A reciclable bifuctional acid-base organocatalyst with ionic liquid character. The role of sites separation and spatial configuration on different condensation reaction

A series of bifunctional organic catalysts containing acid and basic sites with ionic liquid characteristics have been prepared and their catalytic activity and reaction coordinate for aldol and Knoevenagel condensations have been compared. While the only factor controlling catalyst activity for the Knoevenagel condensation was the distance between the acid and base sites, the spatial orientation of the organocatalyst is also key to achieve high activity and selectivity in the Claisen-Schmidt condensation. Mechanistic studies based on theoretical DFT calculations show that the acid-base bifunctional organocatalyst follows a mechanism inspired in natural aldolases for the synthesis of trans-chalcones, being able to produce a large variety of these compounds of industrial interest. The combination of the acid-base pairs within the proper geometry and the ionic liquid nature makes this catalyst active, selective and recyclable.We thank Consolider-Ingenio 2010 (project MULTICAT), Spanish MICINN (Project MAT2006-14274-C02-01), Generalitat Valenciana (Project PROMETEO/2008/130), and Fundacion Areces for financial support.Corma Canós, A.; Boronat Zaragoza, M.; Climent Olmedo, MJ.; Iborra Chornet, S.; Montón Molina, R.; Sabater Picot, MJ. (2011). A reciclable bifuctional acid-base organocatalyst with ionic liquid character. The role of sites separation and spatial configuration on different condensation reaction. Physical Chemistry Chemical Physics. 13(38):17255-17261. https://doi.org/10.1039/c1cp21986cS17255172611338Motokura, K., Tada, M., & Iwasawa, Y. (2008). Acid-Base Bifunctional Catalytic Surfaces for Nucleophilic Addition Reactions. Chemistry - An Asian Journal, 3(8-9), 1230-1236. doi:10.1002/asia.200800126Gröger, H. (2001). The Development of New Monometallic Bifunctional Catalysts with Lewis acidand Lewis Base Properties, and their Application in Asymmetric Cyanation Reactions. Chemistry - A European Journal, 7(24), 5246-5251. doi:10.1002/1521-3765(20011217)7:243.0.co;2-oKanai, M., Kato, N., Ichikawa, E., & Shibasaki, M. (2005). Recent progress in Lewis acid-Lewis base bifunctional asymmetric catalysis. Pure and Applied Chemistry, 77(12), 2047-2052. doi:10.1351/pac200577122047Shen, Y., Feng, X., Li, Y., Zhang, G., & Jiang, Y. (2003). A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid–Lewis base bifunctional catalyst. Tetrahedron, 59(30), 5667-5675. doi:10.1016/s0040-4020(03)00908-6Kanemasa, S., & Ito, K. (2004). Double Catalytic Activation with Chiral Lewis Acid and Amine Catalysts. European Journal of Organic Chemistry, 2004(23), 4741-4753. doi:10.1002/ejoc.200400277Ma, J.-A., & Cahard, D. (2004). Towards Perfect Catalytic Asymmetric Synthesis: Dual Activation of the Electrophile and the Nucleophile. Angewandte Chemie International Edition, 43(35), 4566-4583. doi:10.1002/anie.200300635Wang, Y., Li, H., Wang, Y.-Q., Liu, Y., Foxman, B. M., & Deng, L. (2007). Asymmetric Diels−Alder Reactions of 2-Pyrones with a Bifunctional Organic Catalyst. Journal of the American Chemical Society, 129(20), 6364-6365. doi:10.1021/ja070859hLin, Y.-M., Boucau, J., Li, Z., Casarotto, V., Lin, J., Nguyen, A. N., & Ehrmantraut, J. (2007). A Lewis Acid−Lewis Base Bifunctional Catalyst from a New Mixed Ligand. Organic Letters, 9(4), 567-570. doi:10.1021/ol0626903Corma, A., Ródenas, T., & Sabater, M. (2010). A Bifunctional Pd/MgO Solid Catalyst for the One-Pot Selective N-Monoalkylation of Amines with Alcohols. Chemistry - A European Journal, 16(1), 254-260. doi:10.1002/chem.200901501Ruiz, V. R., Corma, A., & Sabater, M. J. (2010). New route for the synthesis of benzimidazoles by a one-pot multistep process with mono and bifunctional solid catalysts. Tetrahedron, 66(3), 730-735. doi:10.1016/j.tet.2009.11.048Boronat, M., Climent, M. J., Corma, A., Iborra, S., Montón, R., & Sabater, M. J. (2010). Bifunctional Acid-Base Ionic Liquid Organocatalysts with a Controlled Distance Between Acid and Base Sites. Chemistry - A European Journal, 16(4), 1221-1231. doi:10.1002/chem.200901519Boronat, M., Concepción, P., Corma, A., Navarro, M. T., Renz, M., & Valencia, S. (2009). Reactivity in the confined spaces of zeolites: the interplay between spectroscopy and theory to develop structure–activity relationships for catalysis. Physical Chemistry Chemical Physics, 11(16), 2876. doi:10.1039/b821297jCorma, A., & Renz, M. (2007). A General Method for the Preparation of Ethers Using Water-Resistant Solid Lewis Acids. Angewandte Chemie International Edition, 46(1-2), 298-300. doi:10.1002/anie.200604018Boronat, M., Corma, A., Renz, M., & Viruela, P. M. (2006). Predicting the Activity of Single Isolated Lewis Acid Sites in Solid Catalysts. Chemistry - A European Journal, 12(27), 7067-7077. doi:10.1002/chem.200600478Climent, M. J., Corma, A., De Frutos, P., Iborra, S., Noy, M., Velty, A., & Concepción, P. (2010). Chemicals from biomass: Synthesis of glycerol carbonate by transesterification and carbonylation with urea with hydrotalcite catalysts. The role of acid–base pairs. Journal of Catalysis, 269(1), 140-149. doi:10.1016/j.jcat.2009.11.001Climent, M. J., Corma, A., Iborra, S., Mifsud, M., & Velty, A. (2010). New one-pot multistep process with multifunctional catalysts: decreasing the E factor in the synthesis of fine chemicals. Green Chem., 12(1), 99-107. doi:10.1039/b919660aCorma, A., Iborra, S., & Velty, A. (2007). Chemical Routes for the Transformation of Biomass into Chemicals. Chemical Reviews, 107(6), 2411-2502. doi:10.1021/cr050989dCliment, M. J., Corma, A., & Iborra, S. (2011). Heterogeneous Catalysts for the One-Pot Synthesis of Chemicals and Fine Chemicals. Chemical Reviews, 111(2), 1072-1133. doi:10.1021/cr1002084Koshland, D. E. (1958). Application of a Theory of Enzyme Specificity to Protein Synthesis. Proceedings of the National Academy of Sciences, 44(2), 98-104. doi:10.1073/pnas.44.2.98Bass, J. D., Solovyov, A., Pascall, A. J., & Katz, A. (2006). Acid−Base Bifunctional and Dielectric Outer-Sphere Effects in Heterogeneous Catalysis:  A Comparative Investigation of Model Primary Amine Catalysts. Journal of the American Chemical Society, 128(11), 3737-3747. doi:10.1021/ja057395cVasella, A., Davies, G. J., & Böhm, M. (2002). Glycosidase mechanisms. Current Opinion in Chemical Biology, 6(5), 619-629. doi:10.1016/s1367-5931(02)00380-0Drexler, M. (2003). The effect of solvents on the heterogeneous synthesis of flavanone over MgO. Journal of Catalysis, 214(1), 136-145. doi:10.1016/s0021-9517(02)00013-1Fuentes, A., Marinas, J. M., & Sinisterra, J. V. (1987). Catalyzed synthesis of chalcones under interfacial solid-liquid conditions with ultrasound. Tetrahedron Letters, 28(39), 4541-4544. doi:10.1016/s0040-4039(00)96558-4Climent, M. ., Corma, A., Iborra, S., & Velty, A. (2004). Activated hydrotalcites as catalysts for the synthesis of chalcones of pharmaceutical interest. Journal of Catalysis, 221(2), 474-482. doi:10.1016/j.jcat.2003.09.012Shen, J., Wang, H., Liu, H., Sun, Y., & Liu, Z. (2008). Brønsted acidic ionic liquids as dual catalyst and solvent for environmentally friendly synthesis of chalcone. Journal of Molecular Catalysis A: Chemical, 280(1-2), 24-28. doi:10.1016/j.molcata.2007.10.021Ballesteros, J. F., Sanz, M. J., Ubeda, A., Miranda, M. A., Iborra, S., Paya, M., & Alcaraz, M. J. (1995). Synthesis and Pharmacological Evaluation of 2’-Hydroxychalcones and Flavones as Inhibitors of Inflammatory Mediators Generation. Journal of Medicinal Chemistry, 38(14), 2794-2797. doi:10.1021/jm00014a032Yit, C. C., & Das, N. P. (1994). Cytotoxic effect of butein on human colon adenocarcinoma cell proliferation. Cancer Letters, 82(1), 65-72. doi:10.1016/0304-3835(94)90147-3Becke, A. D. (1993). Density‐functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, 98(7), 5648-5652. doi:10.1063/1.464913Perdew, J. P., & Wang, Y. (1992). Accurate and simple analytic representation of the electron-gas correlation energy. Physical Review B, 45(23), 13244-13249. doi:10.1103/physrevb.45.13244Dewar, M. J. S., & Thiel, W. (1977). Ground states of molecules. 39. MNDO results for molecules containing hydrogen, carbon, nitrogen, and oxygen. Journal of the American Chemical Society, 99(15), 4907-4917. doi:10.1021/ja00457a005Davis, L. P., Guidry, R. M., Williams, J. R., Dewar, M. J. S., & Rzepa, H. S. (1981). MNDO calculations for compounds containing aluminum and boron. Journal of Computational Chemistry, 2(4), 433-445. doi:10.1002/jcc.540020412Hill, H. A. O., Lobb, R. R., Sharp, S. L., Stokes, A. M., Harris, J. I., & Jack, R. S. (1976). Metal-replacement studies in Bacillus stearothermophilus aldolase and a comparison of the mechanisms of class I and class II aldolases. Biochemical Journal, 153(3), 551-560. doi:10.1042/bj153055

Enhancement in hydrophilicity of different polymer phase-inversion ultrafiltration membranes by introducing PEG/Al2O3 nanoparticles

The influence of the modification by additives in the characteristics of several ultrafiltration polymeric membranes was studied. Three asymmetric membranes with similar pore size (molecular weight cutoff (MWCO) of around 30 kDa) but different materials and pore microstructures – polysulfone, polyethersulfone and polyetherimide – were used. Effects of two different hydrophilic additives on membrane structure and the resulting performance were compared to determine the material with the best antifouling properties. Polyethyleneglycol (PEG) and alumina (Al2O3) were employed as additives in the phaseinversion method, N,N-Dimethylacetamide and deionized water were used as solvent and coagulant, respectively. Membranes were characterized in terms of hydraulic permeability, membrane resistance, MWCO profile and hydrophilicity (by membrane porosity and contact angle). The cross-sectional and membrane surface were also examined by microscopic techniques. Membrane antifouling properties were analysed by the experimental study of fouling/rinsing cycles using feed solutions of PEG of 35 kDa. Permeation and morphological studies showed that the addition of PEG/Al2O3 results in formation of a hydrophilic finger-like structure with macrovoids, whereas the addition of Al2O3 results in the formation of a hydrophilic structure with a dense top layer with Al2O3 nanoparticles and a porous sponge-like sublayer. Furthermore, polyethersulfone/PEG/Al2O3 membranes displayed superior antifouling properties and desirable ultrafiltration performance.The authors of this work thank the financial support of CDTI (Centre for Industrial Technological Development) depending on the Spanish Ministry of Science and Innovation. The authors also thank the Center for Biomaterials and Tissue Engineering (Universitat Politecnica de Valencia) for contact angle measurements and BASF (Germany) and General Electric (United States) for supplying the polymers used.García Ivars, J.; Alcaina Miranda, MI.; Iborra Clar, MI.; Mendoza Roca, JA.; Pastor Alcañiz, L. (2014). Enhancement in hydrophilicity of different polymer phase-inversion ultrafiltration membranes by introducing PEG/Al2O3 nanoparticles. Separation and Purification Technology. 128:45-57. doi:10.1016/j.seppur.2014.03.012S455712

Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a−/− cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a−/− cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson’s disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD

Transcription and Chromatin Organization of a Housekeeping Gene Cluster Containing an Integrated β-Globin Locus Control Region

The activity of locus control regions (LCR) has been correlated with chromatin decondensation, spreading of active chromatin marks, locus repositioning away from its chromosome territory (CT), increased association with transcription factories, and long-range interactions via chromatin looping. To investigate the relative importance of these events in the regulation of gene expression, we targeted the human β-globin LCR in two opposite orientations to a gene-dense region in the mouse genome containing mostly housekeeping genes. We found that each oppositely oriented LCR influenced gene expression on both sides of the integration site and over a maximum distance of 150 kilobases. A subset of genes was transcriptionally enhanced, some of which in an LCR orientation-dependent manner. The locus resides mostly at the edge of its CT and integration of the LCR in either orientation caused a more frequent positioning of the locus away from its CT. Locus association with transcription factories increased moderately, both for loci at the edge and outside of the CT. These results show that nuclear repositioning is not sufficient to increase transcription of any given gene in this region. We identified long-range interactions between the LCR and two upregulated genes and propose that LCR-gene contacts via chromatin looping determine which genes are transcriptionally enhanced

Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis

All rights reserved. Visceral leishmaniasis (VL) is one of the most important tropical diseases worldwide. Although chemotherapy has been widely used to treat this disease, problems related to the development of parasite resistance and side effects associated with the compounds used have been noted. Hence, alternative approaches for VL control are desirable. Some methods, such as vector control and culling of infected dogs, are insufficiently effective, with the latter not ethically recommended. The development of vaccines to prevent VL is a feasible and desirable measure for disease control, for example, some vaccines designed to protect dogs against VL have recently been brought to market. These vaccines are based on the combination of parasite fractions or recombinant proteins with adjuvants that are able to induce cellular immune responses, however, their partial efficacy and the absence of a vaccine to protect against human leishmaniasis underline the need for characterization of new vaccine candidates. This review presents recent advances in control measures for VL based on vaccine development, describing extensively studied antigens, as well as new antigenic proteins recently identified using immuno-proteomic techniquesThis work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Rede Nanobiotec/Brasil-Universidade Federal de Uberlândia/CAPES, PRONEX-FAPEMIG (APQ-01019-09), FAPEMIG (CBB-APQ-00819-12 and CBB-APQ-01778-2014), and CNPq (APQ-482976/2012-8, APQ-488237/2013-0, and APQ-467640/2014-9). EAFC and LRG are recipients of the grant from CNPq. MACF is the recipient of grants from FAPEMIG/CAPE

The origins and spread of domestic horses from the Western Eurasian steppes

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: All collapsed and paired-end sequence data for samples sequenced in this study are available in compressed fastq format through the European Nucleotide Archive under accession number PRJEB44430, together with rescaled and trimmed bam sequence alignments against both the nuclear and mitochondrial horse reference genomes. Previously published ancient data used in this study are available under accession numbers PRJEB7537, PRJEB10098, PRJEB10854, PRJEB22390 and PRJEB31613, and detailed in Supplementary Table 1. The genomes of ten modern horses, publicly available, were also accessed as indicated in their corresponding original publications57,61,85-87.NOTE: see the published version available via the DOI in this record for the full list of authorsDomestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 BC. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1