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

A phase I trial assessing the safety, pharmacokinetics, cerebrospinal fluid penetrance, and food effect of BTK inhibitor tolebrutinib in healthy volunteers

Abstract Tolebrutinib is an oral, brain‐penetrant, covalent Bruton's tyrosine kinase inhibitor in development to treat multiple sclerosis at 60 mg/day with food. A phase I trial was conducted in healthy volunteers to assess the safety and pharmacokinetics of tolebrutinib at oral doses higher than 60 mg with food and during fasting, and to determine cerebrospinal fluid (CSF) exposure after a single dose of 60 or 120 mg with food. The trial included double‐blind, placebo‐controlled single ascending dose (120, 240, and 300 mg; fed and fasted) and multiple ascending dose (120, 180, and 240 mg) arms. Additional open‐label cohorts received a single 60 mg dose with a high‐fat meal and during fasting using a crossover design or a single 60 or 120 mg dose with food and lumbar puncture to obtain CSF. Tolebrutinib was rapidly absorbed and converted to an active metabolite (designated “M2”), both of which had a terminal half‐life of ~5 h. Tolebrutinib and M2 exposures increased following administration with food versus fasting, and plasma levels were generally dose proportional. For up to 4 h (the last measurement timepoint) after a 60 mg dose, CSF concentrations of tolebrutinib exceeded its in vitro cellular potency (half‐maximal inhibitory concentration [IC50]) for microglia, and tolebrutinib and M2 surpassed their biochemical IC50. Tolebrutinib was well‐tolerated, and treatment‐emergent adverse events were generally mild. Concentration‐QTc modeling showed no effects on QT/QTc intervals for any tolebrutinib dose or fed status. In conclusion, tolebrutinib has an acceptable safety profile at supratherapeutic doses and achieved bioactive CSF exposures at the phase III dose

De l’objet à la société romaine: Études archéologiques et épigraphiques offertes à Jean-Claude Béal

International audienceThis volume brings together some twenty contributions reflecting many of the research themes of Prof. Jean-Claude Béal, to whom these studies are offered. They are mainly centred on Roman Gaul, and more generally on the western Roman provinces, reflecting the geographical areas in which he works.Ce livre réunit une vingtaine de contributions regroupées dans cinq parties : - De l’atelier à l’objet : artisanats, productions et instrumentum ; - Croyances et cultes ; - Iconographie, épigraphie et archéologie funéraire ; - Habiter et organiser un territoire ; - Décorer un édifice, qui reflètent une grande partie des thèmes de recherche de Jean-Claude Béal à qui ces études sont offertes. Elles sont essentiellement centrées sur la Gaule romaine, et plus marginalement sur les provinces romaines occidentales, à l’image des aires géographiques sur lesquelles il travaille

当代游牧法律人类学：法国-蒙古比较视角

International audienceThis article proposes a comparative and interdisciplinary study of nomadism in France and Mongolia based on Anthropology and Law. These two countries are, at first glance, diametrically opposed in the approach of nomadism. Indeed, Mongolia is currently the country with the largest number of nomads. Conversely, the process of sedentarization has been strongly anchored in France since the Neolithic, and even since the Upper Palaeolithic. In view of this multi-millennium trend, can nomads exist outside the sedentary norm? A first part situates the theme of nomadism on the long-time of hominization and then its perception in the recent history of these two countries. A second part specifically details the constraints on this lifestyle using examples of French and European standards and jurisprudence. A third and final part shows that the tropism for sedentarization is also exerted in Mongolia, the matry of nomads.Este artículo propone un estudio comparativo e interdisciplinario del nomadismo a partir de la Antropología y del Derecho en Francia y Mongolia. Estos dos países son, a primera vista, diametralmente opuestos en el enfoque del nomadismo. De hecho, Mongolia es actualmente el país que comprende el mayor número de nómadas. Por el contrario, el proceso de sedentarización está fuertemente enraizado en Francia desde el Neolítico, e incluso desde el Paleolítico Superior. Ante esta tendencia multimilenaria, ¿puede el nómada existir fuera de la norma sedentaria? Una primera parte coloca el tema del nomadismo en el largo tiempo de la hominización y su percepción en la historia reciente de ambos países. Una segunda parte detalla más concretamente las limitaciones que condicionan este modo de vida a partir de ejemplos de las normas y de la jurisprudencia francesa y europea. Una tercera y última parte muestra que el trofismo por sedentarismo también se ejerce en Mongolia, matriz de los nómadas.Cet article propose une étude comparée et interdisciplinaire du nomadisme en France et en Mongolie, à partir de l’Anthropologie et du Droit. Ces deux pays sont, à première vue, diamétralement opposés dans l’approche du nomadisme. En effet, la Mongolie est actuellement le pays qui comprend le plus grand nombre de nomades. Inversement, le processus de sédentarisation est puissamment ancré en France depuis le Néolithique, voire depuis le Paléolithique supérieur. Face à cette tendance multimillénaire, le nomade peut-il exister hors de la norme sédentaire ? Une première partie replace le thème du nomadisme sur le temps long de l’hominisation puis sa perception dans l’histoire récente de ces deux pays. Une deuxième partie détaille plus spécifiquement les contraintes conditionnant ce mode de vie à partir d’exemples des normes et de la jurisprudence française et européenne. Une troisième et dernière partie montre que le tropisme pour la sédentarisation s’exerce également en Mongolie, matrie des nomades.该文从人类学和法律的角度对法国和蒙古的游牧问题进行比较和跨学科研究。从表面上看，这两个国家在游牧做法上截然相反。事实上，蒙古目前是游牧民族最多的国家。相反，法国从新石器时代甚至从旧石器时代的后期开始大力推行定居。面对几千年来的定居趋势，在定居已然成为一种标准的情况下，是否还存在游牧？论文的第一部分，阐述了从人类自身演进的时间视角来看待游牧的问题，以及这个问题在两国近年历史中的反响。第二部分，从法律规范的举例以及法国和欧盟的司法案例出发，具体阐述了影响这种生活方式的限制因素。第三也是最后一部分阐明了，在游牧民族的蒙古也存在着定居的倾向

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

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