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This paper presents the work carried out within the European project RENAISSANCE-ITN, which was dedicated to the development of innovative polyelectrolytes for energy and environmental applications. Within the project different types of innovative polyelectrolytes were synthesized such as poly(ionic liquid)s coming from renewable or natural ions, thiazolium cations, catechol functionalities or from a new generation of cheap deep eutectic monomers. Further, macromolecular architectures such as new poly(ionic liquid) block copolymers and new (semi)conducting polymer/polyelectrolyte complexes were also developed. As the final goal, the application of these innovative polymers in energy and the environment was investigated. Important advances in energy storage technologies included the development of new carbonaceous materials, new lignin/conducting polymer biopolymer electrodes, new iongels and single-ion conducting polymer electrolytes for supercapacitors and batteries and new poly(ionic liquid) binders for batteries. On the other hand, the use of innovative polyelectrolytes in sustainable environmental technologies led to the development of new liquid and dry water, new materials for water cleaning technologies such as flocculants, oil absorbers, new recyclable organocatalyst platforms and new multifunctional polymer coatings with antifouling and antimicrobial properties. All in all this paper demonstrates the potential of poly(ionic liquid)s for high-value applications in energy and enviromental areas. © 2017 Society of Chemical Industry

Combining the redox activity and remarkable adhesion propensity of polyphenols (such as catechol or pyrogallol) with the numerous tunable properties of poly(ionic liquid)s (PILs) is an attractive route to design inventive multifunctional macromolecular platforms. In this contribution, we describe the first synthesis of a novel family of structurally well-defined PILs functionalized with catechol/pyrogallol/phenol pendants by organometallic-mediated radical polymerization (OMRP) using an alkyl–cobalt(III) complex as initiator and mediating agent. The living character of the chains is also exploited to produce di- and triblock PILs, and the facile counteranion exchange reactions afforded a library of PILs-bearing free phenol/catechol/pyrogallol moieties. Electrochemical investigations of catechol/pyrogallol-derived PILs in aqueous medium demonstrated the characteristic catechol to o-quinone transformations, whereas, quasi-reversible doping/undoping with supporting electrolyte cations (Li+/tetrabutylammonium...

Cobalt-mediated radical polymerization (CMRP) of vinyl acetate (VAc) is successfully achieved in supercritical carbon dioxide (scCO2). CMRP of VAc is conducted using an alkyl-cobalt(III) adduct that is soluble in scCO2. Kinetics studies coupled to visual observations of the polymerization medium highlight that the melt viscosity and PVAc molar mass (Mn) are key parameters that affect the CMRP in scCO2. It is noticed that CMRP is controlled for Mn up to 10 000 g mol(-1), but loss of control is progressively observed for higher molar masses when PVAc precipitates in the polymerization medium. Low molar mass PVAc macroinitiator, prepared by CMRP in scCO2, is then successfully used to initiate the acrylonitrile polymerization. PVAc-b-PAN block copolymer is collected as a free flowing powder at the end of the process although the dispersity of the copolymer increases with the reaction time. Although optimization is required to decrease the dispersity of the polymer formed, this CMRP process opens new perspectives for macromolecular engineering in scCO2 without the utilization of fluorinated comonomers or organic solvents.

International audience; Nanogels of controlled kinetic chain length were synthesized by cobalt-mediated radical cross-linking copolymerization (CMRccP) involving a vinyl monomer and a divinyl cross-linker. This strategy was first validated to achieve neutral poly(vinyl acetate) nanogels by CMRccP of vinyl acetate and divinyl adipate as a cross-linker at 40 degrees C in the presence of an alkyl-cobalt(III) serving both as an initiator and a controlling agent using ethyl acetate as a solvent. Poly(ionic liquid) nanogels were then directly obtained by CMRccP of N-vinyl-3-ethyl imidazolium bromide in the presence of 1,13-divinyl-3-decyl diimidazolium bromide as a cross-linker. CMRccP experiments could be conducted either in an organic solvent using dimethyl formamide or, more interestingly, in aqueous solution, demonstrating the robustness and versatility of this one-step process. Chain extensions of PIL nanogels were also carried out in water, forming core-shell structures, thus opening new avenues in the design of functional nanogels.

International audience; The organometallic-mediated radical polymerization (OMRP) of N-vinyl-3-alkylimidazolium-type monomers, featuring the bis(trifluoromethylsulfonyl)imide counter-anion (Tf2N-) in the presence of Co(acac)(2) as controlling agent, is reported. Polymerizations of monomers with methyl, ethyl, and butyl substituents are fast, reaching high monomer conversion in ethyl acetate as solvent at 30 degrees C, and afford structurally well-defined hydrophobic poly(ionic liquid)s (PILs) of N-vinyl type. Block copolymer synthesis is also achieved by sequential OMRP of N-vinyl-3-alkyldazolium salts carrying different alkyl chains and different counteranions (Tf2N- or Br-). These block copolymerizations are carried out at 30 degrees C, either under homogeneous solution in methanol or in a biphasic medium consisting of a mixture of ethyl acetate and water. Unprecedented PIL-b-PIL block copolymers are thus prepared under these conditions. However, anion exchange occurs at the early stage of the growth of the second block. Finally, diblock copolymers generated in the biphasic medium can be readily coupled by addition of isoprene, forming all PIL-based and symmetrical ABA-type triblock copolymers in a one-pot process. Such a direct block copolymerization method, involving vinylimidazolium monomers bearing different alkyl chains, thus opens new opportunities in the precision synthesis of all PIL-based block copolymers of tunable properties.

Poly(ionic liquid)s (PILs) have attracted considerable attention as innovative single-ion solid polyelectrolytes (SPEs) in substitution to the more conventional electrolytes for a variety of electrochemical devices. Herein, we report the precise synthesis, characterization, and use as single-ion SPEs of a novel double PIL-based amphiphilic diblock copolymer (BCP), i.e., where all monomer units are of N-vinyl-imidazolium type, with triethylene glycol pendant groups in the first block and a statistical distribution of N-vinyl-3-ethyl- and N-vinyl-3-perfluorooctyl-imidazolium bromides in the second block. BCP synthesis is achieved directly in water by a one-pot process, by cobalt-mediated radical polymerization-induced self-assembly (CMR-PISA). A subsequent anion exchange reaction substituting bis(trifluoromethylsulfonyl)imide (Tf2N–) for bromide (Br–) counter-anions leads to PIL BCPs with two different lengths of the first block. They demonstrate ionic conductivity σDC = 1–3 × 10–7 S cm–1, as determined by ...

Rationale: The impact of diabetes mellitus on bone marrow (BM) structure is incompletely understood. Objective: Investigate the effect of type-2 diabetes mellitus (T2DM) on BM microvascular and hematopoietic cell composition in patients without vascular complications. Methods and Results: Bone samples were obtained from T2DM patients and nondiabetic controls (C) during hip replacement surgery and from T2DM patients undergoing amputation for critical limb ischemia. BM composition was assessed by histomorphometry, immunostaining, and flow cytometry. Expressional studies were performed on CD34 pos immunosorted BM progenitor cells (PCs). Diabetes mellitus causes a reduction of hematopoietic tissue, fat deposition, and microvascular rarefaction, especially when associated with critical limb ischemia. Immunohistochemistry documented increased apoptosis and reduced abundance of CD34 pos -PCs in diabetic groups. Likewise, flow cytometry showed scarcity of BM PCs in T2DM and T2DM+critical limb ischemia compared with C, but similar levels of mature hematopoietic cells. Activation of apoptosis in CD34 pos -PCs was associated with upregulation and nuclear localization of the proapoptotic factor FOXO3a and induction of FOXO3a targets, p21 and p27 kip1 . Moreover, microRNA-155, which regulates cell survival through inhibition of FOXO3a, was downregulated in diabetic CD34 pos -PCs and inversely correlated with FOXO3a levels. The effect of diabetes mellitus on anatomic and molecular end points was confirmed when considering background covariates. Furthermore, exposure of healthy CD34 pos -PCs to high glucose reproduced the transcriptional changes induced by diabetes mellitus, with this effect being reversed by forced expression of microRNA-155. Conclusions: We provide new anatomic and molecular evidence for the damaging effect of diabetes mellitus on human BM, comprising microvascular rarefaction and shortage of PCs attributable to activation of proapoptotic pathway.

International audience; Amphiphilic double poly(ionic liquid) (PIL) block copolymers are directly prepared by cobaltmediated radical polymerization induced self-assembly (CMR-PISA) in water of N-vinyl imidazolium monomers carrying distinct alkyl chains. The cobalt-mediated radical polymerization of N-vinyl-3-ethyl imidazolium bromide (VEtImBr) is first carried out until high conversion in water at 30 degrees C, using an alkyl bis(acetylacetonate) cobalt(III) adduct as initiator and controlling agent. The as-obtained hydrophilic poly(N-vinyl-3ethyl imidazolium bromide) (PVEtImBr) is then used as a macroinitiator for the CMR-PISA of N-vinyl-3-octyl imidazolium bromide (VOcImBr). Self-assembly of the amphiphilic PVEtImBr-b-PVOcImBr block copolymer, i.e., of PIL-b-PIL-type, rapidly takes place in water, forming polymer nanoparticles consisting of a hydrophilic PVEtImBr corona and a hydrophobic PVOcImBr core. Preliminary investigation into the effect of the size of the hydrophobic block on the dimension of the nanoparticles is also described.

International audience; A novel photoinitiator based on a spiroxanthene scaffold in the presence of an iodonium salt is proposed for the cationic ring-opening polymerization of a diepoxide, as well as for the free-radical polymerization of an acrylate upon violet LED exposure (385 and 405 nm). Good-to-excellent rates of polymerization and final conversions are obtained. These systems are characterized by a higher reactivity compared with that of anthracene/iodonium salt used as reference for cationic near UV polymerization. The addition of a poly(ionic liquid) improves the cationic polymerization profiles. The photochemical mechanisms are studied by steady-state photolysis, fluorescence, and electron spin resonance spin-trapping techniques. Molecular orbital calculations give an insight into the light absorption properties. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43213

Rationale: Homing of proangiogenic cells (PACs) is guided by chemoattractants and requires proteases to disrupt the extracellular matrix. The possibility that PAC recruitment involves an interaction between proteases and chemotactic factor receptors remains largely unexplored. Objective: To determine the role of human tissue kallikrein (hK1) in PAC invasion and its dependency on kinin receptor signaling. Methods and Results: Human mononuclear cells (MNCs) and culture-selected PACs express and release mature hK1 protein. HK1 gene ( KLK1 ) silencing reduced PACs migratory, invasive, and proangiogenic activities. KLK1 -knockout mouse bone marrow–derived MNCs showed similar impairments and were unable to support reparative angiogenesis in a mouse model of peripheral ischemia. Conversely, adenovirus-mediated KLK1 ( Ad.KLK1 ) gene transfer enhanced PAC-associated functions, whereas the catalytically inactive variant R53H-KLK1 was ineffective. HK1-induced effects are mediated by a kinin B 2 receptor (B 2 R)-dependent mechanism involving inducible nitric oxide synthase and metalloproteinase-2 (MMP2). Lower hK1 protein levels were observed in PACs from type 2 diabetic (T2D) patients, whereas KLK1 mRNA levels were similar to those of healthy subjects, suggesting a post-transcriptional defect. Furthermore, B 2 R is normally expressed on T2D-PACs but remains uncoupled from downstream signaling. Importantly, whereas Ad.KLK1 alone could not restore T2D-PAC invasion capacity, combined KLK1 and B 2 R expression rescued the diabetic phenotype. Conclusions: This study reveals new interactive components of the PACs invasive machinery, acting via protease- and kinin receptor–dependent mechanisms.

Novel organocobalt complexes featuring weak C-CoL2 bonds (L = acetylacetonate) are prepared and used as sources of halomethyl radicals. They permit the precision synthesis of α-halide functionalized and telechelic polymers in organic media or in water. Substitution of halide by azide allows derivatization of polymers using the CuAAC click reaction.

We demonstrate electrically and ionically conducting nacre-mimetic nanocomposites prepared using self-assembly of synthetic nanoclay in combination with PEDOT:PSS and a poly(ionic liquid) polymer from aqueous dispersions. The resulting nacre-mimetics show high degrees of mesoscale order and combine high stiffness and high strength. In terms of conductivities, the resulting hybrids exceed simple additive behavior and display synergetic conductivities due to high levels of interfaces and anisotropic conductivity pathways. The approach highlights the integration of relevant functionalities into stiff and strong bioinspired materials, and shows that synergetic properties beyond mechanical performance can be realized in advanced multifunctional nanocomposites using nacre-inspired design principles.

Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted nonconservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.

Statolith and gladius were investigated for their suitability as tools for age and growth studies in the loliginid squid Loligo plei off southern Brazil. Statoliths when polished, revealed a series of concentric increments deposited around a nucleus. Consistent increment counts covered the squid's entire life-time and could be considered suitable for individual age estimation. Growth increments were observed on the dorsal surface as delimited by consecutive marks formed during low growth periods. Because early growth was masked during chitin deposition, total increment counts underestimated individual age. Gladius growth was highly correlated with somatic growth, and gladius increments could be used to reconstruct individual growth histories. Both statolith and gladius increments were deposited with the same, possibly daily, periodicity. It could be inferred that L. plei off southern Brazil might live up to around nine months of age.Foi avaliada a viabilidade do estatólito e do gladius como ferramentas para estudos de idade e crescimento da lula loliginídea Loligo plei no sul do Brasil. Estatólitos são estruturas calcificadas que, após polimento, revelaram uma serie de incrementos concêntricos depositados em torno de um núcleo. Contagens consistentes desses incrementos cobriram toda a vida do animal e puderam ser consideradas apropriadas para a estimativa de idade desse organismo. O gladius é a concha interna que cresce pela deposição longitudinal de camadas de quitina. Incrementos foram observados na superfície dorsal, delimitados por consecutivas marcas formadas durante períodos de crescimento lento. Ao longo da deposição de quitina o crescimento do início da vida é progressivamente mascarado fazendo com que as contagens de incrementos totais subestimem a idade da lula. Devido ao crescimento do gladius correlacionar-se fortemente com o crescimento somático, os incrementos puderam ser utilizados para a reconstrução do crescimento. Os incrementos do estatólito e do gladius foram depositados com a mesma, possivelmente diária, periodicidade. Infere-se que L. plei no sul do Brasil possa atingir até cerca de 9 meses de vida.

International audience; The precision synthesis of poly(ionic liquid)s (PILs) in water is achieved for the first time by the cobalt-mediated radical polymerization (CMRP) of N-vinyl-3-alkylimidazolium-type monomers following two distinct protocols. The first involves the CMRP of various 1-vinyl-3-alkylimidazolium bromides conducted in water in the presence of an alkyl cobalt(III) complex acting as a monocomponent initiator and mediating agent. Excellent control over molar mass and dispersity is achieved at 30 degrees C. Polymerizations are complete in a few hours, and PIL chain-end fidelity is demonstrated up to high monomer conversions. The second route uses the commercially available bis(acetylacetonato)cobalt(II) (Co(acac)2) in conjunction with a simple hydroperoxide initiator (tertbutyl hydroperoxide) at 30, 40, and 50 degrees C in water, facilitating the scaling-up of the technology. Both routes prove robust and straightforward, opening new perspectives onto the tailored synthesis of PILs under mild experimental conditions in water.

Context: Heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance, characterized by isolated nonautoimmune hyperthyrotropinemia (NAHT). The prevalence and management of this condition is controversial. Objective: Our objective was to investigate the prevalence and clinical impact of TSHR alterations in a large series of pediatric patients with NAHT and to dissect their mechanism of action. Design and Setting: For this prospective multicenter study, clinical data and samples were collected in the clinical units and conveyed to a centralized laboratory for analysis. Patients: Subjects included 153 unrelated patients with NAHT aged G), and five novel missense (p.P162L, p.Y466C, p.I583T, p.I607T, and p.R609Q) variations. The missense variations variably affected TSHR membrane expression and G(s) and/or Gq/11 signaling. Several variations cosegregated with NAHT in the affected families. Parameters of thyroid function were similar between affected and unaffected family members. Conclusions: Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT. The identification of TSHR defects may thus be helpful for a tailored management of subclinical hypothyroidism. We provide further evidence that besides the well-known defects in G(s) signaling, TSHR genetic alternations found in NAHT may frequently impair the Gq/11 pathway. (J Clin Endocrinol Metab 97: E156-E160, 2012)

ContextMost germline-activating mutations of theRETproto-oncogene associated with inherited medullary thyroid cancer (MTC) are localized in exons 10, 11 and 13–15. Four novelRETvariants, located in the extracellular domain (p.A510V, p.E511K and p.C531R) coded by exon 8 and in the intracellular juxtamembrane region (p.K666N) coded by exon 11, were identified on the leukocyte DNA from apparently sporadic cases.MethodsPlasmids carrying Ret9-wild-type (Ret9-WT), Ret9-C634R and all Ret9 variants were transfected, and the phosphorylation levels of RET and ERK were evaluated by western blot analyses. The transforming potentials were assessed by the focus formation assay.ResultsThe p.A510V, p.E511K and p.C531R variants were found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of Ret9-WT variant, but lower than that of Ret9-C634R variant. Differently, the p.K666N variant, located immediately downstream of the transmembrane domain, and involving a conserved residue, displayed high kinase and transforming activities. Computational analysis predicted non-conservative alterations in the mutant proteins consistent with putative modifications of the receptor conformation.ConclusionsThe molecular analyses revealed an oncogenic potential for all the novel germlineRETvariants. Therefore, the prevalence of exon 8 genomic variations with an oncogenic potential may be higher than previously thought, and the analysis of this exon should be considered after the exclusion of mutations in the classical hotspots. In addition, on the basis of these functional data, it is advisable to extend the genetic screening to all the first-degree relatives of the MTC patients, and to perform a strict follow-up of familial carriers.

The resistance to thyrotropin (TSH) action is the disease associated with molecular defects hampering the adequate transmission of TSH stimulatory signal into thyroid cells. The defect may in principle affect every step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes. After the description of the first family affected with loss-of-function (LOE) TSHR mutations in 1995, there is now evidence that TSH resistance is a disease with a broad range of expressivity going from severe congenital hypothyroidism (CH) with thyroid hypoplasia to mild hyperthyrotropinemia (hyperTSH) associated with an apparent euthyroid state. More severe forms occur in patients with disrupting biallelic TSHR mutations and follow a recessive pattern of inheritance. Differential diagnosis in these cases includes the exclusion of other causes of thyroid dysgenesis, such as mutations in thyroid transcription factors. More mild forms may instead occur in patients with monoallelic TSHR defects following a dominant mode of inheritance. In these cases we described the dominant negative effect exerted by some LOF mutants on the activity of the wild-type TSHR. Differential diagnosis involves the exclusion of mild hypothyroidism in autoimmune thyroid disease or pseudohypoparathyroidism associated with genetic or epigenetic defects at the GNAS locus. This review will focus on the prevalence of TSHR mutations, on the molecular mechanisms leading to TSH resistance and on the variable clinical expression of this disease. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Summary Background Highly discrepant data about the different distribution of RET germline single nucleotide polymorphisms (SNPs) among patients with sporadic medullary thyroid cancer (sMTC) and controls are available. Design and patients In the present case-control study, a wide panel of seven RET SNPs has been tested in the largest sMTC series and in a matched control group. Results None of the investigated polymorphisms show a significantly different distribution in patients with sMTC when compared to controls. Twenty haplotypes and 57 genotypes were generated, and their association with the disease and with the clinical features were statistically evaluated. Interestingly, 14 genotypes were found to be unique to sMTC patients and 25 to controls. Two haplotypes and three genotypes, all including the intronic variants IVS1-126 and IVS14-24, were significantly associated with sMTC patients and with a higher tumour aggression. The functional activity of the only nonsynonymous RET variant (c.2071C > A, G691S) was tested for the first time. Interestingly, Western blot analyses showed that the fraction of Ret9-G691S protein located at the plasma membrane level was overrepresented when compared to Ret9-WT, suggesting facilitated targeting at the cell membrane for this variant. However, no transforming activity was shown in a focus formation assay on cells carrying the Ret9-G691S, against a possible oncogenic role of G691S variant. Conclusions RET genotypes including two intronic RET variants were associated with the risk of developing sMTC and to more aggressive behaviour. Further studies are warranted to elucidate whether these RET genotypes are in linkage disequilibrium with another susceptibility gene or whether these variants could play a role in the genesis of sMTC per se.

Population structure and reproductive patterns of the long-finned squid Loligo plei off the coast of Santa Catarina, southern Brazil, were analysed from the biological samples of commercial catches landed in the Itajai harbour from April 1995 to February 1998. The species were recruited to the trawl fishery at 130 mm mantle length (ML) and males were, on average, nearly 1.3 times larger than females. The exponents of males and females ML–weight relationships were 1.89 and 2.07, respectively, and differed significantly between maturity stages. Cohorts of both sexes did not persist into their second year, a feature that, coupled with the scarcity of spent animals, provided evidence for semelparity with nearly 1 year life span. An extended seasonal breeding and spawning pattern was characterised with a large reproduction event concentrated during the summer months extending through autumn and winter. It is suggested that the summer spawners hatch during the summer–early autumn, recruit to the fishery in the spring and reach maturity in the following summer, at the age of nearly 1 year. Squid spawned during the winter will hatch during winter–early spring, recruit to the fishery during the summer and autumn and spawn in their second winter. Between summer and winter spawning events, continuous spawning activity produce several microcohorts detected in trawlers catch. Summer spawners sustain the most important commercial concentrations. The relationship between L. plei population structure, seasonal abundance and the dynamics of environmental conditions off southern Brazil is discussed.