Search

Graphical abstract, Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.

© 2017 The Authors. Palaeontology published by John Wiley & Sons Ltd on behalf of The Palaeontological Association. The fossil record of chondrichthyans (sharks, rays and chimaeroids) principally consists of isolated teeth, spines and dermal denticles, their cartilaginous skeleton being rarely preserved. Several Late Jurassic chondrichthyan assemblages have been studied in Europe based on large bulk samples, mainly in England, France, Germany and Spain. The first study of this kind in Switzerland is based on controlled excavations in Kimmeridgian deposits related to the construction of the A16 motorway in the Swiss Jura (Porrentruy, NW Switzerland). This study is based on more than 2000 isolated chondrichthyan remains (teeth, dental plates, spines and dermal denticles) and adds to our knowledge of the chondrichthyan distribution at a regional scale in Europe. We describe and identify this new fauna, define a new species of hybodont with crushing-type dentition (Asteracanthus udulfensis sp. nov.) and report for the first time the carcharhiniform Corysodon cirinensis in Switzerland. By the Late Jurassic, modern neoselachian sharks had overtaken hybodonts in European marine realms, the latter being gradually confined to brackish or freshwater environments. However, while the associated fauna of the Porrentruy platform indicates marine conditions, neoselachian sharks are surprisingly rare. The chondrichthyan assemblage is largely dominated by hybodonts, guitarfishes (rays) and chimaeroids that are all known to be euryhaline. This unexpected chondrichthyan faunal composition questions the presence of fresh to brackish water in the vicinity of the platform, and the occurrence of salinity fluctuations within a general context marine. This could explain the scarcity of neoselachian sharks and the extended success of hybodonts in the Porrentruy area as late as the Late Jurassic.

International audience

Many scientists working on pathogens (viruses, bacteria, fungi, parasites) are betting heavily on data generated by longitudinal genomic-transcriptomic-proteomic studies to explain biochemical host-vector-pathogen interactions and thus to contribute to disease control. Availability of genome sequences of various organisms, from viruses to complex metazoans, led to the discovery of the functions of the genes themselves. The postgenomic era stimulated the development of proteomic and bioinformatics tools to identify the locations, functions, and interactions of the gene products in tissues and/or cells of living organisms. Because of the diversity of available methods and the level of integration they promote, proteomics tools are potentially able to resolve interesting issues specific not only to host-vector-pathogen interactions in cell immunobiology, but also to ecology and evolution, population biology, and adaptive processes. These new analytical tools, as all new tools, contain pitfalls directly related to experimental design, statistical treatment, and protein identification. Nevertheless, they offer the potency of building large protein-protein interaction networks for in silica, analysis of novel biological entities named "interactomes," a way of modeling host-vector-pathogen interactions to define new interference strategies.

International audience; Objective To review the geography and history of sleeping sickness (Human African trypanosomiasis; HAT) over the past 100 years in West Africa, to identify priority areas for sleeping sickness surveillance and areas where HAT no longer seems active.Method History and geography of HAT were summarized based on a review of old reports and recent publications and on recent results obtained from medical surveys conducted in West Africa up to 2006.Results/conclusions Active HAT foci seem to have moved from the North to the South. Endemic HAT presently appears to be limited to areas where annual rainfall exceeds 1200 mm, although the reasons for this remain unknown. There has also been a shift towards the south of the isohyets and of the northern distribution limit of tsetse. Currently, the most severely affected countries are Guinea and Ivory Coast, whereas the northern countries seem less affected. However, many parts of West Africa still lack information on HAT and remain to be investigated. Of particular interest are the consequences of the recent political crisis in Ivory Coast and the resulting massive population movements, given the possible consequences on HAT in neighbouring countries.

Parasitic manipulations of host behaviour are known from a wide range of host-parasite associations. However, the understanding of these phenomena is far from complete and detailed investigation of their proximate causes is needed. Many studies report behavioural modifications, such as altered feeding rates in tsetse fly (Glossina) infected with the mature transmissible stage (i.e. metacyclic) of the trypanosomes. Here, bidimensional (2D) gel electrophoresis and mass spectrometry were employed to analyse and compare the head proteome between four Glossina palpalis gambiensis categories (uninfected, refractory, mature infection, immature infection). Twenty-four protein spots specifically present or absent in the head of metacyclic-infected flies were observed. These protein spots were subsequently identified and functionally classified as glycolitic, neurotransmiter synthesis, signalling, molecular chaperone and transcriptional regulation proteins. Our results indicate altered energy metabolism in the head of metacyclic-infected tsetse flies. Some of the proteins identified, such as casein kinase 2 and jun kinase have previously been shown to play critical roles in apoptosis in insect neurones. In addition, we found two pyridoxal-dependent decarboxylases (dopa decarboxylase and alpha methyldopa hypersensitive protein), suggesting a modification of serotonin and/or dopamine in the brain of metacyclic-infected tsetse flies. Our data pave the way for future investigation of the alteration of the glossina central nervous system during infection by trypanosomes.

Trichomoniasis is recognised as a major sexually transmitted disease (STD) in the world and may act as an acquired immunodeficiency syndromes (AIDS) co-factor by enhancing the transmission of human immunodeficiency virus (HIV). Diagnosis of Trichomonas vaginalis can be achieved by several methods, but sensitive detection means are still lacking. In this study a 2000-bp repeated DNA fragment of T. vaginalis was cloned. Part of a conserved region of this insert was sequenced, two primers (TVK3 and TVK4) were chosen and a highly sensitive detection by polymerase chain reaction (PCR) was then developed for T. vaginalis. All strains of T. vaginalis analysed with these primers gave the expected 350-bp fragment and a 450-bp additional fragment. Sequence analysis of these PCR amplification products revealed that the 450-bp fragment contained the 350-bp with a 100-bp insertion characterised by a TGG microsatellite. A second primer set, namely TVK3 and TVK7 (determined at the border of the insertion), yielded PCR products of expected sizes. After amplification we were able to detect a single parasite. We also detected T. vaginalis in vaginal fluids of patients with STD. There was no reaction with human DNA or other infectious agents. It appears that the two set primers are highly specific of T. vaginalis and provide a useful tool for PCR diagnosis in asymptomatic and symptomatic patients especially among the HIV at risk individuals.