Estudio de la expresión, secreción y mecanismos inductores de apoptosis de los ligandos mortales en células hematológicas

Apo2L/TRAIL es un ligando mortal inductor de apoptosis vía extrínseca. Entre otras funciones, TRAIL, junto con FasL, son secretados asociados a exosomas y regulan la respuesta inmune. El objetivo de este trabajo ha sido profundizar en el papel de TRAIL en los procesos de regulación del sistema inmune. Se analizó la expresión de este ligando mortal así como su secreción y la contribución de TRAIL expresado en superficie o secretado a la capacidad citotóxica de linfocitos T normales activados obtenidos a partir de sangre periférica antes y después de ser reestimulados, comparándolo con la expresión y secreción en células tumorales de estirpe hematológica. También se analizó el efecto que tiene la inhibición de la proteína VCP (valosin-containing protein) implicada en la secreción de exosomas en células de origen tumoral mediante el uso de un inhibidor específico, DeBQ. Por último, se generaron líneas celulares tumorales de estirpe hematológica provenientes de mieloma múltiple resistentes a TRAIL para profundizar en el estudio de los mecanismos de resistencia que las células tumorales desarrollan frente a este ligando mortal. Se vieron diferencias entre los patrones de expresión de TRAIL en superficie e intracelular entre la línea celular tumoral Jurkat y los linfocitos T normales activados (blastos T) así como entre las subpoblaciones de blastos T CD4+ y CD8+. Se observó que la contribución principal de los ligandos mortales a la citotoxicidad de los blastos T se realiza a través de su secreción asociada a exosomas, sin apenas contribución de los ligandos mortales de superficie. Por último se vio que el inhibidor de la proteína VCP DeBQ utilizado a dosis subtóxica fue capaz de inhibir la expresión de TRAIL en superficie en la línea celular tumoral Jurkat pero no en blastos T, indicando que el DeBQ podría inhibir los mecanismos de transporte de TRAIL a superficie. Finalmente, se vio que uno de los mecanismos de adquisición de resistencia a TRAIL en líneas hematológicas provenientes de mieloma múltiple fue la disminución de la expresión de DR5 (receptor pro-apoptótico de TRAIL) en superficie

El Puerto Bajo de Góriz (Parque Nacional de Ordesa y Monte Perdido). Ocupación y explotación de un paisaje de alta montaña desde la prehistoria hasta el siglo XX

El Puerto Bajo de Góriz forma parte de las extensas super cies de pastizal del Parque Nacional de Ordesa y Monte Perdido. El actual paisaje vegetal de la zona no es estrictamente natural, sino consecuencia también de la actividad antrópica. Su explotación ganadera a lo largo de miles de años ha contribuido a ampliar la super cie de los pastos, que han descendido hasta cotas que corresponderían a la expansión del bosque. Parque. Se han documentado 59 puntos de interés arqueológico que incluyen cuevas, abrigos, rediles y casetas de pastores, de los que 17 han sido sondeados y 2 excavados en extensión. Los resultados de esos trabajos han con rmado la ocupación y la explotación del territorio desde al menos la segunda mitad del iii milenio cal a. C. En 2014 dio comienzo un plan de prospecciones al amparo de un proyecto del Organismo de Parques Nacionales para comprobar en qué momento comenzó el impacto humano en ese territorio y si podía remontarse, al igual que en otras zonas pirenaicas y prepirenaicas, a tiempos prehistóricos, rebasando los contrastados datos medievales. Con esa nalidad se han desarrollado tres campañas de prospección intensiva, excavaciones y sondeos en un territorio de unas 400 hectáreas situado en la zona sureste del arque. Se han documentado 59 puntos de interés arqueológico que incluyen cuevas, abrigos, rediles y casetas de pastores, de los que 17 han sido sondeados y 2 excavados en extensión. Los resultados de esos trabajos han con rmado la ocupación y la explotación del territorio desde al menos la segunda mitad del iii milenio cal a. C. The Puerto Bajo de Góriz (Low Góriz Greenhill) belongs to the wide pasture areas of the Ordesa and Monte Perdido National Park. The current vegetal landscape is not totally natural as anthropic activity has influenced its evolution. Thousands of years of husbandry exploitation has contributed to the widening of the pasture surface which nowadays covers lower altitudes, originally expected to be forested areas. In 2014, a survey plan was initiated within a research project promoted by the National Parks Authority, in order to check when human action started to have an impact on natural development, and if this influence could go back to Prehistoric times, far before the documented Middle Age data, similarly to other Pyrenean and Prepyrenean areas. To this end, three intensive survey campaigns have been carried out in an 400 ha territory in the SE part of the Park. Selected test pits and excavations have also been included. Fifty-nine points of archaeological interest, that include caves, rock shelters, cotes and shepherds huts have been documented, including seventeen test pits and two extensive excavations. The first results have confirmed the occupation and exploitation of this territory since at least the second half of the 3rd millennium cal BC

Le canyon de la Pardina et ses estives : approche archéologique d’un territoire de haute montagne dans le parc national d’Ordesa et du mont Perdu (Fanlo, Huesca, Espagne)

Le Puerto Bajo de Góriz fait partie des vastes surfaces pastorales subalpines du parc national d’Ordesa et du mont Perdu. Le paysage actuel n’est pas strictement naturel, car il a été modifié tout au long du temps par des activités anthropiques, notamment l’élevage, qui a abaissé la limite des pâturages en les étendant sur des surfaces qui devraient être occupées par la forêt. Depuis 2014, des prospections et sondages archéologiques ont été engagés pour appréhender les premières manifestations de cet impact anthropique et voir si des transformations sont déjà perceptibles au cours de la préhistoire, antérieurement, donc, à la documentation médiévale bien connue. Trois campagnes ont permis de renseigner 59 points d’intérêt archéologique dont des grottes, abris, enclos et cabanes de bergers. Dix-sept d’entre eux ont été sondés et deux étudiés en fouilles extensives. Les premiers résultats confirment l’occupation et exploitation du territoire depuis le iiie millénaire cal. BC.The Puerto Bajo de Góriz is one of the pasture areas in the National Park of Ordesa and Monte Perdido, within the subalpine floor zone. The current landscape is not strictly natural: human activities (shepherding) have modified it, lowering the pastures level to altitudes that should be occupied by forests. Starting in 2014, we have carried out archaeological surveys and excavations in order to test when the human impact can be detected in the area and if those affections were already visible during prehistoric times, before the well-known medieval documentation. After three fieldwork campaigns we have explored 59 archaeologically relevant spots comprising caves, rockshelters, pens and herder huts; test-pits have been carried out in 17 of them, while 2 have been excavated in full. First results confirm the occupation and exploitation of this territory at least since the 3rd millennium cal. BC

Reply to Ben-Dor and Barkai: A low Zn isotope ratio is not equal to a low Zn content

However, we are afraid that there was a misunderstanding in the interpretation of our data. Ben-Dor and Barkai (2) wrote that "One explanation presented in the [our] paper was that Neandertals may have consumed body parts and animals that were relatively poor in zinc, like the liver or deer." This sentence is not reflecting our conclusions: We discussed Zn isotope ratios (i.e., 66Zn/64Zn ratio expressed as a δ66Zn value) and not Zn concentrations. To explain low δ66Zn values of the Neandertal tooth, we propose that Neandertals ate food items depleted in heavy Zn isotopes (and therefore enriched in light Zn isotopes), but those foods can have variable Zn contents, independent of the Zn isotope composition as such

Survival of Late Pleisticene Hunter-gatherer ancestry in the Iberian Peninsula

The Iberian Peninsula in southwestern Europe represents an important test case for the study of human population movements during prehistoric periods. During the Last Glacial Maximum (LGM), the peninsula formed a periglacial refugium for hunter-gatherers (HGs) and thus served as a potential source for the re-peopling of northern latitudes. The post-LGM genetic signature was previously described as a cline from Western HG (WHG) to Eastern HG (EHG), further shaped by later Holocene expansions from the Near East and the North Pontic steppes. Western and central Europe were dominated by ancestry associated with the 14,000-year-old individual from Villabruna, Italy, which had largely replaced earlier genetic ancestry, represented by 19,000-15,000-year-old individuals associated with the Magdalenian culture. However, little is known about the genetic diversity in southern European refugia, the presence of distinct genetic clusters, and correspondence with geography. Here, we report new genome-wide data from 11 HGs and Neolithic individuals that highlight the late survival of Paleolithic ancestry in Iberia, reported previously in Magdalenian-associated individuals. We show that all Iberian HGs, including the oldest, a 19,000-year-old individual from El Mirón in Spain, carry dual ancestry from both Villabruna and the Magdalenian-related individuals. Thus, our results suggest an early connection between two potential refugia, resulting in a genetic ancestry that survived in later Iberian HGs. Our new genomic data from Iberian Early and Middle Neolithic individuals show that the dual Iberian HG genomic legacy pertains in the peninsula, suggesting that expanding farmers mixed with local HGs

Genomic transformation and social organization during the Copper Age-Bronze Age transition in southern Iberia

The emerging Bronze Age (BA) of southeastern Iberia saw marked social changes. Late Copper Age (CA) settlements were abandoned in favor of hilltop sites, and collective graves were largely replaced by single or double burials with often distinctive grave goods indirectly reflecting a hierarchical social organization, as exemplified by the BA El Argar group. We explored this transition from a genomic viewpoint by tripling the amount of data available for this period. Concomitant with the rise of El Argar starting ∼2200 cal BCE, we observe a complete turnover of Y-chromosome lineages along with the arrival of steppe-related ancestry. This pattern is consistent with a founder effect in male lineages, supported by our finding that males shared more relatives at sites than females. However, simple two-source models do not find support in some El Argar groups, suggesting additional genetic contributions from the Mediterranean that could predate the BA.This work was supported by the Max Planck Society (V.V.-M. and W.H.); European Research Council (ERC) grant 771234—PALEoRIDER (W.H.); Spanish Ministry of Economy, Industry and Competitiveness project HAR2017-85962-P (C.O., C.R.-H., M.I.F., E.C.B., C.V.-F., V.L., R.M., and R.R.); AGAUR 2017SGR1044 (C.O., C.R.-H., M.I.F., E.C.B., C.V.-F., V.L., R.M., and R.R.); ICREA Academia program (R.R.); John Templeton Foundation grant 61220 (D.R.); and Paul Allen Family Foundation (D.R.). D.R. is an Investigator of the Howard Hughes Medical Institute

The genomic history of the Iberian Peninsula over the past 8000 years

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula.We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming.We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry.We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean

Genomic transformation and social organization during the Copper Age-Bronze Age transition in southern Iberia

[EN]The emerging Bronze Age (BA) of southeastern Iberia saw marked social changes. Late Copper Age (CA) settlements were abandoned in favor of hilltop sites, and collective graves were largely replaced by single or double burials with often distinctive grave goods indirectly reflecting a hierarchical social organization, as exemplified by the BA El Argar group. We explored this transition from a genomic viewpoint by tripling the amount of data available for this period. Concomitant with the rise of El Argar starting similar to 2200 cal BCE, we observe a complete turnover of Y-chromosome lineages along with the arrival of steppe-related ancestry. This pattern is consistent with a founder effect in male lineages, supported by our finding that males shared more relatives at sites than females. However, simple two-source models do not find support in some El Argar groups, suggesting additional genetic contributions from the Mediterranean that could predate the BA.This work was supported by the Max Planck Society (V.V.-M. and W.H.); European Research Council (ERC) grant 771234-PALEoRIDER (W. H.); Spanish Ministry of Economy, Industry and Competitiveness project HAR2017-85962-P (C.O., C.R.-H., M.I.F., E.C.B., C.V.-F., V.L., R.M., and R.R.); AGAUR 2017SGR1044 (C.O., C.R.-H., M.I.F., E. C.B., C.V.-F., V. L., R.M., and R.R.); ICREA Academia program (R.R.); John Templeton Foundation grant 61220 (D.R.); and Paul Allen Family Foundation (D.R.). D.R. is an Investigator of the Howard Hughes Medical Institute

Anthropic resource exploitation and use of the territory at the onset of social complexity in the Neolithic-Chalcolithic Western Pyrenees: a multi-isotope approach

Carbon (δ13C) and nitrogen (δ15N) stable isotope analyses from bone collagen provide information about the dietary protein input, while strontium isotopes (87Sr/86Sr) from tooth enamel give us data about provenance and potential territorial mobility of past populations. To date, isotopic results on the prehistory of the Western Pyrenees are scarce. In this article, we report human and faunal values of the mentioned isotopes from the Early-Middle Neolithic site of Fuente Hoz (Anuntzeta) and the Late Neolithic/Early Chalcolithic site of Kurtzebide (Letona, Zigoitia). The main objectives of this work are to analyze the dietary and territorial mobility patterns of these populations. Furthermore, as an additional aim, we will try to discuss social ranking based on the isotope data and existing literature on this topic in the region of study. Our results show that, based on the bioavailable Sr values, both purported local and non-local humans were buried together at the sites. Additionally, they suggest similar resource consumption based on C3 terrestrial resources (i.e. ovicaprids, bovids, and suids) as the main part of the protein input. Overall, this study sheds light on how individuals from different backgrounds were still buried together and shared the same dietary lifestyle at a time in the Prehistory of Iberia when social complexities started to appear

Genomic and dietary discontinuities during the Mesolithic and Neolithic in Sicily

Sicily is a key region for understanding the agricultural transition in the Mediterranean because of its central position. Here, we present genomic and stable isotopic data for 19 prehistoric Sicilians covering the Mesolithic to Bronze Age periods (10,700-4,100 yBP). We find that Early Mesolithic hunter-gatherers (HGs) from Sicily are a highly drifted lineage of the Early Holocene western European HGs, whereas Late Mesolithic HGs carry ∼20% ancestry related to northern and (south) eastern European HGs, indicating substantial gene flow. Early Neolithic farmers are genetically most similar to farmers from the Balkans and Greece, with only ∼7% of ancestry from local Mesolithic HGs. The genetic discontinuities during the Mesolithic and Early Neolithic match the changes in material culture and diet. Three outlying individuals dated to ∼8,000 yBP; however, suggest that hunter-gatherers interacted with incoming farmers at Grotta dell'Uzzo, resulting in a mixed economy and diet for a brief interlude at the Mesolithic-Neolithic transition.Funding. The Max Planck Society financed the genetic, isotopic, and radiocarbon analyses. S. Talamo has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement No. 803147 RESOLUTION, https://site.unibo.it/resolution-erc/en).Peer reviewe