Phosphonate Decomposition-Induced Polyoxomolybdate Dumbbell-Type Cluster Formation: Structural Analysis, Proton Conduction, and Catalytic Sulfoxide Reduction

The reaction of MoO4^2− with a number of phosphonic acids [bis-(phosphonomethyl)glycine, R,S-hydroxyphosphonoacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, phenylphosphonic acid, aminotris(methylene phosphonic acid), and 1,2- ethylenediphosphonic acid] under oxidizing (H2O2) hydrothermal conditions at low pH leads to rupture of the P−C bond, release of orthophosphate ions, and generation of the octanuclear, phosphate-bridged, polyoxometalate molybdenum cluster (NH4)5[Mo8(OH)2O24(μ8-PO4)](H2O)2 (POMPhos). This cluster has been fully characterized and its structure determined. It was studied as a proton conductor, giving moderate values of σ = 2.13 × 10−5 S·cm−1 (25 °C) and 1.17 × 10−4 S·cm−1 (80 °C) at 95% relative humidity, with Ea = 0.27 eV. The POMPhos cluster was then thermally treated at 310 °C, yielding (NH4)2.6(H3O)0.4(PO4Mo12O36) together with an amorphous impurity containing phosphate and molybdenum oxide. This product was also studied for its proton conductivity properties, giving rise to an impressively high value of σ = 2.43 × 10−3 S· cm−1 (25 °C) and 6.67 × 10−3 S·cm−1 (80 °C) at 95% relative humidity, 2 orders of magnitude higher than those corresponding to the “as-synthesized” solid. The utilization of POMPhos in catalytic reduction of different sulfoxides was also evaluated. POMPhos acts as an efficient homogeneous catalyst for the reduction of diphenyl sulfoxide to diphenyl sulfide, as a model reaction. Pinacol was used as a low-cost, environmentally friendly, and highly efficient reducing agent. The effects of different reaction parameters were investigated, namely the type of solvent and reducing agent, presence of acid promoter, reaction time and temperature, loading of catalyst and pinacol, allowing to achieve up to 84−99% yields of sulfide products under optimized conditions. Substrate scope was tested on the examples of diaryl, alkylaryl, dibenzyl, and dialkyl sulfoxides and excellent product yields were obtained.Proyecto MAT2016-77648-R del MINECO y proyectos P12-FQM-1656 y FQM-113 de la Junta de Andalucí

Identification of genes in trinucleotide repeat RNA toxicity pathways in C. elegans

Myotonic dystrophy disorders are caused by expanded CUG repeats in non-coding regions. To reveal mechanisms of CUG repeat pathogenesis we used C. elegans expressing CUG repeats to identify gene inactivations that modulate CUG repeat toxicity. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and modulate formation of nuclear RNA foci by CUG repeats. These genes regulated CUG repeat-induced toxicity through distinct mechanisms including RNA export and RNA clearance, suggesting that CUG repeat toxicity is mediated by multiple pathways. A subset is shared with other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway plays a conserved role regulating CUG repeat RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3′UTR GC nucleotide content. Our studies suggest a broader surveillance role for NMD where variations in this pathway influence multiple degenerative diseases

Imidazole-containing Co2+ and Ni2+ etidronates: crystal structures and electrochemical behaviour

Proyecto Nacional PID2019-110249RB-I00, PAIDI2020 de la Junta de Andalucia, Ayudas del Plan Propio de Investigación de la Universidad de Málaga para la contratación predoctoral (PRE2020-094459).Metal phosphonates-based coordination polymers (CPs) are known to exhibit versatile structural diversity and functionality. Thus, they have been used, among other applications, as electrocatalyst precursors for both, PEMFCs and electrolysers. In this work, we report the synthesis, crystal structure and electrochemical properties of imidazole-containing Co2+, Ni2+ and Zn2+ derivatives of the etidronic acid, (HO)2P(O)-C(CH3)(OH)-P(O)(OH)2 (ETID). Analyses of the crystal structures reveals that these solids are 1D, in which the imidazole molecules form part of the coordination sphere of the cations (Co2+, Ni2+) or act as charge-compensating imidazolium cations (Zn2+). Co2+ and Ni2+ solids were pyrolysed under 5% H2/Ar atmosphere at different temperatures. The resulting metal phosphides were tested as electrocatalysts for the Oxygen Evolution and Reduction Reactions (OER and ORR, respectively) and the Hydrogen Evolution Reaction (HER). Preliminary results indicate that Co2+ derivatives exhibit better performance.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Three-Component Copper-Phosphonate-Auxiliary Ligand Systems: Proton Conductors and Efficient Catalysts in Mild Oxidative Functionalization of Cycloalkanes

The synthesis, structural characterization, topological analysis, proton conductivity, and catalytic properties are reported of two Cu(II)-based compounds, namely a dinuclear Cu(II) complex [Cu2(μ-VPA)2(phen)2(H2O)2]· 8H2O (1) (H2VPA = vinylphosphonic acid, phen = 1,10- phenanthroline) and a 1D coordination polymer [Cu(μ- SO4)(phen)(H2O)2]∞ (2). Their structural features and Hbonding interactions were investigated in detail, showing that the metal−organic structures of 1 and 2 are extended by multiple hydrogen bonds to more complex 2D or 1D Hbonded architectures with the kgd [Shubnikov plane net (3.6.3.6)/dual] and SP 1-periodic net (4,4)(0,2) topology, respectively. These nets are primarily driven by the H-bonding interactions involving water ligands and H2O molecules of crystallization; besides, the (H2O)4/(H2O)5 clusters were identified in 1. Both 1 and 2 are moderate proton conductors, with proton conductivity values, σ = 3.65 × 10−6 and 3.94 × 10−6 S·cm−1, respectively (measured at 80 °C and 95% relative humidity). Compounds 1 and 2 are also efficient homogeneous catalysts for the mild oxidative functionalization of C5−C8 cycloalkanes (cyclopentane, cyclohexane, cycloheptane, and cyclooctane), namely for the oxidation by H2O2 to give cyclic alcohols and ketones and the hydrocarboxylation by CO/H2O and S2O82− to the corresponding cycloalkanecarboxylic acids as major products. The catalytic reactions proceed under mild conditions (50−60 °C) in aqueous acetonitrile medium, resulting in up to 34% product yields based on cycloalkane substrate.Proyecto MAT2016-77648-R del MINECO y proyecto FQM-1656 de la Junta de Andalucí

Exploiting the Multifunctionality of M2+/Imidazole-Etidronates for Proton Conductivity (Zn2+) and Electrocatalysis (Co2+, Ni2+) toward the HER, OER, and ORR

This work deals with the synthesis and characterization of one-dimensional (1D) imidazole-containing etidronates, [M(ETID)(Im)]·nHO (M = Co and Ni; n = 0, 1, 3) and [Zn(ETID)(HO)](Im), as well as the corresponding Co/Ni solid solutions, to evaluate their properties as multipurpose materials for energy conversion processes. Depending on the water content, metal ions in the isostructural Co and Ni derivatives are octahedrally coordinated (n = 3) or consist of octahedral together with dimeric trigonal bipyramidal (n = 1) or square pyramidal (n = 0) environments. The imidazole molecule acts as a ligand (Co, Ni derivatives) or charge-compensating protonated species (Zn derivative). For the latter, the proton conductivity is determined to be ∼6 × 10 S·cm at 80 °C and 95% relative humidity (RH). By pyrolyzing in 5%H-Ar at 700-850 °C, core-shell electrocatalysts consisting of Co-, Ni-phosphides or Co/Ni-phosphide solid solution particles embedded in a N-doped carbon graphitic matrix are obtained, which exhibit improved catalytic performances compared to the non-N-doped carbon materials. Co phosphides consist of CoP and CoP in variable proportions according to the used precursor and pyrolytic conditions. However, the Ni phosphide is composed of NiP exclusively at high temperatures. Exploration of the electrochemical activity of these metal phosphides toward the oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and hydrogen evolution reaction (HER) reveals that the anhydrous Co(ETID)(Im) pyrolyzed at 800 °C (CoP/CoP = 80/20 wt %) is the most active trifunctional electrocatalyst, with good integrated capabilities as an anode for overall water splitting (cell voltage of 1.61 V) and potential application in Zn-air batteries. This solid also displays a moderate activity for the HER with an overpotential of 156 mV and a Tafel slope of 79.7 mV·dec in 0.5 M HSO. Ni- and Co/Ni-phosphide solid solutions show lower electrochemical performances, which are correlated with the formation of less active crystalline phases.A.V.-C. thanks MICIU for PRE2020-094459 student grant; M.B.-G. thanks PAIDI2020-DOC_00272 research grant (Junta de Andalucia, Spain) and R.M.P.C. thanks University of Malaga under Plan Propio de Investigación for financial support. Funding for open access charge: Universidad de Málaga/CBUA. The work at UMA was funded by PID2019-110249RB-I00 (MICIU/AEI, Spain) and PY20-00416 (Junta de Andalucia, Spain/FEDER) research projects. D.C.-L. acknowledges funding by project no. PGC2018-102047-B-I00 (MICIU/AEI/FEDER, UE). The work at UoC was funded by the Special Account of Research, Program Innovative Materials and Applications INNOVAMAT, KA 10694

Exploiting the Multifunctionality of M2+/Imidazole−Etidronates for Proton Conductivity (Zn2+) and Electrocatalysis (Co2+, Ni2+) toward the HER, OER, and ORR

This work deals with the synthesis and characterization of one-dimensional (1D) imidazole-containing etidronates, [M2(ETID)(Im)3]·nH2O (M = Co2+ and Ni2+; n = 0, 1, 3) and Zn2(ETID)2(H2O)2](Im)2, as well as the corresponding Co2+/Ni2+ solid solutions. Depending on the water content, metal ions in the isostructural Co2+ and Ni2+ derivatives are octahedrally coordinated (n = 3) or consist of octahedral together with dimeric trigonal bipyramidal (n = 1) or square pyramidal (n = 0) environments. The imidazole molecule acts as a ligand (Co2+, Ni2+ derivatives) or charge-compensating protonated species (Zn2+ derivative). For the latter, the proton conductivity is determined to be ∼6 × 10−4 S·cm−1 at 80 °C and 95% relative humidity (RH). By pyrolyzing in 5%H2−Ar at 700−850 °C, core−shell electrocatalysts consisting of Co2+-, Ni2+-phosphides or Co2+/Ni2+-phosphide solid solution particles embedded in a N-doped carbon graphitic matrix are obtained, which exhibit improved catalytic performances compared to the non-N-doped carbon materials. Co2+ phosphides consist of CoP and Co2P in variable proportions according to the used precursor and pyrolytic conditions. However, the Ni2+ phosphide is composed of Ni2P exclusively at high temperatures. Exploration of the electrochemical activity of these metal phosphides toward the OER, ORR, and HER reactions reveals that the anhydrous Co2(ETID)(Im)3 pyrolyzed at 800 °C (CoP/Co2P = 80/20 wt %) is the most active trifunctional electrocatalyst, with good integrated capabilities as an anode for overall water splitting (cell voltage of 1.61 V) and potential application in Zn−air batteries. This solid also displays a moderate activity for the HER with an overpotential of 156 mV and a Tafel slope of 79.7 mV·dec−1 in 0.5 M H2SO4. Ni2+- and Co2+/Ni2+-phosphide solid solutions show lower electrochemical performances, which are correlated with the formation of less active crystalline phases.The work at UMA was funded by PID2019-110249RB-I00 (MICIU/AEI, Spain) and PY20-00416 (Junta de Andalucia, Spain/FEDER) research projects. A.V.-C. thanks MICIU for PRE2020-094459 student grant; M.B.-G. thanks PAIDI2020-DOC_00272 research grant (Junta de Andalucia, Spain) and R.M.P.C. thanks University of Malaga under Plan Propio de Investigación for financial support. Funding for open access charge: Universidad de Málaga/CBUA (PMCID# PMC8915163

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis

The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date

CuII Frameworks from Di-2-pyridyl Ketone and Benzene-1,3,5-triphosphonic Acid

In our effort to develop new synthetic strategies for the isolation of new phosphonate frameworks, we exploited the possibility of simultaneously utilizing benzene-1,3,5-triphosphonic acid (H(6)btp) and di-2-pyridyl ketone (py(2)CO), which is a major player in the field of polynuclear metal complexes. This ligand blend in Cu-II chemistry afforded a 2D framework comprising tetranuclear [Cu-4(II)] secondary building units. A thorough investigation of the Cu-II/di-2-pyridyl ketone/benzene-1,3,5-triphosphonic acid reaction system also revealed a hydrogen-bonded framework. The structure of the latter comprises the cationic [Cupy(2)C(OH)(2)(2)](2+) complex [py(2)C(OH)(2) is the hydrate of py(2)CO], the dianion of benzene-1,3,5-triphosphonic acid (H(4)btp(2-)) and water solvates. The magnetic properties of the coordination polymer were rationalized on the basis of magnetically isolated [Cu-4(II)] units dominated by antiferromagnetic interactions

Structural Systematics and Topological Analysis of Coordination Polymers with Divalent Metals and a Glycine-Derived Tripodal Phosphonocarboxylate

A novel family of four hybrid metal phosphonate coordination polymers is reported that are constructed from divalent metal ions (Ca, Sr, Ba, and Pb) and <b>BPMGLY</b> (bis-phosphonomethylglycine, a phosphonated derivative of glycine). These compounds (and their compositions) are <b>Ca-BPMGLY</b> (CaBPMGLY·H₂O), <b>Sr-BPMGLY</b> (SrBPMGLY·H₂O), <b>Ba-BPMGLY</b> (Ba_3.5(BPMGLY)₂·6H₂O), and <b>Pb-BPMGLY</b> (PbBPMGLY·H₂O). They were obtained by hydrothermal reactions in acidic aqueous solutions (pH range 2.3–5.7) and fully characterized by physicochemical methods and structural analysis. <b>Ca-BPMGLY</b>, <b>Sr-BPMGLY</b>, and <b>Pb-BPMGLY</b> have very similar 3D coordination polymer structures, and the latter two are isostructural. In contrast to the Ca, Sr, and Pb analogs, <b>Ba-BPMGLY</b> possesses a different 2D layered network. These four new compounds, together with our previously reported 2D coordination polymer <b>Mg-BPMGLY</b> (MgBPMGLY·2H₂O, Demadis et al.<i> Inorg. Chem.</i> <b>2012</b>, 51, 7889–7896), were topologically classified revealing (i) the uninodal 3-connected net with the <b>hcb</b> topology in <b>Mg-BPMGLY</b>, (ii) the uninodal 5-connected nets with the <b>bnn</b> and <b>vbj</b> topology in <b>Ca-BPMGLY</b> and <b>Sr-BPMGLY</b>, respectively, and (iii) the very complex topologically unique hexanodal 4,4,6,6,7,8-connected net in <b>Ba-BPMGLY</b>. The <b>vbj</b> topology was also identified in the related <b>Pb-BPMGLY</b> 3D framework. These topological features show that the complexity of BPMGLY-driven 2D and 3D metal–organic networks increases periodically following the Mg < Ca ≤ Sr ≪ Ba trend