A Systemic Evaluation of the State of Affairs Following the Negative Outcome of the Referendum in Cyprus Using the Structured Dialogic Design Process

This paper reports the results of the first of a series of co-laboratories organized by Cypriot peace pioneers 30 months after the negative outcome of the referendum concerning UN General Secretary’s plan for reunification of the island. The purpose of this co-laboratory was to support a diverse group of disengaged and disappointed peace pioneers and activists representing Turkish and Greek communities of Cyprus develop a shared understanding of factors contributing to the perceived widening of the gap between the two divided communities in Cyprus. The co-laboratory was organized using the structured dialogic design process (SDDP) approach within the context of a rich web-based communication environment. The root causes contributing to the widening of the gap are discussed and are also compared with those identified during a similar co-laboratory employing the Interactive Management methodology 12 years earlier.

Exploring Options for Enhancement of Social Dialogue Between the Turkish and Greek Communities in Cyprus Using the Structured Dialogic Design Process

This paper summarizes results of a co-laboratory that took place 33 months after the negative outcome of the referendum on the UN’s proposal for the solution of the Cyprus problem, and which was a follow-up (3 months later) of a previous co-laboratory. The earlier co-laboratory explored factors contributing to the increasing gap between the two conflicting communities. The co-laboratory reported here engaged relevant stakeholders (peace pioneers, academics, business people, activists and others representing the Turkish and Greek speaking communities of Cyprus) to come up with options aiming to enhance the social dialogue between the two communities. The Structured Dialogic Design Process was used to structure 27 proposed options and develop an influence map. The deep drivers, i.e., most influential factors, determined decisions taken by the participating peace pioneers regarding their future interventions. The results are also discussed within the framework of current (analysis reflects the political situation during the period reported here) political developments.     

Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia

Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.     

Subunit arrangement and function in NMDA receptors

Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.     

Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1

We identified 11 human pedigrees with dominantly inherited hemolytic anemias in both the hereditary stomatocytosis and spherocytosis classes. Affected individuals in these families had an increase in membrane permeability to Na and K that is particularly marked at 0 degrees C. We found that disease in these pedigrees was associated with a series of single amino-acid substitutions in the intramembrane domain of the erythrocyte band 3 anion exchanger, AE1. Anion movements were reduced in the abnormal red cells. The 'leak' cation fluxes were inhibited by SITS, dipyridamole and NS1652, chemically diverse inhibitors of band 3. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal Na and K fluxes in the oocytes, and the induced Cl transport was low. These data are consistent with the suggestion that the substitutions convert the protein from an anion exchanger into an unregulated cation channel.