Structural effects on the pH-dependent fluorescence of naphthalenic derivatives and consequences for sensing/switching

Naphthalenic compounds are a rich resource for designers of fluorescent sensing/switching/logic systems. The degree of internal charge transfer (ICT) character in the fluorophore excited states can vary from negligible to substantial. Naphthalene-1,8;4,5-diimides (11–13), 1,8-naphthalimides (16) and 4-chloro-1,8-naphthalimides (15) are of the former type. The latter type is represented by the 4-alkylamino-1,8-naphthalimides (1). Whether ICT-based or not, these serve as the fluorophore in ‘fluorophore-spacer-receptor’ switching systems where PET holds sway until the receptor is bound to H+. On the other hand, 4-dialkylamino-1,8-naphthalimides (3–4) show modest H+-induced fluorescence switching unless the 4-dialkylamino group is a part of a small ring (5). Electrostatic destabilization of a non-emissive twisted internal charge transfer (ICT) excited state is the origin of this behaviour. An evolution to the non-emissive twisted ICT excited state is responsible for the weak emission of the model compound 6 (and related structures 7 and 8) across the pH range. Twisted ICT excited states are also implicated in the switch 9 and its model compound 10, which are based on the 6-dialkylamino-3H-benzimidazo[2,1-a]benz[d,e]isoquinolin-3-one fluorophore.

Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.

Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of CN-AML.

The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis and therapeutic intervention based on improved patient stratification. Relevant pre-clinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML) and a conditional transplantation mouse model was developed that demonstrated oncogene-dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity Map (sscMap) analysis identified Entinostat as a drug with the potential to alter the leukemic condition towards the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal AML. © 2013 AlphaMed Press

Fragmentos de Soto de Rojas: a ‘new’ mythological fable of the Spanish Baroque

The twentieth-century poet Gerardo Diego’s commitment to the recovery of a ‘sub-genre’, the mythological fable, evident in his Fábula de Equis y Zeda (1930) has been acknowledged by Peinado Elliot (2006), among others. However a recent discovery in his archive has revealed a hitherto unknown aspect of the poet’s scholarly commitment to this endeavour. A transcription of a previously unpublished, and until recently, unknown Baroque mythological fable with the title ‘Fábula de Alfeo y Aretusa’ was recently found by his daughter Elena, alongside an unpublished study by the young poet of said fable entitled ‘Un poema manuscrito del siglo XVII de la biblioteca Menéndez Pelayo’. Rosa Navarro Durán (2012) is convinced that the correspondences with Soto de Rojas’ 'Los fragmentos de Adonis' and the clear imprint of Góngora’s 'Soledades' and his 'Fábula de Píramo y Tisbe' permit us to attribute it, with some confidence, to Pedro Soto de Rojas. This essay will consider the significance of this exciting discovery for our reading of Soto de Rojas’ existing corpus, exploring in particular the poem’s links with the dark eroticism of the Fragmentos de Adonis, (1652) and the early Fábula de la Naya.(1623)

Concise Reviews: Cancer Stem Cells: From Concept to Cure

n 1953, noting a remarkable consistency between the agents causing mutations and those associated with cancer, Carl Nordling, a Finnish-born architect, proposed that cancer results from an accumulation of genetic mutations. It is now generally accepted that inherited mutations and environmental carcinogens can lead to the development of premalignant clones. After further mutations, one cell reaches a critical state which confers a survival or growth advantage over normal cells. Such cells have the ability to initiate a malignant tumour. They share many of the features of normal stem cells, including the capacity for self-renewal and differentiation, and are widely termed cancer stem cells (CSCs). Although CSCs have been well characterized in hematological malignancies, their existence in some other tissues has been questioned. Here, we review recent work in which stem cells and stem cell-like cells have been used to investigate the pathogenesis of cancer and potential anticancer treatment strategies, in the context of both hematological and somatic tissue disease.

Multiplication of microbes below 0.690 water activity: implications for terrestrial and extraterrestrial life

Since a key requirement of known life forms is available water (water activity; aw), recent searches for signatures of past life in terrestrial and extraterrestrial environments have targeted places known to have contained significant quantities of biologically available water. However, early life on Earth inhabited high-salt environments, suggesting an ability to withstand low water-activity. The lower limit of water activity that enables cell division appears to be ∼ 0.605 which, until now, was only known to be exhibited by a single eukaryote, the sugar-tolerant, fungal xerophile Xeromyces bisporus. The first forms of life on Earth were, though, prokaryotic. Recent evidence now indicates that some halophilic Archaea and Bacteria have water-activity limits more or less equal to those of X. bisporus. We discuss water activity in relation to the limits of Earth's present-day biosphere; the possibility of microbial multiplication by utilizing water from thin, aqueous films or non-liquid sources; whether prokaryotes were the first organisms able to multiply close to the 0.605-aw limit; and whether extraterrestrial aqueous milieux of ≥ 0.605 aw can resemble fertile microbial habitats found on Earth.

Distributed MPC for Frequency Regulation in Multi-Terminal HVDC Grids

High Voltage Direct Current (HVDC) lines allow large quantities of power to be
transferred between two points in an electrical power system. A Multi-Terminal HVDC (MTDC) grid consists of a meshed network of HVDC lines, and this allows energy reserves to be shared between a number of AC areas in an efficient manner. Secondary Frequency Control (SFC) algorithms return the frequencies in areas connected by AC or DC lines to their original setpoints after Primary Frequency Controllers have been called following a contingency. Where multiple
TSOs are responsible for different parts of a MTDC grid it may not be possible to implement SFC from a centralised location. Thus, in this paper a simple gain based distributed Model Predictive Control strategy is proposed for Secondary Frequency Control of MTDC grids which allows TSOs to cooperatively perform SFC without the need for centralised coordination.

Session organiser/chair: Architecture, Infrastructure and the Making of Modern Ireland

‘A free Ireland would drain the bogs, would harness the rivers, would plant the wastes, would nationalise the railways and the waterways, would improve agriculture, would protect fisheries, would foster industries, would promote commerce, and beautify the cities …’ (Padraig Pearse, ‘From a Hermitage’, 1913)

Somewhat unusually in his often romantic writings Padraig Pearse – poet, pedagogue and revolutionary – chose to describe the future of an independent Ireland in terms of infrastructure and technological processes. Terence Brown’s locating of this excerpt at the beginning his seminal work Ireland: A Social and Cultural History 1922-2002 highlights the simultaneous and interlinking construction of both a new physical and cultural landscape for an independent modern nation. Lacking any significant industrial complex, the construction of new infrastructures in Ireland was seen throughout the 20th century as a key element in the building of the new State, just as the adoption of an international style modernism in architecture was perceived as a way to escape the colonial past. For Paul N. Edwards modernity and infrastructure are intimately connected.

‘infrastructures simultaneously shape and are shaped – in other words, co-construct – the condition of modernity. By linking macro, meso, and micro scales of time, space and social organisation, they form the stable foundation of modern social worlds’ (2003: 186).
Simultaneously omnipresent and invisible – infra means beneath – Edwards also points out that infrastructure tends only to become apparent when it is either new or broken. Interpreting the meso scale as being that of the building, this session calls for papers that critically and analytically investigate aspects of the architectures of infrastructure in 20th-century Ireland. Like the territory they explore these papers may range across scales to oscillate between a concern for the artefact and its physical landscape, and the larger, often hidden systems and networks that co-define this architecture.

Switching ‘on’ the Luminescence of One Metal Ion with Another: Selectivity Characteristics with Respect to the Emitting and Triggering Metal

Complexes 1a·EuIII and 1b·EuIII, but not 1a·TbIII and 1b·TbIII, display strong ‘off–on’ switching of delayed luminescence with alkali cations; the switching efficiency of 1b·EuIII is stronger with K+ rather than Na+.

A small supramolecular system which emulates the unidirectional, path-selective photoinduced electron transfer (PET) of the bacterial photosynthetic reaction centre (PRC)

The singlet excited state of the 4-aminonaphthalimide fluorophore in 1a and 1b directs electron transfer from intramolecular but external amine groups along only one of two available paths.