A configuration space of homologous proteins conserving mutual information and allowing a phylogeny inference based on pair-wise Z-score probabilities

BACKGROUND: Popular methods to reconstruct molecular phylogenies are based on multiple sequence alignments, in which addition or removal of data may change the resulting tree topology. We have sought a representation of homologous proteins that would conserve the information of pair-wise sequence alignments, respect probabilistic properties of Z-scores (Monte Carlo methods applied to pair-wise comparisons) and be the basis for a novel method of consistent and stable phylogenetic reconstruction. RESULTS: We have built up a spatial representation of protein sequences using concepts from particle physics (configuration space) and respecting a frame of constraints deduced from pair-wise alignment score properties in information theory. The obtained configuration space of homologous proteins (CSHP) allows the representation of real and shuffled sequences, and thereupon an expression of the TULIP theorem for Z-score probabilities. Based on the CSHP, we propose a phylogeny reconstruction using Z-scores. Deduced trees, called TULIP trees, are consistent with multiple-alignment based trees. Furthermore, the TULIP tree reconstruction method provides a solution for some previously reported incongruent results, such as the apicomplexan enolase phylogeny. CONCLUSION: The CSHP is a unified model that conserves mutual information between proteins in the way physical models conserve energy. Applications include the reconstruction of evolutionary consistent and robust trees, the topology of which is based on a spatial representation that is not reordered after addition or removal of sequences. The CSHP and its assigned phylogenetic topology, provide a powerful and easily updated representation for massive pair-wise genome comparisons based on Z-score computations

Clustering Libraries of Compounds into Families: Asymmetry-Based Similarity Measure to Categorize Small Molecules

International audienceClustering Libraries of Compounds into Families: Asymmetry-Based Similarity Measure to Categorize Small Molecule

Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?

The organization and mining of malaria genomic and post-genomic data is highly motivated by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should therefore be as reliable and versatile as possible. In this context, we examined five aspects of the organization and mining of malaria genomic and post-genomic data: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from X-omic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Progresses toward a grid-enabled chemogenomic knowledge space are discussed.Comment: 43 pages, 4 figures, to appear in Malaria Journa

NuSTAR + XMM-Newton monitoring of the neutron star transient AX J1745.6-2901

AX J1745.6-2901 is a high-inclination (eclipsing) transient neutron star (NS) Low Mass X-ray Binary (LMXB) showcasing intense ionised Fe K absorption. We present here the analysis of 11 XMM-Newton and 15 NuSTAR new data-sets (obtained between 2013-2016), therefore tripling the number of observations of AX J1745.6-2901 in outburst. Thanks to simultaneous XMM-Newton and NuSTAR spectra, we greatly improve on the fitting of the X-ray continuum. During the soft state the emission can be described by a disk black body ($kT\sim1.1-1.2$ keV and inner disc radius $r_{DBB}\sim14$ km), plus hot ($kT\sim2.2-3.0$ keV) black body radiation with a small emitting radius ($r_{BB}\sim0.5-0.8$ km) likely associated with the boundary layer or NS surface, plus a faint Comptonisation component. Imprinted on the spectra are clear absorption features created by both neutral and ionised matter. Additionally, positive residuals suggestive of an emission Fe K$\alpha$ disc line and consistent with relativistic ionised reflection are present during the soft state, while such residuals are not significant during the hard state. The hard state spectra are characterised by a hard ($\Gamma\sim1.9-2.1$) power law, showing no evidence for a high energy cut off ($kT_e>60-140$ keV) and implying a small optical depth ($\tau<1.6$). The new observations confirm the previously witnessed trend of exhibiting strong Fe K absorption in the soft state, that significantly weakens during the hard state. Optical (GROND) and radio (GMRT) observations suggest for AX J1745.6-2901 a standard broad band SED as typically observed in accreting neutron stars.Comment: Accepted for publication in MNRA

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Modelling the pharmacological screening: controlling the processes and the chemical, biological and experimental information

International audienc

Contribution a l'insertion d'un modele thermodynamique dans un logiciel de localisation et d'evaluation des gisements petroliers

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : TD 78268 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc