Assessable Learning Outcomes for the EU Education and Training Framework core and Function A specific modules: Report of an ETPLAS Working Group

Article 23(2) of the European Union Directive 2010/63/EU, which regulates welfare provisions for animals used for scientific purposes, requires that staff involved in the care and use of animals for scientific purposes be adequately educated and trained before they undertake any such work. However, the nature and extent of such training is not stipulated in the Directive. To facilitate Member States in fulfilling their education and training obligations, the European Commission developed a common Education and Training Framework, which was endorsed by the Member States Competent Authorities. An Education & Training Platform for Laboratory Animal Science (ETPLAS) Working Group was recently established to develop further guidance to the Learning Outcomes in the Framework, with the objective to clarify the levels of knowledge and understanding required by trainees, and to provide the criteria by which these Learning Outcomes should be assessed. Using the Framework document as a starting point, assessment criteria for the Learning Outcomes of the modules required for Function A persons (carrying out procedures on animals) for rats, mice and zebrafish were created with sufficient detail to enable trainees, providers and assessors to appreciate the level of knowledge, understanding and skills required to pass each module. Adoption and utilization of this document by training providers and accrediting or approving bodies will harmonize introductory education and training for those involved in the care and use of animals for scientific purposes within the European Union, promote mutual recognition of training within and between Member States and therefore free movement of personnel

Technological persistence in ceramic production in the southeastern Hispaniola: The case study of El Cabo (600-1502 CE)

Archaeology of the America

Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia (vol 32, pg 788, 2018)

Following the publication of this article the authors noted that data describing precisely where phosphorylation sites in proteins modulated following JAK1 or JAK3 inhibition in mutant T-ALL samples was not clearly annotated. Therefore an additional sheet has been added to Supplementary Table 2

Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia

Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens

桂林寺下附近地図（堀割再検分のため寺社奉行鳥居小八郎）

OnabotulinumtoxinA has been shown to reduce headache-days among patients with chronic migraine (CM). The objective of this analysis was to determine whether onabotulinumtoxinA has an impact on headache-day severity in patients with CM among those patients who were deemed non-responders based on reduction in the frequency of headache days alone. Data from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trial program (a 24-week, 2-treatment cycle, double-blind, randomized, placebo-controlled, parallel-group phase, followed by a 32-week, 3-treatment cycle, open-label phase) were pooled for analysis. Patients kept a daily diary to record headache severity on a 4-point scale (from none to severe), and a 6-domain Headache Impact Test (HIT-6) was used to determine the clinical impact of headaches. Analysis was undertaken to assess whether the subset of patients that were headache-day frequency non-responders at week 24 (patients with <50% reduction in headache-day frequency) experienced a reduction in headache severity whilst receiving onabotulinumtoxinA. For headache-day frequency non-responders, significant reductions in the number of severe headache days, average daily headache severity, pooled percentage of severe headache days and headache severity score were observed at week 24 for patients who had received onabotulinumtoxinA compared with those who had received placebo. The between-group differences were reduced and non-significant at week 56. Similarly, headache-day frequency non-responders receiving onabotulinumtoxinA were found to have an improvement in the clinical impact of headaches using results from the HIT-6. These results suggest that even those patients with CM who are deemed non-responders based on analysis of headache frequency alone experience clinically meaningful relief from headache intensity following treatment with onabotulinumtoxinA. The online version of this article (doi:10.1186/s10194-017-0784-4) contains supplementary material, which is available to authorized users

Back to the Eneolithic: Exploring the Rudki-type ornaments from Poland

For a long time, the Eneolithic attribution of the Rudki-type double spiral ornaments was contested by a wide academic audience, and therefore, this new and extraordinary category of the copper metalwork seemed to have fallen into scientific oblivion. In this paper, we contribute to the debate about cultural attribution of the Rudki-type double spiral ornaments considering their chemical and isotope characteristics (using ED XRF and MC-ICP-MS) and the manufacturing technology (OM, X-ray, CT). Noticeably, this study represents the first documented implementation of the lead isotope analysis (LIA) for the Eneolithic metalwork from Poland. The new scientific analyses give ground to the hypothesis that the Rudki-type double spiral ornaments were produced by the Baden culture metalworker(s) who practiced somewhere in the Carpathian Basin and who have used copper ore mined in the Slovak Ore Mountains (Spania Dolina-Banska Bystrica-Kremnica mine complex). These ornaments were redistributed towards the northern ecumene of the Baden culture complex. The new owners, the Funnel Beaker (TRB) culture communities from the region of modern Poland, deposited the ornaments in hoards (Kaldus, Przeuszyn and Rudki) during the mid-4th millennium BC. The results, furthermore, indicate that the so-called Baden spiral metalwork package must be now complemented by the Rudki-type double spiral ornaments. Remarkably, this package also found an echo in pottery decoration, as documented by a narrative scene incised on an amphora from Kaldus, which could be also interpreted as one of the earliest known proofs for the wagon transport in Europe, alongside the famous ones reported from Bronocice or Flintbek.Material Culture Studie