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8. Large outbreaks of Ips acuminatus in Scots pine stands of the Italian Alps

Author

D’Ambros E, Battisti A, Finozzi V, Dal Pont C, Colombari F, and Faccoli M

Subjects
Ips acuminatus, Scots pine, Pine decline, Bark beetles, Mass-trapping, Sanitation felling, Forestry, SD1-669.5
Abstract

In the last years, many Scots pine (Pinus sylvestris) stands have been severely attacked by the bark beetle Ips acuminatus (Coleoptera Curculionidae Scolytinae). In the outbreak area of San Vito di Cadore (Eastern Dolomites), the number of attacked trees since 2005 and both the emergence of bark beetles and natural enemies have been assessed. The investigated forests showed dozens of easily recognizable infestation spots with size ranging from about 20-30 trees (small spots) up to 300 trees (large spots). These infested spots evolved quickly, while new ones appeared within a radius of few hundreds of meters. During the last 5 years (2006-2010) we sampled branches from small and large spots and lodged them into emergence cages: adults of I. acuminatus as well as natural enemies were collected weekly, identified and counted. At the same time, a monitoring program of the surveyed pine stands was carried out to check the enlargement of old spots and the appearance of new ones. Voltinism and phenology of I. acuminatus were investigated by pheromone traps baited with different lures (Austrian vs. Spanish lures). The effects of a sanitation felling of about 4500 infested trees, carried out by the Regional Forest Service in autumn 2007 on I. acuminatus population were also assessed. Throughout the whole sampling area I. acuminatus resulted bivoltine, with the highest density attained during the first generation. However, a part of the population still evidenced a monovoltine behaviour. The realized sanitation felling strongly reduced both breeding sites and the number of infested trees observed during the following year. Moreover the pheromone-baited traps gave useful information about changes in bark beetle population density; the trapping efficiency of Spanish lure resulted clearly higher than the Austrian one. Finally, the recorded parasitism may have a role in outbreak dynamics as it was significantly higher during the second host generation, in both small and large spots.

Published
2010
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16. Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes

Author

Koedoot, E. (Esmee), Fokkelman, M. (Michiel), Rogkoti, V.-M., Smid, M. (Marcel), van de Sandt, I. (Iris), de Bont, H. (Hans), Pont, C., Klip, J.E. (Janna E.), Wink, S. (Steven), Timmermans, A.M. (Mieke), Wiemer, E.A.C. (Erik), Stoilov, P. (Peter), Foekens, J.A. (John), Le Dévédec, S.E. (Sylvia E.), Martens, J.W.M. (John), Van de Water, B. (Bob), Koedoot, E. (Esmee), Fokkelman, M. (Michiel), Rogkoti, V.-M., Smid, M. (Marcel), van de Sandt, I. (Iris), de Bont, H. (Hans), Pont, C., Klip, J.E. (Janna E.), Wink, S. (Steven), Timmermans, A.M. (Mieke), Wiemer, E.A.C. (Erik), Stoilov, P. (Peter), Foekens, J.A. (John), Le Dévédec, S.E. (Sylvia E.), Martens, J.W.M. (John), and Van de Water, B. (Bob)

Abstract

Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential for cancer cell migration, amplified in human primary breast tumors and associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF causes primarily down regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B is essential for TNBC metastasis formation in vivo, making PRPF4B a candidate for further drug development.

Published
2019
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17. Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes

Author

Koedoot, E, Fokkelman, M, Rogkoti, VM, Smid, Marcel, van de Sandt, I, de Bont, H, Pont, C, Klip, JE, Wink, S, Timmermans, EA, Wiemer, Erik, Stoilov, P, Foekens, John, Le Devedec, SE, Martens, John, van de Water, B, Koedoot, E, Fokkelman, M, Rogkoti, VM, Smid, Marcel, van de Sandt, I, de Bont, H, Pont, C, Klip, JE, Wink, S, Timmermans, EA, Wiemer, Erik, Stoilov, P, Foekens, John, Le Devedec, SE, Martens, John, and van de Water, B

Published
2019

18. IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer

Author

Zhang, YH, Wester, L, He, JC, Geiger, T, Moerkens, M, Siddappa, R, Helmijr, JA, Timmermans, MM, Look, MP, van Deurzen, Carolien, Martens, John, Pont, C, de Graauw, M, Danen, EHJ, Berns, E, Meerman, JHN, Jansen, Maurice, van de Water, B, Zhang, YH, Wester, L, He, JC, Geiger, T, Moerkens, M, Siddappa, R, Helmijr, JA, Timmermans, MM, Look, MP, van Deurzen, Carolien, Martens, John, Pont, C, de Graauw, M, Danen, EHJ, Berns, E, Meerman, JHN, Jansen, Maurice, and van de Water, B

Published
2018

21. Annexin A1 regulates TGF-beta signaling and promotes metastasis formation of basal-like breast cancer cells

Author

Graauw, M. de, Miltenburg, M.H. van, Schmidt, M.K., Pont, C., Lalai, R., Kartopawiro, J., Pardali, E., Devedec, S.E. le, Smit, V.T., Wal, A. van der, Van't Veer, L.J., Cleton-Jansen, A.M., Dijke, P. ten, and Water, B. van de

Subjects
endocrine system, skin and connective tissue diseases, epithelial-mesenchymal transition mammary adenocarcinoma down-regulation early endosomes expression gene lines subtypes differentiation internalization
Abstract

Annexin A1 (AnxA1) is a candidate regulator of the epithelial-to mesenchymal (EMT)-like phenotypic switch, a pivotal event in breast cancer progression. We show here that AnxA1 expression is associated with ahighly invasivebasal- likebreast cancer subtypeboth in apanel of human breast cancer cell lines as in breast cancer patients and that AnxA1 is functionally related to breast cancer progression. AnxA1 knockdownininvasivebasal- likebreast cancer cells reduced the number of spontaneous lung metastasis, whereas additional expression of AnxA1 enhanced metastatic spread. AnxA1 promotes metastasis formation by enhancingTGF beta/Smad signalingandactin reorganization, which facilitates an EMT-like switch, thereby allowing ef. cient cell migration and invasion of metastatic breast cancer cells.

Published
2010

22. Palaeogenomics of plants: syntenybased modelling of extinct ancestors

Author

Abrouk, M., Murat, François, Pont, C., Messing, J., Jackson, S., Faraut, T., Tannier, Eric, Plomion, Christophe, Cooke, R., Feuillet, C., Salse, J., Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT]
Published
2010

27. The European experience with vascular injuries

Author

Fingerhut, A Leppaniemi, AK Androulakis, GA Archodovassilis, F Bouillon, B Cavina, E Chaloner, E Chiarugi, M and Davidovic, L Delgado-Millan, MA Goris, J Gunnlaugsson, GH and Jover, JM Konstandoulakis, MM Kurtoglu, M Lepantalo, M and Llort-Pont, C Meneu-Diaz, JC Moreno-Gonzales, E and Navarro-Soto, S Panoussis, P Ryan, JM Salenius, JP and Seccia, M Takolander, R Taviloglu, K Tiesenhausen, K and Torfason, B Uranus, S

Abstract

There is great variation in the epidemiology of vascular injuries in the 45 independent countries of Europe. In countries with a low incidence of penetrating trauma and increasing use of interventional vascular procedures, the proportion of iatrogenic vascular trauma exceeds 40% of all vascular injuries, whereas in other parts of the continent where armed conflicts are still a major cause of vascular trauma, the statistics are different. National vascular registries produce data about vascular trauma and its management and, despite a relatively low incidence of vascular trauma in most European countries, the results are satisfactory, probably in most cases because of active and early management by surgeons on call who may have vascular training or not, but who treat all kinds of vascular surgical emergencies.

Published
2002

28. Annexin A2 depletion delays EGFR endocytic trafficking via cofilin activation and enhances EGFR signaling and metastasis formation

Author

de Graauw, M, primary, Cao, L, additional, Winkel, L, additional, van Miltenburg, M H A M, additional, le Dévédec, S E, additional, Klop, M, additional, Yan, K, additional, Pont, C, additional, Rogkoti, V-M, additional, Tijsma, A, additional, Chaudhuri, A, additional, Lalai, R, additional, Price, L, additional, Verbeek, F, additional, and van de Water, B, additional

Published
2013
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31. Structure and expression analysis of rice paleo duplications

Author

Throude, M., primary, Bolot, S., additional, Bosio, M., additional, Pont, C., additional, Sarda, X., additional, Quraishi, U. M., additional, Bourgis, F., additional, Lessard, P., additional, Rogowsky, P., additional, Ghesquiere, A., additional, Murigneux, A., additional, Charmet, G., additional, Perez, P., additional, and Salse, J., additional

Published
2008
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33. Fast-track program in cardiovascular surgery

Author

Haag, FF, primary, Gonnelli, CA, additional, Costa, R, additional, Paes Leme, J, additional, Fukuhara, L, additional, Girardi, A, additional, Dal Pont, C, additional, Oppi, E, additional, Haadad, V, additional, Simões, R, additional, Santos, G, additional, Puig, L, additional, and Stolf, N, additional

Published
2005
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35. Development of new SSR markers for homoeologous WFZPgene loci based on the study of the structure and location of microsatellites in gene-rich regions of chromosomes 2AS, 2BS, and 2DS in bread wheat

Author

Dobrovolskaya, O., Pont, C., Orlov, Yu., and Salse, J.

Abstract

Microsatellites, or simple sequence repeats, are widely distributed in eukaryotic genomes, including plant genomes. The peculiarities of the structure and location of the microsatellite loci determine their potential as molecular genetic markers and can influence the assumed function of microsatellites in important biological processes. The identification and study of the distribution of microsatellite loci in gene-rich genome regions of the bread wheat and the development (based on them) of new microsatellite markers are of practical interest and are important for the study of the organization of the bread wheat genome. The sequences of BAC clones that contain the homoeologous WFZPgenes of the bread wheat (Triticum aestivumL.) controlling the development of the ear were the basis for the identification and localization of microsatellite loci in gene-rich regions of the 2AS, 2BS, and 2DS chromosomes. Diand trinucleotide microsatellite repeats are the most widespread in the studied sequences. The AG and GA/TC motifs prevail among the dinucleotide motifs; the dinucleotide repeats are found in noncoding gene regions, mobile elements, and nonannotated DNA sequences. Most of the trinucleotide repeats are associated with mobile genetic elements. It was found that homoeologous microsatellite loci are located either in the genes or in the nonannotated DNA sequences. The comparison of the structure of homoeologous loci demonstrated that the divergence in them is associated both with a change in the number of repeats and with nucleotide substitutions. The new microsatellite markers, which are colocalized in the genetic maps with the WFZP-A-B-Dgenes and can be used for marking these genes in molecular genetic studies and in breeding controlled by markers, were developed.

Published
2016
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37. Gravi infestazioni di bostrico acuminato in formazioni alpine di pino silvestre.

Author

Faccoli, M., Colombari, F., Dal Pont, C., Finozzi, V., D'Ambros, E., and Battisti, A.

Subjects
SCOTS pine, AGRICULTURE, BARK beetles, SANITATION, IPS (Genus), TREES, FOREST insects
Abstract

In the last years, many Scots pine (Pinus sylvestris) stands have been severely attacked by the bark beetle Ips acuminatus (Coleoptera Curculionidae Scolytinae). In the outbreak area of San Vito di Cadore (Eastern Dolomites), the number of attacked trees since 2005 and both the emergence of bark beetles and natural enemies have been assessed. The investigated forests showed dozens of easily recognizable infestation spots with size ranging from about 20-30 trees (small spots) up to 300 trees (large spots). These infested spots evolved quickly, while new ones appeared within a radius of few hundreds of meters. During the last 5 years (2006-2010) we sampled branches from small and large spots and lodged them into emergence cages: adults of I. acuminatus as well as natural enemies were collected weekly, identified and counted. At the same time, a monitoring program of the surveyed pine stands was carried out to check the enlargement of old spots and the appearance of new ones. Voltinism and phenology of I. acuminatus were investigated by pheromone traps baited with different lures (Austrian vs. Spanish lures). The effects of a sanitation felling of about 4500 infested trees, carried out by the Regional Forest Service in autumn 2007 on I. acuminatus population were also assessed. Throughout the whole sampling area I. acuminatus resulted bivoltine, with the highest density attained during the first generation. However, a part of the population still evidenced a monovoltine behaviour. The realized sanitation felling strongly reduced both breeding sites and the number of infested trees observed during the following year. Moreover the pheromone-baited traps gave useful information about changes in bark beetle population density; the trapping efficiency of Spanish lure resulted clearly higher than the Austrian one. Finally, the recorded parasitism may have a role in outbreak dynamics as it was significantly higher during the second host generation, in both small and large spots. [ABSTRACT FROM AUTHOR]

Published
2010
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40. (Medicina Clinica (2007) 129, 12, (446-450))

Author

Jiménez, M. A., Adarriaga, M. D., Luna, A. A., Linares, E. J. A., Mugica, F. A., Martínez, J. L. A., García, G. A., Martín, J. A., Recalde, N. M. A., Fernández, L. J. Á, Auñón, A. Á, Novales, J. A., Revilla, E. A., Alvarez, J. A., Serrano, J. A. A., Castaño, J. C. A., Arroyo, A., Rojas, I. A. S., Perez, E. B., Barrios, A., Prados, J. G. B., Gotarda, M. N. B., López, J. B., Ruiz, O. B., Garcia, J. M. B., González, M. B., Lobo, A. B., Sierra, J. C. B., Díaz, A. B., Loidi, V. B., Cortada, J. B., Cazón, A. C., Perez, P. C., Castellote, M. C., Gómez, C. C., Azcargorta, I. C., Rodriguez, A. B. C., Femenia, J. C., Coll, P. C., Álvarez, J. A. C., Hernández, M. C. C., Menendez, I. C., Naranjo, I. C., Sánchez, J. C., Sanz, P. C., Ramos, J. I. C., Martínez, A. C., Fayos, J. C., Lázaro, P. R. C., Chevannes, A. B. C., Clausell, B. C., Paya, V. C., Rubio, J. C., Bergua, P. C., Hernando, J. C., Lopez, F. C., Caceres, C. C., Ramos, M. F. D., Fernández, M. D. P. D. L., Del Pilar, M., Pérez, F. D., Robert, I. D., Herrero, J. A. E., Soriano, J. -B E., Villa, J. M. E., Montpo, E. E., Plaza, A. C. E., Rosso, R. E., Morán, C. F., Álvarez, O. F., La Cigoña, F. F., Lebrato, J. R. F., Ros, M. F., Pedauye, A. F., Ruiz, J. -J F., La Fuente, R. M. F., Pérez, F. F., Cebrián, J. F., Aranda, C. F., Castroseiros, E. F., Zafra, M. G., Del Pulgar, J. G. P., González, J. P. G., Colodro, J. M. G., Corrales, F. G., Tays, J. M. G. D. A., Rico, F. G. D. B., Redondo, B. G. D. L. V., Díaz, J. D. D. G., Gutiérrez, G. G., Perez, B. G., Polo, I. G., Carra, J. C. G. -M, Sclarsky, D. E. G., Castromil, R. G., Ubeda, J. M. G., Gil, R., Opacua, I. G., Gómez, J., Cerezo, J. F. G., Perez, F. G., Angiada, M. I. G., Gómez, C. G., Cocina, E. G., Masegosa, A. G., Ortega, M. G., Naya, M. G., Tragant, G. G., Martínez, G. G., Nava, J. S. H., Ordóñez, M. L. H., Aranda, P. H., Candela, M. I., Gastearena, A. I., Carvajal, M. I., Gay, J. I., Latasa, M. I., Longares, J. A. I., Ayuso, G. I., Chaparro, S. J., Hernández, M. D. J., Araque, B. J., Corral, C. J., Creus, E. J., Bretones, F. L., Leucona, I., Ramos, J. M. L., Muñoz, J. M. L., Lois, D., Pujol, S. L., Pont, C. L., Verdugo, A. L., La Osa, A. L., Fernández, J. C. L., Mouriño, V. M. L., Ubero, L. L., Lozano, P. J. L. -I, Gutiérrez, F. L., Cano, M. D. L. R. L., Montero, J. L. M., Latorre, L. M., Delgado, J. M. M., Lopez, J. M., Marin, J. M., Conejero, A. M., La Torre, E. M., Escudero, J. C. M., Infante, A. M., Jadraque, L. M., Asensio, A. M. -B, Perez, M. M., Ferres, R. M., Vázquez, C. M., Vallejo, J. M., Sánchez, A. M., Gonzalez, T. M., Martínez, V. M., Klein, J. M., Alfaro, A. A. M., Davood, S. M., Ferrer, C. M., Molina, F. M., Jorda, J. -M M., Pérez-Barquero, M. M., Gaspar, M. A. M., Plaza, M. -J M., Orbe, P. M., Lomas, F. J. M., Gorjon, E. M., Blasco, P. J. M., Duono, M. M., Garcia, A. M., Miguel, R. N., Martín, P. N., Andreu, R. N., Álvarez, E. N., Preciado, F. O., Varela, N. M. O., Bernal, J. O., Marcos, J. O., Soler, E. O., Fernández, A. O., Sánchez, A. J. P., Bermejo, M. A. P., Somovilla, J. L. P., Castellanos, A. P. D. M., Ojeda, G. P., Pérez-Burkhardt, J. L., Iglesias, G. P., Rodríguez, J. P., Macías, I. P., Martinez, A. P., Sempere, J. M. P., Navarro, J. C. P., Suso, A. P., Ramos, Y. P., Gómez, F. P., Bofill, M. I. P., Mallagray, E. P., Rivera, J. R., Salado, J. L. R., Collado, J. T. R., Lopez, S. R., Engel, W. R., Corral, M. Á R., Davi, A. R., Solsona, J. M. R., Sala, E. R., Padial, L. R., Domínguez, M. R., Collado, J. R., Fernandez, J. A. R., Gaspar, M. A. R., Rincón, A. C. R., Hinojosa, J. A. R., González, J. R., Fernandez, J. R., Barbon, S. R., Vela, T. R., Borrell, M. R., Del Campo, J. R. D. C., Díaz, J. I. R., Ortiz, M. R., García, Ó S., Ruíz, J. S., Serasolces, J. S., García, J. A. S. D. Q., Martin, L. S., Nieto, J. S., Martínez, M. S., Salvador, A., Estomba, L. M. S. V., Ayaso, P. A. S., Rodríguez, J. M. S., SANTOS LASAOSA, Salvado, J. S., Díaz, J. M. S., Martín, T. S., Aisa, P. J. S., Hernando, F. J. S., Villa, J. S., Soriano, C., Marti, J. F. S., Ruiz, I. S., Cabrera, M. S., Fernández, C. S., Hernandez, J. M. S., Calle, P. T., Gutiérrez, L. M. T., García, L. T., Tobaruela, A., Gabriel Y Galan, J. M. T., Gómez, J. T., Rosales, D. T., Ocariz, M. U., Pérez, E. V., Oliveras, M. V., Urbaneja, J. V., Morillo, F. V., Franco, L. V., Garcia, A. V., Fernández, J. V., Vega-Rollán, F., Lerones, A. V., Vera, T. V., Martínez, J. A. V., Arroyo, B. V., Joya, R. V., Gómez, I. V., González, J. V., Pérez, G. V., Zabala, S., and Navarro, J. Z.

41. Transcriptomic differences in MSA clinical variants

Author

Perez-Soriano, A., Arnal Segura, M., Botta-Orfila, T., Giraldo, D., Fernandez, M., Compta, Y., Fernandez-Santiago, R., Ezquerra, M., Tartaglia, G. G., Marti, M. J., Munoz, E., Pagonabarraga, J., Valldeoriola, F., Hernandez-Vara, J., Classen, S. J., Puente, V., Pont, C., Caballol, N., de Fabregues, O., Avila, A., Calopa, M., Gaig, C., Pastor, P., Pujol, M., Santamaria, J., Planellas, L., and Camara, A.

Subjects
Male, Multiple system atrophy (MSA), Parkinson's disease, lcsh:Medicine, Disease, Transcriptome, 0302 clinical medicine, Malaltia de Parkinson, Cerebellum, Gene expression, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Parkinsonism, Cerebel, Parkinson Disease, Middle Aged, Phenotype, parkinsonism (MSA-P), 3. Good health, Neurology, Differential diagnosis, Female, Biology, cerebellar dysfunction (MSA-C), Article, Diagnosis, Differential, 03 medical and health sciences, Atrophy, stomatognathic system, Cerebellar Diseases, parasitic diseases, mental disorders, medicine, Humans, Movement disorders, Gene, 030304 developmental biology, Aged, Synucleinopathies, Gene Expression Profiling, lcsh:R, Diagnòstic diferencial, Multiple System Atrophy, medicine.disease, Expressió gènica, nervous system diseases, Computational biology and bioinformatics, nervous system, Case-Control Studies, lcsh:Q, 030217 neurology & neurosurgery, Neurological disorders, Neuroscience
Abstract

Background: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). Objective: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes. Methods: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients. Results: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies. Conclusions: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results. We would like to thank all the patients for their always willing and generous collaboration. This project has been possible thanks to the funding from the Fundació Marató TV3 and CERCA Programme from Generalitat de Catalunya. We also thank the European Research Council RIBOMYLOME_309545 and Spanish Ministry of Economy and Competitiveness (BFU2017-86970-P). A.P.-S. was funded by a PHD4MD grant, which is a collaborative research training program for medical doctors. R.F.-S. was supported by a Jóvenes Investigadores (JIN) grant of the Spanish Ministry of Economy and Competitiveness (MINECO) and the Agencia Estatal de Investigación (AEI) (AEI/FEDER/UE) (grant # SAF2015-73508-JIN), and a Miguel Servet grant from the Instituto de Salud Carlos III (grant # CP19/00048). M.F. was funded by María de Maeztu programme (grant # MDM-2017-0729). Thanks to Lara Nonell, head of the Human Computational Biology group in IMIM, for offering the computational resources in the institution and the help with data management.

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45. From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Author

Matthias Scheiner, Elsa M. Arce, María Isabel Loza, Marina Naldi, F. Javier Luque, Angela De Simone, Manuela Bartolini, Maria Laura Bolognesi, Michael Decker, Yolanda Soriano-Fernández, José Brea, Caterina Pont, Noemí Martínez, Diego Muñoz-Torrero, Alexia Mattellone, Belén Pérez, Marta Barenys, Raimon Sabaté, Jesús Gómez-Catalán, Christian Griñán-Ferré, Tiziana Ginex, Vincenza Andrisano, Mercè Pallàs, Pont C., Ginex T., Grinan-Ferre C., Scheiner M., Mattellone A., Martinez N., Arce E.M., Soriano-Fernandez Y., Naldi M., De Simone A., Barenys M., Gomez-Catalan J., Perez B., Sabate R., Andrisano V., Loza M.I., Brea J., Bartolini M., Bolognesi M.L., Decker M., Pallas M., Luque F.J., and Munoz-Torrero D.

Subjects
Zebra danio, Peix zebra, Drug Evaluation, Preclinical, tau Proteins, Alzheimer's disease, Cryptic pocket, Multitarget compound, SAMP8, Zebrafish embryo, Disease, Molecular Dynamics Simulation, Heterocyclic Compounds, 4 or More Rings, chemistry.chemical_compound, Structure-Activity Relationship, Alzheimer Disease, Drug Discovery, Healthy control, Aspartic Acid Endopeptidases, Humans, Pharmacology, Virtual screening, Anti alzheimer, Amyloid beta-Peptides, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Envelliment cerebral, Organic Chemistry, Brain, General Medicine, Recombinant Proteins, Cell biology, Malaltia d'Alzheimer, Neuroprotective Agents, Tau phosphorylation, Synaptophysin, biology.protein, Aging brain, Aminoquinolines, Amyloid Precursor Protein Secretases, Lead compound
Abstract

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

Published
2021

46. A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

Author

Santiago Vázquez, Deborah Pivetta, Vincenza Andrisano, Diego Muñoz-Torrero, Andreea L. Turcu, Belén Pérez, Alba Espargaró, F. Javier Pérez-Areales, Caterina Pont, Angela De Simone, Raimon Sabaté, Francesc X. Sureda, Manuela Bartolini, Marta Barniol-Xicota, Perez-Areales F.J., Turcu A.L., Barniol-Xicota M., Pont C., Pivetta D., Espargaro A., Bartolini M., De Simone A., Andrisano V., Perez B., Sabate R., Sureda F.X., Vazquez S., Munoz-Torrero D., and Universitat de Barcelona

Subjects
Multi-target-directed ligands, NMDA antagonists, Química farmacèutica, Adamantane, Pharmacology, 01 natural sciences, chemistry.chemical_compound, Drug Discovery, Cholinesterase Inhibitor, Butyrylcholinesterase, Butyrylcholinesterase inhibitors, 0303 health sciences, Molecular Structure, Chemistry, Butyrylcholinesterase inhibitor, Malalties neurodegeneratives, Memantine, Neurodegenerative Diseases, General Medicine, Alzheimer's disease, Cerebral cortex, Acetylcholinesterase inhibitors, Brain permeability, Multitarget compounds, Acetylcholinesterase, Escorça cerebral, Neuroprotective Agents, Tacrine, NMDA receptor, medicine.drug, Human, Neuroprotective Agent, NMDA antagonist, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Structure-Activity Relationship, Alzheimer Disease, Multi-target-directed ligand, medicine, Potency, Structure–activity relationship, Humans, IC50, 030304 developmental biology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, 0104 chemical sciences, Malaltia d'Alzheimer, Acetylcholinesterase inhibitor, Multitarget compound, Cholinesterase Inhibitors, Pharmaceutical chemistry
Abstract

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.

Published
2019

47. Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

Author

Codony Gisbert, Sandra, Pont Masanet, Caterina, Griñán Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José, Bartolini, Pérez, Belén, Bartra, Clara, Sanfeliu i Pujol, Coral, Juárez Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs i Llibería, Mercè, 1964, Vázquez Cruz, Santiago, Muñoz-Torrero López-Ibarra, Diego, Codony S., Pont C., Grinan-Ferre C., Di Pede-Mattatelli A., Calvo-Tusell C., Feixas F., Osuna S., Jarne-Ferrer J., Naldi M., Bartolini M., Loza M.I., Brea J., Perez B., Bartra C., Sanfeliu C., Juarez-Jimenez J., Morisseau C., Hammock B.D., Pallas M., Vazquez S., Munoz-Torrero D., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Xunta de Galicia, European Commission, Generalitat de Catalunya, National Institute of Environmental Health Sciences (US), European Research Council, National Institute of Neurological Disorders and Stroke (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Ministerio de Educación, Cultura y Deporte (España), Griñán-Ferré, Christian, Calvó-Tusell, Carla, Osuna, Sílvia, Bartolini, Manuela, Loza, María Isabel, Juárez-Jiménez, Jordi, Pallàs, Mercè, Vázquez, Santiago, and Muñoz-Torrero, Diego

Subjects
Aging, Medicinal & Biomolecular Chemistry, Química farmacèutica, Drug development, Neurodegenerative, Alzheimer's Disease, Desenvolupament de medicaments, Medicinal and Biomolecular Chemistry, Mice, Alzheimer Disease, Drug Discovery, Acquired Cognitive Impairment, Animals, acetylcholinesterase, Alzheimer's disease, soluble epoxide hydrolase, Epoxide Hydrolases, Animal, Organic Chemistry, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Pharmacology and Pharmaceutical Sciences, Brain Disorders, Disease Models, Animal, Malaltia d'Alzheimer, 5.1 Pharmaceuticals, Disease Models, Neurological, Acetylcholinesterase, Molecular Medicine, Dementia, Cholinesterase Inhibitors, Development of treatments and therapeutic interventions, Pharmaceutical chemistry
Abstract

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration., This work was supported by grants PID2020-118127RB-I00, SAF2017-82771-R, PID2020-115683GA-I00, PGC2018- 102192-B-I00, PID2019-106285RB, and RTI2018-101032-JI00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, ED431C 2018/21 and ED431G 2019/02 from Xunta de Galicia, and 2017SGR106, 2017SGR1707, and 2019LLAV00017 from AGAUR. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Fellowships from Ministerio de Educación, Cultura y Deporte to C.P. (FPU15/01131), from the University of Barcelona to S.C., and a starting grant from the European Research Council (ERC-2015-StG-679001- NetMoDEzyme) to S.O. are gratefully acknowledged. We thank Ms. Cecilia Mariani for technical assistance in the assays with mAChE.

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48. Assessing the metabolism of the olfactory circuit by use of 18 F-FDG PET-CT imaging in patients suspected of suffering from Alzheimer's disease or frontotemporal dementia.

Author

Loewenstein DSL, van Grinsven M, de Pont C, Dautzenberg PLJ, van Strien AM, and Henssen D

Subjects
Humans, Male, Female, Aged, Middle Aged, Radiopharmaceuticals, Olfactory Pathways diagnostic imaging, Olfactory Pathways metabolism, Brain diagnostic imaging, Brain metabolism, Prospective Studies, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Frontotemporal Dementia diagnostic imaging, Frontotemporal Dementia metabolism, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography methods
Abstract

Purpose: The loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer's disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([ 18 F]-FDG) can distinguish these entities in different subsets of patients., Methods: Patients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed., Results: The metabolism of subdivisions of the olfactory circuit as assessed by [ 18 F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA., Conclusion: Metabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed., (© 2024. The Author(s).)

Published
2024
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49. Genetic erosion in domesticated barley and a hypothesis of a North African centre of diversity.

Author

Civáň P, Fricano A, Russell J, Pont C, Özkan H, Kilian B, and Brown TA

Abstract

Barley is one of the founder crops of the Neolithic transition in West Asia. While recent advances in genomics have provided a rather detailed picture of barley domestication, there are contradictory views on how the domestication process affected genetic diversity. We set out to revisit this question by integrating public DNA sequencing data from ancient barley and wide collections of extant wild and domesticated accessions. Using two previously overlooked approaches - analyses of chloroplast genomes and genome-wide proportions of private variants - we found that the barley cultivated six millennia ago was genetically unique and more diverse when compared to extant landraces and cultivars. Moreover, the chloroplast genomes revealed a link between the ancient barley, an obscure wild genotype from north-eastern Libya, and a distinct population of barley cultivated in Ethiopia/Eritrea. Based on these results, we hypothesize past existence of a wider North African population that included both wild and cultivated types and suffered from genetic erosion in the past six millennia, likely due to a rapid desertification that ended the Holocene African humid period. Besides providing clues about the origin of Ethiopian landraces, the hypothesis explains the post-domestication loss of diversity observed in barley. Analyses of additional samples will be necessary to resolve the history of African barley and its contribution to the extant cultivated gene pool., Competing Interests: The authors declare no competing interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Published
2024
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50. Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties.

Author

Pont C, Sampietro A, Pérez-Areales FJ, Cristiano N, Albalat A, Pérez B, Bartolini M, De Simone A, Andrisano V, Barenys M, Teixidó E, Sabaté R, Loza MI, Brea J, and Muñoz-Torrero D

Abstract

Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein-huprine hybrid lead by hydroxy group removal-ring contraction-ring opening-ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC 50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC 50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification.

Published
2024
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