The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Constraints on the structure and seasonal variations of Triton's atmosphere from the 5 October 2017 stellar occultation and previous observations

Context. A stellar occultation by Neptune's main satellite, Triton, was observed on 5 October 2017 from Europe, North Africa, and the USA. We derived 90 light curves from this event, 42 of which yielded a central flash detection. Aims. We aimed at constraining Triton's atmospheric structure and the seasonal variations of its atmospheric pressure since the Voyager 2 epoch (1989). We also derived the shape of the lower atmosphere from central flash analysis. Methods. We used Abel inversions and direct ray-tracing code to provide the density, pressure, and temperature profiles in the altitude range similar to 8 km to similar to 190 km, corresponding to pressure levels from 9 mu bar down to a few nanobars. Results. (i) A pressure of 1.18 +/- 0.03 mu bar is found at a reference radius of 1400 km (47 km altitude). (ii) A new analysis of the Voyager 2 radio science occultation shows that this is consistent with an extrapolation of pressure down to the surface pressure obtained in 1989. (iii) A survey of occultations obtained between 1989 and 2017 suggests that an enhancement in surface pressure as reported during the 1990s might be real, but debatable, due to very few high S/N light curves and data accessible for reanalysis. The volatile transport model analysed supports a moderate increase in surface pressure, with a maximum value around 2005-2015 no higher than 23 mu bar. The pressures observed in 1995-1997 and 2017 appear mutually inconsistent with the volatile transport model presented here. (iv) The central flash structure does not show evidence of an atmospheric distortion. We find an upper limit of 0.0011 for the apparent oblateness of the atmosphere near the 8 km altitude.J.M.O. acknowledges financial support from the Portuguese Foundation for Science and Technology (FCT) and the European Social Fund (ESF) through the PhD grant SFRH/BD/131700/2017. The work leading to these results has received funding from the European Research Council under the European Community's H2020 2014-2021 ERC grant Agreement nffi 669416 "Lucky Star". We thank S. Para who supported some travels to observe the 5 October 2017 occultation. T.B. was supported for this research by an appointment to the National Aeronautics and Space Administration (NASA) Post-Doctoral Program at the Ames Research Center administered by Universities Space Research Association (USRA) through a contract with NASA. We acknowledge useful exchanges with Mark Gurwell on the ALMA CO observations. This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium).Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. J.L.O., P.S.-S., N.M. and R.D. acknowledge financial support from the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award to the Instituto de Astrofisica de Andalucia (SEV-2017-0709), they also acknowledge the financial support by the Spanish grant AYA-2017-84637-R and the Proyecto de Excelencia de la Junta de Andalucia J.A. 2012-FQM1776. The research leading to these results has received funding from the European Union's Horizon 2020 Research and Innovation Programme, under Grant Agreement no. 687378, as part of the project "Small Bodies Near and Far" (SBNAF). P.S.-S. acknowledges financial support by the Spanish grant AYA-RTI2018-098657-J-I00 "LEO-SBNAF". The work was partially based on observations made at the Laboratorio Nacional de Astrofisica (LNA), Itajuba-MG, Brazil. The following authors acknowledge the respective CNPq grants: F.B.-R. 309578/2017-5; R.V.-M. 304544/2017-5, 401903/2016-8; J.I.B.C. 308150/2016-3 and 305917/2019-6; M.A. 427700/20183, 310683/2017-3, 473002/2013-2. This study was financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior -Brasil (CAPES) -Finance Code 001 and the National Institute of Science and Technology of the e-Universe project (INCT do e-Universo, CNPq grant 465376/2014-2). G.B.R. acknowledges CAPES-FAPERJ/PAPDRJ grant E26/203.173/2016 and CAPES-PRINT/UNESP grant 88887.571156/2020-00, M.A. FAPERJ grant E26/111.488/2013 and A.R.G.Jr. FAPESP grant 2018/11239-8. B.E.M. thanks CNPq 150612/2020-6 and CAPES/Cofecub-394/2016-05 grants. Part of the photometric data used in this study were collected in the frame of the photometric observations with the robotic and remotely controlled telescope at the University of Athens Observatory (UOAO; Gazeas 2016). The 2.3 m Aristarchos telescope is operated on Helmos Observatory by the Institute for Astronomy, Astrophysics, Space Applications and Remote Sensing of the National Observatory of Athens. Observations with the 2.3 m Aristarchos telescope were carried out under OPTICON programme. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 730890. This material reflects only the authors views and the Commission is not liable for any use that may be made of the information contained therein. The 1. 2m Kryoneri telescope is operated by the Institute for Astronomy, Astrophysics, Space Applications and Remote Sensing of the National Observatory of Athens. The Astronomical Observatory of the Autonomous Region of the Aosta Valley (OAVdA) is managed by the Fondazione Clement Fillietroz-ONLUS, which is supported by the Regional Government of the Aosta Valley, the Town Municipality of Nus and the "Unite des Communes valdotaines Mont-Emilius". The 0.81 m Main Telescope at the OAVdA was upgraded thanks to a Shoemaker NEO Grant 2013 from The Planetary Society. D.C. and J.M.C. acknowledge funds from a 2017 'Research and Education' grant from Fondazione CRT-Cassa di Risparmio di Torino. P.M. acknowledges support from the Portuguese Fundacao para a Ciencia e a Tecnologia ref. PTDC/FISAST/29942/2017 through national funds and by FEDER through COMPETE 2020 (ref. POCI010145 FEDER007672). F.J. acknowledges Jean Luc Plouvier for his help. S.J.F. and C.A. would like to thank the UCL student support observers: Helen Dai, Elise Darragh-Ford, Ross Dobson, Max Hipperson, Edward Kerr-Dineen, Isaac Langley, Emese Meder, Roman Gerasimov, Javier Sanjuan, and Manasvee Saraf. We are grateful to the CAHA, OSN and La Hita Observatory staffs. This research is partially based on observations collected at Centro Astronomico HispanoAleman (CAHA) at Calar Alto, operated jointly by Junta de Andalucia and Consejo Superior de Investigaciones Cientificas (IAA-CSIC). This research was also partially based on observation carried out at the Observatorio de Sierra Nevada (OSN) operated by Instituto de Astrofisica de Andalucia (CSIC). This article is also based on observations made with the Liverpool Telescope operated on the island of La Palma by Liverpool John Moores University in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias with financial support from the UK Science and Technology Facilities Council. Partially based on observations made with the Tx40 and Excalibur telescopes at the Observatorio Astrofisico de Javalambre in Teruel, a Spanish Infraestructura Cientifico-Tecnica Singular (ICTS) owned, managed and operated by the Centro de Estudios de Fisica del Cosmos de Aragon (CEFCA). Tx40 and Excalibur are funded with the Fondos de Inversiones de Teruel (FITE). A.R.R. would like to thank Gustavo Roman for the mechanical adaptation of the camera to the telescope to allow for the observation to be recorded. R.H., J.F.R., S.P.H. and A.S.L. have been supported by the Spanish projects AYA2015-65041P and PID2019-109467GB-100 (MINECO/FEDER, UE) and Grupos Gobierno Vasco IT1366-19. Our great thanks to Omar Hila and their collaborators in Atlas Golf Marrakech Observatory for providing access to the T60cm telescope. TRAPPIST is a project funded by the Belgian Fonds (National) de la Recherche Scientifique (F.R.S.-FNRS) under grant PDR T.0120.21. TRAPPIST-North is a project funded by the University of Liege, and performed in collaboration with Cadi Ayyad University of Marrakesh. E.J. is a FNRS Senior Research Associate

Constraints on the structure and seasonal variations of Triton’s atmosphere from the 5 October 2017 stellar occultation and previous observations⋆

Context. A stellar occultation by Neptune's main satellite, Triton, was observed on 5 October 2017 from Europe, North Africa, and the USA. We derived 90 light curves from this event, 42 of which yielded a central flash detection. Aims. We aimed at constraining Triton's atmospheric structure and the seasonal variations of its atmospheric pressure since the Voyager 2 epoch (1989). We also derived the shape of the lower atmosphere from central flash analysis. Methods. We used Abel inversions and direct ray-tracing code to provide the density, pressure, and temperature profiles in the altitude range ∼8 km to ∼190 km, corresponding to pressure levels from 9 μbar down to a few nanobars. Results. (i) A pressure of 1.18 ± 0.03 μbar is found at a reference radius of 1400 km (47 km altitude). (ii) A new analysis of the Voyager 2 radio science occultation shows that this is consistent with an extrapolation of pressure down to the surface pressure obtained in 1989. (iii) A survey of occultations obtained between 1989 and 2017 suggests that an enhancement in surface pressure as reported during the 1990s might be real, but debatable, due to very few high S/N light curves and data accessible for reanalysis. The volatile transport model analysed supports a moderate increase in surface pressure, with a maximum value around 2005-2015 no higher than 23 μbar. The pressures observed in 1995-1997 and 2017 appear mutually inconsistent with the volatile transport model presented here. (iv) The central flash structure does not show evidence of an atmospheric distortion. We find an upper limit of 0.0011 for the apparent oblateness of the atmosphere near the 8 km altitude

L'affiliation sociale comme voie d'accès aux stratégies interpersonnelles de régulation des émotions

La plupart des modèles de la régulation des émotions est centrée sur des processus individuels d'autorégulation. De façon complémentaire, les émotions peuvent aussi être régulées socialement. Nous défendons l'idée que les individus qui éprouvent des difficultés d'autorégulation de leurs émotions pourraient ainsi s'affilier socialement pour mettre en œuvre des stratégies interpersonnelles de régulation émotionnelle susceptibles de compenser leurs difficultés. L'efficacité de telles stratégies serait toutefois conditionnée par le fait que le partenaire affiliatif présente des caractéristiques informatives. Ces hypothèses sont testées par le biais de trois études expérimentales. Les deux premières visent à évaluer distinctement les effets de la similarité situationnelle et de la similarité émotionnelle du partenaire potientiel sur la production de comportement affiliatifs en situation émotionnelle (Article 1). Mener la troisième étude a nécessité l'adaptation préalable, en français, d'un outil de mesure subjective des difficultés de régulation émotionnelle (Article 2). Cette troisième étude teste en effet l'hypothèse selon laquelle un partenaire affiliatif qui exprime ses émotions sera préféré en situation émotionnelle, en particulier par les individus qui éprouvent des difficultés d'autorégulation de leurs émotions (Article 3). Une quatrième étude, menée par le biais d'auto-questionnaires dans le domaine de l'oncologie médicale, concerne enfin les effets de la régulation émotionnelle sur la prise en charge médicale et sur le vécu des traitements (Article 4). Nos résultats sont discutés à la fois dans des perspectives fondamentales et appliquées au domaine de la santéMost of emotion regulation models focus on individual self-regulation processes. In a complementary way, emotions may also be socially regulated. We assume that individuals who experience difficulties in emotion self-regulation may thus affiliate to implement interpersonal emotion regulation strategies which could compensate for their difficulties. However, the efficiency of such strategies would depend on wether the characteristics of the partner are informative or not. These hypotheses are tested by means of three experimental studies. The first and the second one aim to assess distinctly the effects of the potential partner's situational similarity on social affiliation during an emotional situation (Article1). To conduct the third study has been made possible because we have adapted in French a questionnaire assessing people's subjective difficulties in emotion regulation beforehand (Article 2). Indeed, this third study tests the hypothesis that a partner who expresses his emotions is a prefered affiliation target during an emotional situation, especially when people experience difficulties to self-regulate their emotions (Article 3). A fourth study, carried out in the field of medical oncology by means of self-assessing questionnaires, deals with the effects of emotion regulation on patients' medical care and their experience of the treatments (Article 4). Our results are discussed both from fundamental and applied to health points of viewLILLE3-BU (590092101) / SudocSudocFranceF

Crossed views of burden and emotional distress of cancer patients and family caregivers during palliative care

International audienceObjective. Studies regarding natural caregivers’ burden (CB) in palliative situations, as well as its determinants and consequences, have been numerous during the last twenty years. Yet, studies regarding how terminally-ill cancer patients perceive their caregivers’ burden (self-perceived burden, SPB) are less common. This study aims to assess the links between CB and SPB evaluated by means of the very same items. It also aims at identifying the determinants of potential differences between CB and SPB and their consequences on emotional distress among both members of the dyad.Methods. Sixty cancer patients from a palliative care unit and their principal natural caregiver completed questionnaires concerning the subjective burden of the caregiver, their own personal emotional distress and that of the other member of the dyad.Results. Globally, patients had a good perception of their caregivers’ burden, although a little overestimated, except for their difficulties in managing their time. Caregivers overestimated patients’ distress. The minimisation by patients of caregivers’ burden was a source of emotional distress for the latter, and the perception of being a burden to others was a source of depression for patients. These results did not depend on the nature of the relationship between patients and their caregivers.Conclusions. This data confirmed the need to study the experiences of the patient-caregiver dyad as well as their communication of their respective experiences, with a prospect to offer clinical interventions to optimise the quality of life and health of patients and their close relatives

La modélisation comme support à la négociation dans la réorganisation de l'approvisionnement d'industries agro-alimentaires

International audienceQuel modèle utiliser comme support à une négociation inter-firmes visant à améliorer la coordination de leurs échanges ? Partant d'un ensemble de travaux issus de divers cadres théoriques, les auteurs proposent une approche basée sur la modélisation des flux physiques entre entreprises et visant à mettre en lumière les interdépendances conditionnant l'efficacité d'ensemble du système étudié. Cette approche fournit des supports opérationnels à la négociation entre différents acteurs dans le cadre de réorganisations d'une filière. Deux applications (filières viti-vinicole et sucrière) sont proposées

Transmission de l'information dans les familles à risque héréditaire de cancer du sein et de l'ovaire mutées BRCA1/2 et taux de consultation des apparentés

International audienceFive to 10 % of breast and ovarian cancer are linked to a BRCA1 or BRCA2 mutation. In our country, the information given to the relatives is inevitably mediated by the persons who have consulted. The report of a gap between the number of presumed persons concerned by the genetic information according to our genealogies and the actual number of consultants brought us to question about the transmission of the information in the family, about the possible motives for the lack of transmission, about the rate of consultation of the concerned relatives and on the presumed motives of non-consultation. This sample includes 31 target consultants (index cases) of mutated families which received the result of the genetic test during the period from January, 2003 till June, 2005. According to the information gathered, most of the relatives (73.1 %) are informed about the presence of a deleterious mutation in the family, especially women (80.7 %). The motives for non-information are the social and emotional distance, as well as the stressful character of the information. Apparently the information is disclosed through the family by the women who are alive and carry the mutation. On the other hand, a minority of the women (39.7 %) who are supposed to be informed and living in the region attended the oncogenetic consultation, which represents 32 % of all concerned women who come of age. The motives for short-term absence of consultation can just be presumed. The characteristics which we studied do not allow us to point out some particularities among women who consulted except the nearness with one mutated relative.Cinq à 10 % des cancers du sein et de l'ovaire sont liés à une mutation délétère sur BRCA1 ou BRCA2. Dans notre pays, l'information familiale passe nécessairement par les personnes qui ont consulté. Le constat d'un décalage entre le nombre de personnes présumées concernées par l'information génétique d'après les généalogies et le nombre effectif de consultants nous a amenés à nous interroger sur la transmission de l'information dans la famille, sur les motifs possibles de non-transmission, sur le taux de consultation des apparentés concernés et sur les motifs présumés de non-consultation des apparentés. La série comprend 31 consultantes cibles (cas index) de familles mutées qui ont reçu le résultat du test génétique durant la période de janvier 2003 à juin 2005. Selon les informations recueillies, la plupart des apparentés (73,1 %) sont informés de la présence d'une mutation délétère dans la famille, surtout les femmes (80,7 %). Les motifs de non-information sont la distance sociale et affective, ainsi que le caractère anxiogène de l'information. L'information se transmet apparemment dans la famille de proche en proche par les femmes en vie mutées et proches socialement. Par contre, une minorité des femmes (39,7 %) supposées informées habitant la région ont consulté en oncogénétique, ce qui représente 32 % de l'ensemble des femmes concernées majeures. Les motifs de non-consultation à court terme ne peuvent qu'être présumés. Les caractéristiques que nous avons étudiées ne permettent pas de relever de particularités des femmes qui ont consulté si ce n'est la proximité avec une parente mutée

Social affiliation as a way to socially regulate emotions: Effects of others’ situational and emotional similarities

International audienceTo consider social affiliation as an emotion regulation strategy raises the question of the distinct roles of the situational and emotional similarities of a potential partner. In study 1, 46 female participants briefly described a personal event of a low or high negative intensity. They then had the opportunity to either remain alone or to affiliate with another person, who either supposedly participated in the same experiment (situational similarity) or did not. In the same task, the 48 female participants of study 2 had the opportunity to be alone or with another person, who either supposedly experienced the same emotions (emotional similarity) or did not. The results showed that situational and emotional similarities increased affiliation. We discuss the potential personal and social benefits of these two similarities to individuals who experience an emotion and, more globally, we discuss the role of social affiliation in emotion regulation