Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals.

IFIT (interferon-induced with tetratricopeptide repeats) proteins are critical mediators of mammalian innate antiviral immunity. Mouse IFIT1 selectively inhibits viruses that lack 2'O-methylation of their mRNA 5' caps. Surprisingly, human IFIT1 does not share this antiviral specificity. Here, we resolve this discrepancy by demonstrating that human and mouse IFIT1 have evolved distinct functions using a combination of evolutionary, genetic and virological analyses. First, we show that human IFIT1 and mouse IFIT1 (renamed IFIT1B) are not orthologs, but are paralogs that diverged >100 mya. Second, using a yeast genetic assay, we show that IFIT1 and IFIT1B proteins differ in their ability to be suppressed by a cap 2'O-methyltransferase. Finally, we demonstrate that IFIT1 and IFIT1B have divergent antiviral specificities, including the discovery that only IFIT1 proteins inhibit a virus encoding a cap 2'O-methyltransferase. These functional data, combined with widespread turnover of mammalian IFIT genes, reveal dramatic species-specific differences in IFIT-mediated antiviral repertoires

IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis

Signaling through the IL-17 receptor (IL-17R) is required to prevent oropharyngeal candidiasis (OPC) in mice and humans. However, the IL-17-responsive cell type(s) that mediate protection are unknown. Using radiation chimeras we were able to rule out a requirement for IL-17RA in the hematopoietic compartment. We saw remarkable concordance of IL-17-controlled gene expression in C. albicans-infected human oral epithelial cells (OECs) and in tongue tissue from mice with OPC. To interrogate the role of the IL-17R in OECs, we generated mice with conditional deletion of IL-17RA in superficial oral and esophageal epithelial cells (Il17ra(ΔK13)). Following oral Candida infection, Il17ra(ΔK13) mice exhibited fungal loads and weight loss indistinguishable from Il17ra(−/−) mice. Susceptibility in Il17ra(ΔK13) mice correlated with expression of the antimicrobial peptide β-defensin 3 (BD3, Defb3). Consistently, Defb3(−/−) mice were susceptible to OPC. Thus, OECs dominantly control IL-17R-dependent responses to OPC through regulation of BD3expression

European grapevine moth, Lobesia botrana Part I: biology and ecology

Though the European grapevine moth, Lobesia botrana (Denis & Schiffermüller) (Lepidoptera: Tortricidae) can feed on more than forty plant species, grapevine is the preferred crop worldwide. This moth is a western palearctic species that has recently spread to Chile, Argentina, and California. The possible further expansion in other regions of the Americas is greatly feared and should be monitored carefully in the near future. In this framework, we provide an updated review of the current knowledge on its taxonomy, morphology, biology, ecology, genomics, geographic distribution, and invasiveness. Then, in the last section, we develop a research agenda pointing out significant challenges for future investigations on bio-ecology and invasion biology, which are tightly connected with the prevention and management strategie

European grapevine moth, Lobesia botrana Part II: prevention and management

Lobesia botrana (Denis & Schiffermüller) (Lepidoptera: Tortricidae), commonly known as the European grapevine moth (EGVM), is a primary pest of vineyards. This article provides an updated review of its monitoring, modelling, and management tools. EGVM management strategies analysed here include insecticide-based control, insecticide resistance, side-effects (particularly those caused by the exposure to sublethal doses of pesticides), cultural control, sterile insect technique, pheromone-mediated control strategies (with special reference to pheromone-based mating disruption), biological control, and area-wide control programs. Lastly, we outline significant challenges for future EGVM research and sustainable control implementatio

Host plant quality, spatial heterogeneity, and the stability of mite predator–prey dynamics

Population dynamics models suggest that both the over-all level of resource productivity and spatial variability in productivity can play important roles in community dynamics. Higher productivity environments are predicted to destabilize consumer–resource dynamics. Conversely, greater heterogeneity in resource productivity is expected to contribute to stability. Yet the importance of these two factors for the dynamics of arthropod communities has been largely overlooked. I manipulated nutrient availability for strawberry plants in a multi-patch experiment, and measured effects of overall plant quality and heterogeneity in plant quality on the stability of interactions between the phytophagous mite Tetranychus urticae and its predator Phytoseiulus persimilis. Plant size, leaf N content and T. urticae population growth increased monotonically with increasing soil nitrogen availability. This gradient in plant quality affected two correlates of mite population stability, population variability over time (i.e., coefficient of variation) and population persistence (i.e., proportion of plant patches colonized). However, the highest level of plant quality did not produce the least stable dynamics, which is inconsistent with the “paradox of enrichment”. Heterogeneity in plant productivity had modest effects on stability, with the only significant difference being less variable T. urticae densities in the heterogeneous compared to the corresponding homogeneous treatment. These results are generally congruent with metapopulation theory and other models for spatially segregated populations, which predict that stability should be governed largely by relative movement rates of predators and prey—rather than patch quality

Gamma-Ray Burst Energy Spectra: Theoretical Models, Old and New

The modelling of gamma-ray burst (GRB) spectra has considerable potential for increasing the understanding of these enigmatic sources. A diversity of ideas and analyses has been generated over the last two decades to explain line features and continuum shapes, encompassing both older galactic neutron star and ``new age'' cosmological source models. This paper reviews some of the highlights of these studies, discussing the merits and limitations of various ideas, and in particular their compatibility with the observational data. The first focus will be on continuum models for GRBs, which include optically thin synchrotron emission and resonant Compton upscattering near galactic neutron stars, while the synchrotron and non-magnetic inverse Compton scattering mechanisms are prominent in the less well-developed cosmological scenarios. Line formation scenarios will then be discussed, in particular the scattering model for producing cyclotron features, which remains the only viable explanation for the Ginga observations of double lines. Absorption-like line production in cosmological burst models is generally difficult, though interesting notions such as femtolensing interference patterns have been proffered.Comment: 8 pages with no figures, as a compressed, uuencoded, Postscript file. Invited review, to appear in Astrophysics and Space Science as part of the proceedings of the 29th ESLAB Symposium ``Towards the Source of Gamma-Ray Bursts'' held in Noordwijk, 199

Glutamine versus Ammonia Utilization in the NAD Synthetase Family

NAD is a ubiquitous and essential metabolic redox cofactor which also functions as a substrate in certain regulatory pathways. The last step of NAD synthesis is the ATP-dependent amidation of deamido-NAD by NAD synthetase (NADS). Members of the NADS family are present in nearly all species across the three kingdoms of Life. In eukaryotic NADS, the core synthetase domain is fused with a nitrilase-like glutaminase domain supplying ammonia for the reaction. This two-domain NADS arrangement enabling the utilization of glutamine as nitrogen donor is also present in various bacterial lineages. However, many other bacterial members of NADS family do not contain a glutaminase domain, and they can utilize only ammonia (but not glutamine) in vitro. A single-domain NADS is also characteristic for nearly all Archaea, and its dependence on ammonia was demonstrated here for the representative enzyme from Methanocaldococcus jannaschi. However, a question about the actual in vivo nitrogen donor for single-domain members of the NADS family remained open: Is it glutamine hydrolyzed by a committed (but yet unknown) glutaminase subunit, as in most ATP-dependent amidotransferases, or free ammonia as in glutamine synthetase? Here we addressed this dilemma by combining evolutionary analysis of the NADS family with experimental characterization of two representative bacterial systems: a two-subunit NADS from Thermus thermophilus and a single-domain NADS from Salmonella typhimurium providing evidence that ammonia (and not glutamine) is the physiological substrate of a typical single-domain NADS. The latter represents the most likely ancestral form of NADS. The ability to utilize glutamine appears to have evolved via recruitment of a glutaminase subunit followed by domain fusion in an early branch of Bacteria. Further evolution of the NADS family included lineage-specific loss of one of the two alternative forms and horizontal gene transfer events. Lastly, we identified NADS structural elements associated with glutamine-utilizing capabilities

Parps: Rapidly Evolving Weapons in the War against Viral Infection

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts

Through a Glass, Darkly:The CIA and Oral History

This article broaches the thorny issue of how we may study the history of the CIA by utilizing oral history interviews. This article argues that while oral history interviews impose particular demands upon the researcher, they are particularly pronounced in relation to studying the history of intelligence services. This article, nevertheless, also argues that while intelligence history and oral history each harbour their own epistemological perils and biases, pitfalls which may in fact be pronounced when they are conjoined, the relationship between them may nevertheless be a productive one. Indeed, each field may enrich the other provided we have thought carefully about the linkages between them: this article's point of departure. The first part of this article outlines some of the problems encountered in studying the CIA by relating them to the author's own work. This involved researching the CIA's role in US foreign policy towards Afghanistan since a landmark year in the history of the late Cold War, 1979 (i.e. the year the Soviet Union invaded that country). The second part of this article then considers some of the issues historians must confront when applying oral history to the study of the CIA. To bring this within the sphere of cognition of the reader the author recounts some of his own experiences interviewing CIA officers in and around Washington DC. The third part then looks at some of the contributions oral history in particular can make towards a better understanding of the history of intelligence services and the CIA

Virology—the path forward

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US