Can firms grow without credit?: evidence from the Euro Area, 2005-2011: a quantile panel analysis

This paper explores the effects of bank credit on firm growth before and after the recent financial crisis, taking into account different structural characteristics of banking sectors and domestic economies. Panel quantile analysis is used on a sample of 2075 euro area firms in 2005-2011. The post-2008 credit crunch is found to seriously affect only small, slow-growth firms and especially those operating in concentrated and domestic-dominated banking systems, and in riskier and less financially developed economies. Large, high-growth firms seem to be able to find alternative financial sources and, thus, may act as carriers and facilitators of a credit-less recovery

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia.

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.We would like to thank all the members of the Huntly laboratory and our funders Leukaemia Lymphoma Research, Kay Kendall Leukaemia fund, the Medical Research Council UK, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, Leukemia & Lymphoma Society US, the Academy of Medical Sciences UK and Lady Tata Memorial Trust. We apologise to writers whose work we have failed to cite due to space constraints.This is the author accepted manuscript. The final version is available via SAGE at http://dx.doi.org/10.1177/204062071557761

Fuenteovejuna: como se trata de los temas de la comunidad, del honor, de la religión y de la monarquía y cuáles fueron sus extensiones políticas en dos periodos históricos concretos.

Fuenteovejuna fue escrita entre 1612 y 1614. Basada en una fuente de 1572 y bajo el reino de Felipe II (1556-1598) trata de promover temas de valores comunes que existen en la comunidad española de la época y sobre todo de un contexto político que favorecía la institución de la monarquía. En este trabajo se investigan los temas de la comunidad, del honor, de la religión y de la monarquía y también las extensiones políticas impuestas por las autoridades de la época hacia el pueblo

Scientix και Εκπαίδευση. Μια προστιθέμενη αξία για τους εκπαιδευτικούς.

Σε αυτή την εργαστηριακή παρουσίαση θα γίνει αρχικά γνωριμία με την ευρωπαϊκή πύλη Scientix. Μέσα από την ανάλυση του Scientix θα προκύψουν τα οφέλη από τη χρήση του καθώς και οι δυνατότητες που αυτό προσφέρει στον εκπαιδευτικό με σκοπό να εμπλουτίσει – εκτός από τα εργαστηριακά μαθήματα – και τα θεωρητικά. Αρχικά θα γίνει η παρουσίαση του European Schoolnet, το οποίο είναι ο συντονιστής φορέας του Scientix. Κατόπιν θα γίνει η παρουσίαση του τρόπου εγγραφής των νέων χρηστών στην πύλη και ύστερα θα γίνει επίδειξη και πρακτική εξάσκηση του τρόπου με τον οποίο πραγματοποιείται η αναζήτηση έργων (projects) καθώς και η αναζήτηση πόρων (resources). Ο σκοπός της εργαστηριακής παρουσίασης είναι να μυήσει τους εκπαιδευτικούς σε έναν διαφορετικό τρόπο προσέγγισης του γνωστικού τους αντικειμένου και να τους βοηθήσει να εμπλουτίσουν τον τρόπο διδασκαλίας των μαθημάτων που διδάσκουν. Η επιτυχία του εργαστηρίου θα οδηγήσει στην υιοθέτηση εκ μέρους των συμμετεχόντων εκπαιδευτικών της μεθοδολογίας και της ευρύτερης φιλοσοφίας που διακατέχει την πύλη του Scientix, προκειμένου να την εφαρμόσουν στη συνέχεια, στις σχολικές αίθουσες, με τους μαθητές τους

Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.

MLL-AF4+ infant B cell acute lymphoblastic leukemia is characterized by an early onset and dismal survival. It initiates before birth, and very little is known about the early stages of the disease's development. Using a conditional Mll-AF4-expressing mouse model in which fusion expression is targeted to the earliest definitive hematopoietic cells generated in the mouse embryo, we demonstrate that Mll-AF4 imparts enhanced B lymphoid potential and increases repopulation and self-renewal capacity during a putative pre-leukemic state. This occurs between embryonic days 12 and 14 and manifests itself most strongly in the lymphoid-primed multipotent progenitor population, thus pointing to a window of opportunity and a potential cell of origin. However, this state alone is insufficient to generate disease, with the mice succumbing to B cell lymphomas only after a long latency. Future analysis of the molecular details of this pre-leukemic state will shed light on additional events required for progression to acute leukemia.Core facilities at the Cambridge Institute for Medical Research are supported by Strategic Award WT100140 and equipment grant 093026; core facilities at the Edinburgh MRC Centre for Regenerative Medicine are supported by centre grant MR/K017047/1. This work was funded by a Bloodwise Bennett Senior Fellowship (10015 to K.O.), a Wellcome Trust Clinical PhD Studentship (097454/z/11/z to N.A.B.) the Gabrielle’s Angel Foundation for Cancer Research (to K.O.), and the Kay Kendall Leukaemia Fund (to K.O.).This is the final version of the article. It first appeared from Cell Press/Elsevier at http://dx.doi.org/10.1016/j.celrep.2016.06.046

Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5(+/-) leukemia.

BACKGROUND: B-cell precursor acute lymphoblastic leukemia (B-ALL) is amongst the leading causes of childhood cancer-related mortality. Its most common chromosomal aberration is the ETV6-RUNX1 fusion gene, with ~25% of ETV6-RUNX1 patients also carrying PAX5 alterations. METHODS: We have recreated this mutation background by inter-crossing Etv6-RUNX1 (Etv6 (RUNX1-SB)) and Pax5(+/-) mice and performed an in vivo analysis to find driver genes using Sleeping Beauty transposon-mediated mutagenesis and also exome sequencing. RESULTS: Combination of Etv6-RUNX1 and Pax5(+/-) alleles generated a transplantable B220 + CD19+ B-ALL with a significant disease incidence. RNA-seq analysis showed a gene expression pattern consistent with arrest at the pre-B stage. Analysis of the transposon common insertion sites identified genes involved in B-cell development (Zfp423) and the JAK/STAT signaling pathway (Jak1, Stat5 and Il2rb), while exome sequencing revealed somatic hotspot mutations in Jak1 and Jak3 at residues analogous to those mutated in human leukemias, and also mutation of Trp53. CONCLUSIONS: Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5(+/-)

DIGITAL TRANSITION STRATEGIES AND TRAINING PROGRAMS FOR DIGITAL CURATION OF MUSEUM

Small and medium-sized museums have been particularly impacted by the COVID-19 pandemic, as they often have limited resources and staff to manage the challenges posed by the pandemic. In order for them to survive during the pandemic but also embracing the extensive use of technology in our everyday lives, museums have to adapt to this new reality. The aim of the Museum-Next project is to provide small and medium-sized museums with a new generation of specialised EU professionals working in the Cultural Heritage sector, equipped with a recognised, cross-cutting and high-level digital skillset: the Digital Curators. In the digital age, museum digital curators play a critical role in preserving, organising, and presenting museum collections online. As part of the project, our research performed a desk analysis on the state of the art on museum digital transition strategies and museum digital curator training programs already implemented at EU scale in order to map good practices and tools already existing so as to highlight the current situation and the gaps that may appear in the topic

L∞L_{\infty}-Algebras of Einstein-Cartan-Palatini Gravity

We give a detailed account of the cyclic $L_\infty$-algebra formulation of general relativity with cosmological constant in the Einstein-Cartan-Palatini formalism on spacetimes of arbitrary dimension and signature, which encompasses all symmetries, field equations and Noether identities of gravity without matter fields. We present a local formulation as well as a global covariant framework, and an explicit isomorphism between the two $L_\infty$-algebras in the case of parallelizable spacetimes. By duality, we show that our $L_\infty$-algebras describe the complete BV-BRST formulation of Einstein-Cartan-Palatini gravity. We give a general description of how to extend on-shell redundant symmetries in topological gauge theories to off-shell correspondences between symmetries in terms of quasi-isomorphisms of $L_\infty$-algebras. We use this to extend the on-shell equivalence between gravity and Chern-Simons theory in three dimensions to an explicit $L_\infty$-quasi-isomorphism between differential graded Lie algebras which applies off-shell and for degenerate dynamical metrics. In contrast, we show that there is no morphism between the $L_\infty$-algebra underlying gravity and the differential graded Lie algebra governing $BF$ theory in four dimensions.Comment: 84 pages; v2: minor corrections and changes; v3: exposition improved and references added; Final version to be published in Journal of Mathematical Physic

The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.This is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.9