Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

Le rôle des anaphores dans la mise en place des relations de cohérence dans le discours: l'hypothèse de J.R. Hobbs

International audiencePour Hobbs (1979), l'interprétation des anaphoriques inter-phrastiques 'découle' ('falls out') en tant qu'effet secondaire de l'emploi d'une relation de cohérence pour intégrer deux unités de discours. En essayant de mettre au clair la nature des interactions entre relations de cohérence et fonctionnement des anaphores dans la compréhension de textes multi-propositionnels, l'article cherche à démontrer que l'hypothèse de Hobbs n'est valable qu'en partie. D'abord, la référence complète des anaphoriques ne 'découle' pas seulement du choix de telle ou telle relation de cohérence pour intégrer deux unités de discours: elle est essentielle pour la mise en œuvre effective de cette relation. Ensuite, elle sert également à sélectionner l'unité de discours avec laquelle l'unité arrivante va s'intégrer, ainsi qu'à articuler le discours en une structure hiérarchique. Enfin l'intégration des unités de discours n'a pas lieu d'un seul coup, mais peut être étalée sur au moins trois étapes distinctes

The Prograde Orbit of Exoplanet TrES-2b

We monitored the Doppler shift of the G0V star TrES-2 throughout a transit of its giant planet. The anomalous Doppler shift due to stellar rotation (the Rossiter-McLaughlin effect) is discernible in the data, with a signal-to-noise ratio of 2.9, even though the star is a slow rotator. By modeling this effect we find that the planet's trajectory across the face of the star is tilted by -9 +/- 12 degrees relative to the projected stellar equator. With 98% confidence, the orbit is prograde.Comment: ApJ, in press [15 pages

Impact of population growth and population ethics on climate change mitigation policy

Future population growth is uncertain and matters for climate policy: higher growth entails more emissions and means more people will be vulnerable to climate-related impacts. We show that how future population is valued importantly determines mitigation decisions. Using the Dynamic Integrated Climate-Economy model, we explore two approaches to valuing population: a discounted version of total utilitarianism (TU), which considers total wellbeing and is standard in social cost of carbon dioxide (SCC) models, and of average utilitarianism (AU), which ignores population size and sums only each time period’s discounted average wellbeing. Under both approaches, as population increases the SCC increases, but optimal peak temperature decreases. The effect is larger under TU, because it responds to the fact that a larger population means climate change hurts more people: for example, in 2025, assuming the United Nations (UN)-high rather than UN-low population scenario entails an increase in the SCC of 85% under TU vs. 5% under AU. The difference in the SCC between the two population scenarios under TU is comparable to commonly debated decisions regarding time discounting. Additionally, we estimate the avoided mitigation costs implied by plausible reductions in population growth, finding that large near-term savings ($billions annually) occur under TU; savings under AU emerge in the more distant future. These savings are larger than spending shortfalls for human development policies that may lower fertility. Finally, we show that whether lowering population growth entails overall improvements in wellbeing—rather than merely cost savings—again depends on the ethical approach to valuing population

Patient-delivered tDCS on chronic neuropathic pain in prior responders to TMS (a randomized controlled pilot study)

Background: Successful response to repetitive transcranial magnetic stimulation (rTMS) of the motor cortex requires continued maintenance treatments. Transcranial Direct Current Stimulation (tDCS) may provide a more convenient alternative. Methods: This pilot study aimed to examine the feasibility of a randomized, double-blind, double-crossover pilot study for patients to self-administer tDCS motor cortex stimulation for 20 minutes/day over five consecutive days. Primary outcomes were as follows: usability of patient-administered tDCS, compliance with device, recruitment, and retention rates. Secondary outcomes were as follows: effect on overall pain levels and quality of life via Short Form-36 anxiety and depression via Hospital Anxiety and Depression Scale, and Mini-Mental State scores. Results: A total of 24 subjects with neuropathic pain, who had previously experienced rTMS motor cortex stimulation (13 with reduction in pain scores, 11 nonresponders) were recruited at the Pain Research Institute, Fazakerley, UK. A total of 21 subjects completed the study. Recruitment rate was 100% but retention rate was only 87.5%. All patients reported satisfactory usability of the tDCS device. No significant difference was shown between Sham vs Anodal (-0.16, 95% CI: -0.43 to 0.11) P=0.43, Sham vs Cathodal (0.11, 95% CI: -0.16 to 0.37) P=0.94, or Cathodal vs Anodal (-0.27, 95% CI: -0.54 to 0.00) P=0.053 treatments. Furthermore, no significant changes were demonstrated in anxiety, depression, or quality of life measurements. The data collected to estimate sample size for a definitive study suggested that the study's sample size was already large enough to detect a change of 15% in pain levels at 90% power for the overall group of 21 patients. Conclusion: This study did not show a beneficial effect of tDCS in this group of patients and does not support the need for a larger definitive study using the same experimental paradigm

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Fear and Exploration in European Starlings (Sturnus vulgaris): A Comparison of Hand-Reared and Wild-Caught Birds

The revision of EU legislation will ban the use of wild-caught animals in scientific procedures. This change is partially predicated on the assumption that captive-rearing produces animals with reduced fearfulness. Previously, we have shown that hand-reared starlings (Sturnus vulgaris) indeed exhibit reduced fear of humans compared to wild-caught conspecifics. Here, we asked whether this reduction in fear in hand-reared birds is limited to fear of humans or extends more generally to fear of novel environments and novel objects. Comparing 6–8 month old birds hand-reared in the lab with age-matched birds caught from the wild as fledged juveniles a minimum of 1 month previously, we examined the birds' initial reactions in a novel environment (a small cage) and found that wild-caught starlings were faster to initiate movement compared to the hand-reared birds. We interpret this difference as evidence for greater escape motivation in the wild-caught birds. In contrast, we found no differences between hand-reared and wild-caught birds when tested in novel object tests assumed to measure neophobia and exploratory behaviour. Moreover, we found no correlations between individual bird's responses in the different tests, supporting the idea that these measure different traits (e.g. fear and exploration). In summary, our data show that developmental origin affects one measure of response to novelty in young starlings, indicative of a difference in either fear or coping style in a stressful situation. Our data contribute to a growing literature demonstrating effects of early-life experience on later behaviour in a range of species. However, since we did not find consistent evidence for reduced fearfulness in hand-reared birds, we remain agnostic about the welfare benefits of hand-rearing as a method for sourcing wild birds for behavioural and physiological research

The predictive value of early behavioural assessments in pet dogs: a longitudinal study from neonates to adults

Studies on behavioural development in domestic dogs are of relevance for matching puppies with the right families, identifying predispositions for behavioural problems at an early stage, and predicting suitability for service dog work, police or military service. The literature is, however, inconsistent regarding the predictive value of tests performed during the socialisation period. Additionally, some practitioners use tests with neonates to complement later assessments for selecting puppies as working dogs, but these have not been validated. We here present longitudinal data on a cohort of Border collies, followed up from neonate age until adulthood. A neonate test was conducted with 99 Border collie puppies aged 2–10 days to assess activity, vocalisations when isolated and sucking force. At the age of 40–50 days, 134 puppies (including 93 tested as neonates) were tested in a puppy test at their breeders' homes. All dogs were adopted as pet dogs and 50 of them participated in a behavioural test at the age of 1.5 to 2 years with their owners. Linear mixed models found little correspondence between individuals' behaviour in the neonate, puppy and adult test. Exploratory activity was the only behaviour that was significantly correlated between the puppy and the adult test. We conclude that the predictive validity of early tests for predicting specific behavioural traits in adult pet dogs is limited

A new bovine conjunctiva model shows that Listeria monocytogenes invasion is associated with lysozyme resistance.

AbstractListerial keratoconjunctivitis (‘silage eye’) is a wide spread problem in ruminants causing economic losses to farmers and impacts negatively on animal welfare. It results from direct entry of Listeria monocytogenes into the eye, often following consumption of contaminated silage. An isolation protocol for bovine conjunctival swabbing was developed and used to sample both infected and healthy eyes bovine eyes (n=46). L. monocytogenes was only isolated from one healthy eye sample, and suggests that this organism can be present without causing disease. To initiate a study of this disease, an infection model was developed using isolated conjunctiva explants obtained from cattle eyes post slaughter. Conjunctiva were cultured and infected for 20h with a range of L. monocytogenes isolates (n=11), including the healthy bovine eye isolate and also strains isolated from other bovine sources, such as milk or clinical infections. Two L. monocytogenes isolates (one from a healthy eye and one from a cattle abortion) were markedly less able to invade conjunctiva explants, but one of those was able to efficiently infect Caco2 cells indicating that it was fully virulent. These two isolates were also significantly more sensitive to lysozyme compared to most other isolates tested, suggesting that lysozyme resistance is an important factor when infecting bovine conjunctiva. In conclusion, we present the first bovine conjunctiva explant model for infection studies and demonstrate that clinical L. monocytogenes isolates from cases of bovine keratoconjunctivitis are able to infect these tissues