thus propose to name the c.629T>C allele in donkeys the e allele, which further enlarges the panel of recessive MC1R loss-of-function alleles described in animals and humans.