Microvesicles: ROS scavengers and ROS producers

This review analyzes the relationship between microvesicles and reactive oxygen species (ROS). This relationship is bidirectional; on the one hand, the number and content of microvesicles produced by the cells are affected by oxidative stress conditions; on the other hand, microvesicles can directly and/or indirectly modify the ROS content in the extra- as well as the intracellular compartments. In this regard, microvesicles contain a pro-oxidant or antioxidant machinery that may produce or scavenge ROS: direct effect. This mechanism is especially suitable for eliminating ROS in the extracellular compartment. Endothelial microvesicles, in particular, contain a specific and well-developed antioxidant machinery. On the other hand, the molecules included in microvesicles can modify (activate or inhibit) ROS metabolism in their target cells: indirect effect. This can be achieved by the incorporation into the cells of ROS metabolic enzymes included in the microvesicles, or by the regulation of signaling pathways involved in ROS metabolism. Proteins, as well as miRNAs, are involved in this last effect

The long-lived Type IIn SN 2015da: Infrared echoes and strong interaction within an extended massive shell star star star

In this paper we report the results of the first similar to four years of spectroscopic and photometric monitoring of the Type IIn supernova SN 2015da (also known as PSN J13522411+3941286, or iPTF16tu). The supernova exploded in the nearby spiral galaxy NGC 5337 in a relatively highly extinguished environment. The transient showed prominent narrow Balmer lines in emission at all times and a slow rise to maximum in all bands. In addition, early observations performed by amateur astronomers give a very well-constrained explosion epoch. The observables are consistent with continuous interaction between the supernova ejecta and a dense and extended H-rich circumstellar medium. The presence of such an extended and dense medium is difficult to reconcile with standard stellar evolution models, since the metallicity at the position of SN 2015da seems to be slightly subsolar. Interaction is likely the mechanism powering the light curve, as confirmed by the analysis of the pseudo bolometric light curve, which gives a total radiated energy greater than or similar to 10(51) erg. Modeling the light curve in the context of a supernova shock breakout through a dense circumstellar medium allowed us to infer the mass of the prexisting gas to be similar or equal to 8 M-circle dot, with an extreme mass-loss rate for the progenitor star similar or equal to 0.6 M-circle dot yr(-1), suggesting that most of the circumstellar gas was produced during multiple eruptive events. Near- and mid-infrared observations reveal a fluxexcess in these domains, similar to those observed in SN 2010jl and other interacting transients, likely due to preexisting radiatively heated dust surrounding the supernova. By modeling the infrared excess, we infer a mass greater than or similar to 0.4 x 10(-3) M-circle dot for the dustSpanish MICINN gran

La gran erupción de hace 4.2 ka cal en Cerro Blanco, Zona Volcánica Central, Andes: nuevos datos sobre los depósitos eruptivos holocenos en la Puna sur y regiones adyacentes

The eruption of the Cerro Blanco Volcanic Complex, in the southern Puna, NW Argentina dated at 4410–4150 a cal BP, was investigated to produce new information on stratigraphy, geomorphology, physical volcanology, radiocarbon dating, petrography, and geochemistry. Identification of pre–, syn–, and post–caldera products allowed us to estimate the distribution of the Plinian fallout during the paroxysmal syn–caldera phase of the eruption. The new results provide evidence for a major rhyolitic explosive eruption that spread volcanic deposits over an area of ~500,000 km2, accumulating > 100 km3 of tephra (bulk volume). This last value exceeds the lower threshold of Volcanic Explosive Index (VEI) of 7. Ash-fall deposits mantled the region at distances > 400 km from source and thick pyroclastic-flow deposits filled neighbouring valleys up to 35 km away. This eruption is the largest documented during the past five millennia in the Central Volcanic Zone of the Andes, and is probably one of the largest Holocene explosive eruptions in the world. We have also identified two additional rhyolitic eruptions in the region from two other eruptive sources: one during the Early–Holocene and another in the Late–Holocene. The identification and characterisation of these significant volcanic events provide new constraints into regional Holocene geological and archaeological records, and offer extensive regional chronostratigraphic markers over a wide geographical area of South America.La erupción del Complejo Volcánico Cerro Blanco en el sur de la Puna, noroeste de Argentina (4410–4150 a BP) se investigó para obtener nueva información sobre estratigrafía, geomorfología, volcanología física, dataciones por radiocarbono, petrografía y geoquímica. La caracterización de los productos en relación a la evolución de la caldera de Cerro Blanco permitió estimar la distribución de los depósitos de ceniza de la fase paroxísmica Plineana de la erupción. Estos novedosos resultados evidencian una gran erupción explosiva riolítica que generó depósitos cineríticos en un área de aproximadamente 500.000 km2, acumulando > 100 km3 de tefra (volumen total). Este último valor supera el umbral inferior del Índice de Explosividad Volcánica (IEV) de 7. Los depósitos de caída de ceniza cubrieron la región, llegando a más de 400 km desde el Complejo Volcánico de Cerro Blanco, y los potentes depósitos de flujos piroclásticos rellenaron los valles vecinos alcanzando una distancia de 35 km. Esta erupción es la más grande documentada durante los últimos cinco milenios en la Zona Volcánica Central de los Andes y es probablemente una de las mayores erupciones explosivas holocenas del mundo. Además, se han identificado otras dos erupciones riolíticas en la región procedentes de otros dos centros eruptivos: una durante el Holoceno temprano y otra en el Holoceno tardío. La identificación y caracterización de estos grandes eventos volcánicos proporcionan nuevas guías para los registros geológicos y arqueológicos regionales del Holoceno, siendo marcadores cronostratigráficos de aplicación a una extensa área geográfica de América del Sur

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer

Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies

Site fidelity and movement patterns of short-finned pilot whales within the Canary Islands : evidence for resident and transient populations

Funding: co-funded by the Canary Government (Consejería de Política Territorial, Sostenibilidad y Seguridad), the Spanish Government (Fundación Biodiversidad and Ministerio de Medio Ambiente, Medio Rural y Marino), Fundación La Caixa, and by a number of international projects funded by EU programmes MACETUS (FEDER/INTERREG III-B MAC/4.2/M10), EMECETUS (FEDER/INTERREG III-B56105/MAC/4.2/M10), LIFE (LIFE03NAT0062), INDEMARES LIFE+ (LIFE07/NAT/E/00732).1. The geographic location and oceanographic, physical, and chemical water properties make the Canary Islands one of the planet's biodiversity hotspots. The short‐finned pilot whale (Globicephala macrorhynchus) is one of the archipelago's most commonly encountered species and is potentially vulnerable to a range of anthropogenic pressures, including habitat degradation, acoustic pollution, fishing, whale‐watching operations, and shipping. Assessment of impact has not been possible because of a lack of even basic information about occurrence and distribution. 2. Spatial and temporal distributions, ranging behaviour, and residence patterns of short‐finned pilot whales were explored for the first time using survey and photo‐identification data collected in the Canary Islands between 1999 and 2012. In total, 1,081 pilot whale sightings were recorded during 70,620 km of search effort over 1,782 survey days. 3. Pilot whales were detected year round and distributed non‐uniformly within the archipelago, with greater densities concentrated in patchy areas mainly on the leeward side of the main islands. In total, 1,320 well‐marked individuals were identified, which exhibited a large degree of variability in site fidelity. 4. Different but not isolated subpopulations of pilot whales that share ranges and maintain social interactions were apparently present in the Canary Islands. Strong evidence of an island‐associated subpopulation was found, with a group of 50 ‘core resident’ individuals associated particularly with Tenerife. There were also ‘transient’ individuals or temporary migrants, which, probably driven by inter‐ and intra‐specific competition, may travel long distances whilst using the archipelago as part of a larger range. 5. These findings fill a major gap in the knowledge of this species’ occurrence, distribution, movements, and site fidelity in the archipelago and provide much needed data to allow the initiation of informed conservation assessments and management actions.PostprintPeer reviewe

A relocatable ocean model in support of environmental emergencies

During the Costa Concordia emergency case, regional, subregional, and relocatable ocean models have been used together with the oil spill model, MEDSLIK-II, to provide ocean currents forecasts, possible oil spill scenarios, and drifters trajectories simulations. The models results together with the evaluation of their performances are presented in this paper. In particular, we focused this work on the implementation of the Interactive Relocatable Nested Ocean Model (IRENOM), based on the Harvard Ocean Prediction System (HOPS), for the Costa Concordia emergency and on its validation using drifters released in the area of the accident. It is shown that thanks to the capability of improving easily and quickly its configuration, the IRENOM results are of greater accuracy than the results achieved using regional or subregional model products. The model topography, and to the initialization procedures, and the horizontal resolution are the key model settings to be configured. Furthermore, the IRENOM currents and the MEDSLIK-II simulated trajectories showed to be sensitive to the spatial resolution of the meteorological fields used, providing higher prediction skills with higher resolution wind forcing.MEDESS4MS Project; TESSA Project; MyOcean2 Projectinfo:eu-repo/semantics/publishedVersio

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade