Variabilidad de los conjuntos líticos en el Paleolítico Medio del Abric Romaní (Capellades, Barcelona)

El Abric Romaní cuenta con una potente secuencia del Paleolítico Medio de la que hasta el momento se han excavado 13 niveles arqueológicos. Estos niveles muestran un patrón de ocupación basado en la aparición de espacios domésticos en torno a hogares en los que se concentra la mayor parte de las actividades, especialmente las relacionadas con el procesamiento de los recursos líticos. Este patrón permite caracterizar el Abric Romaní como un espacio residencial, lo que es fundamental para entender el registro arqueológico y el comportamiento técnico. La variabilidad de los conjuntos líticos se ha abordado desde una triple perspectiva, relacionada con las diferentes escalas temporales a las que es posible acceder a través de la metodología arqueológica: la variabilidad que refleja procesos de larga duración y que se expresa en los cambios que se producen a lo largo de la secuencia; la variabilidad en el interior de conjunto lítico definido a partir de criterios estratigráficos; y la variabilidad accesible a través de contextos temporales de alta resolución. Esta última aproximación a la variabilidad se centra en el estudio de los diferentes comportamientos discernibles en un mismo nivel arqueológico. En este trabajo utilizaremos el nivel J como ejemplo de este tipo de análisis.L'Abric Romaní compta amb una potent seqüència del Paleolític Mitjà de qual, fins al moment, s'han excavat 13 nivells arqueològics. Aquests nivells mostren un patró d'ocupació basat en l'aparició d'espais domèstics entorn a fogars en els quals es concentren la major part de les activitats, especialment les relacionades amb el processament dels recursos lítics. Aquest patró permet caracteritzar l'Abric Romaní com un espai residencial, fet que és fonamental per entendre el registre arqueològic i el comportament tècnic. La variabilitat dels conjunts lítics s'ha tractat des d'una triple perspectiva, relacionada amb les diferents escales temporals a les quals és possible accedir a través de la metodologia arqueològica: la variabilitat que reflecteix processos de llarga duració i que s'expressa en els canvis que es produeixen al llarg de la seqüència; la variabilitat en l'interior del conjunt lític definit a partir de criteris estratigràfics; i la variabilitat accessible a través de contextos temporals d'alta resolució. Aquesta última aproximació a la variabilitat se centra en l'estudi dels diferents comportaments discernibles en un mateix nivell arqueològic. En aquest treball utilitzarem el nivell J com a exemple d'aquest tipus d'anàlisi.L'Abric Romaní compte avec une puissante séquence du Paléolithique Moyen dont, actuellement, ont uniquement été fouillés 13 niveaux archéologiques. Ces niveaux montrent un patron d'occupation basé sur l'apparition d'espaces domestiques autour des foyers dans lesquels se concentrent la plupart des activités, spécialement celles qui sont en relation avec la taille des ressources lithiques. Ce patron permet de caractériser l'Abri Romaní comme espace résidentiel, ce qui est fondamental pour comprendre le registre archéologique et le comportement technique. La variabilité des ensembles lithiques a été traitée suivant une triple perspective, mise en relation avec les différentes échelles temporelles auxquelles il est possible d'y accéder par la méthodologie archéologique: la variabilité qui montre des processus de longue durée et qui se donne par les changements produits tout le long de la séquence ; la variabilité à l'intérieur de l'ensemble lithique défini suivant des critères stratigraphiques ; et la variabilité accessible à partir des contextes temporels d'haute résolution. Cette dernière approche à la variabilité se centre sur l'étude des différents comportements discernables dans un même niveau archéologique. Dans ce travail, on utilisera le niveau J comme exemple de ce type d'analyse.Abric Romani contains a thick Middle Palaeolithic sequence of which 13 archaeological levels have been excavated so far. Occupation patterns in these levels are organized in domestic spaces around hearths in which most of activities are concentrated, especially those concerning the management of lithic material. This pattern portrays Abric Romani as a residential space, and that is essential to understanding its archaeological record and technical behaviour. Variability of the lithic assemblages has been assessed according to three different temporal scales feasible of being investigated with archaeological methods; variability in long term scales, as shown by changes throughout the sequence; variability in lithic assemblages within a single stratigraphic level; and variability in high resolution temporal contexts. The latter is approached through the study of different behaviours detected within the same archaeological level. In this paper, level J will be used as a case study to tackle this type of analysis

Virtual Trip to the Abric Romaní site and its lithic procurement areas

This paper introduces the virtual field trip organised on the occasion of the 13th International Symposium on Knappable Materials in Tarragona from 4th to 6th October 2021, showing the Abric Romaní site (NE Iberian Peninsula) and the chert procurement areas located within a 30 km radius. The Abric Romaní section consists of a general presentation of the Middle Palaeolithic site, including a brief description of its 50 m stratigraphic sequence, where more than 20 archaeological levels have been identified dating from 110 to 39 ka BP, and some of the main traits of the archaeological assemblages have been recovered. This was followed by an introduction of the siliceous outcrops of the Panadella cherts approximately 24 km from the Abric Romaní; the Sant Martí de Tous chert outcrops 16 km away and the Valldeperes and Ca l’Alemany chert outcrops at distances of 24 and 25 km, respectively. In all cases, the geological formations, as well as the main chert macroscopic and microscopic characteristics, are described. This paper yields the most relevant aspects of a field trip that had to be recorded due to the COVID-19 pandemic, but which brought us back together and facilitated the presentation of the main source areas frequented by the Neanderthals groups of this referential site.En este trabajo se presenta la salida de campo virtual organizada con motivo del 13th International Symposium on Knappable Materials organizado en Tarragona del 4 al 6 de octubre de 2021, en el que se muestra el yacimiento de Abric Romaní (NE de la Península Ibérica) y las zonas de captación de sílex situadas en un radio de 30 km. La sección del Abric Romaní consiste en una presentación general del yacimiento del Paleolítico Medio, incluyendo una breve descripción de su secuencia estratigráfica de 50 m, donde se han identificado más de 20 niveles arqueológicos datados entre 110 y 39 ka BP, y se presentan de manera general los principales rasgos de los conjuntos arqueológicos. A continuación, se han introducido los afloramientos silíceos de los sílex de la Panadella a unos 24 km del Abric Romaní; los afloramientos de sílex de Sant Martí de Tous a 16 km y los afloramientos de sílex de Valldeperes y Ca l'Alemany a distancias de 24 y 25 km, respectivamente. En todos los casos se describen las formaciones geológicas, así como las principales características macroscópicas y microscópicas del sílex. En este trabajo se recogen los aspectos más relevantes de la salida de campo que tuvo que ser grabada debido a la pandemia del COVID-19, pero que nos volvió a reunir y facilitó la presentación de las principales zonas de captación silícea frecuentadas por los grupos neandertales de este yacimiento en cuestión

Using GIS and geostatistical techniques to identify Neanderthal campsites at archaeolevel Ob at Abric Romaní

Although intra-site spatial approaches are considered a key factor when interpreting archaeological assemblages, these are often based on descriptive, qualitative, and subjective observations. Currently, within the framework of research into spatial taphonomy and palimpsest dissection, several studies have begun to employ more quantitative and objective techniques, implementing tools such as geostatistics and geographic information system (GIS) methods. This is precisely the approach that the Abric Romaní team is following. In this work, we present GIS and geostatistics methods applied to the faunal and lithic assemblages from archaeolevel Ob, including an analysis of the spatial structure, the identification of clusters and sectors, size and fabric analyses, the projection of vertical profiles, and the reconstruction of a digital elevation model of the paleosurface. The results obtained indicate a clustered distribution, primarily concentrated into four dense accumulations. The predominance of remains < 3 cm in length and the absence of preferential orientations make it possible to rule out a generalised postdepositional movement affecting most of the site, although some local movement has been identified. The horizontal and vertical spatial analyses allow us to identify accumulations of a single material (lithic or faunal) in addition to mixed accumulations (lithic and faunal). Integrating all this data with the results of previous studies (zooarchaeological, refits, combustion structures, and partial lithic technological analyses), we evaluate and combine the interpretations proposed previously using different approaches, thereby improving the overall interpretation of the archaeolevel Ob. Finally, we also develop a preliminary comparison between Ob and some other levels at the same site (in particular M and P)The Catalan Government (Generalitat de Catalunya) supported this research with the Quadrennial Project CLT009/18/00054, the project “Territoris prehistòrics de la Conca de l’Anoia (2022–2025)” (exp. ARQ001SOL-201–2022) and the research groups 2017SGR-1040, 2017SGR-859, and 2017SGR-836. This research is also funded by the Spanish Government projects PID2019- 103987 GB-C31 and EIN2020-112374. M.J.G. (IJC2020-044412-I) and A.B. (IJC-2019–041546-I) research is founded by the program Juan de la Cierva Incoporación of the Spanish Ministry of Science and Innovation. P.S., M.G.C., M.V. and J.V. research is funded by CERCA Programme/ Generalitat de Catalunya. F.R. research is supported by the Comunidad de Madrid and Universidad Autónoma de Madrid through the project SI1-PJI-2019–00488 and the Spanish Ministry of Science and Innovation through the project PID-2019-103987 GB-C33. M.G.C., J.V. and M.V. research is funded by the project PID2019-103987 GB-C31 of the Spanish Government. Finally, the Institut Català de Paleoecologia Humana i Evolució Social (IPHES-CERCA) has received financial support from the Spanish Ministry of Science and Innovation through the “María de Maeztu” excellence accreditation (CEX2019-000945-M

Fludarabine inhibits KV1.3 currents in human B lymphocytes

Fludarabine (F-ara-A) is a purine analog commonly used in the treatment of indolent B cell malignancies that interferes with different aspects of DNA and RNA synthesis. KV1.3 K+ channels are membrane proteins involved in the maintenance of K+ homeostasis and the resting potential of the cell, thus controlling signaling events, proliferation and apoptosis in lymphocytes. Here we show that F-ara-A inhibits KV currents in human B lymphocytes. Our data indicate that KV1.3 is expressed in both BL2 and Dana B cell lines, although total KV1.3 levels were higher in BL2 than in Dana cells. However, KV currents in the plasma membrane were similar in both cell lines and were abrogated by the specific KV1.3 channel inhibitor PAP-1, indicating that KV1.3 accounts for most of the KV currents in these cell lines. F-ara-A, at a concentration (3.5 μM) similar to that achieved in the plasma of fludarabine phosphate-treated patients (3 μM), inhibited KV1.3 currents by 61 ± 6.3% and 52.3 ± 6.3% in BL2 and Dana B cells, respectively. The inhibitory effect of F-ara-A was concentration-dependent and showed an IC50 value of 0.36 ± 0.04 μM and a nH value of 1.07 ± 0.15 in BL2 cells and 0.34 ± 0.13 μM (IC50) and 0.77 ± 0.11 (nH) in Dana cells. F-ara-A inhibition of plasma membrane KV1.3 was observed irrespective of its cytotoxic effect on the cells, BL2 cells being sensitive and Dana cells resistant to F-ara-A cytotoxicity. Interestingly, PAP-1, at concentrations as high as 10 μM, did not affect the viability of BL2 and Dana cells, indicating that blockage of KV1.3 in these cells is not toxic. Finally, F-ara-A had no effect on ectopically expressed KV1.3 channels, suggesting an indirect mechanism of current inhibition. In summary, our results describe the inhibitory effect of F-ara-A on the activity of KV1.3 channel. Although KV1.3 inhibition is not sufficient to induce cell death, further research is needed to determine whether it might still contribute to F-ara-A cytotoxicity in sensitive cells or be accountable for some of the clinical side effects of the drug.This study was supported by MINECO (SAF2013-45800-R, SAF2016-75021-R, RD12/0042/0019, CB/11/00222) and ISCIII (PI12/01135 and PI16/00895). The cost of this publication was paid in part by funds from the European Fund for Economic and Regional Development (FEDER). TG is supported by the Ramón y Cajal Program.Peer reviewedPeer Reviewe

A Novel Human Ghrelin Variant (In1-Ghrelin) and Ghrelin-O-Acyltransferase Are Overexpressed in Breast Cancer: Potential Pathophysiological Relevance

The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with nativeghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cance

A multi-technique approach to characterization: the Sant Martí de Tous chert as a prehistoric resource for the NE of the Iberian Peninsula

The Sant Genis Formation is located in the NE of the Iberian Peninsula (Catalonia, Spain) and is dated to the Priabonian (upper Eocene), being part of the evaporitic formations of the margin of the Ebro Basin. It is formed by a succession of sandy lutites, occasional limestone layers, marls, and local stratified gypsum and cherts, including the Sant Marti de Tous chert. The Sant Marti de Tous chert type is confirmed by its abundance at specific locations within the territory (NE Iberian Peninsula). This is an important raw material procurement area, as evidenced by the presence of this chert in the main prehistoric sites of the region (e.g., Abric Romani) and the constant discovery of new sites in the area around the Sant Genis Formation, especially from the Neolithic period onwards (e.g., Cal Sitjo, La Guinardera Nord workshop). All these features, together with the great heterogeneity of the Cenozoic evaporitic cherts, prompted us to carry out a multi-proxy characterization for obtaining a valid criterion by which to identify this chert in the archaeological record. This very heterogeneity hampers the macroscopic characterization of archaeological cherts (e.g., at Abric Romani), but through petrographic analysis we have been able to identify their origins and, albeit to a lesser extent, their lithostratigraphic unit of provenance within the formation. The complementary mineralogical and geochemical techniques applied in this study show that, although it is difficult to establish an exact origin, through intensive sampling and criteria such as the differential presence of Fe and Ca, some differences among the siliceous varieties within a formation can be detected.CLT009/22/000044; PID2019-103987 GB-C3; PID2021-123092NB-C21; PID2019-105796 GB-I00; GV/2021/054; CEX2019-000945-Minfo:eu-repo/semantics/publishedVersio

New macaque fossil remains from Morocco

Altres ajuts: CERCA Programme/Generalitat de Cataluny

Case Report: An EGFR-Targeted 4-1BB-agonistic Trimerbody Does Not Induce Hepatotoxicity in Transgenic Mice With Liver Expression of Human EGFR

Agonistic monoclonal antibodies (mAbs) targeting the co-stimulatory receptor 4-1BB are among the most effective immunotherapeutic agents across pre-clinical cancer models. However, clinical development of full-length 4-1BB agonistic mAbs, has been hampered by dose-limiting liver toxicity. We have previously developed an EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) that induces potent anti-tumor immunity without systemic toxicity, in immunocompetent mice bearing murine colorectal carcinoma cells expressing human EGFR. Here, we study the impact of human EGFR expression on mouse liver in the toxicity profile of 1D8N/CEGa1. Systemic administration of IgG-based anti-4-1BB agonist resulted in nonspecific immune stimulation and hepatotoxicity in a liver-specific human EGFR-transgenic immunocompetent mouse, whereas in 1D8N/CEGa1-treated mice no such immune-related adverse effects were observed. Collectively, these data support the role of FcγR interactions in the major off-tumor toxicities associated with IgG-based 4-1BB agonists and further validate the safety profile of EGFR-targeted Fc-less 4-1BB-agonistic trimerbodies in systemic cancer immunotherapy protocols.This study was supported by grants from the European Union [IACT Project (602262)], the Spanish Ministry of Science and Innovation; the Spanish Ministry of Economy and Competitiveness (SAF2017-89437-P, PID2019-110405RB-100, RTC-2016-5118-1, RTC-2017-5944-1), partially supported by the European Regional Development Fund; the Carlos III Health Institute (PI16/00357), co-founded by the Plan Nacional de Investigación and the European Union; the CRIS Cancer Foundation (FCRIS-IFI-2018), and the Spanish Association Against Cancer (AECC, 19084).Peer reviewe

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

BACKGROUND: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. METHODS: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. RESULTS: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. CONCLUSION: Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.This work was partially supported by grant IPT-2012-0198-090000 (“MARINMAB” project) from Ministerio de Economía y Competitividad (MINECO) and European Regional Development’s funds (ERDF) and by CSIC grant 2019AEP146.S