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International audience; Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT 1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT 1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT 1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.

International audience; 15-Deoxy-∆12,14-prostaglandin J2 (15d‑PGJ2) is a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that displays anticancer activity. Various studies have indicated that the effects of 15d‑PGJ2 are due to both PPARγ-dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15d‑PGJ2 (b‑15d‑PGJ2) on hormone-dependent MCF‑7 and triple‑negative MDA‑MB‑231 breast cancer cell lines. b‑15d‑PGJ2 inhibited cell proliferation more efficiently than 15d‑PGJ2 or the synthetic PPARγ agonist, efatutazone. b‑15d‑PGJ2 was also more potent than its non-biotinylated counterpart in inducing apoptosis. We then analyzed the mechanisms underlying this improved efficiency. It was found not to be the result of biotin receptor-mediated increased incorporation, since free biotin in the culture medium did not decrease the anti-proliferative activity of b‑15d‑PGJ2 in competition assays. Of note, b‑15d‑PGJ2 displayed an improved PPARγ agonist activity, as measured by transactivation experiments. Molecular docking analyses revealed a similar insertion of b‑15d‑PGJ2 and 15d‑PGJ2 into the ligand binding domain of PPARγ via a covalent bond with Cys285. Finally, PPARγ silencing markedly decreased the cleavage of the apoptotic markers, poly(ADP-ribose) polymerase 1 (PARP‑1) and caspase‑7, that usually occurs following b‑15d‑PGJ2 treatment. Taken together, our data indicate that biotinylation enhances the anti-proliferative and pro-apoptotic activity of 15d‑PGJ2, and that this effect is partly mediated via a PPARγ-dependent pathway. These results may aid in the development of novel therapeutic strategies for breast cancer treatment.

International audience; Homoleptic lithium tri- and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine-metal exchanges were realized at room temperature with a substoichiometric amount of nBu4ZnLi2*TMEDA reagent (1/3 equiv; TMEDA=N,N,N',N'-tetramethylethylenediamine). This reactivity contrasted with that of tBu4ZnLi2*TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N***Li stabilized polypyridyl zincates in the reaction. The one-pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C Zn bonds in bromopyridines enabled us to perform efficient Negishi-type cross-couplings.

Election systems must ensure that representatives are chosen by voters. Moreover, each voter should have equal influence. Traditionally, this has been achieved by permitting voters to cast at most one ballot. More recently, this has been achieved by tallying the last ballot cast by each voter. We show this is not achieved by the Helios election system, because an adversary can cause a ballot other than a voter's last to be tallied. Moreover, we show how the adversary can choose the contents of such a ballot, thus the adversary can unduly influence the selection of representatives.

Online grooming is a major problem in todays society where more and more time is spent online. To become friends and establish a relationship with their young victims in online communities, groomers often pretend to be children. In this paper we describe an approach that can be used to detect if an adult is pretending to be a child in a chat room conversation. The approach involves a two step process wherein authors are first classified as being children or adults, and then each child is being examined and false children distinguished from genuine children. Our results show that even if it is hard to separate ordinary adults from children in chat logs it is possible to distinguish real children from adults pretending to be children with a high accuracy. In this paper we will discuss the accuracy of the methods proposed, as well as the features that were important in their success. We believe that this work is an important step towards automated analysis of chat room conversation to detect and possible attempts of grooming. Our approach where we use text analysis to distinguish adults who are pretending to be children from actual children could be used to inform children about the true age of the person that they are communicating. This would be a step towards making the Internet more secure for young children and eliminate grooming.

International audience; In the course of our ongoing program dedicated to the synthesis of anti-proliferative compounds, we prepared new troglitazone derivatives bearing a biphenyle moiety. The chromane heterocycle was further replaced by imidazole and triazole derivatives. Many compounds exhibited fair to high activity towards various cancer cell lines. Among them, compound 17b reduced cell viability leading to only 22-34% viable cells in four cancer cell lines at 10 mu M, but unfortunately also led to a low (13%) cell viability of non-malignant primary cultured human hepatocytes at 200 mu M. Interestingly, compound 11b also reduced cell viability in colon and liver cancer cell lines (29% and 24% cell viability respectively at 10 mu M), but maintained a high cell viability of non-malignant hepatocytes (reaching 71% cell viability at 200 mu M), thus exhibiting a huge selectivity.

Tatarstan : a Paradigm for the Old Autonomous Regions of Russia, by Maxime Meyer This article deals with Russia's relations with its former autonomous régions, which now aspire to independence. Tatarstan, the most powerful, with the strongest tendencies in this direction, is used here as an example to demonstrate the problems. The author analyses the political situation and the forces at work in this republic., Cet article est consacré aux relations entre la Russie et ses anciennes républiques autonomes qui aspirent à l'indépendance. Ce problème est analysé à travers l'exemple du Tatarstan, la plus puissante des républiques, dont la tendance indépendantiste est la plus forte. L'auteur accorde une attention particulière à l'étude de la situation politique du Tatarstan eflout spécialement à l'analyse du rapport des forces politiques., Meyer Maxime. Une ancienne république autonome de la Russie : le Tatarstan. In: Politique étrangère, n°1 - 1992 - 57ᵉannée. pp. 43-48.