The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells

Acute myeloid leukaemia (AML) is a clonal haematological malignancy affecting the myeloid lineage, with generally poor patient outcomes owing to the lack of targeted therapies. The histone lysine demethylase 4A (KDM4A) has been established as a novel therapeutic target in AML, due to its selective oncogenic role within leukaemic cells. We identify that the transcription factor nuclear factor of activated T cells 2 (NFATC2) is a novel binding and transcriptional target of KDM4A in the human AML THP-1 cell line. Furthermore, cytogenetically diverse AML cell lines, including THP-1, were dependent on NFATC2 for colony formation in vitro, highlighting a putative novel mechanism of AML oncogenesis. Our study demonstrates that NFATC2 maintenance of cell cycle progression in human AML cells was driven primarily by CCND1. Through RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), NFATc2 was shown to bind to the promoter region of genes involved in oxidative phosphorylation and subsequently regulate their gene expression in THP-1 cells. Furthermore, our data show that NFATC2 shares transcriptional targets with the transcription factor c-MYC, with MYC knockdown phenocopying NFATC2 knockdown. These data suggest a newly identified co-ordinated role for NFATC2 and MYC in the maintenance of THP-1 cell function, indicative of a potential means of therapeutic targeting in human AML

Star and Planet Formation with ALMA: an Overview

Submillimeter observations with ALMA will be the essential next step in our understanding of how stars and planets form. Key projects range from detailed imaging of the collapse of pre-stellar cores and measuring the accretion rate of matter onto deeply embedded protostars, to unravelling the chemistry and dynamics of high-mass star-forming clusters and high-spatial resolution studies of protoplanetary disks down to the 1 AU scale.Comment: Invited review, 8 pages, 5 figures; to appear in the proceedings of "Science with ALMA: a New Era for Astrophysics". Astrophysics & Space Science, in pres

Efficiency of a gyroscopic device for conversion of mechanical wave energy to electrical energy:Technical report from ESGI-83 workshop in industrial mathematics 2011

We consider a recently proposed gyroscopic device for conversion of mechanical ocean wave energy to electrical energy. Two models of the device derived from standard engineering mechanics from the literature are analysed, and a model is derived from analytical mechanics considerations. From these models, estimates of the power production, efficiency, forces and moments are made. We find that it is possible to extract a significant amount of energy from an ocean wave using the described device. Further studies are required for a full treatment of the device.Resulting from the interaction with Joltech A/S at ESGI-83 (European Study Group with Industry) workshop on industrial mathematics, Sønderborg Denmark, 2011.</p

An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells

Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that PAs are effective in inhibiting E2F1 TF activity which results in a temporal reduction in BC-CML cell number. We envisage that PAs could be used in the future to map genes under E2F1 control in CML LSCs

Studies of Dense Cores with ALMA

Dense cores are the simplest star-forming sites that we know, but despite their simplicity, they still hold a number of mysteries that limit our understanding of how solar-type stars form. ALMA promises to revolutionize our knowledge of every stage in the life of a core, from the pre-stellar phase to the final disruption by the newly born star. This contribution presents a brief review of the evolution of dense cores and illustrates particular questions that will greatly benefit from the increase in resolution and sensitivity expected from ALMAComment: 6 pages, 2 figures, to appear in Astrophysics and Space Science, special issue of "Science with ALMA: a new era for Astrophysics" conference, ed. Dr. Bachille

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness