L'écologie alimentaire d'Eucladoceros ctenoides : un outil pour suivre les variations environnementales régionales en Europe au Pléistocène inférieur

The early Pleistocene is represented by a succession of glacial-interglacial cycles character-ized by a general tendency towards global cooling, with increasing aridity and seasonality.The large deer Eucladoceros is found in abundance in Europe during this period of faunaldispersions. The dietary plasticity of Eucladoceros and how it can mirror early Pleistoceneclimatic variations will be explored here using Dental Microwear Texture Analysis. Thewide range of dental microwear textures for Eucladoceros reflects a low selectivity and highplasticity in its diet. It is an appropriate proxy to track vegetal resource availability. Oscil-lations were identified between a browsing and a grazing signal. This study proposes thata browsing signal is associated with a fossil assemblage deposited during an interglacialevent characterized by warmer temperatures and deciduous vegetation. A grazing signalmore likely indicates a glacial event with cooler temperatures and a developed herbaceous,bushy layer.Le Pléistocène inférieur correspond à une succession de cycles glaciaires-interglaciairescaractérisée par une tendance générale au refroidissement global, avec une aridité et unesaisonnalité croissantes. Le cervidé de grande taille Eucladoceros est abondant en Europedurant cette période de dispersions fauniques. Grâce à l'analyse de texture de la micro-usuredentaire, nous explorons la plasticité alimentaire d'Eucladoceros et la manière dont celle-ci reflète les variations climatiques du Pléistocène inférieur. La large gamme de texturesde micro-usure dentaire d'Eucladoceros reflète sa faible sélectivité et sa forte plasticité ali-mentaire. De fait, il constitue un outil approprié pour aborder la disponibilité en ressources végétales dans le milieu. Nous identifions des oscillations entre un signal brouteur et unsignal paisseur. Nous proposons qu'un signal brouteur soit associé à un assemblage fossiledéposé lors d'un évènement interglaciaire caractérisé par des températures plus chaudeset une végétation décidue, tandis qu'un signal paisseur correspondrait plutôt à un évène-ment glaciaire, avec des températures plus froides et la présence d?une strate herbacée etarbustive développée.This project was supported by the “Agence nationale dela recherche” (ANR TRIDENT: grant number: ANR-13-JSV7-0008-01; PI.: Gildas Merceron)

Deer in an arid habitat: dental microwear textures track feeding adaptability

Teeth constitute a bridge between an organism and its environment. Dental wear is a good proxy for (paleo) ecologists to better comprehend the ecology and habitat of modern and extinct species. In this study, we showed Dental Microwear Texture Analysis to be a useful tool, integrating not only specific plant selection but also dietary quality and digestibility in order to understand resource use. Resource-partitioning, seasonal and sexual variations in the diet of two deer species on a Spanish game estate are explored here through Dental Microwear Texture Analysis. This Mediterranean área is on the fringes of the average European environments in terms of constraints and diet for extant red and fallow deer, resulting in an opportunity to understand their ability to live in harsh conditions and the feeding strategies they developed. These two taxa already experienced harsh living conditions during the Pleistocene. Dental microwear texture shows both deer feeding differently on the herbaceous layer in a context where it is the main resource consumed annually. These differences are linked to body mass. With its smaller incisor arcade, Dama dama is able to be more selective, hence focusing on less fibrous parts of forages. Cervus elaphus is more plastic, with dietary variations corresponding to seasonal plant availability and the physiological requirements of stags and does. In general, C. elaphus consumes a more fibrous and less digestible vegetable material tan D. dama. This study brings light on the feeding behavior of the two game species under constraint conditions. The results of this study are discussed in terms of realized vs potential ecological niches.This work was supported by the Agence Nationale de la Recherche (ANR TRIDENT: grant number: ANR-13-JSV7-0008-01; PI: Gildas MERCERON) and the project P07-RNM-03087 from the Consejería de Innovacion Ciencia y Empresa, Junta de Andalucía, by the Organismo Autonomo de Parques Nacionales, Ministerio de Medio Ambiente, Medio Rural y Marino, Spain, and by the European Fund for Regional Development (FEDER)

Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules

Household Exposure to Pesticides and Risk of Childhood Hematopoietic Malignancies: The ESCALE Study (SFCE)

International audienceOBJECTIVES: We investigated the role of household exposure to pesticides in the etiology of childhood hematopoietic malignancies. METHODS: The national registry-based case-control study ESCALE (Etude sur les cancers de l'enfant) was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and sex. Maternal household use of pesticides during pregnancy and paternal use during pregnancy or childhood were reported by the mothers in a structured telephone questionnaire. Insecticides (used at home, on pets, or for garden crops), herbicides, and fungicides were distinguished. We estimated odds ratios (ORs) using unconditional regression models closely adjusting for age, sex, degree of urbanization, and type of housing (flat or house). RESULTS: We included a total of 764 cases of acute leukemia (AL), 130 of Hodgkin lymphoma (HL), 166 of non-Hodgkin lymphoma (NHL), and 1,681 controls. Insecticide use during pregnancy was significantly associated with childhood AL [OR = 2.1; 95% confidence interval (CI), 1.7-2.5], both lymphoblastic and myeloblastic, NHL (OR = 1.8; 95% CI, 1.3-2.6), mainly for Burkitt lymphoma (OR = 2.7; 95% CI, 1.6-4.5), and mixed-cell HL (OR = 4.1; 95% CI, 1.4-11.8), but not nodular sclerosis HL (OR = 1.1; 95% CI, 0.6-1.9). Paternal household use of pesticides was also related to AL (OR = 1.5; 95% CI, 1.2-1.8) and NHL (OR = 1.7; 95% CI, 1.2-2.6); but for AL the relationships did not remain after adjustment for maternal pesticide use during pregnancy. CONCLUSION: The study findings strengthen the hypothesis that domestic use of pesticides may play a role in the etiology of childhood hematopoietic malignancies. The consistency of the findings with those of previous studies on AL raises the question of the advisability of preventing pesticide use by pregnant women

A whole-grain cereal-rich diet increases plasma betaine, and tends to decrease total and LDL-cholesterol compared with a refined-grain diet in healthy subjects

Epidemiological studies have repeatedly found that whole-grain (WG) cereal foods reduce the risk of several lifestyle-related diseases, though consistent clinical outcomes and mechanisms are elusive. To compare the effects of a WG-rich diet with a matched refined-grain (RG) diet on plasma biomarkers and bowel health parameters, seventeen healthy subjects (eleven females and six males) completed an exploratory cross-over study with a 2-week intervention diet based on either WG- or RG-based foods, separated by a washout of at least 5 weeks. Both diets were the same except for the use of WG (150g/d) or RG foods. Subjects undertook a 4h postprandial challenge on day 8 of each intervention diet. After 2 weeks, the WG diet tended to decrease plasma total and LDL-cholesterol (both P=0·09), but did not change plasma HDL-cholesterol, fasting glucose, C-reactive protein or homocysteine compared with the RG diet. Plasma betaine and alkylresorcinol concentrations were elevated after 1 week of the WG diet (P=0·01 and P<0·0001, respectively). Clostridium leptum populations in faeces were increased after the WG diet, along with a trend for decreased faecal water pH (P=0·096) and increased stool frequency (P<0·0001) compared with the RG diet. A short controlled intervention trial with a variety of commercially available WG-based products tended to improve biomarkers of CVD compared with a RG diet. Changes in faecal microbiota related to increased fibre fermentation and increased plasma betaine concentrations point to both fibre and phytochemical components of WG being important in mediating any potential health effect

Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

International audienceBACKGROUND: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome. CONCLUSION/SIGNIFICANCE: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL

Antihypertensive Drug Guanabenz Is Active In Vivo against both Yeast and Mammalian Prions

Background: Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans. [br/] Methodology/Principal Findings: Here we report the discovery of the in vivo antiprion activity of Guanabenz (GA), an agonist of a2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast prions using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrPSc clearance in a cell-based assay. These effects are very specific as evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on a2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prolonging slightly but significantly the survival of treated animals. [br/] Conclusion/Significance: GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based diseases. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men