ARTEFACTS: How do we want to deal with the future of our one and only planet?

The European Commission’s Science and Knowledge Service, the Joint Research Centre (JRC), decided to try working hand-in-hand with leading European science centres and museums. Behind this decision was the idea that the JRC could better support EU Institutions in engaging with the European public. The fact that European Union policies are firmly based on scientific evidence is a strong message which the JRC is uniquely able to illustrate. Such a collaboration would not only provide a platform to explain the benefits of EU policies to our daily lives but also provide an opportunity for European citizens to engage by taking a more active part in the EU policy making process for the future. A PILOT PROGRAMME To test the idea, the JRC launched an experimental programme to work with science museums: a perfect partner for three compelling reasons. Firstly, they attract a large and growing number of visitors. Leading science museums in Europe have typically 500 000 visitors per year. Furthermore, they are based in large European cities and attract local visitors as well as tourists from across Europe and beyond. The second reason for working with museums is that they have mastered the art of how to communicate key elements of sophisticated arguments across to the public and making complex topics of public interest readily accessible. That is a high-value added skill and a crucial part of the valorisation of public-funded research, never to be underestimated. Finally museums are, at present, undergoing something of a renaissance. Museums today are vibrant environments offering new techniques and technologies to both inform and entertain, and attract visitors of all demographics.JRC.H.2-Knowledge Management Methodologies, Communities and Disseminatio

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C-N Bond Activation

The reaction of the low valent metallocene(II) sources Cp'Ti-2(eta(2)-Me3SiC2SiMe3) (Cp' = eta(5)-cyclopentadienyl, 1a or eta(5)-pentamethylcyclopentadienyl, 1b) with different carbodiimide substrates RN=C=NR' 2-R-R' (R = t-Bu; R' = Et; R = R' = i-Pr; t-Bu; SiMe3; 2,4,6-Me-C6H2 and 2,6-i-Pr-C6H3) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles 5-R. The product complexes show dismantlement, isomerization, or C-C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles 5-R, which presents an intriguing situation of M-C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3

Acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase (FLT3) is a clinically unresolved problem. AML cells frequently have a dysregulated expression and activity of epigenetic modulators of the histone deacetylase (HDAC) family. Therefore, we tested whether a combined inhibition of mutant FLT3 and class I HDACs is effective against AML cells. Low nanomolar doses of the FLT3 inhibitor (FLT3i) AC220 and an inhibition of class I HDACs with nanomolar concentrations of FK228 or micromolar doses of the HDAC3 specific agent RGFP966 synergistically induce apoptosis of AML cells that carry hyperactive FLT3 with an internal tandem duplication (FLT3-ITD). This does not occur in leukemic cells with wild-type FLT3 and without FLT3, suggesting a preferential toxicity of this combination against cells with mutant FLT3. Moreover, nanomolar doses of the new FLT3i marbotinib combine favorably with FK228 against leukemic cells with FLT3-ITD. The combinatorial treatments potentiated their suppressive effects on the tyrosine phosphorylation and stability of FLT3-ITD and its downstream signaling to the kinases ERK1/ERK2 and the inducible transcription factor STAT5. The beneficial pro-apoptotic effects of FLT3i and HDACi against leukemic cells with mutant FLT3 are associated with dose- and drug-dependent alterations of cell cycle distribution and DNA damage. This is linked to a modulation of the tumor-suppressive transcription factor p53 and its target cyclin-dependent kinase inhibitor p21. While HDACi induce p21, AC220 suppresses the expression of p53 and p21. Furthermore, we show that both FLT3-ITD and class I HDAC activity promote the expression of the checkpoint kinases CHK1 and WEE1, thymidylate synthase, and the DNA repair protein RAD51 in leukemic cells. A genetic depletion of HDAC3 attenuates the expression of such proteins. Thus, class I HDACs and hyperactive FLT3 appear to be valid targets in AML cells with mutant FLT3

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes

Reactions of Titanocene Bis(trimethylsilyl)acetylene Complexes with Carbodiimides: An Experimental and Theoretical Study of Complexation versus C–N Bond Activation

The reaction of the low valent metallocene­(II) sources Cp′₂Ti­(η²-Me₃SiC₂SiMe₃) (Cp′ = η⁵-cyclopentadienyl, <b>1a</b> or η⁵-penta­methylcyclopentadienyl, <b>1b</b>) with different carbodiimide substrates RNCNR′ <b>2-R-R</b>′ (R = <i>t</i>-Bu; R′ = Et; R = R′ = <i>i</i>-Pr; <i>t</i>-Bu; SiMe₃; 2,4,6-Me-C₆H₂ and 2,6-<i>i</i>-Pr-C₆H₃) was investigated to explore the frontiers of ring strained, unusual four-membered heterometallacycles <b>5-R</b>. The product complexes show dismantlement, isomerization, or C–C coupling of the applied carbodiimide substrates, respectively, to form unusual mono-, di-, and tetranuclear titanium­(III) complexes. A detailed theoretical study revealed that the formation of the unusual complexes can be attributed to the biradicaloid nature of the unusual four-membered heterometallacycles <b>5-R</b>, which presents an intriguing situation of M–C bonding. The combined experimental and theoretical study highlights the delicate interplay of electronic and steric effects in the stabilization of strained four-membered heterometallacycles, accounting for the isolation of the obtained complexes