Pyrrolo[3,2-h]quinazolines as photochemotherapeutic agents

Heteroanalogues of angelicin, pyrrolo[3,2-h]quinazolines, were synthesized with the aim of obtaining new potent photochemotherapeutic agents. Many derivatives caused a significant decrease in cell proliferation in several human tumor cell lines after irradiation with UVA light (GI(50) =15.2-0.2 μM). Their phototoxicity effected apoptosis in Jurkat cells with the involvement of mitochondria (as determined by the loss of mitochondrial membrane potential and production of reactive oxygen species) and lysosomes. The phototoxicity of these compounds could be explained by lipid peroxidation.     

Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates

A series of inhibitors of plant enzymes of the non-mevalonate pathway from herbicide research efforts at BASF were screened for antimalarial activity in a cell-based assay. A 1,3-diiminoisoindoline carbohydrazide was found to inhibit the growth of Plasmodium falciparum with an IC(50) value <100 nM. Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC(50) =18 nM for the most potent compound, the establishment of a structure-activity relationship, and the evaluation of the cytotoxic profile of the diiminoisoindolines. Furthermore, interesting configurational and conformational aspects for this class of compounds were studied by computational and X-ray crystal structure analysis. Some of the compounds can act as tridentate ligands, forming 2:1 ligand-iron(III) complexes, which also display antimalarial activity in the nanomolar IC(50) range, paired with low cytotoxicity.     

Invited Article: Polarization "Down Under": The polarized time-of-flight neutron reflectometer PLATYPUS

This review presents the implementation and full characterization of the polarization equipment of the time-of-flight neutron reflectometer PLATYPUS at the Australian Nuclear Science and Technology Organisation (ANSTO). The functionality and efficiency of individual components are evaluated and found to maintain a high neutron beam polarization with a maximum of 99.3% through polarizing Fe/Si supermirrors. Neutron spin-flippers with efficiencies of 99.7% give full control over the incident and scattered neutron spin direction over the whole wavelength spectrum available in the instrument. The first scientific experiments illustrate data correction mechanisms for finite polarizations and reveal an extraordinarily high reproducibility for measuring magnetic thin film samples. The setup is now fully commissioned and available for users through the neutron beam proposal system of the Bragg Institute at ANSTO.     

Improved ICT Infrastructure

The global WAN infrastructure originally followed the hierarchical structure in the telephony networks. The present evolution is going in the direction of uncoordinated loosely coupled ad hoc networks without an overall commonly agreed upon architecture. The convergence towards a unified global WAN platform, providing a comprehensive set of services spanning from best effort to guaranteed high quality services, sets the agenda for the design and implementation of the next generation Global Information Infrastructure. These problems were presented and discussed during the Extraordinary Brainstorming Panel: “EC FP7 Call 5” at the SW09 at Rebild, Denmark, May 15–17, 2009. There was a general consensus on the need for initiatives to ensure an improved and needed long term evolution towards a more well organized and structured approach to identify the key parameters for a new global ICT Infrastructure Reference Architecture. This paper reflects some of the elements of the discussions, some examples presented and some initiatives taken in order to follow up on the conclusions.     

H1153Y-KCNH2 Mutation Identified in a Sudden Arrhythmic Death Syndrome Case Alters Channel Gating

Long QT syndrome is one of the most common hereditary channelopathies inducing fatal arrhythmias and sudden cardiac death. We identified in a sudden arrhythmic death syndrome case a C-term KCNH2 mutation (c.3457C > T; p.His1153Tyr) classified as variant of unknown significance and functional impact. Heterologous expression in HEK293 cells combined with western-blot, flow-cytometry, immunocytochemical and microscope analyses shows no modification of channel trafficking to the cell membrane. Electrophysiological studies reveal that the mutation causes a loss of HERG channel function through an alteration of channel biophysical properties that reduces the current density leading to LQT2. These results provide the first functional evidence for H1153Y-KCNH2 mutation-induced abnormal channel properties. They concur with previous biophysical and clinical presentations of a survived patient with another variant that is G1036D. Therefore, the present report importantly highlights the potential severity of variants that may have useful implications for treatment, surveillance, and follow-up of LQT2 patients.     

40 years of Dogger aquifer management in Ile-de-France, Paris Basin, France

Geothermal energy has been supplying heat to district networks in the Paris Basin for more than 40 years. The most serious difficulties have been corrosion and scaling related problems that occurred in many geothermal loops in the mid-1980s. The main target of all exploration and exploitation projects has been the Dogger aquifer. Most of the operating facilities use the “doublet” technology which consists of a closed loop with one production well and one injection well. Injection of the cooled brines leads to the progressive exhaustion of the resource at the local doublet scale. Consequently, most of the research effort has been focused on quantifying the temporal evolution of the cooling, and to forecast the lifetimes of doublets and the occurrence of the “thermal breakthrough”. At the turn of the 21st century, there was a revival of geothermal energy development in France and new projects are presently being considered. The 40 years of experience in geothermal exploitation of the Paris basin constitutes a firm basis upon which to devise a sustainable regional management approach for the geothermal resource. Several governmental policies seek to promote further geothermal development of the Dogger aquifer with structures in place to facilitate technical studies.     

Dense SiOC cap for damage-less ultra low k integration with direct CMP in C45 architecture and beyond

Deposited on a porous a-SiOC:H intermetal dielectric (IMD), a dense a-SiOC:H cap was successfully integrated in a C45 dual damascene architecture. The paper demonstrates that, stopping the CMP with around 10 nm of the cap left, the IMD integrity is preserved. As a consequence, a 3.5% decrease in RC delay, a 7.3% decrease in IMD integrated k-value and an increase of the time to failure by a 100 factor are reached relative to direct CMP. The cap also allowed to achieve straight lines and to improve the lines height uniformity as if CMP stopped on the IMD.