Mitochondrial morphodynamics alteration induced by influenza virus infection as a new antiviral strategy

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection.     

Tumor microenvironment indoctrination: An emerging hallmark of cancer

Nastiness of cancer does not only reside in the corruption of cancer cells by genetic aberrations that drive their sustained proliferative power—the roots of malignancy—but also in its aptitude to reciprocally sculpt its surrounding environment and cellular stromal ecosystem, in such a way that the corrupted tumor microenvironment becomes a full pro-tumorigenic entity. Such a contribution had been appreciated three decades ago already, with the discovery of tumor angiogenesis and extracellular matrix remodeling. Nevertheless, the recent emergence of the tumor microenvironment as the critical determinant in cancer biology is paralleled by the promising therapeutic potential it carries, opening alternate routes to fight cancer. The study of the tumor microenvironment recruited numerous lead-scientists over the years, with distinct perspectives, and some of them have kindly accepted to contribute to the elaboration of this special issue entitled Tumor microenvironment indoctrination: An emerging hallmark of cancer.     

Differences in sensitivity to NADH of purified pyruvate dehydrogenase complexes of Enterococcus faecalis, Lactococcus lactis, Azotobacter vinelandii and Escherichia coli: Implications for their activity in vivo

Abstract The effect of NADH on the activity of the purified pyruvate dehydrogenase complexes (PDHc) of Enterococcus (Ec.) faecalis, Lactococcus lactis, Azotobacter vinelandii and Escherichia coli was determined in vitro. It was found that the PDHc of E. coli and L. lactis was active only at relatively low NADH/NAD ratios, whereas the PDHc of Ec. faecalis was inhibited only at high NADH/NAD ratios. The PDHc of Azotobacter vinelandii showed an intermediate sensitivity. The organisms were grown in chemostat culture under conditions that led to different intracellular NADH/NAD ratios and the PDHc activities in vivo could be calculated from the specific rates of product formation. Under anaerobic growth conditions, only Ec. faecelis expressed PDHc activity in vivo. The activities in vivo of the complexes of the different organisms were in good agreement with their properties determined in vitro. The physiological consequences of these results are discussed.     

Technology and ispection of air conditioning systems

Summary A technical approach, in terms of air quality, implies the review of all components within the air conditioning system and the check of their characteristics, as far as contamination sources are concerned. The contribution introduces the parameters to be examined and specifies the importance of validation.     

Several classes of binding sites for metals and nucleotides on yeast mitochondrial oligomycin sensitive ATPase.

The binding properties of Mg2+, Mn2+ and Co2+ to yeast mitochondrial oligomycin sensitive ATPase complex are studied, as reflected by their catalytic effect (hydrolysis of ATP or pNPP, a pseudo substrate) or by a physical parameter (atomic absorption, electron paramagnetic reasonance of Mn2+, enhanced fluorescence of chelating chlorotetracyclin). At least two classes of sites with very different affinities respectively around 10(-5) M and 10(-4) M are demonstrated: high affinity sites for cations which participate in pNPP hydrolysis and can bind ADP or ATP, although they have a poor efficiency for ATP hydrolysis, and low affinity sites for cations which participate efficiently in both pNPP and ATP hydrolysis. The possibility that the tight site class has itself two sub-classes is also discussed.     

Effect of age and environmental conditions on the movement characteristics of Pacific oyster (Crassostrea gigas) trochophores

The movement characteristics of Pacific oyster trochophores have received very little coverage in the scientific literature. Described here are not only changes in the swimming characteristics of Crassostrea gigas trochophores (size: 53–77 μm) in relation to time after fertilization and to inter‐female variation but also the effects of salinity and pH on movement characteristics. The percentage of motile trochophores was measured on images obtained through a dissecting microscope and the Velocity Average Path (VAP) was assessed using a Computer Assisted Sperm Analysis (CASA) system. At 20°C, the first movements of the trochophores were observed at 6.5 h post‐fertilization. The mean (± SD) percentage of swimming trochophores and the VAP observed in seawater at 11.5 h post‐fertilization were 85 ± 10% and 146 ± 75 μm s^?1, respectively (n = 8 females). Significant inter‐female variation in the percentage of motile trochophores (range: 66 ± 16–93 ± 3%) and in the VAP (55 ± 47–180 ± 90 μm s^?1) was detected. Most of the trochophores were motile in a 9‰ salinity solution. Adjusting the pH of the seawater to values from 5.10 to 9.08 had no effect on swimming characteristics. The present study shows that the movement of oyster trochophores exhibits high plasticity in relation to environmental conditions because the highest percentages of swimming trochophores and optimal velocity values were recorded within large ranges of salinity and pH. Further research is required to determine whether the swimming performances of trochophores can be used to assess embryo quality in commercial hatcheries.     

Combined Approaches for Drug Design Points the Way to Novel Proline Racemase Inhibitor Candidates to Fight Chagas’ Disease

Chagas’ disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.     

Tolerance of free‐living nematode species to imidacloprid and diuron

The neonicotinoid imidacloprid and the herbicide diuron are long‐lived pesticides commonly detected in European rivers. Both have lethal as well as sublethal effects on aquatic invertebrates dwelling in streambeds. Here, we performed lethality tests of imidacloprid and diuron on seven species of widespread, free‐living nematodes and the model organism Caenorhabditis elegans. Our results indicated that nematodes were relatively tolerant to both pesticides, and only two species (Diploscapter coronatus and Plectus opisthocirculus) showed mortality at high nominal concentrations of imidacloprid (119 mg/L) and diuron (33 mg/L). The changes observed in nematode community structure after imidacloprid and diuron exposure may have been related to trade‐offs between sensitivity to toxicants and changes in competitive abilities of the species. While the former can be tested using single‐species tests, we recommend that the latter be tested in further experiments using multispecies communities. Our results suggest that the presence of these pesticides could favor nematodes over other meiofaunal groups found in freshwater sediments.     

Conservation by trans-border cooperation: population genetic structure and diversity of geoffroy’s bat (Myotis emarginatus) at its north-western european range edge

Biodiversity and Conservation - In the European Union, all bat species are strictly protected and member states must ensure their conservation. However, if populations are genetically structured,...