Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

Measles virus (MV) infection causes an acute childhood disease that can include infection of the central nervous system and can rarely progress to severe neurological disease for which there is no specific treatment. We generated potent antiviral peptide inhibitors of MV entry and spreading and MV-induced cell fusion. Dimers of MV-specific peptides derived from the C-terminal heptad repeat region of the MV fusion protein, conjugated to cholesterol, efficiently protect SLAM transgenic mice from fatal MV infection. Fusion inhibitors hold promise for the prophylaxis of MV infection in unvaccinated and immunocompromised people, as well as potential for the treatment of grave neurological complications of measles.     

HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition

Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies.     

New information on Bobosaurus forojuliensis (Reptilia: Sauropterygia): implications for plesiosaurian evolution

Preparation of the holotype specimen of Bobosaurus forojuliensis, a large sauropterygian from the lower Carnian of northeastern Italy, revealed new morphological data relevant in establishing its phylogenetic affinities among pistosauroid taxa and its relationships with plesiosaurians. Inclusion of B. forojuliensis in two phylogenetic analyses focusing, respectively, on sauropterygians and pistosauroids agreed in placing the Italian taxon as closer to plesiosaurians than to other pistosauroids. The phylogenetic interpretation of Bobosaurus was not biased by assumptions on character weighting, is consistent with its relatively younger age compared to most pistosauroids, extends the fossil record of the plesiosaurian basal lineage back to the Carnian and supports the earliest diversification of the clade during the Late Triassic in agreement with the record of several distinct lineages of rhomaleosaurids, plesiosauroids and pliosauroids in the lowermost Jurassic. Bobosaurus shows that the evolution of the plesiosaurian body plan from the ancestral pistosauroid grade was a step-wise process, and that some of the vertebral and appendicular specialisations of Jurassic and Cretaceous plesiosaurians had already developed in the earliest Late Triassic.     

The integration of multiple independent data reveals an unusual response to Pleistocene climatic changes in the hard tick Ixodes ricinus

In the last few years, improved analytical tools and the integration of genetic data with multiple sources of information have shown that temperate species exhibited more complex responses to ice ages than previously thought. In this study, we investigated how Pleistocene climatic changes affected the current distribution and genetic diversity of European populations of the tick Ixodes ricinus, an ectoparasite with high ecological plasticity. We first used mitochondrial and nuclear genetic markers to investigate the phylogeographic structure of the species and its Pleistocene history using coalescent‐based methods; then we used species distribution modelling to infer the climatic niche of the species at last glacial maximum; finally, we reviewed the literature on the I. ricinus hosts to identify the locations of their glacial refugia. Our results support the scenario that during the last glacial phase, I. ricinus never experienced a prolonged allopatric divergence in separate glacial refugia, but persisted with interconnected populations across Southern and Central Europe. The generalist behaviour in host choice of I. ricinus would have played a major role in maintaining connections between its populations. Although most of the hosts persisted in separate refugia, from the point of view of I. ricinus, they represented a continuity of ‘bridges’ among populations. Our study highlights the importance of species‐specific ecology in affecting responses to Pleistocene glacial–interglacial cycles. Together with other cases in Europe and elsewhere, it contributes to setting new hypotheses on how species with wide ecological plasticity coped with Pleistocene climatic changes.     

Integrated analysis of recurrent properties of cancer genes to identify novel drivers

The heterogeneity of cancer genomes in terms of acquired mutations complicates the identification of genes whose modification may exert a driver role in tumorigenesis. In this study, we present a novel method that integrates expression profiles, mutation effects, and systemic properties of mutated genes to identify novel cancer drivers. We applied our method to ovarian cancer samples and were able to identify putative drivers in the majority of carcinomas without mutations in known cancer genes, thus suggesting that it can be used as a complementary approach to find rare driver mutations that cannot be detected using frequency-based approaches.     

Real-time tumor tracking with an artificial neural networks-based method: A feasibility study

The purpose of this study was to develop and assess the performance of a tumor tracking method designed for application in radiation therapy. This motion compensation strategy is currently applied clinically only in conventional photon radiotherapy but not in particle therapy, as greater accuracy in dose delivery is required.We proposed a tracking method that exploits artificial neural networks to estimate the internal tumor trajectory as a function of external surrogate signals. The developed algorithm was tested by means of a retrospective clinical data analysis in 20 patients, who were treated with state of the art infra-red motion tracking for photon radiotherapy, which is used as a benchmark. Integration into a hardware platform for motion tracking in particle therapy was performed and then tested on a moving phantom, specifically developed for this purpose.Clinical data show that a median tracking error reduction up to 0.7 mm can be achieved with respect to state of the art technologies. The phantom study demonstrates that a real-time tumor position estimation is feasible when the external signals are acquired at 60 Hz.The results of this work show that neural networks can be considered a valuable tool for the implementation of high accuracy real-time tumor tracking methodologies.     

Tropospheric ozone reduces carbon assimilation in trees: estimates from analysis of continuous flux measurements

High ground‐level ozone concentrations are typical of Mediterranean climates. Plant exposure to this oxidant is known to reduce carbon assimilation. Ozone damage has been traditionally measured through manipulative experiments that do not consider long‐term exposure and propagate large uncertainty by up‐scaling leaf‐level observations to ecosystem‐level interpretations. We analyzed long‐term continuous measurements (>9 site‐years at 30 min resolution) of environmental and eco‐physiological parameters at three Mediterranean ecosystems: (i) forest site dominated by Pinus ponderosa in the Sierra Mountains in California, USA; (ii) forest site composed of a mixture of Quercus spp. and P. pinea in the Tyrrhenian sea coast near Rome, Italy; and (iii) orchard site of Citrus sinensis cultivated in the California Central Valley, USA. We hypothesized that higher levels of ozone concentration in the atmosphere result in a decrease in carbon assimilation by trees under field conditions. This hypothesis was tested using time series analysis such as wavelet coherence and spectral Granger causality, and complemented with multivariate linear and nonlinear statistical analyses. We found that reduction in carbon assimilation was more related to stomatal ozone deposition than to ozone concentration. The negative effects of ozone occurred within a day of exposure/uptake. Decoupling between carbon assimilation and stomatal aperture increased with the amount of ozone pollution. Up to 12–19% of the carbon assimilation reduction in P. ponderosa and in the Citrus plantation was explained by higher stomatal ozone deposition. In contrast, the Italian site did not show reductions in gross primary productivity either by ozone concentration or stomatal ozone deposition, mainly due to the lower ozone concentrations in the periurban site over the shorter period of investigation. These results highlight the importance of plant adaptation/sensitivity under field conditions, and the importance of continuous long‐term measurements to explain ozone damage to real‐world forests and calculate metrics for ozone‐risk assessment.     

Effects of egg testosterone on female mate choice and male sexual behavior in the pheasant

Evidence is accumulating that sex steroids in the eggs, besides affecting progeny phenotype and behavior in the short term, also have enduring effects until adulthood, when they may translate into differences in reproductive strategies and success. Maternal steroids transfer may therefore affect both agonistic behavior and mate choice decisions, either through the promotion of body size and condition or through a priming effect on the neuroendocrine system. However, owing to the prevalence of a short-term perspective, relevance of maternal transfer of sex steroids to sexual selection processes has been seldom studied. Here we investigate the effects of an experimental increase in egg testosterone on male dominance and copulation success in the ring-necked pheasant, Phasianus colchicus, a polygynous galliform with multiple male ornamental traits, in captivity. We found that females from testosterone (T) injected eggs copulated less than control females. Males from T-injected eggs obtained more copulations than control males, specifically with control females. The effect of male ‘ordinary’ and secondary sexual traits on either dominance or copulation frequency did not depend on early exposure to T, nor did T treatment affect male dominance. Present results demonstrate that variation in the early hormonal environment set up by mothers affects sexual behavior of the offspring, which might translate into fitness differences.