Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events. (Blood. 2009; 113: 646-648)

Copyright and Parody:Taking Backward the Gowers Review

In 2006 the Gowers Review of Intellectual Property made a series of recommendations for reforming the intellectual property regime to better serve the interests of both consumers and industry. Among the proposed recommendations was that an exception for parody be introduced within the Copyright Designs and Patents Act 1988. In January 2008 the Intellectual Property Office (the IPO) launched the first part of a two-stage consultation process on exceptions to copyright. As part of that consultation process, the IPO proposed a ‘fair dealing style exception’ for parody, and sought views on whether a new exception should be introduced as well as what form it might take. In December 2009 the IPO launched the second stage of this consultation process. The second consultation document rejected the case for a new parody exception. This article considers the place of parody within the copyright regime and the objections levelled against the introduction of an exception set out within the IPO's second consultation document. It invites the IPO to reconsider its decision not to recommend the introduction of a specific exception for parody within the UK.

Enteric methane emissions and nitrogen utilisation efficiency for two genotype of hill hoggets offered fresh, ensiled and pelleted ryegrass

Thirty-six 12-month-old hill hoggets were used in a 2 genotype (18 Scottish Blackface vs. 18 Swaledale×Scottish Blackface)×3 diet (fresh vs. ensiled vs. pelleted ryegrass) factorial design experiment to evaluate the effects of hogget genotype and forage type on enteric methane (CH4) emissions and nitrogen (N) utilisation. The hoggets were offered 3 diets ad libitum with no concentrate supplementation in a single period study with 6 hoggets for each of the 6 genotype×diet combinations (n=6). Fresh ryegrass was harvested daily in the morning. Pelleted ryegrass was sourced from a commercial supplier (Aylescott Driers & Feeds, Burrington, UK) and the ryegrass silage was ensiled with Ecosyl (Lactobacillus plantarum, Volac International Limited, Hertfordshire, UK) as an additive. The hoggets were housed in individual pens for at least 14 d before being transferred to individual respiration chambers for a further 4 d with feed intake, faeces and urine outputs and CH4 emissions measured. There was no significant interaction between genotype and forage type on any parameter evaluated. Sheep offered pelleted grass had greater feed intake (e.g. DM, energy and N) but less energy and nutrient apparent digestibility (e.g. DM, N and neutral detergent fibre (NDF)) than those given fresh grass or grass silage (P<0.001). Feeding pelleted grass, rather than fresh grass or grass silage, reduced enteric CH4 emissions as a proportion of DM intake and gross energy (GE) intake (P<0.01). Sheep offered fresh grass had a significantly lower acid detergent fibre (ADF) apparent digestibility, and CH4 energy output (CH4-E) as a proportion of GE intake than those offered grass silage (P<0.001). There was no significant difference, in CH4 emission rate or N utilisation efficiency when compared between Scottish Blackface and Swaledale × Scottish Blackface. Linear and multiple regression techniques were used to develop relationships between CH4 emissions or N excretion and dietary and animal variables using data from sheep offered fresh ryegrass and grass silage. The equation relating CH4-E (MJ/d) to GE intake (GEI, MJ/d), energy apparent digestibility (DE/GE) and metabolisability (ME/GE) resulted in a high r2 (CH4-E=0.074 GEI+9.2 DE/GE−10.2 ME/GE−0.37, r2=0.93). N intake (NI) was the best predictor for manure N excretion (Manure N=0.66 NI+0.96, r2=0.85). The use of these relationships can potentially improve the precision and decrease the uncertainty in predicting CH4 emissions and N excretion for sheep production systems managed under the current feeding conditions.

National climate policies across Europe and their impacts on cities strategies

Globally, efforts are underway to reduce anthropogenic greenhouse gas emissions and to adapt to climate change impacts at the local level. However, there is a poor understanding of the relationship between city strategies on climate change mitigation and adaptation and the relevant policies at national and European level. This paper describes a comparative study and evaluation of cross-national policy. It reports the findings of studying the climate change strategies or plans from 200 European cities from Austria, Belgium, Estonia, Finland, France, Germany, Ireland, Italy, Netherlands, Spain and the United Kingdom. The study highlights the shared responsibility of global, European, national, regional and city policies. An interpretation and illustration of the influences from international and national networks and policy makers in stimulating the development of local strategies and actions is proposed. It was found that there is no archetypical way of planning for climate change, and multiple interests and motivations are inevitable. Our research warrants the need for a multi-scale approach to climate policy in the future, mainly ensuring sufficient capacity and resource to enable local authorities to plan and respond to their specific climate change agenda for maximising the management potentials for translating environmental challenges into opportunities.

MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

BackgroundThe recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.Design and MethodsThe expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.ResultsWe found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.ConclusionsIn conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.

Desire and Divorce in Serglige Con Culainn

This paper examines the expression of ideas about love, marriage and divorce in Serglige Con Culainn. It is argued that the two versions of the tale, both of which are incomplete, exhibit distinctive approaches to love and the portrayal of the female characters. The earlier recension depicts male desire as a violent attack by Otherworld women that renders the man incapacitated. The later version provides a radically different view, offering a strikingly sympathetic portrait of the two female protagonists which may suggest a female audience. This version gives a remarkable insight into sexual mores and marital breakdown in a protracted and detailed negotiation involving the three main characters. It reveals tensions between male and female views of marriage and particularly of the practice of concubinage. It values loyalty between married partners over the fulfilment of desire and demonstrates the enduring and destructive effects of passion which are healed here only through magical interventions.