Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5

Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.     

The macroecology of infectious diseases: a new perspective on global‐scale drivers of pathogen distributions and impacts

Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.     

A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere maintenance

RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere length maintenance and protection has remained elusive. RAP1 also binds subtelomeric repeats and along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres, and its deficiency causes a premature aging in humans and mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact on mouse survival, mice lacking both RAP1 and telomerase show a progressively decreased survival with increasing mouse generations compared to telomerase single mutants. Telomere shortening is more pronounced in Rap1^?/? Terc^?/? doubly deficient mice than in the single‐mutant Terc^?/? counterparts, leading to an earlier onset of telomere‐induced DNA damage and degenerative pathologies. Telomerase deficiency abolishes obesity and liver steatohepatitis provoked by RAP1 deficiency. Using genomewide ChIP sequencing, we find that progressive telomere shortening owing to telomerase deficiency leads to re‐localization of RAP1 from telomeres and subtelomeric regions to extratelomeric sites in a genomewide manner. These findings suggest that although in the presence of sufficient telomere reserve RAP1 is not a key factor for telomere maintenance and protection, it plays a crucial role in the context of telomerase deficiency, thus in agreement with its evolutionary conservation as a telomere component from yeast to humans.     

Effect of dietary vegetable oils on the fatty acid profile of plasma lipoproteins in dairy cows

The aim of this study was to elucidate the effect of dietary supplementation of soybean oil (SO) and hydrogenated palm oil (HPO) on the transport of fatty acids (FA) within plasma lipoproteins in lactating and non-lactating cows. Three lactating and three non-lactating Holstein cows were used in two different 3 × 3 Latin square experiments that included three periods of 21 d. Dietary treatments for lactating cows consisted of a basal diet (control; no fat supplement) and fat-supplemented diets containing SO (500 g/d per cow) or HPO (500 g/d per cow). For non-lactating cows, dietary treatments consisted of a basal diet (control; no fat supplement) and fat-supplemented diets containing SO (170 g/d per cow) or HPO (170 g/d per cow). Compared with the control and SO diet, HPO addition increased (p < 0.05) the concentration of C16:0, C18:0, C18:2cis-9,12, C18:3cis-9,12,15 and total saturated and polyunsaturated FA in the plasma of lactating cows. In non-lactating cows, the SO addition increased the plasma concentration of C18:1trans-11. In lactating cows, concentrations of C16:0, C18:0 and total saturated FA were increased (p < 0.05) by HPO addition in the high-density lipoprotein (HDL). Total saturated FA were increased (p < 0.05) by HPO in very-low-density lipoprotein (VLDL). In non-lactating cows, the concentration of C18:0 was increased (p < 0.05) by HPO in HDL, whereas C18:1trans-11 was increased (p < 0.05) by SO in the low-density lipoprotein. Overall, it was found that distribution and transport of FA within the bovine plasma lipoproteins may be influenced by chain length and degree of unsaturation of dietary lipids. Also, the distribution of individual FA isomers such as C18:1trans-11 and C18:2cis-9,trans-11 may vary depending on the physiological state of the cow (lactating or non-lactating), and are increased in plasma (lactating cows) and the HDL (non-lactating cows) when cows are fed SO.     

Predicting the success of an invader: Niche shift versus niche conservatism

Invasive species can encounter environments different from their source populations, which may trigger rapid adaptive changes after introduction (niche shift hypothesis). To test this hypothesis, we investigated whether postintroduction evolution is correlated with contrasting environmental conditions between the European invasive and source ranges in the Asian tiger mosquito Aedes albopictus. The comparison of environmental niches occupied in European and source population ranges revealed more than 96% overlap between invasive and source niches, supporting niche conservatism. However, we found evidence for postintroduction genetic evolution by reanalyzing a published ddRADseq genomic dataset from 90 European invasive populations using genotype–environment association (GEA) methods and generalized dissimilarity modeling (GDM). Three loci, among which a putative heat‐shock protein, exhibited significant allelic turnover along the gradient of winter precipitation that could be associated with ongoing range expansion. Wing morphometric traits weakly correlated with environmental gradients within Europe, but wing size differed between invasive and source populations located in different climatic areas. Niche similarities between source and invasive ranges might have facilitated the establishment of populations. Nonetheless, we found evidence for environmental‐induced adaptive changes after introduction. The ability to rapidly evolve observed in invasive populations (genetic shift) together with a large proportion of unfilled potential suitable areas (80%) pave the way to further spread of Ae. albopictus in Europe.     

Desert travels in the Atacama: making place through movement (c. 2500-1500 cal BP)

Social worlds are constituted by movement. Mobility entails the circulation not only of people, but also of material goods, imaginaries, experiences, flows of information, and knowledge. In this article, we examine different forms of movement in the Atacama Desert during the Formative Period (c. 2500-1500 cal BP), such as pedestrian travels, llama caravans, and navigation on sea lion-skin vessels along the Pacific, incorporating various material means and encompassing a wide array of incentives. We present different case studies that challenge monolithic assumptions about mobility in the South-Central Andes, commonly understood through the lens of ecological complementarity and primarily driven by economic exchange. Extending Binford's classic distinction between residential and logistical mobility as two ideal types of hunter-gatherers’ settlement systems to include groups of early farmers, in combination with the territorial categories of local and extra-local, we interrogate the spatial and temporal scale of these journeys – from daily to seasonal, from short to long distance – and its materialization. In these examples, we approach movement and travel as a way of life, expanding the traditional view of mobility through an exploration of the varied ways in which it was practised and integrated into the social lives of desert dwellers.