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Several decades have passed since the generation of the first embryonic stem cell (ESC) lines both in mice and in humans. Since then, stem cell biologists have tried to understand their potential biological and clinical uses for their implementation in regenerative medicine. The hematopoietic field was a pioneer in establishing the potential use for the development of blood cell products and clinical applications; however, early expectations have been truncated by the difficulty in generating bonafide hematopoietic stem cells (HSCs). Despite some progress in understanding the origin of HSCs during embryonic development, the reproduction of this process in vitro is still not possible, but the knowledge acquired in the embryo is slowly being implemented for mouse and human pluripotent stem cells (PSCs). In contrast, ESC-derived hematopoietic cells may recapitulate some leukemic transformation processes when exposed to oncogenic drivers. This would be especially useful to model prenatal leukemia development or other leukemia-predisposing syndromes, which are difficult to study. In this review, we will review the state of the art of the use of PSCs as a model for hematopoietic and leukemia development. This work was funded by grants from PID2019-104695RB-I00 and PDC2021-120817-I00from AgenciaEstatal de Investigación (AEI) to AB, ERA PerMed GATA2-HuMo Funding Mechanism (Spain: Acció instrumental de SLT011/18/00006 and SLT011/18/00007 of the Department of Health of the Government of Catalonia to AG and A, the Spanish Ministry of Economy, Industry, and Competitiveness (MINECO PID2020-15591RB-100), La Marató de TV3 (202001-32) and CERCA Programme/Generalitat de Catalunya for institutional support to AG. LGP is a recipient of 2021 FI_B2 00188, AGAUR, Generalitat de Cataluña.

This Science Project (SP) contributes to the estimation of the impacts of the invasive species on the European Biodiversity and Ecosystems. This topic is important for European Green Deal and the new European Biodiversity Strategy. The SP is also linked with the socio-economic issues because of the NIS implications to the local ecosystems and their services, and their societal goods and services. Since many of the above impacts may be of local scale, they may alter common practices in circular economies. The SP is implemented by: (a) Combining different sources of data and information; (b) Using a dual workflow to analyse the data; (c) Integrating its resources with core EOSC services and potentially horizontal services available; (d) Engaging the relevant scientific communities. The users will be able to: (a) Analyse distribution patterns of invasive species from different sources of data; (b) Compare the above patterns; (c) Provide managerial suggestions to relevant authorities; (d) Build on the existing infrastructure to address more complex questions (e.g. future scenarios).

This document describes the landscaping exercise proposed for deliverable 4.2 (D4.2) within Work Package (WP) 4 of the FAIR Earth Sciences & Environment services project (FAIR-EASE, FE). The goal of this exercise is to analyse different special use case (UC) datasets per pilot and the requirements they must meet to be included in the data lake infrastructure proposed in D4.1 (landscaping exercise: the (meta)data, software, and cloud needs for the data lake). The pilots per UC are: UC1 - Earth and Environmental Dynamics: Coastal waters dynamics (Pilot 5.1.1), Earth Critical zones observatory (Pilot 5.1.2), and Volcano Space Observatory (Pilot 5.1.3), UC2 - Environmental Bio-geochemical Assets: Ocean Bio-Geo-Chemical Observatory (Pilot 5.2.1) and, UC3 - Biodiversity Observation: Marine Omics Observatory (Pilot 5.3.1). Datasets from each pilot were selected from Table 1 in Annex A of D5.1 (report on key requirements from Use Cases and Pilots, [1]) and with a prior selection from a representative from each pilot. These datasets were selected to cover as much diversity as possible and to reflect the multidisciplinary nature of each UC. The deliverable aims to analyse and highlight the criticalities of the selected datasets considering their current limitations and needs and how they could fit into the “data provider” view proposed for the “data lakes” architecture in D4.1. Bear in mind that the datasets described should not be taken as the only source for the data lake ingestion. As stated, before a few special UCs datasets were selected using the minimum selection and maximum diversity criteria, to analyse the requirements for them to be ingested in the data lakes proposed.

The overall objective of the EOSC Horizon Europe FAIR-EASE project is to develop and operate distributed and integrated services for observation and modelling of the earth system, environment and biodiversity implemented in close cooperation with user-communities and research infrastructures in their very design and sustainable availability and evolution. The FAIR-EASE WP5 (Work Package) is in charge of coordinating the activities tackling three different use cases (UCs): 1) the Earth and Environment dynamics; 2) The Environmental Biogeochemical Asset; 3) The Biodiversity Observations. As documented in the FAIR-EASE work plan, all the use cases represent “Real Life-Science” challenges. During the progress of the project, specific Pilots will be considered per UC, each of them addressing specific objectives. This deliverable reports on the assessment of the key requirements and the mapping of main resources to be considered in the project to fulfill the aims and scope of the Pilots included in each use case.

The importance of predisposition to leukaemia in clinical practice is being increasingly recognized. This is emphasized by the establishment of a novel WHO disease category in 2016 called "myeloid neoplasms with germline predisposition". A major syndrome within this group is GATA2 deficiency, a heterogeneous immunodeficiency syndrome with a very high lifetime risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). GATA2 deficiency has been identified as the most common hereditary cause of MDS in adolescents with monosomy 7. Allogenic haematopoietic stem cell transplantation is the only curative option; however, chances of survival decrease with progression of immunodeficiency and MDS evolution. Penetrance and expressivity within families carrying GATA2 mutations is often variable, suggesting that co-operating extrinsic events are required to trigger the disease. Predictive tools are lacking, and intrafamilial heterogeneity is poorly understood; hence there is a clear unmet medical need. On behalf of the ERAPerMed GATA2 HuMo consortium, in this review we describe the genetic, clinical, and biological aspects of familial GATA2-related MDS, highlighting the importance of developing robust disease preclinical models to improve early detection and clinical decision-making of GATA2 carriers. This work was supported by ERA PerMed GATA2-HuMo Funding Mechanism (Spain: Acció instrumental de SLT011/18/00006 of the Department of Health of the Government of Catalonia, to AG and AB; Hungary: ED-18-1-2019-001 grant from the National Research, Development and Innovation Office to CB; and Germany: German Federal Ministry of Education and Research (BMBF) 2018-123/01KU1904 to MWW), ÚNKP-21-2-I-SE-21 and Hungarian National Academy of Scientist Education grant to KL, TKP2021-NVA-15, TKP2021-EGA-24 and EU's Horizon 2020 research and innovation programme under grant agreement no. 739593 and Elixir Hungary to CB, MSCA No 101029927-scGATA2track (H2020-MSCA-IF-2020) to OM-B, the Spanish Ministry of Economy, Industry, and Competitiveness (MINECO PID2020-15591RB-100), La Marató de TV3 (202001-32), FPS Grant 2018 by Fondazione Pisana per la Scienza ONLUS and CERCA Programme/Generalitat de Catalunya for institutional support to AG, Vera and Joseph Dresner Foundation, Evans MDS Foundation, American Lebanese Syrian Associated Charities, and BMBF MyPred 01GM1911A to MWW. Open access funding enabled and organized by ProjektDEAL.

The ocean observing system needs to be ensured by high-level integration and coordination to guarantee its longterm sustainability, efficient accessibility and usability by a wide range of users. Enormous advancements and efforts toward these objectives have been already conducted in Europe, partly through the activities of the IOC-UNESCO's International Oceanographic Data and Information Exchange (IODE) and EuroGOOS DATAMEQ working group, although there is still room for additional progress and gaps to be addressed. During the past two decades, a series of standards for data and metadata formats as well as exchange protocols have been established within the marine community where projects, organizations and data integrators like JCOMM, RDA (Research Data Alliance), EuroGOOS, EMODnet, SeaDataNet and Copernicus played a significant role. Taking into consideration that harmonized data are a key element in maintaining a usable and interoperable ocean observing system, this paper aims to provide some recommendations for the harmonization of the marine in situ networks involved in EuroSEA, which would be a useful product for the European data integrators, particularly EMODnet, SeaDataNet and Copernicus Marine service. This document proposes recommendations to enhance the in situ networks based on the assessment of what has been previously done.

Germline heterozygous GATA2 mutations underlie a complex disorder characterized by bone marrow failure, immunodeficiency and high risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our understanding about GATA2 deficiency is limited due to the lack of relevant disease models. Here we generated high quality human induced pluripotent stem cell (iPSC) lines carrying two of the most recurrent germline GATA2 mutations (R389W and R396Q) associated with MDS, using CRISPR/Cas9. These hiPSCs represent an in vitro model to study the molecular and cellular mechanisms underlying GATA2 deficiency, when differentiated into blood progenitors.

EMODnet Chemistry is one of the seven thematic portals of EMODnet (European Marine Observation and Data Network), the long-term initiative aiming to ensure that European marine data are findable, accessible, interoperable and re-usable. EMODnet was launched by DG MARE in 2009 as the pillar of the Blue Growth strategy, Marine Knowledge 2020.Eutrophication (e.g. nutrients, oxygen and chlorophyll), contaminants (e.g. hydrocarbons, pesticides, heavy metals, antifoulants) and marine litter (e.g. beach litter, seafloor litter and floating micro litter) are the main categories of quality assured marine data sets and data products made available through the EMODnet Chemistry portal.45 marine research and monitoring institutes and oceanographic data management experts from 30 countries comprise the EMODnet Chemistry network, including National Oceanographic Data Centres (NODC), National Environmental Monitoring Agencies and Marine Research Institutes actively involved in managing, processing and providing access to data sets from European marine waters and global oceans.During 2020 EMODnet Chemistry consolidated fundamental international collaborations and upgraded cooperation actions on the European and global level to share and harmonize data, knowledge and services, following decision-makers’ needs to implement EU directives, such as MSFD, MSPD, INSPIRE directive, and the Agenda 2030 Sustainable Development Goals of the United NationsMain EMODnet Chemistry 2020 transnational cooperation actions are:The MSFD Technical Group on Marine Litter used the EMODnet Chemistry Marine Litter Database to compute the EU beach litter quantitative Baselines and Threshold values. The European Environment Agency confirmed the use of EMODnet Chemistry data for three environmental state indicators relating to eutrophication and contaminants. Mercator Ocean International and EMODnet Chemistry set up the first joint portfolio of products in support of the MSFD implementation. The two partners are also exploring opportunities to support the aquaculture sector. EMODnet -Chemistry and the In Situ Thematic Assembly Centre of the Copernicus Marine Environment Monitoring Service (CMEMS INSTAC) collaborated with ENVRI Marine European Research Infrastructures (Euro-Argo, EMSO, ICOS, Lifewatch and SeaDataNet) to enhance FAIRness of in situ data. Mercator Ocean international, UNDESA, SULITEST NGO and EMODnet Chemistry have been creating an awareness questionnaire to raise awareness on the Goal 14 of the UN Agenda 2030 for Sustainable Development. The EU asked EMODnet Chemistry to share its experience at the G20 workshop on harmonized monitoring and data compilation of marine plastic litter organized by the Ministry of the Environment, Japan. The international Oxygen data portal and Ocean Acidification data portal received contributions from EMODnet Chemistry and CMEMS in situ TAC for their implementation. The National Marine Data and Information Service of China collaborates with EMODnet to strengthen international ocean data through the EMOD-PACE project.

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas., Maroni, Bassal, Krishnan et al. characterise human non-small cell lung cancer (NSCLC) carrying Kras-mutations by single-cell RNA sequencing. They identify a tumour-specific population that is conserved in mice and responds to the drug, PTC596, which is currently in clinical trials and may offer a potential avenue for treating aggressive NSCLC expressing mutated Kras.

39 pages, 6 figures, 2 tables, This paper presents major gaps and challenges for implementing the UN Decade of Ocean Science for Sustainable Development (2021-2030) in the Mediterranean region. The authors make recommendations on the scientific knowledge needs and co-design actions identified during two consultations, part of the Decade preparatory-phase, framing them in the Mediterranean Sea’s unique environmental and socio-economic perspectives. According to the ‘Mediterranean State of the Environment and Development Report 2020’ by the United Nations Environment Programme Mediterranean Action Plan and despite notable progress, the Mediterranean region is not on track to achieve and fully implement the Sustainable Development Goals of Agenda 2030. Key factors are the cumulative effect of multiple human-induced pressures that threaten the ecosystem resources and services in the global change scenario. The basin, identified as a climate change vulnerability hotspot, is exposed to pollution and rising impacts of climate change. This affects mainly the coastal zones, at increasing risk of extreme events and their negative effects of unsustainable management of key economic assets. Transitioning to a sustainable blue economy is the key for the marine environment’s health and the nourishment of future generations. This challenging context, offering the opportunity of enhancing the knowledge to define science-based measures as well as narrowing the gaps between the Northen and Southern shores, calls for a joint (re)action. The paper reviews the state of the art of Mediterranean Sea science knowledge, sets of trends, capacity development needs, specific challenges, and recommendations for each Decade’s societal outcome. In the conclusions, the proposal for a Mediterranean regional programme in the framework of the Ocean Decade is addressed. The core objective relies on integrating and improving the existing ocean-knowledge, Ocean Literacy, and ocean observing capacities building on international cooperation to reach the “Mediterranean Sea that we want”, With the institutional support of the ‘Severo OchoaCentre of Excellence’ accreditation (CEX2019-000928-S)

Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolated from the hemorrhagic cerebrospinal fluid obtained during therapeutic neuroendoscopic lavage in preterm infants with severe intraventricular hemorrhage. Our analyses demonstrate that these neural stem cells, although similar to human fetal cell lines, display distinctive hallmarks related to their regional and developmental origin in the germinal zone of the ventral forebrain, the ganglionic eminences that give rise to interneurons and oligodendrocytes. These cells can be expanded, cryopreserved, and differentiated in vitro and in vivo in the brain of nude mice and show no sign of tumoral transformation 6 months after transplantation. This novel class of neural stem cells poses no ethical concerns, as the fluid is usually discarded, and could be useful for the development of an autologous therapy for preterm infants, aiming to restore late neurogliogenesis and attenuate neurocognitive deficits. Furthermore, these cells represent a valuable tool for the study of the final stages of human brain development and germinal zone biology., Germinal zone neural stem cells (Gz‐NSC) are isolated from the hemorrhagic cerebrospinal fluid of preterm infants with severe intraventricular hemorrhage. These cells express ventral and posterior forebrain markers, can be differentiated and do not cause tumors. Gz‐NSC represent a valuable tool for the development of new cell therapies and the study of human Gz biology.

A major challenge in regenerative medicine is the generation of functionally effective target cells to replace or repair damaged tissues. The finding that most somatic cells can be directly converted into cells of another lineage by the expression of specific transcription factors has paved the way to novel applications. Induced neurons (iNs) represent an alternative source of neurons for disease modeling, drug screening, and potentially, for cell replacement therapy. This unit describes methods for the efficient conversion of blood cells into iNs, including protocols to isolate cord blood CD133+ cells, infect them with Sendai virus vectors that express SOX2 and c-MYC, and differentiate the infected cells (PB-MNCs) into mature neurons. A method to reprogram peripheral blood mononuclear cells into iNs is also described. Support protocols describe how to culture rat astrocytes and characterize the electrophysiology of iNs. © 2016 by John Wiley & Sons, Inc.

High quality and integrated information able to show marine litter distribution at a global scale is a crucial goal to tackle the environmental problem. One of the important gaps is the definition of a global monitoring protocol and reporting. Large data infrastructures can provide a sustainable framework to host harmonized and standard litter data that can be used and re-used for any purpose, including assessment. EMODnet Chemistry has collected marine litter data since 2016 and has adopted different strategies for the management of the diverse litter data types, exploiting the advantages deriving from the application of the FAIR principles in marine litter data stewardship. The quality of the released data sets is improved allowing a better consistency within data values collected in different contexts (several countries, different techniques, …).

The European Union set the ambitious objective to reach within 2020 the goal of Good Environmental Status. The European Commission (2008) represents the legislative framework that drives member state efforts to reach it. The Integrated Maritime Policy supported the need to provide a European knowledge base able to drive sustainable development by launching in 2009 a new European Marine Observation and Data Network (EMODnet). Through a stepwise approach, EMODnet Chemistry aims to provide high-quality marine environmental data and related products at the scale of regions and sub-regions defined by the Marine Strategy Framework Directive. The chemistry lot takes advantage and further develops the SeaDataNet pan-European infrastructure and the distributed approach, linking together a network of more than 100 National Oceanographic Data Centres providing data from more than 500 data originators. The close interaction with EEA, RSCs, ICES and EMODnet–MSFD coordination group facilitated the identification of the most appropriate set of information required for the MSFD process. EMODnet Chemistry provides aggregated and validated regional data collections for nutrients, dissolved gasses, chlorophyll, and contaminants, properly visualized with OGC WMS and WPS viewing services. Concentration maps with 10-year moving window from 1960 to 2014, by season and for selected vertical layers, are computed and made available.

Marine litter is a growing problem for environmental and human health and policies have included monitoring as an important tool to evaluate both trends and the efficiency of reduction measures. The Marine Strategy Framework Directive is the main driver in Europe for the monitoring of the marine environment; it has included the evaluation of marine litter in order to support policies and achieve good environmental status. This assessment depends on the availability of robust, homogeneous data-sets at the European scale. A data management plan for marine litter has been developed at European level within the existing EMODnet network to collect, homogenise and provide access to standardised data-sets and data products that may be used as a basis for marine litter assessment at pan-European scale. As a long term perspective, it also provides a scientific and technical basis for further global monitoring.

Summary In vertebrates, GATA2 is a master regulator of hematopoiesis and is expressed throughout embryo development and in adult life. Although the essential role of GATA2 in mouse hematopoiesis is well established, its involvement during early human hematopoietic development is not clear. By combining time-controlled overexpression of GATA2 with genetic knockout experiments, we found that GATA2, at the mesoderm specification stage, promotes the generation of hemogenic endothelial progenitors and their further differentiation to hematopoietic progenitor cells, and negatively regulates cardiac differentiation. Surprisingly, genome-wide transcriptional and chromatin immunoprecipitation analysis showed that GATA2 bound to regulatory regions, and repressed the expression of cardiac development-related genes. Moreover, genes important for hematopoietic differentiation were upregulated by GATA2 in a mostly indirect manner. Collectively, our data reveal a hitherto unrecognized role of GATA2 as a repressor of cardiac fates, and highlight the importance of coordinating the specification and repression of alternative cell fates., Graphical Abstract, Highlights • GATA2 promotes hemogenic emergence during human iPSC differentiation • GATA2 enhances hematopoietic differentiation of human iPSCs • GATA2 acts as a direct repressor of cardiac fates during mesoderm specification, Giorgetti A. and colleagues demonstrate that GATA2 induction in early mesodermal cells leads to the robust generation of hemogenic endothelial and hematopoietic cells from human iPSCs. They show the ability of GATA2 to instruct mesodermal precursors toward a hematopoietic cell fate and concurrently inhibit cardiac fates. This study expands our understanding of the regulatory networks that control early human hematopoiesis.

We have generated two human induced pluripotent stem cell (iPSC) lines from CD133+ cells isolated from umbilical cord blood (CB) of a female child using non-integrative Sendai virus. Here we describe the complete characterization of these iPSC lines: PRYDi-CB5 and PRYDi-CB40.

Scientific research as well as management of the marine environment, and sustainable blue growth are based on the availability of quality-assured observations, reliable data and solid scientific-based information. These represent three consecutive steps of Data-Information-Knowledge-Wisdom paradigm on the pyramid of wisdom, providing different layers of information. EMODnet (European Marine Observation and Data network) is one of the key infrastructures engaged in collecting, facilitating access and promoting use and re-use of marine observation and data products for both scientific research and marine environmental management. Its Spatial Data Infrastructure (SDI) represents a powerful mechanism to support the implementation of the Marine Strategy Framework Directive Article 19.3 in accordance with the INSPIRE Directive standards and implementing rules. Standardized, harmonized and validated chemical data collections are made available for water quality evaluation at a regional scale, establishing interoperability between the data sets from the many different providers (more than 60 in EMODnet Chemistry). Concentration maps of nutrients, chlorophyll-a and dissolved oxygen are computed on a standard grid, providing information at a regular time interval, per season and over several vertical layers, including the deepest one. Dedicated Open Geospatial Consortium standard services for browsing, viewing and downloading chemistry observation data and data products for the European waters have been developed, and are actively maintained and monitored. These results can provide knowledge layers and can also answer the needs of the directive on Maritime Spatial Planning (EU, 2014), which requires the integration of multidisciplinary data and information on the state of the marine environment with maritime and human activities.

Data sharing, interoperability and quality check are only a short part of the activities connected to the data management. Create a procedure to harmonize and disseminate heterogeneous data, collected by different meteo-oceanographic buoys in near real-time, is a challenge. In this paper, we describe a system for data validation, conversion in a homogeneous and standard format and dissemination adopting Sensor Web Enablement (SWE) using XML (eXtensible Markup Language) and OGC’s (Open Geospatial Consortium) standards. To meet the needs of different scientific communities as RITMARE (La Ricerca ITaliana per il MARE), Jerico (Towards a joint European research infrastructure network for coastal observatories), Copernicus, ODIP (Ocean Data Interoperability Platform) and FixO3 (Fixed-point Open Ocean Observatories), we decided to adopt SWE standard allowing interoperability between data in near real-time, using Sensor Model Language (SensorML) and Observations and Measurements(O&M) standards in a Sensor Observation Service (SOS).

Sensor engineering is continuously evolving as devices become cheaper, smaller, more intelligent, and more efficient. Today, oceanographic sensors aim at monitoring marine processes by means of physical, chemical, and biological variables, and use different data formats, units, parameters, resolutions, data quality standards, and protocols. Therefore, integration and interoperability at European level represent a challenge. To cope with this challenge, the Sensor Web Enablement (SWE) standards, developed by the Open Geospatial Consortium (OGC), are a good solution, as they ensure interoperability and long-term archiving of data series with complete information for all devices. The interoperability allows integrating information from different sources or pre-existing architectures, such as those developed in the SANY project ( http://www.opengeospatial.org/ogc/regions/SANY ) or by the US Integrated Ocean Observing System ( https://github.com/ioos ). In this paper, we illustrate the real-time data management system, developed by the Italian National Oceanographic Data Centre (NODC) at the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale, OGS in Trieste – Italy, designed to share data acquired by a large number of heterogeneous observing platforms. This system adopts Observations and Measurements (O&M) and Sensor Model Language (SensorML) as data and metadata formats, as well as the Sensor Observation Service (SOS) released by the 52°North as server and Web client for open data access. The work done shows that the choice to manage real-time data using OGC Sensor Web Enablement (SWE) standards can be considered a valid solution with pros and cons. Nevertheless, in the future, the SWE community will grow, and with it, the number of applications to manage SWE standards to simplify their adoption.

et al., Coenzyme Q (CoQ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ biosynthesis (COQ genes) cause primary CoQ deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype–phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ], CoQ biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4-iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4-iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation., This work was supported by the ISCIII/FEDER (E-Rare-2 Call PI12/03112 to P.M.), FIS/ISCIII/FEDER project (PI14/01962 to P.N.) and the European Research Council (ERC-2014-CoG646903 to P.M.). D.R.M. and C.P. are supported by PFIS scholarships (FI11/0511 and FI12/00468, respectively). C.B is supported by a Miguel Servet II contract (CPII13/00011). P.M. also acknowledges the financial support from The Obra Social La Caixa-Fundacio Josep Carreras and The Generalitat de Catalunya (SGR330). P.M. and J.L.-B. are investigators of the Spanish Cell Therapy cooperative network (TERCEL). A.G. is supported by Ramon y Cajal Program (RyC-2013–13221).

Recent studies in zebrafish and mice have revealed that proinflammatory signaling is a positive regulator of definitive hematopoietic development. Whether proinflammatory signaling also regulates human hematopoietic specification remains unknown. Here, we explored the impact of the proinflammatory cytokines tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), and interleukin-1β (IL1β) on in vitro hematopoietic differentiation using human pluripotent stem cells. Gene expression analysis and enzyme-linked immunosorbent assay revealed the absence of a proinflammatory signature during hematopoietic development of human pluripotent stem cells. Functionally, the emergence of hemogenic endothelial progenitors (CD31+CD34+CD45- or CD34+CD43-CD73-) and hematopoietic cells (CD43+CD45+) was not affected by treatment with increasing doses of TNFα, IFNγ, and IL1β irrespective of the developmental window or the differentiation protocol used (embryoid body or OP9 co-culture based). Similarly, knockdown of endogenous NF-kB signaling had no impact on hematopoietic differentiation of human pluripotent stem cells. This study serves as a demonstration that TNFα, IFNγ, and IL1β signals do not improve hematopoietic differentiation of human pluripotent stem cells using current protocols and suggests that proinflammatory signaling is insufficient to drive definitive hematopoietic specification of human hematopoietic stem cells in vitro. This work was supported by the European Research Council (646903 to PM) and the Spanish Ministry of Economy and Competitiveness (SAF2013-43072R to AG, SAF2013-43065R to PM, and ISCIII/FEDER-PI14/01119 to CB). CB is supported by a Miguel Servet contract (CPII13/00011). AG is supported by the Ramon y Cajal Program (RyC-2013-13221). PM also acknowledges support from Obra Social La Caixa-Fundacio Josep Carreras and Generalitat de Catalunya (SGR330).

Metadata, by definition, is information associated with data, covering where, how, when and by whom the data were acquired. The chance to take part in European projects such as the EU-SeaDataNet (the Pan-European infrastructure for ocean and marine data management) made it necessary to use XML (Extensible Markup Language) as a standard file format for sharing data and metadata. At present, the Italian National Oceanographic Data Centre (OGS/NODC) has all its data and metadata contained in an Oracle relational database, and the metadata is managed using XML formats and schema (XSD; XML Schema Definition), giving common vocabularies for parameters, instruments, ships, etc. in agreement with European project standards. One problem with XML is the dynamic change in metadata schemas (XSD), necessitating development of a system which is flexible and capable of managing the changes. This paper describes a system for managing oceanographic metadata using XML files and the functionalities provided by the Oracle database. To better manage the XML format, we chose to load into the OGS/NODC database the whole XML file, using a dedicated field. The database Oracle gives us the flexibility to manage the XML format locally, within the OGS/NODC information system, using the XML DB (XML DataBase) Oracle features. This, through the use of XMLType, allows the inclusion of the XML into the database. Furthermore, through the use of the XQuery functions it is possible to create a set of views through which information contained in the XML can be viewed more immediately in a relational form. Using the XML and the XQuery functions, it is possible to store, extract and manage different kinds of information that might be exchanged at the European level. Moreover, with a RESTful (Representational State Transfer) Web Service, we have a simple and standard interface for rapidly and easily creating, modifying and deleting records containing XML files inside the database. Finally, through the use of a RESTful Web Service, it is possible to decouple the application from the database, so that through the use of software that manages HTTP URLs, such as the Mikado (SeaDataNet project), the XML file can be inserted, updated and deleted inside the database without the need for a direct connection to it.

Coenzyme Q

Summary Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming “boosters” also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency., Graphical Abstract, Highlights • Neither primary B-ALL blasts nor leukemic B cell lines can be reprogrammed to iPSCs • Global transcriptome and DNA methylome suggest a developmental refractoriness, Despite the interest in generating iPSCs from human primary acute leukemias for disease modeling, reprogramming leukemias is an extremely inefficient process. In this article, Menéndez, Bueno, and colleagues show that many reprogramming strategies reported to date are not sufficient to generate B-ALL-derived iPSCs. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of B-ALL to reprogramming into pluripotency.

Induced pluripotent stem cells (iPSCs) represent an invaluable tool in a chromosomal instability syndrome such as Fanconi anemia (FA), as they can allow to study of the molecular defects underlying this disease. Many other applications, such as its use as a platform to test different methods or compounds, could also be of interest. But the greatest impact of iPSCs may be in bone marrow failure diseases, as iPSCs could represent an unlimited source of autologous cells to apply in advanced treatments such as gene therapy. At the same time, genome editing constitutes the next generation of technology to further develop a safer, personalized, targeted gene therapy. Despite the promising advantages that these two technologies would present in a disease such as FA, the specific characteristics of the disease make both of these processes especially challenging. Efficient and safer FA-hiPSC (human induced pluripotent stem cell) generation methods, robust and reliable differentiation protocols for iPSCs, as well as really efficient delivery methods to perform targeted gene correction should be developed.