TranscriptAchilles: a genome-wide platform to predict isoform biomarkers of gene essentiality in cancer

Background Aberrant alternative splicing plays a key role in cancer development. In recent years, alternative splicing has been used as a prognosis biomarker, a therapy response biomarker, and even as a therapeutic target. Next-generation RNA sequencing has an unprecedented potential to measure the transcriptome. However, due to the complexity of dealing with isoforms, the scientific community has not sufficiently exploited this valuable resource in precision medicine. Findings We present TranscriptAchilles, the first large-scale tool to predict transcript biomarkers associated with gene essentiality in cancer. This application integrates 412 loss-of-function RNA interference screens of >17,000 genes, together with their corresponding whole-transcriptome expression profiling. Using this tool, we have studied which are the cancer subtypes for which alternative splicing plays a significant role to state gene essentiality. In addition, we include a case study of renal cell carcinoma that shows the biological soundness of the results. The databases, the source code, and a guide to build the platform within a Docker container are available at GitLab. The application is also available online. Conclusions TranscriptAchilles provides a user-friendly web interface to identify transcript or gene biomarkers of gene essentiality, which could be used as a starting point for a drug development project. This approach opens a wide range of translational applications in cancer

p53 Aberrations do not predict individual response to fludarabine in patients with B-cell chronic lymphocytic leukaemia in advanced stages Rai III/IV

Abnormalities of p53 have been associated with short survival and non-response to therapy in chronic lymphocytic leukaemia (CLL). We have evaluated the rate of response to fludarabine as first-line therapy in 54 patients with advanced stage CLL, analysing the cytogenetic profile, aberrations in p53, including the methylation status of its promoter, and the immunoglobulin heavy-chain variable-region (IGVH) mutation status. According to the advanced stage of the disease in this series, 75% of patients presented genetic aberrations associated with poor prognosis: del(17p) and/or del(11q), and no-mutated IGVH genes. Ten patients (18.5%) had methylation in the promoter region of p53. Eighty-three per cent of patients treated achieved a response, with a high rate of complete remission (47.6%). Although we found a significant correlation between failures and the presence of p53 aberrations (P = 0.0065), either with methylation (P = 0.018) or deletion (P = 0.015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of p53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL

In-silico gene essentiality analysis of polyamine biosynthesis reveals APRT as a potential target in cancer

Constraint-based modeling for genome-scale metabolic networks has emerged in the last years as a promising approach to elucidate drug targets in cancer. Beyond the canonical biosynthetic routes to produce biomass, it is of key importance to focus on metabolic routes that sustain the proliferative capacity through the regulation of other biological means in order to improve in-silico gene essentiality analyses. Polyamines are polycations with central roles in cancer cell proliferation, through the regulation of transcription and translation among other things, but are typically neglected in in silico cancer metabolic models. In this study, we analysed essential genes for the biosynthesis of polyamines. Our analysis corroborates the importance of previously known regulators of the pathway, such as Adenosylmethionine Decarboxylase 1 (AMD1) and uncovers novel enzymes predicted to be relevant for polyamine homeostasis. We focused on Adenine phosphoribosyltransferase (APRT) and demonstrated the detrimental consequence of APRT gene silencing on diferent leukaemia cell lines. Our results highlight the importance of revisiting the metabolic models used for in-silico gene essentiality analyses in order to maximize the potential for drug target identifcation in cance

Inventario y distribución de la herpetofauna en Jaizkibel

Se ha actualizado el conocimiento de la comunidad herpetológica del macizo de Jaizkibel, después de largo tiempo de ausencia de publicaciones, mediante un inventario basado en trabajo de campo comprendido entre los meses de Abr. a Oct. de 2012, al que se han añadido observaciones acumuladas durante el último decenio. La comunidad está compuesta por 4 especies de anfibios y 11 especies dereptiles, en general distribuidas por la mayor parte del enclave y cuyo origen filogenético mayoritario es el continente europeo. No se ha podido confirmar la presencia del lagarto verdinegro Lacerta schreiberiBedriaga, 1878, citado una sola vez en 198

Identifying main interactions in marine predator-prey networks of the Bay of Biscay

Identifying the role that environmental factors and biotic interactions play in species distribution can be essential to better understand and predict how ecosystems will respond to changing environmental conditions. This study aimed at disentangling the assemblage of the pelagic predator–prey community by identifying interspecific associations and their main drivers. For this purpose, we applied the joint species distribution modelling approach, JSDM, to the co-occurrence patterns of both prey and top predator communities obtained from JUVENA surveys during 2013–2016 in the Bay of Biscay. Results showed that the co-occurrence patterns of top predators and prey were driven by a combination of environmental and biotic factors, which highlighted the importance of considering both components to fully understand the community structure. In addition, results also revealed that many biotic interactions, such as schooling in prey (e.g. anchovy–sardine), local enhancement/facilitation in predators (e.g. Cory’s shearwater–fin whale), and predation between predator–prey species (e.g. northern gannet–horse mackerel), were led by positive associations, although predator avoidance behaviour was also suggested between negatively associated species (e.g. striped dolphin–blue whiting). The identification of interspecific associations can therefore provide insights on the functioning of predators–prey network and help advance towards an ecosystem-based managementThis research was funded by the Basque Government (Department of Agriculture, Fishing, and Food Policy) and the Spanish Ministry of Economy, Industry, and Competitiveness through the CHALLENGES project (CTM2013-47032-R). A. Astarloa has benefited from a Basque Government scholarship (PRE_2016_1_0134) and M. Louzao was funded by the Ramo´n y Cajal (RYC-2012-09897) researcher programme of the Spanish Ministry of Economy, Industry, and Competitiveness. JUVENA survey series was sponsored since 2003 by the “Viceconsejerı´a de Agricultura, Pesca y Polı´ticas Alimentarias—Departamento de Desarrollo Econo´mico y Competitividad” of the Basque Government and the “Secretarı´a General de Pesca, Ministerio de Agricultura, Alimentacio´ n y Medio Ambiente” of the Spanish Government

Social Economy in the Basque Country

In the social economy area and, more concretely, in the cooperative field, the Basque Country has, no doubt unintentionally, become a worldwide benchmark. The dynamism that energizes Basque social initiatives has resulted in outstanding examples of good practices where firms' priorities are guided by social aims that respond to social needs, steering clear of the commercial profit mechanisms that are the main global driver of private economic initiative. This work, in nine chapters, addresses a wide range of contemporary aspects of the contemporary Basque social sector; legal framework; reality and development in the Autonomous Community of Euskadi; promotion of the Social Economy in Navarre; typology of public policies for the advancement of the Social Economy in Europe; associated work cooperatives in the Northern Basque Country; viability of globalization of cooperatives without risking loss of their hallmark principles and values; and tenant cooperatives. With this book we hope to make a modest contribution to encourage knowledge and reflection on the rich and complex dynamic that informs the Basque social economy today.This book looks at the social economy in the Basque Country, gathering scholars on the social economic structure, its framework, public policies and the viability of globalization of cooperative.This book was published with generous financial support from the Basque Government

The Global Stratotype Sections and Points for the bases of the Selandian (Middle Paleocene) and Thanetian (Upper Paleocene) stages at Zumaia, Spain

The global stratotype sections and points for the bases of the Selandian (Middle Paleocene) and Thanetian (Upper Paleocene) stages have been defined in the coastal cliff along the Itzurun Beach at the town of Zumaia in the Basque Country, northern Spain. In the hemipelagic section exposed at Zumaia the base of the Selandian Stage has been placed at the base of the Itzurun Formation, ca. 49 m above the Cretaceous/ Paleogene boundary. At the base of the Selandian, marls replace the succession of Danian red limestone and limestone-marl couplets. The best marine, global correlation criterion for the basal Selandian is the second radiation of the important calcareous nannofossil group, the fasciculiths. Species such as Fasciculithus ulii, F. billii, F. janii, F. involutus, F.pileatus and F. tympaniformis have their first appearance in the interval from a few decimetres below up to 1.1 m above the base of the Selandian. The marker species for nannofossil Zone NP5, F. tympaniformis, first occurs 1.1 m above the base. Excellent cyclostratigraphy and magnetostratigraphy in the section creates further correlation potential, with the base of the Selandian occuring 30 precession cycles (630 kyr) above the top of magnetochron C27n. Profound changes in sedimentology related to a major sea-level fall characterize the Danian-Selandian transition in sections along the margins of the North Atlantic. The base of the Thanetian Stage is placed in the same section ca. 78 m above the Cretaceous/Paleogene boundary. It is defined at a level 2.8 m or eight precession cycles above the base of the core of the distinct clay-rich interval associated with the Mid-Paleocene Biotic Event, and it corresponds to the base of magnetochron C26n in the section. The base of the Thanetian is not associated with any significant change in marine micro-fauna or flora. The calcareous nannofossil Zone NP6, marked by the first occurrence of Heliolithus kleinpelli starts ca. 6.5 m below the base of the Thanetian. The definitions of the global stratotype points for the bases of the Selandian and Thanetian stages are in good agreements with the definitions in the historical stratotype sections in Denmark and England, respectively