The Golgi Protein ACBD3, an Interactor for Poliovirus Protein 3A,Modulates Poliovirus Replication

We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all of these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 [PVS2-3A(CV-A17)]. The small interfering RNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors and may thus be one of the factors favoring their emergence.     

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.     

Evidence for contemporary and historical gene flow between guppy populations in different watersheds,with a test for associations with adaptive traits

In dendritic river systems, gene flow is expected to occur primarily within watersheds. Yet, rare cross‐watershed transfers can also occur, whether mediated by (often historical) geological events or (often contemporary) human activities. We explored these events and their potential evolutionary consequences by analyzing patterns of neutral genetic variation (microsatellites) and adaptive phenotypic variation (male color) in wild guppies (Poecilia reticulata) distributed across two watersheds in northern Trinidad. We found the expected signatures of within‐watershed gene flow; yet we also inferred at least two instances of cross‐watershed gene flow—one in the upstream reaches and one further downstream. The upstream cross‐watershed event appears to be very recent (41 ± 13 years), suggesting dispersal via recent flooding or undocumented human‐mediated transport. The downstream cross‐watershed event appears to be considerably older (577 ± 265 years), suggesting a role for rare geological or climatological events. Alongside these strong signatures of both contemporary and historical gene flow, we found little evidence of impacts on presumably adaptive phenotypic differentiation, except perhaps in the one instance of very recent cross‐watershed gene flow. Selection in this system seems to overpower gene flow—at least on the spatiotemporal scales investigated here.     

Relation Between Basophilia and Fine Structure of Cytoplasm in the Fungus Allomyces macrogynus Em

In a fungus, Allomyces macrogynus Em., staining tests have revealed changes in the location of cytoplasmic basophilia following different phases of the developmental cycle. These variations in location were used to observe which fine structures correspond to basophile and non-basophile areas of the cytoplasm. Hyphae, gametangia, zygotes, and plants were fixed at various developmental stages in OsO₄, pH 6.1, and embedded in vestopal. Sections were examined in the electron microscope. Comparison of basophile and non-basophile cytoplasms leads to the conclusion that cytoplasmic particles of 150 to 200 A in diameter are responsible for basophilia. The possibility of these particles being ribosomes is discussed and confirmed. The present paper also describes some observations on the fine structure of other cellular components of this fungus, such as nuclei, mitochondria, various granules, and flagella.     

The double life of the ribosome: When its protein folding activity supports prion propagation

It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation.

In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.     

Guilds or functional groups: does it matter?

Although most researchers use the terms "guild" and "functional group" more or less synonymously, these two concepts bear different meanings. The guild concept refers primarily to the mechanisms of resource sharing by species in a competitive context whereas the functional groups concept is concerned with how a resource or any other ecological component is processed by different species to provide a specific ecosystem service or function. In many cases but not necessarily all, the two concepts are the two "faces" or "sides" of the same coin: the sharing by species of a similar resource is the guild facet (structural), while the ecosystem processes these species eventually perform through resource exploitation is the functional group facet. The two concepts differ in that competitive relationships within groups of species are not the focus of the functional group approach, exactly as processes or functions are not the focus of the guild approach. A group of species can be considered either as a guild or a functional group depending on the question addressed. Guild and functional group membership is independent of phylogenetic relationships but because species tend to share similar life history traits and adaptations through common evolutionary history, guild and functional group associates are often closely related. The concept of guild has had broader application in animal studies than in plant studies, whereas the reverse is true for the concept of functional group. Recent methodological advances to objectively partition species into guilds and functional groups, taking into consideration the most relevant characters or traits for delineating them, provide the means to construct an operational framework for making in situ and ex situ experiments that are urgently needed for a better understanding of the role of species in ecosystem functioning, especially in relation to global change concerns.     

Group Colocation Behavior in Technological Social Networks

We analyze two large datasets from technological networks with location and social data: user location records from an online location-based social networking service, and anonymized telecommunications data from a European cellphone operator, in order to investigate the differences between individual and group behavior with respect to physical location. We discover agreements between the two datasets: firstly, that individuals are more likely to meet with one friend at a place they have not visited before, but tend to meet at familiar locations when with a larger group. We also find that groups of individuals are more likely to meet at places that their other friends have visited, and that the type of a place strongly affects the propensity for groups to meet there. These differences between group and solo mobility has potential technological applications, for example, in venue recommendation in location-based social networks.     

A yeast-based assay identifies drugs that interfere with immune evasion of the Epstein-Barr virus

Epstein-Barr virus (EBV) is tightly associated with certain human cancers, but there is as yet no specific treatment against EBV-related diseases. The EBV-encoded EBNA1 protein is essential to maintain viral episomes and for viral persistence. As such, EBNA1 is expressed in all EBV-infected cells, and is highly antigenic. All infected individuals, including individuals with cancer, have CD8⁺ T cells directed towards EBNA1 epitopes, yet the immune system fails to detect and destroy cells harboring the virus. EBV immune evasion depends on the capacity of the Gly-Ala repeat (GAr) domain of EBNA1 to inhibit the translation of its own mRNA in cis, thereby limiting the production of EBNA1-derived antigenic peptides presented by the major histocompatibility complex (MHC) class I pathway. Here we establish a yeast-based assay for monitoring GAr-dependent inhibition of translation. Using this assay we identify doxorubicin (DXR) as a compound that specifically interferes with the GAr effect on translation in yeast. DXR targets the topoisomerase-II–DNA complexes and thereby causes genomic damage. We show, however, that the genotoxic effect of DXR and various analogs thereof is uncoupled from the effect on GAr-mediated translation control. This is further supported by the observation that etoposide and teniposide, representing another class of topoisomerase-II–DNA targeting drugs, have no effect on GAr-mediated translation control. DXR and active analogs stimulate, in a GAr-dependent manner, EBNA1 expression in mammalian cells and overcome GAr-dependent restriction of MHC class I antigen presentation. These results validate our approach as an effective high-throughput screening assay to identify drugs that interfere with EBV immune evasion and, thus, constitute candidates for treating EBV-related diseases, in particular EBV-associated cancers.KEY WORDS: EBV-associated cancers, Cell-based drug screening, EBNA1 GAr domain, Yeast-based models, Immune evasion, Doxorubicin, Daunorubicin, 5-fluorouracil     

The end of Invasion Biology: intellectual debate does not equate to nonsensical science

Valéry et al. recently proposed to end the field of Invasion Biology on the grounds that it is based on an inadequate definition of the concept of biological invasion and that, as exotic species, native species should also be called invasive whenever they outbreak. We argue, on the contrary, that the sudden demographic dominance of native species cannot be termed invasion. Moreover, we claim that the suggestion of ending a fruitful and useful discipline because it does not conform to a subjective definition or because it still encompasses some debatable ideas and unresolved questions is both irrelevant and excessive. We believe that the thousands of researchers working in this discipline do not perform nonsensical science, and that their efforts to understand and limit biological invasions are compatible with debating on the key concept of that field.     

Morphological variation in the freshwater blenny Salaria fluviatilis from Corsican rivers: adaptive divergence,phenotypic plasticity or both?

The first goal of this study was to determine whether morphological variation in the freshwater blenny Salaria fluviatilis results in spatially structured populations distributed around Corsica, France, which would suggest genetically differentiated populations through reproductive isolation by distance. The second goal was to determine whether some morphological traits are related to water velocity, one of the most contrasting habitat characteristics in these rivers, which would suggest an adaptation to local conditions. The results showed that the morphology of S. fluviatilis differed among the three main geographic areas studied in Corsica and that geographically distant populations of S. fluviatilis were less similar morphologically and genetically than close ones. The results also indicated that the morphological differences among populations conformed to functional expectations. Overall, the results suggest that the morphological variation of S. fluviatilis from Corsican rivers is an adaptive response to water velocity and that these populations are in a process of reproductive isolation by distance.