Behavior of a Dynamic Covalent Library Driven by Combined Pd(II) and Biphasic Effectors for Metal Transport between Phases.

This work reports the effect of Pd(II) as chemical effector on an acylhydrazone-based dynamic covalent library (DCL) in biphasic systems (water/chloroform). The constituents of the DCL are self-built and distributed in the two phases, two of them are lipophilic enough to play the role of a carrier agent that may transfer Pd(II) from the aqueous phase to the organic phase. Upon addition of Pd(II), the DCL of components exhibits a strong amplification of the constituent that is the most adapted to stabilize Pd(II) in chloroform as well as its agonist in water. This evolution is driven by the combination of the interaction of the DCL with Pd(II) and the presence of the two phases. This study paves the way to a novel approach for liquid/liquid extraction and metal recovery by means of adaptive extractant species generated in situ by a DCL.

The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation.

Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chaperonin T-complex-protein-1-ring (TRiC) or Cytosolic Chaperonin containing TCP-1 (CCT) to assist folding of newly synthesized polypeptides. The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels. Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation. We mapped the interaction of prefoldin with pVHL at the exon2-exon3 junction encoded region. Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations. Our results link the prefoldin complex with pVHL folding and this may impact VHL diseases progression.

Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel-Lindau gene in the ccRCC.

BACKGROUND: The von Hippel-Lindau disease is an autosomal dominant syndrome associated with tumour formation in various tissues, such as retina, central nervous system, kidney, and adrenal glands. VHL gene deletion or mutations support the development of various cancers. Unclassified VHL variants also referred as "of unknown significance" result from gene mutations that have an unknown or unclear effect on protein functions. The P81S mutation has been linked to low penetrance Type 1 disease but its pathogenic function was not clearly determined. METHODS: We established a stable cell line expressing the pVHL213 (c.241C>T, P81S) mutant. Using biochemical and physiological approaches, we herein analysed pVHL folding, stability and function in the context of this VHL single missense mutation. RESULTS: The P81S mutation mostly affects the non-canonical function of the pVHL protein. The cells expressing the pVHL213P81S acquire invasive properties in relation with modified architecture network. CONCLUSION: We demonstrated the pathogenic role of this mutation in tumour development in vhl patients and confirm a medical follow up of family carrying the c.241C>T, P81S.

Tuning the Regioselective Functionalization of Trifluoromethylated Dienes via Lanthanum-Mediated Single C-F Bond Activation.

The development of new fluorine-containing building blocks and their efficient synthetic access is currently a challenging research field. Herein, the highly regio- and stereoselective addition of a large range of aldehydes onto trifluoromethylated benzofulvenes was achieved using a simple La/I2 /DIBAL-Cl system via a selective C-F bond activation process. This versatile methodology provided homodienyl alcohols bearing a terminal CF2 -alkene with potential further applications, as shown by the dehydration to the first benzofulvenes carrying a difluorovinyl group. In addition, for certain electron-poor aldehydes, unprecedented ipso substitution of the CF3 group in a diene was observed, which, according to DFT studies, is related to the presence of the large, Lewis-acidic lanthanum metal.

Ends and middle: Global force balance and septum location in fission yeast.

The fission yeast cell is shaped as a very regular cylinder ending by hemi-spheres at both cell ends. Its conserved phenotypes are often used as read-outs for classifying interacting genes and protein networks. Using Pascal and Young-Laplace laws, we proposed a framework where scaling arguments predicted shapes. Here we probed quantitatively one of these relations which predicts that the division site would be located closer to the cell end with the larger radius of curvature. By combining genetics and quantitative imaging, we tested experimentally whether altered shapes of cell end correlate with a displaced division site, leading to asymmetric cell division. Our results show that the division site position depends on the radii of curvatures of both ends. This new geometrical mechanism for the proper division plane positioning could be essential to achieve even partitioning of cellular material at each cell division.

Direct Observation of the Surface Topography at High Temperature with SEM.

High-temperature scanning electron microscopy allows the direct study of the temperature behavior of materials. Using a newly developed heating stage, tilted images series were recorded at high temperature and 3D images of the sample surface were reconstructed. By combining 3D images recorded at different temperatures, the variations of material roughness can be accurately described and associated with local changes in the topography of the sample surface.

Deciphering the Crystal Structure of a Scarce 1D Polymeric Thorium Peroxo Sulfate.

The preparation and structural characterization of an original Th peroxo sulfate dihydrate, crystallizing at room temperature in the form of stable 1D polymeric microfibres is described. A combination of laboratory and synchrotron techniques allowed solution of the structure of the Th(O2 )(SO4 )(H2 O)2 compound, which crystallizes in a new structure type in the space group Pna21 of the orthorhombic crystal system. Particularly, the peroxide ligand coordinates to the Th cations in an unusual µ3 -η2 :η2 :η2 bridging mode, forming an infinite 1D chain decorated with sulfato ligands exhibiting simultaneously monodentate and bidentate coordination modes.

Liposomes Containing Nickel-Bis(dithiolene) Complexes for Photothermal Theranostics.

New thermosensitive liposomes with a phase transition at 42 °C, containing nickel-bis(dithiolene) complexes as efficient and stable photothermal agents, have been formulated and characterized. These liposomes are highly stable and keep their contents at 37 °C for more than 30 days. On the contrary, the mild hyperthermia generated by the nickel-bis(dithiolene) complex under 940 nm NIR irradiation allows for the fine controlled release of the liposome contents, making such liposomes highly suitable for on-demand drug delivery in the human body under NIR laser irradiation. These liposomes can also be directly used, as shown here, as nanoagents for photothermal therapy. In fact, strong cell death can be generated under laser irradiation in the presence of these photothermally active nanocargos containing less than 10% w/w of metal complex. We also demonstrate, for the first time, that nickel-bis(dithiolene) complexes are good photoacoustic agents, generating easily detectable ultrasonic signals directly proportional to the concentration of complexes and the used laser power.

Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel-Lindau tumor suppressor protein.

Quality control mechanisms promote aggregation and degradation of misfolded proteins. In budding yeast, the human von Hippel-Lindau protein (pVHL, officially known as VHL) is misfolded and forms aggregates. Here, we investigated the aggregation of three pVHL isoforms (pVHL213, pVHL160, pVHL172) in fission yeast. The full-length pVHL213 isoform aggregates in highly dynamic small puncta and in large spherical inclusions, either close to the nucleus or to the cell ends. The large inclusions contain the yeast Hsp104 chaperone. Aggregate clearance is regulated by proteasomal degradation. The pVHL160 isoform forms dense foci and large irregularly shaped aggregates. In silico, prediction of pVHL aggregation propensity identified a key aggregation-promoting region within exon 2. Consistently, the pVHL172 isoform, which lacks exon 2, formed rare reduced inclusions. We studied the aggregation propensity of pVHL variants harbouring missense mutations found in kidney carcinomas. We show that the P86L mutation stimulated small aggregate formation, the P146A mutation increased large inclusion formation, whereas the I151S mutant destabilized pVHL. The prefoldin subunit Pac10 (the human homolog VBP-1 binds to pVHL) is required for pVHL stability. Reduction of soluble functional pVHL might be crucial in VHL-related diseases.

Polyoxometalate/Polyethylene Glycol Interactions in Water: From Nanoassemblies in Water to Crystal Formation by Electrostatic Screening.

In the last decade organic-inorganic hybrid materials have become essential in materials science as they combine properties of both building blocks. Nowadays the main routes for their synthesis involve electrostatic coupling, covalent grafting, and/or solvent effects. In this field, polyoxometalates (POMs) have emerged as interesting inorganic functional building blocks due to their outstanding properties. In the present work the well-known α-Keggin polyoxometalate, α-PW12 O403- (PW), is shown to form hybrid crystalline materials with industrial (neutral) polyethylene glycol oligomers (PEG) under mild conditions, that is, in aqueous medium and at room temperature. The formation of these materials originates from the spontaneous self-assembly of PW with EOx , (EO=ethylene oxide) with at least four EO units (x>4). The PW-PEG nanoassemblies, made of a POM surrounded by about two PEG oligomers, are stabilized by electrostatic repulsions between the negatively charged PW anions. Addition of NaCl, aimed at screening the inter-nanoassembly repulsions, induces aggregation and formation of hybrid crystalline materials. Single-crystal analysis showed a high selectivity of PW towards EO5 -EO6 oligomers from PEG200, which is made of a mixture of EO3-8 . Therefore, a general "soft" route to produce POM-organic composites is proposed here through the control of electrostatic repulsions between spontaneously formed nanoassemblies in water. However, this rational design of new POM hybrid (crystalline) materials with hydrophilic blocks, using such a simple mixing procedure of the components, requires a deep understanding of the molecular interactions.

Impact of the Long-Range Electronic Effect of a Fluorous Ponytail on Metal Coordination during Solvent Extraction.

With the need for a precise description of the long-range electronic effects of a perfloroalkyl chain (F-ponytail) grafted onto metal chelators, we studied in detail the effect of a spacer inserted between the polar complexing head and the F-ponytail, in relation to the metal coordination ability of the resulting molecules. The prepared molecules were then applied for the extraction of various metals from an aqueous phase into an organic phase, and the optimum spacer length could be estimated to be between three and four methylene units, according to the extraction conditions. The study also revealed the difficulty of modeling and anticipating the tiny energy differences involved in the extraction process and the importance in peculiar cases to go beyond only these studied inductive effects to understand better the factors that govern the stabilization of a metallic cation in a complex fluorous phase.

Metal Recognition Driven by Weak Interactions: A Case Study in Solvent Extraction.

Tuning the affinity of a medium for a given metallic cation with the sole modification of weak interactions is a challenge for molecular recognition. Solvent extraction is a key technique employed in the recovery and purification of valuable metals, and it is facing an increased complexity of metal fluxes to deal with. The selectivity of such processes generally relies on the use of specific ligands, designed after their coordination chemistry. In the present study, we illustrate the possibility to employ the sole control of weak interactions to achieve the selective extraction of Pd(II) over Nd(III) : the control over selectivity is obtained by tuning the self-assembly of the organic phase. A model is proposed, after detailed experimental analysis of molecular (XRD, NMR) and supra-molecular (SAXS) features of the organic phases. We thus demonstrate that Pd(II) extraction is driven by metal coordination, whereas Nd(III) extraction requires aggregation of the extractant in addition to metal coordination. These results are of general interest for the applications which rely on the stabilization of metals in organic phases.

Micro-distribution of uranium in bone after contamination: new insight into its mechanism of accumulation into bone tissue.

After internal contamination, uranium rapidly distributes in the body; up to 20 % of the initial dose is retained in the skeleton, where it remains for years. Several studies suggest that uranium has a deleterious effect on the bone cell system, but little is known regarding the mechanisms leading to accumulation of uranium in bone tissue. We have performed synchrotron radiation-based micro-X-ray fluorescence (SR µ-XRF) studies to assess the initial distribution of uranium within cortical and trabecular bones in contaminated rats' femurs at the micrometer scale. This sensitive technique with high spatial resolution is the only method available that can be successfully applied, given the small amount of uranium in bone tissue. Uranium was found preferentially located in calcifying zones in exposed rats and rapidly accumulates in the endosteal and periosteal area of femoral metaphyses, in calcifying cartilage and in recently formed bone tissue along trabecular bone. Furthermore, specific localized areas with high accumulation of uranium were observed in regions identified as micro-vessels and on bone trabeculae. These observations are of high importance in the study of the accumulation of uranium in bone tissue, as the generally proposed passive chemical sorption on the surface of the inorganic part (apatite) of bone tissue cannot account for these results. Our study opens original perspectives in the field of exogenous metal bio-mineralization.

Polymorphic copper iodide clusters: insights into the mechanochromic luminescence properties.

An in-depth study of mechanochromic and thermochromic luminescent copper iodide clusters exhibiting structural polymorphism is reported and gives new insights into the origin of the mechanochromic luminescence properties. The two different crystalline polymorphs exhibit distinct luminescence properties with one being green emissive and the other one being yellow emissive. Upon mechanical grinding, only one of the polymorphs exhibits great modification of its emission from green to yellow. Interestingly, the photophysical properties of the resulting partially amorphous crushed compound are closed to those of the other yellow polymorph. Comparative structural and optical analyses of the different phases including a solution of clusters permit us to establish a correlation between the Cu-Cu bond distances and the luminescence properties. In addition, the local structure of the [Cu4I4P4] cluster cores has been probed by (31)P and (65)Cu solid-state NMR analysis, which readily indicates that the grinding process modifies the phosphorus and copper atoms environments. The mechanochromic phenomenon is thus explained by the disruption of the crystal packing within intermolecular interactions inducing shortening of the Cu-Cu bond distances in the [Cu4I4] cluster core and eventually modification of the emissive state. These results definitely establish the role of cuprophilic interactions in the mechanochromism of copper iodide clusters. More generally, this study constitutes a step further into the understanding of the mechanism involved in the mechanochromic luminescent properties of metal-based compounds.

Phosphorus-stabilized titanium carbene complexes: synthesis, reactivity and DFT studies.

The synthesis of two novel titanium carbene complexes from the bis(thiophosphinoyl)methanediide geminal dianion 1 (SCS(2-) ) is described. Dianion 1 reacts cleanly with 0.5 equivalents of [TiCl4 (thf)2 ] to afford the bis-carbene complex [(SCS)2 Ti] (2) in 86 % yield. The mono-carbene complex [(SCS)TiCl2 (thf)] (3) can also be obtained by using an excess of [TiCl4 (thf)2 ]. The structures of 2 and 3 are confirmed by X-ray crystallography. A strong nucleophilic reactivity towards various electrophiles (ketones and aldehydes) is observed. The reaction of 3 with N,N'-dicyclohexylcarbodiimide (DCC) and phenyl isocyanate leads to the formation of two novel diphosphinoketenimines 8 a and 8 b. The bis-titanium guanidinate complex 9 is trapped as the by-product of the reaction with DCC. The X-ray crystal structures of 8 a and 9 are presented. The mechanism of the reaction between complex 3 and DCC is rationalized by DFT studies.

The Kin1 kinase and the calcineurin phosphatase cooperate to link actin ring assembly and septum synthesis in fission yeast.

BACKGROUND INFORMATION: The Kin1 protein kinase of fission yeast, which regulates cell surface cohesiveness during interphase cell growth, is also present at the cell division site during mitosis; however, its function in cell division has remained elusive. RESULTS: In FK506-mediated calcineurin deficient cells, mitosis is extended and ring formation is transiently compromised but septation remains normal. Here, we show that Kin1 inhibition in these cells leads to polyseptation and defects in membrane closure. Actomyosin ring disassembly is prevented and ultimately the daughter cells fail to separate. We show that the Pmk1 MAP kinase pathway and the type V myosin Myo4 act downstream of the cytokinetic function of Kin1. Kin1 inhibition also promotes polyseptation in myo3Δ, a type II myosin heavy-chain mutant defective in ring assembly. In contrast, Kin1 inactivation rescues septation in a myosin light-chain cdc4-8 thermosensitive mutant. A structure/function analysis of the Kin1 protein sequence identified a novel motif outside the kinase domain that is important for its polarised localisation and its catalytic activity. This motif is remarkably conserved in all fungal Kin1 homologues but is absent in related kinases of metazoans. CONCLUSIONS: We conclude that calcineurin and Kin1 activities must be tightly coordinated to link actomyosin ring assembly with septum synthesis and membrane closure and to ensure separation of the daughter cells.

A tetracoordinated phosphasalen nickel(III) complex.

The oxidation of a Ni(II) complex bearing a tetradentate phosphasalen ligand, which differs from salen by the presence of an iminophosphorane (PN) in place of an imine unit, was easily achieved by addition of a silver salt. The site of this oxidation was investigated with a combination of techniques (NMR, EPR, UV/Vis spectroscopy, X-ray diffraction, magnetic measurements) as well as DFT calculations. All data are in agreement with a high-valent Ni(III) center concentrating the spin density. This markedly differs from precedents in the salen series for which oxidation on the metal was only observed at low temperature or in the presence of additional ligands or anions. Therefore, thanks to the good electron-donating properties of the phosphasalen ligand, [Ni(Psalen)](+) represents a rare example of a tetracoordinated high-valent nickel complex in presence of a phenoxide ligand.

First stabilization of 14-electron rhodium(I) complexes by hemichelation.

Hemichelation is emerging as a new mode of coordination where non-covalent interactions crucially contribute to the cohesion of electron-unsaturated organometallic complexes. This study discloses an unprecedented demonstration of this concept to a Group 9 metal, that is, Rh(I). The syntheses of new 14-electron Rh(I) complexes were achieved by choosing the anti-[(η(6):η(6)-fluorenyl){Cr(CO)3}2] anion as the ambiphilic hemichelating ligand, which was treated with [{Rh(nbd)Cl}2] (nbd=norbornadiene) and [{Rh(CO)2Cl}2]. The new T-shaped Rh(I) hemichelates were characterized by analytical and structural methods. Investigations using the methods of the DFT and electron-density topology analysis (NCI region analysis, QTAIM theory) confirmed the closed-shell, non-covalent and attractive characters of the interaction between the Rh(I) center and the proximal Cr(CO)3 moiety. This study shows that, by appropriate tuning of the electronic properties of the ambiphilic ligand, truly coordination-unsaturated Rh(I) complexes can be synthesized in a manageable form.

Hydrothermal synthesis of (Zr,U)SiO4: an efficient pathway to incorporate uranium into zircon.

The preparation of synthetic (Zr,U)SiO4 solid solution is challenging, as the conventional high-temperature solid-state method limits the solubility of uranium (4 ± 1 mol%) in the orthosilicate phase due to its thermodynamic instability. However, these compounds are of great interest as a result of (Zr,U)SiO4 solid solutions, with uranium contents exceeding this concentration, being observed as corium phases formed during nuclear accidents. It has been identified that hydrothermal synthesis pathways can be used for the formation of the metastable phase, such as USiO4. The investigation carried out in this study has indeed led to the confirmation of metastable (Zr,U)SiO4 compounds with high uranium contents being formed. It was found that (Zr,U)SiO4 forms a close-to-ideal solid solution with uranium loading of up to 60 mol% by means of hydrothermal treatment for 7 days at 250 °C, at pH = 3 and starting from an equimolar reactant concentration equal to 0.2 mol L-1. A purification procedure was developed to obtain pure silicate compounds. After purification, these compounds were found to be stable up to 1000 °C under an inert atmosphere (argon). The characterisation methods used to explore the synthesis and thermal stability included powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) and Raman spectroscopies, scanning electron microscopy (SEM) and thermogravimetric analysis (TGA).

Hemichelation, a way to stabilize electron-unsaturated complexes: the case of T-shaped Pd and Pt metallacycles.

A rational method of synthesis of stable neutral T-shaped 14 electron Pd and Pt complexes is proposed. It takes advantage of the ambiphilic character of the tricarbonyl(η(6)-indenyl)chromium anion, of which the main property is to behave as a hemichelating ligand, that is a nonconventional heteroditopic ligand capable of chelating a metal center by way of covalent and noncovalent bonding, thus preserving its unsaturated valence shell. The reaction of the in situ formed tricarbonyl(η(6)-2-methylindenyl)chromium anion with a series of Pd and Pt metallacycles afforded new air-stable and persistent synfacial heterobimetallic complexes in which the metallacycle binds the indenyl fragment via its metal in an η(1) fashion, leaving the fourth coordination site at the chelated metal virtually vacant. The structures of eight of these novel complexes are disclosed, and their bonding features are investigated by an array of theoretical methods based on the density functional theory (NBO, EDA, ETS-NOCV, AIM, NCI region analysis). Theory shows that the formation of these unusual structures of bimetallic synfacial η(1)-indenyl-Pd/Pt complexes is driven thermodynamically by attractive Coulombic occlusion of the fourth vacant coordination site at Pd/Pt centers by the Cr(CO)3 moiety.