A linear bound on the k-rendezvous time for primitive sets of NZ matrices

A set of nonnegative matrices is called primitive if there exists a product of these matrices that is entrywise positive. Motivated by recent results relating synchronizing automata and primitive sets, we study the length of the shortest product of a primitive set having a column or a row with k positive entries, called its k-rendezvous time (k-RT}), in the case of sets of matrices having no zero rows and no zero columns. We prove that the k-RT is at most linear w.r.t. the matrix size n for small k, while the problem is still open for synchronizing automata. We provide two upper bounds on the k-RT: the second is an improvement of the first one, although the latter can be written in closed form. We then report numerical results comparing our upper bounds on the k-RT with heuristic approximation methods.Comment: 27 pages, 10 figur

Synthesis of New 2-Phenylamino-4H-chromene-3-carbonitrile Derivatives and Their Effects on Tumor Cell Lines and against Protein Kinases

International audienceThe synthesis of 2-phenylimino-4H-chromene-3-carbonitriles 6(a-d) in good overall yields using an efficient and practical methodology in 3 steps has been implemented in this present work. The first step was a heterocyclization between 2-hydroxybenzaldehyde 1 and propanedinitrile 2 which produced 2-iminocoumarin 3 which was submitted to nitrogen/nitrogen displacement in the presence of aromatic primary amine 4. In the third step, reduction of 5 led to the desired 2-phenylimino-4H-chromene-3-carbonitriles 6. Compounds 5(a-d) and 6(a-d) were evaluated for their potential in vitro cytotoxicity against six selected tumor cell lines (Huh7-D12, Caco2, MDA-MB231, HCT 116, PC3 and NCI-H727) and tested for their protein kinase inhibition on eight selected protein kinases. Among them, compounds 5c and 6b exhibited inhibition on HsCK1e (5c: 44% and 6b: 42% at 1 μM) and 5c for cytotoxicity on PC3 cell lines (63% at 25 μM)

Time-resolved protein side-chain motions unraveled by high-resolution relaxometry and molecular dynamics simulations

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Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A

International audienceHere, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC(50) 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC(50) 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved

Structure and Dynamics of an Intrinsically Disordered Protein Region That Partially Folds upon Binding by Chemical-Exchange NMR

International audienceMany intrinsically disordered proteins (IDPs) and protein regions (IDRs) engage in transient, yet specific, interactions with a variety of protein partners. Often, if not always, interactions with a protein partner lead to partial folding of the IDR. Characterizing the conformational space of such complexes is challenging: in solution-­‐state NMR, signals of the IDR in the interacting region become broad, weak and often invisible; while X-­‐ray crystallography only provides information on fully ordered regions. There is thus a need for a simple method to characterize both fully and partially ordered regions in the bound state of IDPs. Here, we introduce an approach based on monitoring chemical ex-­‐ change by NMR to investigate the state of an IDR that folds upon binding through the observation of the free state of the protein. Structural constraints for the bound state are obtained from chemical shifts and site-­‐specific dynamics of the bound state are characterized by relaxation rates. The conformation of the interacting part of the IDR was determined and subsequently docked onto the structure of the folded partner. We apply the method to investigate the interaction between the disordered C-­‐terminal region of Artemis and the DNA binding domain of Ligase IV. We show that we can accurately reproduce the structure of the core of the complex determined by X-­‐ray crystallography and identify a broader interface. The method is widely applicable to the biophysical investigation of complexes of disordered proteins and folded proteins

Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors

International audienceDNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 binds to the PRMT4 active site, displacing strongly the S-adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'

Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school

International audiencePurpose: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities.Methods: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1–3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking.Results: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking.Conclusion: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools

Supplementary Information from Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMTs inhibitors

NMR attribution, complementary Materials & Methods and Biological result

Supplementary Information from Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMTs inhibitors

NMR attribution, complementary Materials & Methods and Biological result