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The unpredictable emergence of new zoonotic diseases with viral etiology is currently a hot issue in the scientific and political circles. Viral emergence and reemergence, as a sanitary event, are only the visible part of the iceberg, while the hidden one corresponds to a multitude of complex and interrelated factors, including societal and environmental factors favoring the advent of the state of viral emergence and reemergence. According to the World Health Organization, 60% of the agents recognized as human pathogens come from the animal kingdom, and 75% of the pathogens responsible for emerging and reemerging animal diseases present a potential transgression of interface between interspecies establishing favorable conditions for genetic exchange leading to the emergence of new highly pathogenic variants and strains of which the animal is often the host reservoir. Therefore any public health prophylactic strategy requires a holistic approach to the health problem, taking into account the interaction between the triad elements of the human, animal, and environment. This globalized approach has been realized by the international community through the new recently established concept of “One Health, One World,” making the old bipolar concept of separated human and animal health issues avoided and obsolete. The extreme diversity of emerging and reemerging viral pathogens, the change of human lifestyle, the globalization of travel, business exchanges, and tourism potentiate the risk of emergence of highly pathogenic zoonotic diseases. Promoting intersectorial collaboration will allow to unify the health and safety policies. The cross-cutting ecological and health data at the national and global scales are effective means for sustaining good health in human, animal, and ecosystem (in particular the viral ecology).

The abnormal activation of AKT/mTOR signaling pathway and overexpression of LMTK3, are the main factors involved in the generation of drug resistance. Therefore, the use of computer-aided drug design in the inhibitors discovery offers an advantage to provide new candidates for the treatment of this resistance. We realised the virtual screening and molecular docking of AKT1 and LMTK3 proteins by the Dockblaster server. In addition, with abundance of candidates under development for AKT1 kinase, we have also conducted a Quantitative Structure-Activity Relationship (QSAR) study based on these compounds, in order to design more active compounds and predict their activity for development of a new inhibitor of AKT1. QSAR tests were performed for AKT1 using the Partial Least Squares method with a correlation coefficient of R2=0.8062 and a cross-validation of q2=0.6995. This test has selected five compounds as competitive inhibitors-AKT1-ATP with a better biological activities. In parallel the molecular screening has selected five other compounds as competitive ATP-inhibitors of LMTK3. One of them is a common inhibitor with AKT1, and it is marketed as a moderate to severe pain therapy. The ADME predictions confirmed the inhibitors pharmacological activity of these compounds for potential consideration as drug candidates.

Aim A collaborative exercise with several institutes was organized by the Forensic DNA Service (FDNAS) and the Institute of the Legal Medicine, 2nd Faculty of Medicine, Charles University in Prague, Czech Republic, with the aim to test performance of different laboratories carrying out DNA analysis of relatively old bone samples. Methods Eighteen laboratories participating in the collaborative exercise were asked to perform DNA typing of two samples of bone powder. Two bone samples provided by the National Museum and the Institute of Archaelogy in Prague, Czech Republic, came from archeological excavations and were estimated to be approximately 150 and 400 years old. The methods of genetic characterization including autosomal, gonosomal, and mitochondrial markers was selected solely at the discretion of the participating laboratory. Results Although the participating laboratories used different extraction and amplification strategies, concordant results were obtained from the relatively intact 150 years old bone sample. Typing was more problematic with the analysis of the 400 years old bone sample due to poorer quality. Conclusion The laboratories performing identification DNA analysis of bone and teeth samples should regularly test their ability to correctly perform DNA-based identification on bone samples containing degraded DNA and potential inhibitors and demonstrate that risk of contamination is minimized. (VLID)5344846

The metabolic activation of benzothiophene, 2—(4-chlorobenzoyl) benzo(b)thiophene and thiophene itself, in vivo in rat and in vitro with rat liver microsomes, leads to the discovery of a new class of reactive metabolites, Thiophene sulfoxides.The in vivo metabolism of benzothiophene affords two major couples of metabolites in rat urine : A, A' and B, B', and three minor products D, D' and E. The spectra analysis (UV, NMR 1H, NMR 13C, MS, IR) reveals that A, A' and B, B' are mercapturic acid derived from benzothiophene sulfoxide or benzothiophene sulfone. These metabolites are formed byconjugation with glutathione and further processing to 3-S-(N-acetylcysteinyl)-2,3-dihydrobenzothiophene sulfoxides or sulfones. The other metabolites D and D' are derived from A and A‘ by non-enzymatic reduction. The last product E was found in old urine and resulted from D and D' by rearomatisation.The in vivo and the in vitro metabolism of 2-(4-chlorobenzoyl)-benzo(b)thiophene undergoes two major pathways : the S-oxidation of the thiophene ring and the reduction of the carbonyl group into an alcohol.The others metabolites are derived from a combination of these two pathways.The in vivo metabolism of thiophene itself leads to two metabolites : the major metabolite 28 as represents about 80% of the total radioactivity and 30% of the administred dose. The minor metabolite 31 represents 2% of the administred dose. A detailed analysis of its UV, NMR 1H, NMR 13C, mass and infra—red spectra shows that as is a 2-S-(N-acetylcysteinyl)—2,5-dihydrothiophene sulfoxide.In vitro the metabolism of thiophene leads to 31 as the major metabolite, and its isomer 32 (minor metabolite). 31 and 32 are dimers of thiophene resulting from a Diels Alder condensation.The formation in vivo of A, A' B, B' and E and 28, and in vitro of 31 and 32 provides evidence for the intermediate formation of benzothiophene S-oxides and thiophene S-oxides as reactive metabolites.This new class of reactive metabolites contradicts the earlier studies of Bray and al (1971) which suggests that thiophene derivatives are metabolized via an epoxide route. The possible reaction of thiophene sulfoxides with cellular nucleophiles should be of great consequences in toxicology., L'activation métabolique du benzothiophene, de benzothiophenes substitués et du thiophène lui-même, in vivo chez le rat et in vitro en présence demicrosomes hépatiques de rat, nous a conduit à la découverte d'une nouvelle classe de métabolites réactifs, les sulfoxydes de thiophène.Le métabolisme in vivo du benzothiophene conduit à la formation de deux couples de métabolites majoritaires retrouvés dans les urines : A et A' et B et 3' (probablement deux couples de diastéréoisomeres) et trois produits minoritaires, D, D' et E. Une analyse spectrale détaillée (UV-visible, RMN 1H, RMN 13C, SM, IR) montre que A et A' at B et B' sont des acides mercapturiques correspondant respectivement à un sulfoxyde etune sulfone de dihydro 2,3-benzothiophène, substitués en position 3 par le soufre de la N-acétylcystéine (via la conjugaison avec le GSH). Lesmétabolites D et D' sont des produits de reéduction de A et A' en sulfure.Le métabolite E, retrouvé dans l'urine conservée durant quelques jours à quelques semaines, est un produit de transformation de D et D', parréaromatisation ou par oxydation à l'air.Le métabolisme in vivo et in vitro du benzothiophène substitué en 2 par un groupe p-chlorobenzoyl, subit deux réactions de métabolisme primaire :une S-oxydation du noyau thiophène et une réduction de la fonction carbonyle en alcool. Les autres métabolites dérivent de ces deux voies.Le métabolisme in vivo du thiophène lui même conduit à deux métabolites principaux. Le composé majoritaire 28 représente 30% de la doseadministrée. Le métabolite minoritaire 31 représente 2% de cette dose. Toutes les études spectroscopiques (UV-visible, RMN 1H RMN 13C, SM,IR) réalisées sur 28 sont en accord avec une structure de type sulfoxyde de 2,5-dihydrothiophène substitué en 2 par le soufre de la N-acétylcystéine.In vitro, le métabolisme oxydatif du thiophène conduit 21 la formation de 31 et son isomere 32, des dimères du sulfoxyde de thiophène (via uneréaction de Diels Alder). La formation in vivo de 28 ainsi que celle des dimères 31 et 32 sont deux preuves supplémentaires de la formation dessulfoxydes de thiophène comme métabolites réactifs des dérivés thiophèniques.La découverte de cette nouvelle classe de métabolites réactifs, permet de remettre en cause les résultats de la littérature sur le métabolisme desdérivés thiopheniques (passage par un époxyde, Bray et coll, 1971) et de montrer que la réaction possible de ces sulfoxydes avec les nucléophilescellulaires devrait avoir des conséquences importantes en toxicologie.