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1. A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis

Author

Li Li, Alejandro P. Ugalde, Colinda L. G. J. Scheele, Sebastian M. Dieter, Remco Nagel, Jin Ma, Abhijeet Pataskar, Gozde Korkmaz, Ran Elkon, Miao-Ping Chien, Li You, Pin-Rui Su, Onno B. Bleijerveld, Maarten Altelaar, Lyubomir Momchev, Zohar Manber, Ruiqi Han, Pieter C. van Breugel, Rui Lopes, Peter ten Dijke, Jacco van Rheenen, and Reuven Agami

Subjects
YAP, Enhancer, TRAM2, Proliferation, Migration, Invasion, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions. Results We first apply genome-wide ChIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Next, we implement a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrate its robustness, and use it to reveal a network of enhancers required for YAP-mediated proliferation. We focus on EnhancerTRAM2, as its target gene TRAM2 shows the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopies the YAP-induced cell proliferation, migration, and invasion phenotypes and correlates with poor patient survival. Mechanistically, we identify FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness. Conclusions YAP is a transcription co-factor that binds to thousands of enhancer loci and stimulates tumor aggressiveness. Using unbiased functional approaches, we dissect YAP enhancer network and characterize TRAM2 as a novel mediator of cellular proliferation, migration, and invasion. Our findings elucidate how YAP induces cancer aggressiveness and may assist diagnosis of cancer metastasis.

Published
2021
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2. Functional CRISPR screen identifies AP1-associated enhancer regulating FOXF1 to modulate oncogene-induced senescence

Author

Ruiqi Han, Li Li, Alejandro Piñeiro Ugalde, Arieh Tal, Zohar Manber, Eric Pinto Barbera, Veronica Della Chiara, Ran Elkon, and Reuven Agami

Subjects
CRISPR, Functional screen, Enhancers, Oncogene-induced senescence, Gene regulation, AP1, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Functional characterization of non-coding elements in the human genome is a major genomic challenge and the maturation of genome-editing technologies is revolutionizing our ability to achieve this task. Oncogene-induced senescence, a cellular state of irreversible proliferation arrest that is enforced following excessive oncogenic activity, is a major barrier against cancer transformation; therefore, bypassing oncogene-induced senescence is a critical step in tumorigenesis. Here, we aim at further identification of enhancer elements that are required for the establishment of this state. Results We first apply genome-wide profiling of enhancer-RNAs (eRNAs) to systematically identify enhancers that are activated upon oncogenic stress. DNA motif analysis of these enhancers indicates AP-1 as a major regulator of the transcriptional program induced by oncogene-induced senescence. We thus constructed a CRISPR-Cas9 sgRNA library designed to target senescence-induced enhancers that are putatively regulated by AP-1 and used it in a functional screen. We identify a critical enhancer that we name Enh AP1-OIS1 and validate that mutating the AP-1 binding site within this element results in oncogene-induced senescence bypass. Furthermore, we identify FOXF1 as the gene regulated by this enhancer and demonstrate that FOXF1 mediates Enh AP1-OIS1 effect on the senescence phenotype. Conclusions Our study elucidates a novel cascade mediated by AP-1 and FOXF1 that regulates oncogene-induced senescence and further demonstrates the power of CRISPR-based functional genomic screens in deciphering the function of non-coding regulatory elements in the genome.

Published
2018
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3. Population ecology and home range of the Mexican Rough-footed Mud Turtle (Kinosternon hirtipes murrayi) in Central Mexico

Author

Alejandro Montiel-Ugalde, Ángeles Aparicio, Eder Gaona Murillo, Taggert Butterfield, and Rodrigo Macip-Ríos

Subjects
Zoology, QL1-991
Abstract

Population ecology and demographic data are fundamental for species management and conservation planning. For Mexican kinosternid turtles there is a need for basic natural history and population ecology data. The Rough-footed Mud Turtle (Kinosternon hirtipes murrayi) is one of the lesser-studied species, even though it is broadly distributed, occurring from Western Texas to Central Mexico. We conducted a study on the species in Michoacán, Mexico for two years. Basic population parameters were estimated, and telemetry was used to measure home range size and movements of males and females. Population size in a 1.42-hectare wetland was calculated to be 301 (± SE 5.89) individuals, mainly adults. The adult sex ratio was skewed toward males (3.1:1). Female home range size was larger than that of males, and males moved larger distances between relocation events. The radio-tracked individuals did not leave the water during winter months and during the dry season. Habitat degradation due to eutrophication may be affecting population survivorship and recruitment.

Published
2018
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4. 3'UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells.

Author

Yonit Hoffman, Debora Rosa Bublik, Alejandro P Ugalde, Ran Elkon, Tammy Biniashvili, Reuven Agami, Moshe Oren, and Yitzhak Pilpel

Subjects
Genetics, QH426-470
Abstract

Most mammalian genes often feature alternative polyadenylation (APA) sites and hence diverse 3'UTR lengths. Proliferating cells were reported to favor APA sites that result in shorter 3'UTRs. One consequence of such shortening is escape of mRNAs from targeting by microRNAs (miRNAs) whose binding sites are eliminated. Such a mechanism might provide proliferation-related genes with an expression gain during normal or cancerous proliferation. Notably, miRNA sites tend to be more active when located near both ends of the 3'UTR compared to those located more centrally. Accordingly, miRNA sites located near the center of the full 3'UTR might become more active upon 3'UTR shortening. To address this conjecture we performed 3' sequencing to determine the 3' ends of all human UTRs in several cell lines. Remarkably, we found that conserved miRNA binding sites are preferentially enriched immediately upstream to APA sites, and this enrichment is more prominent in pro-differentiation/anti-proliferative genes. Binding sites of the miR17-92 cluster, upregulated in rapidly proliferating cells, are particularly enriched just upstream to APA sites, presumably conferring stronger inhibitory activity upon shortening. Thus 3'UTR shortening appears not only to enable escape from inhibition of growth promoting genes but also to potentiate repression of anti-proliferative genes.

Published
2016
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5. Autophagy-linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS-CoV-2 entry into human cells

Author

Alejandro P Ugalde, Gabriel Bretones, David Rodríguez, Víctor Quesada, Francisco Llorente, Raúl Fernández‐Delgado, Miguel Ángel Jiménez‐Clavero, Jesús Vázquez, Enrique Calvo, Isaac Tamargo‐Gómez, Guillermo Mariño, David Roiz‐Valle, Daniel Maeso, Miguel Araujo‐Voces, Yaiza Español, Carles Barceló, José MP Freije, Alejandro López‐Soto, Carlos López‐Otín, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación 'la Caixa', Principado de Asturias, Ministerio de Ciencia e Innovación (España), Fundación La Caixa, and Gobierno del Principado de Asturias (España)

Subjects
Lung Neoplasms, General Immunology and Microbiology, SARS-CoV-2, General Neuroscience, Lysosome-Associated Membrane Glycoproteins, Proteins, COVID-19, Genetic screen, General Biochemistry, Genetics and Molecular Biology, Spns1, Autophagy, Humans, Plac8, Angiotensin-Converting Enzyme 2, Molecular Biology
Abstract

Better understanding on interactions between SARS-CoV-2andhost cells should help to identify host factors that may be tar-getable to combat infection and COVID-19pathology. To this end,we have conducted a genome-wide CRISPR/Cas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate manyfindings from previous screens that used full SARS-CoV-2viruses,but also unveil two novel critical host factors: the lysosomal effluxtransporter SPNS1and the plasma and lysosomal membrane pro-tein PLAC8. Functional experiments with full SARS-CoV-2virusesconfirm that loss-of-function of these genes impairs viral entry.We find that PLAC8is a key limiting host factor, whose overexpres-sion boosts viral infection in eight different human lung cancer celllines. Using single-cell RNA-Seq data analyses, we demonstratethat PLAC8is highly expressed in ciliated and secretory cells of therespiratory tract, as well as in gut enterocytes, cell types that arehighly susceptible to SARS-CoV-2infection. Proteomics and cellbiology studies suggest that PLAC8and SPNS1regulate theautophagolysosomal compartment and affect the intracellular fateof endocytosed virions., This work was supported by Instituto de Salud Carlos III(COV20/00652, MS19/00100, PI20/01267, COV20/00571 and PT17/0019/0003), Ministerio de Ciencia e Innovación (Spain) (PDI2020-118394RB-100, SAF2017-87655-R, PID2021-127534OB-100, and PGC2018-097019-B-I00), “laCaixa” Banking Foundation (HR17-00247) and Consejería de Ciencia, Innovación y Universidad del Gobierno del Principado de Asturias (AYUD/2021/57167). D.R.V and D.M are supported by PhD fellowships from Ministerio de Ciencia e Innovación(Spain).

Published
2022

6. New distributional bird records from the eastern Andean slopes of Ecuador

Author

Alejandro Solano-Ugalde and Galo Real-Jibaja

Subjects
Biology (General), QH301-705.5
Abstract

Distribution of birds is dynamic. Understanding, documentation and appropriate use of new records are essential, especially when managing threatened species. Here we present novel data regarding new distributional records for 17 bird species along the Amazonian slopes of the eastern Ecuadorian Andes. The new records fill gaps on our knowledge in the distribution, both in latitude and altitude.

Published
2010
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7. Brotogeris versicolorus (Statius Müller, 1776) (Aves: Psittacidae): introduced established population in Ecuador

Author

Juan Freile, Jaime Salas, Alejandro Solano-Ugalde, and Ronald Navarrete

Subjects
Biology (General), QH301-705.5
Abstract

We report the first confirmed evidence of a feral introduced population of Brotogeris versicolorus (Statius Müller, 1776) in Guayaquil city, Ecuador, as part of the World Parrot Count led by City Parrots. A total of 216 individuals were counted, at two places within the city, but no direct evidence of breeding was found. A previously unpublished photograph suggesting nesting activity is also presented, along with brief comments on previous and additional observations and the conservation implications of this recently established feral species.

Published
2012
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8. Aves, Thraupidae, Indigo Flowerpiercer Diglossa indigotica (Sclater, 1856): New country records, natural history notes, and occurrence in northwest Ecuador

Author

Alejandro Solano-Ugalde and Dušan Brinkhuizen

Subjects
Biology (General), QH301-705.5
Abstract

Only old records of the Indigo Flowerpiercer Diglossa indigotica are known from Pichincha province, Ecuador. Here we report 26 sight records of this rare species at a new locality, the Bosque Protector Mashpi. These novel records confirm that the species is resident, and represent the first evidence of breeding in the country. The species seems to have a habitat preference for patches of short Ericaceous growth, but occurs locally in mossy cloud forest, typically found in low densities. Adults sang throughout the year, usually from canopy but also from inside short Ericaceous growth. The discovery of this site posses a great opportunity to further studies of this little known Choco endemic species.

Published
2012
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10. The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function

Author

David Roiz-Valle, Manuel Lobo-Gonzalez, Gabriela Desdín-Micó, Xurde M. Caravia, José A. Vega, Gloria Velasco, Alba Morán-Álvarez, Mónica Gómez, María Mittelbrunn, Vicente Andrés, Víctor Fanjul, Héctor Bueno, José M.P. Freije, Francisco Rodríguez, Borja Ibanez, R. Cabo, Eduardo Oliver, Alejandro P. Ugalde, Antonio Fueyo, Carlos López-Otín, Unión Europea. Comisión Europea, European Research Council, Ministerio de Economía, Industria y Competitividad (España), Fundación ProCNIC, Comunidad de Madrid (España), Fundación Cajastur, Instituto de Salud Carlos III, Centro de Investigación Biomedica en Red - CIBER, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), and Progeria Research Foundation

Subjects
0301 basic medicine, Heart disease, Bioinformatics, Biochemistry, Pathogenesis, Mice, 0302 clinical medicine, Fibrosis, Medicine and Health Sciences, Biology (General), Energy-Producing Organelles, General Neuroscience, Heart, Animal Models, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, 3. Good health, Cardiovascular physiology, Mitochondria, Up-Regulation, Nucleic acids, Phenotypes, Experimental Organism Systems, 030220 oncology & carcinogenesis, Hypertension, Anatomy, Cellular Structures and Organelles, General Agricultural and Biological Sciences, Haploinsufficiency, Research Article, Cardiac function curve, QH301-705.5, Cardiology, Mouse Models, Bioenergetics, Biology, Vascular Remodeling, Research and Analysis Methods, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Model Organisms, Genetics, medicine, Animals, Humans, Non-coding RNA, Heart Failure, Natural antisense transcripts, General Immunology and Microbiology, Myocardium, Biology and Life Sciences, Cell Biology, medicine.disease, Gene regulation, Mice, Inbred C57BL, MicroRNAs, 030104 developmental biology, Mitochondrial biogenesis, Heart failure, Animal Studies, Cardiovascular Anatomy, RNA, Gene expression, Developmental Biology
Abstract

Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely. We also found evidence that the absence of miR-29 triggers the up-regulation of its target, the master metabolic regulator PGC1α, which in turn generates profound alterations in mitochondrial biogenesis, leading to a pathological accumulation of small mitochondria in mutant animals that contribute to cardiac disease. Notably, we demonstrate that systemic hypertension and HFpEF caused by miR-29 deficiency can be rescued by PGC1α haploinsufficiency, which reduces cardiac mitochondrial accumulation and extends longevity of miR-29–mutant mice. In addition, PGC1α is overexpressed in hearts from patients with HF. Collectively, our findings demonstrate the in vivo role of miR-29 in cardiovascular homeostasis and unveil a novel miR-29/PGC1α regulatory circuitry of functional relevance for cell metabolism under normal and pathological conditions., Author summary To combat diseases, we first need to gain knowledge on how cells function at the molecular level to maintain normal physiology. One great scientific achievement of the last decade was the identification of thousands of small regulatory RNA molecules, called microRNAs. Strikingly, each microRNA has the potential to fine-tune the expression of hundreds of target genes depending on the spatiotemporal context. Therefore, defects in key microRNAs can contribute to the development of diseases. In the present work, we characterize the role for miR-29 in cardiac function in a mouse model. We found that mice deficient for miR-29 develop life-threatening cardiometabolic alterations that subsequently cause heart failure with diastolic dysfunction and systemic hypertension. We also demonstrate that these pathological phenotypes originate in part by the anomalous up-regulation of the transcriptional coactivator PGC1α, which can lead to mitochondrial hyperplasia in the heart. Genetic removal of one copy of PGC1α significantly attenuated the severity of the cardiovascular phenotype observed in miR-29–deficient mice. In addition, we show that PGC1α expression is misregulated in heart failure patients, suggesting that the implementation of miR-29 replacement therapy could potentially be used to treat these fatal pathologies.

Published
2018

12. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53

Author

Guillermo Mariño, Alejandro P. Ugalde, Jorge de la Rosa, Jun Lu, Andrew J. Ramsay, Carlos López-Otín, Ignacio Varela, Juan Cadiñanos, and José M. Freije

Subjects
Senescence, Regulation of gene expression, 0303 health sciences, Progeria, General Immunology and Microbiology, DNA damage, General Neuroscience, Biology, medicine.disease, Molecular biology, General Biochemistry, Genetics and Molecular Biology, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Physiological Aging, Downregulation and upregulation, 030220 oncology & carcinogenesis, microRNA, medicine, Regulatory Pathway, Molecular Biology, 030304 developmental biology
Abstract

Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson–Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24−/− progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53−/− murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage.

Published
2011

13. Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

Author

Jesús Espada, Karl Tryggvason, Alejandro P. Ugalde, Ignacio Flores, Ignacio Varela, Alberto M. Pendás, Juan Cadiñanos, Maria A. Blasco, José M.P. Freije, Colin L. Stewart, and Carlos López-Otín

Subjects
Premature aging, Keratinocytes, Aging, Nuclear Envelope, Immunology, Stem cell theory of aging, Reviews, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Progeria, Report, Cell Line, Tumor, medicine, Immunology and Allergy, Animals, Research Articles, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Receptors, Notch, Cell growth, Stem Cells, Comment, Wnt signaling pathway, Membrane Proteins, Metalloendopeptidases, Aging, Premature, Cell Biology, Hair follicle, Lamins, 3. Good health, Cell biology, Wnt Proteins, Physiological Aging, medicine.anatomical_structure, embryonic structures, Mutation, Nuclear lamina, Stem cell, Hair Follicle, 030217 neurology & neurosurgery, Signal Transduction
Abstract

et al., Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24 -null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24 -/- Lmna+/- mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24-/- mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction., This work was supported by grants from Ministerio de Educacion y Ciencia (Spain), Fundación Lilly, Fundación La Caixa, Fundación M. Botín, and the European Union. I. Flores is a Ramón y Cajal senior scientist. M.A. Blasco´s laboratory is funded by the Ministerio de Ciencia y Tecnologia (Spain), the regional government of Madrid, the European Union, and Josef Steiner Cancer Research Award 2003. The Instituto Universitario de Oncología is supported by Obra Social Cajastur.

Published
2008
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15. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

Author

Mario F. Fraga, Rubén Cabanillas, Fernando G. Osorio, Jorge de la Rosa, Juan Cadiñanos, M. Soledad Fernández-García, Allan Bradley, Haydn M. Prosser, Alejandro P. Ugalde, Qi Liang, Víctor Fanjul, José M.P. Freije, Carlos López-Otín, Roland Rad, Bradley, Allan [0000-0002-2349-8839], and Apollo - University of Cambridge Repository

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, Aging, Carcinogenesis, Cell, General Physics and Astronomy, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Progeria, Neoplasms, medicine, Gene silencing, Animals, Humans, Neoplasm Invasiveness, Nuclear protein, Protein Precursors, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, integumentary system, Mosaicism, Cancer, Membrane Proteins, Metalloendopeptidases, Nuclear Proteins, General Chemistry, medicine.disease, Lamin Type A, Phenotype, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Female, Lamin, Biomarkers
Abstract

Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

Published
2013

16. Aminopeptidase O

Author

Alejandro P. Ugalde, Araceli Díaz-Perales, and Carlos López-Otín

Subjects
Biochemistry, Chemistry, Aminopeptidase
Published
2013

17. Contributors

Author

Catherine Anne Abbott, Carmela R. Abraham, Hideki Adachi, Osao Adachi, Zach Adam, Michael W.W. Adams, Michael J. Adang, Ibrahim M. Adham, Patrizia Aducci, David A. Agard, Alexey A. Agranovsky, Tetsuya Akamatsu, Yoshinori Akiyama, Reidar Albrechtsen, Alí Alejo, Sean M. Amberg, Alexander Y. Amerik, Piti Amparyup, Felipe Andrade, Germán Andrés, Daniel M. Andrews, Robert K. Andrews, Toni M. Antalis, Colin S. Anthony, Naoya Aoki, Suneel S. Apte, Kazunari Arima, Gérard Arlaud, Raghuvir Krishnaswamy Arni, Pascal Arnoux, Nathan N. Aronson, Michel Arthur, Yasuhisa Asano, Paolo Ascenzi, Marina T. Assakura, David S. Auld, Veridiana de Melo Rodrigues Ávila, Francesc X. Avilés, William M. Awad, Anand K. Bachhawat, Shan Bai, Teaster T. Baird, S. Paul Bajaj, Susan C. Baker, Agnieszka Banbula, Alan J. Barrett, Jemima Barrowman, John D. Bartlett, Jörg W. Bartsch, Nikola Baschuk, Isolda P. Baskova, Jyotsna Batra, Karl Bauer, Ulrich Baumann, Wolfgang Baumeister, Cédric Bauvois, Alex Bayés, Anne Beauvais, Christoph Becker-Pauly, Tadhg P. Begley, Miklós Békés, Robert Belas, Daniah Beleford, Teruhiko Beppu, Ernst M. Bergmann, Bruno A. Bernard, Dominique Bernard, Michael C. Berndt, Giovanna Berruti, Colin Berry, Greg P. Bertenshaw, Christian Betzel, Chetana Bhaskarla, Manoj Bhosale, Gabriele Bierbaum, B. Bjarnason Jón, Michael Blaber, Michael J. Blackman, Alexander Blinkovsky, Jef D. Boeke, Matthew Bogyo, Stefan Bohn, Guy Boileau, Mike Boland, Tové C. Bolken, Judith S. Bond, Jan Bondeson, Javier Bordallo, Claudia Borelli, Tiago O. Botelho, Richard R. Bott, David G. Bourne, Niels Bovenschen, Ralph A. Bradshaw, Klaus Breddam, Keith Brew, Paul J. Brindley, Diane L. Brinkman, Collette Britton, Jeff R. Broadbent, Anne Broadhurst, Dieter Brómme, Murray Broom, Jeremy S. Brown, Mark A. Brown, Iris Bruchhaus, Barbara A. Burleigh, Kristin E. Burns, James F. Burrows, Michael J. Butler, David J. Buttle, Chelsea M. Byrd, Tony Byun, Sandrine Cadel, Conor R. Caffrey, Santiago Cal, Javier Caldentey, Thomas Candela, Clemente Capasso, Daniel R. Capriogilio, Vincenzo Carginale, Adriana Karaoglanovic Carmona, Vern B. Carruthers, Francis J. Castellino, Joseph J. Catanese, Bruce Caterson, George H. Caughey, Naimh X. Cawley, Tim E. Cawston, Juan José Cazzulo, Jijie Chai, Karl X. Chai, Olga Meiri Chaim, L.S. Chang, Julie Chao, Marie-Pierre Chapot-Chartier, Jean-Louis Charli, Paulette Charlier, Karen J. Chave, Jian-Min Chen, Jinq-May Chen, Li-Mei Chen, Ya-Wen Chen, Yu-Yen Chen, Bernard Chevrier, Jean-François Chich, Jeremy Chien, Suneeta Chimalapati, Ki Joon Cho, Kwan Yong Choi, Woei-Jer Chuang, Chin Ha Chung, Ivy Yeuk Wah Chung, Christine Clamagirand, Ian M. Clark, Adrian K. Clarke, Nicola E. Clarke, Steven Gerard Clarke, Philippe Clauziat, Judith A. Clements, Catherine Coffinier, Paul Cohen, Alain Colige, Anne Collignon, Sean D. Colloms, Andreas Conzelmann, Graham H. Coombs, Jakki C. Cooney, Jonathan B. Cooper, Max D. Cooper, Nikki A. Copeland, Graeme S. Cottrell, Joseph T. Coyle, Charles S. Craik, John W.M. Creemers, Daniela Cretu, Jenifer Croce, Keith J. Cross, Rosario Cueva, Sheng Cui, Luis Cunha, Simon Cutting, Christophe d’Enfert, Hugues D’Orchymont, Björn Dahlbäck, Shujia Dai, Ross E. Dalbey, John P. Dalton, Pam M. Dando, R.M. Daniel, Sergei M. Danilov, Donna E. Davies, Heloisa S. De Araujo, Teresa De los Santos, Viviana de Luca, Ingrid De Meester, Ana Karina de Oliveira, Eduardo Brandt de Oliveira, Pedro Lagerblad De Oliveira, Sarah de Vos, Jeroen Declercq, Wim Declercq, Ala-Eddine Deghmane, Niek Dekker, Sonia Del Prete, Marina Del Rosal, Bernard Delmas, Robert DeLotto, Ilya V. Demidyuk, Mark R. Denison, Jan M. Deussing, Lakshmi A. Devi, Eleftherios P. Diamandis, Isabel Diaz, Araceli Díaz-Perales, Bauke W. Dijkstra, Yan Ding, Jack E. Dixon, Johannes Dodt, Terje Dokland, Iztok Dolenc, Ningzheng Dong, Tran Cat Dong, Ying Dong, Mitesh Dongre, Mark Donovan, Timothy M. Dore, Loretta Dorstyn, Hong Dou, Zhicheng Dou, Annette M. Dougall, Marcin Drag, Edward G. Dudley, Ben M. Dunn, Bruno Dupuy, Maria Conceicāo Duque-Magalhāes, M. Asunción Durá, Yves Eeckhout, Vincent Eijsink, Arthur Z. Eisen, Azza Eissa, Sandra Eklund, Ziad M. Eletr, Vincent Ellis, Wolfgang Engel, Ervin G. Erdös, Teresa Escalante, David A. Estell, Michael Etscheid, Herbert J. Evans, Roger D. Everett, Alex C. Faesen, Falk Fahrenholz, Miriam Fanjul-Fernández, Christopher J. Farady, Georges Feller, Hong Feng, Kurt M. Fenster, Claude Férec, Silvia Ferrari, Barbara Fingleton, Jed F. Fisher, Paula M. Fives-Taylor, Loren G. Fong, F. Forneris, Brian M. Forster, Friedrich Forster, Simon J. Foster, Thierry Foulon, Stephen I. Foundling, Jay William Fox, Bruno Franzetti, Alejandra P. Frasch, Hudson H. Freeze, Jean-Marie Frère, Teryl K. Frey, Beate Fricke, Lloyd D. Fricker, Rafael Fridman, Christopher J. Froelich, Camilla Fröhlich, Hsueh-Liang Fu, Cynthia N. Fuhrmann, Satoshi Fujimura, Hiroshi Fujiwara, Jun Fukushima, Keiichi Fukuyama, Robert S. Fuller, Martin Fusek, Christine Gaboriaud, Christian Gache, Oleksandr Gakh, Peter Gal, Junjun Gao, Adolfo García-Sastre, Donald L. Gardiner, John A. Gatehouse, G.M. Gaucher, Francis Gauthier, Jean-Marie Ghuysen, Wade Gibson, Jennifer Gillies, Elzbieta Glaser, Fabian Glaser, Michael H. Glickman, Peter Goettig, Colette Goffin, Eiichi Gohda, Alfred L. Goldberg, Daniel E. Goldberg, Gregory I. Goldberg, Nathan E. Goldfarb, F. Xavier Gomis-Rüth, B. Gopal, Alexander E. Gorbalenya, Stuart G. Gordon, Mark D. Gorrell, Friedrich Götz, Theodoros Goulas, Cécile Gouzy-Darmon, K. Govind, Lászlo Gráf, Robert R. Granados, Melissa Ann Gräwert, Douglas A. Gray, Thomas P. Graycar, Jonathan A. Green, Luiza Helena Gremski, Michael Groll, Tania Yu Gromova, P. Gros, Marvin J. Grubman, Amy M. Grunden, Ágústa Gudmundsdóttir, Micheline Guinand, Djamel Gully, Alla Gustchina, José María Gutiérrez, Byung Hak Ha, Jesper Z. Haeggström, James H. Hageman, Johanna Haiko, Stephan Hailfinger, Hans Michael Haitchi, Ji Seon Han, Chantal Hanquez, Minoru Harada, Ikuko Hara-Nishimura, Marianne Harboe, Torleif Härd, David A. Harris, Ulrich Hassiepen, Shoji Hata, Akira Hattori, Rong-Qiao He, Albert J.R. Heck, Dirk F. Hendricks, Bernhard Henrich, Patrick Henriet, Andrés Hernández-Arana, Irma Herrera-Camacho, Gerhard Heussipp, Toshihiko Hibino, P.M. Hicks, Bradley I. Hillman, B. Yukihiro Hiraoka, Jun Hiratake, Yohei Hizukuri, Heng-Chien Ho, Ngo Thi Hoa, Mark Hochstrasser, Kathryn M. Hodge, Theo Hofmann, Thomas Hohn, John R. Hoidal, Joachim-Volker Höltje, Koichi J. Homma, John F. Honek, Vivian Y.H. Hook, John D. Hooper, Nigel M. Hooper, Kazuo Hosoi, Christopher J. Howe, Dennis E. Hruby, James J.-D. Hseih, Chun-Chieh Hsu, Tony T. Huang, Tur-Fu Huang, Yoann Huet, Clare Hughes, Jean-Emmanuel Hugonnet, Adrienne L. Huston, Oumaïma Ibrahim-Granet, Eiji Ichishima, Yukio Ikehara, Tadashi Inagami, Jessica Ingram, R.E. Isaac, Grazia Isaya, Clara E. Isaza, Shin-ichi Ishii, Amandine Isnard, Kiyoshi Ito, Koreaki Ito, Yoshifumi Itoh, Xavier Iturrioz, Sadaaki Iwanaga, Ralph W. Jack, Mel C. Jackson, Michael N.G. James, Jiří Janata, Claire Janoir, Hanna Janska, Ken F. Jarrell, Mariusz Jaskolski, Sheila S. Jaswal, Ying Y. Jean, Dieter E. Jenne, Young Joo Jeon, Ping Jiang, John E. Johnson, Michael D. Johnson, James A. Johnston, Amanda Jones, Elizabeth W. Jones, Carine Joudiou, Luiz Juliano, Hea-Jin Jung, Ray Jupp, Todd F. Kagawa, Hubert Kalbacher, Yayoi Kamata, Shuichi Kaminogawa, Yoshiyuki Kamio, Makoto Kaneda, Sung Gyun Kang, Sung Hwan Kang, Mary Kania, Tomasz Kantyka, Nobuyuki Kanzawa, Abdulkarim Y. Karim, Takafumi Kasumi, Hiroaki Kataoka, Hardeep Kaur, Shun-Ichiro Kawabata, Mari Kawaguchi, John Kay, Murat Kaynar, Kenneth C. Keiler, R.M. Kelly, Nathaniel T. Kenton, Michael A. Kerr, Kristof Kersse, Jukka Kervinen, Benedikt M. Kessler, Efrat Kessler, Timo K. Khoronen, Simon Kidd, Marjolein Kikkert, Mogens Kilian, Do-Hyung Kim, Doyoun Kim, Eunice EunKyeong Kim, In Seop Kim, Jung-Gun Kim, Kyeong Kyu Kim, Kyung Hyun Kim, Matthew S. Kimber, Yukio Kimura, Heidrun Kirschke, Yoshiaki Kiso, Colin Kleanthous, Jürgen R. Klein, Michael Klemba, Beata Kmiec, Hideyuki Kobayashi, Hiroyuki Kodama, Gerald Koelsch, Jan Kok, P.E. Kolattukody, Fabrice A. Kolb, Harald Kolmar, Yumiko Komori, Jan Konvalinka, Brice Korkmaz, Sergey V. Kostrov, Hans-Georg Kräusslich, Gabi Krczal, Lawrence F. Kress, Magnüs Már Kristjánsson, Tomáš Kučera, Sayali S. Kukday, Hidehiko Kumagai, Sharad Kumar, Malika Kumarasiri, Takashi Kumazaki, Beate M. Kümmerer, Kouji Kuno, Markku Kurkinen, Eva Kutejová, Marie Kveiborg, Agnieszka Kwarciak, Liisa Laakkonen, Nikolaos E. Labrou, Gavin D. Laing, Gayle Lamppa, Thomas Langer, Richard A. Laursen, Richard A. Lawrenson, Matthew D. Layne, Bernard F. Le Bonniec, María C. Leal, Ronald M. Lechan, David H. Lee, Irene Lee, Jae Lee, Kye Joon Lee, Soohee Lee, Xiaobo Lei, Jonathan Leis, Ellen K. LeMosy, Thierry Lepage, Stephen H. Leppla, Adam Lesner, Ivan A.D. Lessard, Guy Lhomond, Huilin Li, Shu-Ming Li, Weiguo Li, Ta-Hsiu Liao, Robert C. Liddington, Toby Lieber, H.R. Lijnen, Christopher D. Lima, Chen-Yong Lin, Gang Lin, Ming T. Lin, Xinli Lin, Yee-Shin Lin, L.L. Lindsay, William N. Lipscomb, John W. Little, Ching-Chuan Liu, Chuan-ju Liu, Mark O. Lively, Nurit Livnat-Levanon, Per O. Ljungdahl, Catherine Llorens-Cortes, Peter Lobel, Y. Peng Loh, Jouko Lohi, G.P. Lomonossoff, Yvan Looze, Carlos López-Otin, Landys Lopez-Quezada, Alex Loukas, Long-Sheng Lu, Áke Lundwall, Liu-Ying Luo, Andrei Lupas, Dawn S. Luthe, Nicholas J. Lynch, Peter J. Lyons, Vivian L. MacKay, Jesica M. Levingston Macleod, Viktor Magdolen, Jean-Luc Mainardi, Kauko K. Mäkinen, Jeremy P. Mallari, Surya P. Manandhar, Fajga R. Mandelbaum, Anne M. Manicone, Johanna Mansfeld, Joseph Marcotrigiano, Michael Mares, Gemma Marfany, Francis S. Markland, Judith Marokházi, Hélène Marquis, Robert A. Marr, Enzo Martegani, Erik W. Martin, Manuel Martinez, L. Miguel Martins, Masato Maruyama, Masugi Maruyama, Sususmu Maruyama, Takeharu Masaki, Ramin Massoumi, Rency T. Mathew, Lynn M. Matrisian, Yoshihiro Matsuda, Osamu Matsushita, Marco Matuschek, Anna Matušková, Krisztina Matúz, Cornelia Mauch, Michael R. Maurizi, Lorenz M. Mayr, Dewey G. McCafferty, J. Ken McDonald, James H. McKerrow, David McMillan, Robert P. Mecham, Darshini P. Mehta, Chris Meisinger, Alan Mellors, Roger G. Melton, Jeffrey A. Melvin, Robert Ménard, Luis Menéndez-Arias, Milene C. Menezes, Andrew Mesecar, Stéphane Mesnage, Diane H. Meyer, Gregor Meyers, Susan Michaelis, Karolina Michalska, Wojciech P. Mielicki, Igor Mierau, Galina V. Mikoulinskaia, Charles G. Miller, Lydia K. Miller, John Mills, Kenneth V. Mills, Jinrong Min, Michel-Yves Mistou, Yoshio Misumi, Shin-ichi Miyoshi, Shigehiko Mizutani, Shahriar Mobashery, Satsuki Mochizuki, William L. Mock, Frank Möhrlen, Nathalie Moiré, Paul E. Monahan, Angela Moncada-Pazos, Véronique Monnet, Michel Monod, Cesare Montecucco, Laura Morelli, Sumiko Mori, Takashi Morita, James H. Morrissey, Richard J. Morse, John S. Mort, Uffe H. Mortensen, Rory E. Morty, Joel Moss, Hidemasa Motoshima, Jeremy C. Mottram, Ana M. Moura-da-Silva, Mary Beth Mudgett, Egbert Mundt, Kazuo Murakami, Mario Tyago Murakami, Kimiko MurakamiMurofoshi, Sawao Murao, Gillian Murphy, M.R.N. Murthy, Tatsushi Muta, Elmarie Myburgh, Nino Mzhavia, A.H.M. Nurun Nabi, Hideaki Nagase, Michael W. Nagle, Dorit K. Nägler, Rajesh R. Naik, Divya B. Nair, Toshiki Nakai, Yoshitaka Nakajima, Yukio Nakamura, Hitoshi Nakatogawa, Toru Nakayama, Natalia N. Nalivaeva, Dipankar Nandi, Maria Clara Leal Nascimento-Silva, Kim Nasmyth, Carl F. Nathan, Fernando Navarro-García, Dayane Lorena Naves, Danny D. Nedialkova, Keir C. Neuman, Jeffrey-Tri Nguyen, Ky-Anh Nguyen, Gabriela T. Niemirowicz, Toshiaki Nikai, Eiichiro Nishi, Wataru Nishii, Makoto Nishiyama, Yasuhiro Nishiyama, Masatoshi Noda, Seiji Nomura, Shigemi Norioka, Desire M.M. Nsangou, Amornrat O’Brien, Michael B. O’Connor, Kohei Oda, Irina V. Odinokova, Joyce Oetjen, Teru Ogura, Dennis E Ohman, Yoshinori Ohsumi, Mukti Ojha, Akinobu Okabe, Yasunori Okada, Keinosuke Okamoto, Kenji Okuda, Nobuaki Okumura, Takashi Okuno, Kjeld Oleson, Priscila Oliveira de Giuseppe, Martin Olivier, Yasuko Ono, Stephen Oroszlan, Nobuyuki Ota, Michael Ovadia, Jiyang O-Wang, Claus Oxvig, Jeremy C.L. Packer, Sergio Padilla-López, Mark Paetzel, Michael J. Page, Andrea Page-McCaw, Mark J.I. Paine, Byoung Chul Park, Eunyong Park, John E. Park, Pyong Woo Park, Sung Goo Park, Kirk L. Parkin, William C Parks, Thaysa Paschoalin, Annalisa Pastore, Alexander Nikolich Patananan, Sudhir Paul, Henry L. Paulson, Ulrich von Pawel-Rammingen, David A. Pearce, Mark S. Pearson, Duanqing Pei, Gunnar Pejler, Alan D. Pemberton, Jianhao Peng, Julien Pernier, Jan-Michael Peters, Thorsten Pfirrmann, Viet-Laï Pham, Iva Pichová, Darren Pickering, Christophe Piesse, David Pignol, Robert N. Pike, Lothaire Pinck, Hubert Pirkle, Henry C. Pitot, Andrew G. Plaut, Hidde Ploegh, László Polgár, Corrine Porter, Rolf Postina, Jan Potempa, Knud Poulsen, Scott D. Power, Rex. F. Pratt, Gerd Prehna, Gilles Prévost, Alexey V. Pshezhetsky, Mohammad A. Qasim, Feng Qian, Jiazhou Qiu, Víctor Quesada, Evette S. Radisky, Stephen D. Rader, Kavita Raman, Andrew J. Ramsay, Derrick E. Rancourt, Najju Ranjit, Narayanam V. Rao, Kiira Ratia, Neil D. Rawlings, Robert B. Rawson, Vijay Reddy, Colvin M. Redman, Maria Elena Regonesi, Andreas S. Reichert, Antonia P. Reichl, Han Remaut, S. James Remington, Martin Renatus, David Reverter, Eric C. Reynolds, Mohamed Rholam, Charles M. Rice, Todd W. Ridky, Howard Riezman, D.C. Rijken, Marie-Christine Rio, Alison Ritchie, Janine Robert-Baudouy, Mark W. Robinson, Michael Robinson, Adela Rodriguez-Romero, Renata Santos Rodriques, John C. Rogers, Camilo Rojas, Floyd E. Romesberg, David J. Roper, Nora Rosas-Murrieta, A.M. Rose, Philip J. Rosenthal, J. Rosing, Ornella Rossetto, Véronique Rossi, Richard A. Roth, Hanspeter Rottensteiner, Andrew D. Rowan, Mikhail Rozanov, Alexandra Rucavado, Andrea Ruecker, Françoise Rul, Till Rümenapf, Ilaria Russo, Martin D. Ryan, Elena Sacco, J. Evan Sadler, W. Saenger, Hans-Georg Sahl, Mohammed Sajid, Masayoshi Sakaguchi, Fumio Sakiyama, Maria L. Salas, Maria Cristina O. Salgado, Guy S. Salvesen, Edith Sánchez, Eladio F. Sanchez, Qing-Xiang Amy Sang, Krishnan Sankaran, Susanta K. Sarkar, Michael P. Sarras, Yoshikiyo Sasagawa, Araki Satohiko, Eric Sauvage, Loredana Saveanu, H.S. Savithri, Hitoshi Sawada, R. Gary Sawers, Isobel A. Scarisbrick, Andreas Schaller, Justin M. Scheer, Friedrich Scheiflinger, Cordelia Schiene-Fischer, Uwe Schlomann, Manfred Schlösser, Alvin H. Schmaier, Walter K. Schmidt, Anette Schneemann, Rick G. Schnellmann, Henning Scholze, Lutz Schomburg, Wilhelm J. Schwaeble, Christopher J. Scott, Rosaria Scudiero, Atsuko Sehara-Fujisawa, Nabil G. Seidah, Motoharu Seiki, Junichi Sekiguchi, Andrea Senff-Ribeiro, Ihn Sik Seong, Mihaela Serpe, Solange M.T. Serrano, Peter Setlow, Tina Shahian, M. Shanks, Feng Shao, Steven D. Shapiro, Navneet Sharma, Lindsey N. Shaw, Aimee Shen, Lei Shen, Roger F. Sherwood, Yun-Bo Shi, Hitoshi Shimoi, Yoichiro Shimura, A.D. Shirras, Viji Shridhar, Jinal K. Shukla, Ene Siigur, Jüri Siigur, Natalie C. Silmon de Monerri, Robert B. Sim, James P. Simmer, William H. Simmons, Jaspreet Singh, Alison Singleton, Tatiana D. Sirakova, Titia K. Sixma, Tim Skern, Randal A. Skidgel, Jeffrey Slack, David E. Sleat, Barbara S. Slusher, Janet L. Smith, Matthew A. Smith, Mark J. Smyth, Erik J. Snijder, Solmaz Sobhanifar, Kenneth Söderhaäll, Istvan Sohar, Peter Sonderegger, Marcos Henrique Ferreira Sorgine, Hiroyuki Sorimachi, Karen E. Soukhodolets, Tatiana de Arruda Campos Brasil de Souza, Tamás Sperka, Shiranee Sriskandan, Joseph W. St. Geme, Raymond J. St. Leger, Peter Staib, James L. Steele, Bjarki Stefansson, Christian Steinkühler, Leisa M. Stenberg, Johan Stenflo, Henning R. Stennicke, Valentin M. Stepanov, Olga A. Stepnaya, Frank Steven, Richard L. Stevens, Kenneth J. Stevenson, Mathieu St-Louis, Christopher C. Stobart, Walter Stöcker, Andrew C. Storer, Norbert Sträter, Ellen G. Strauss, James H. Strauss, Kvido Stříšovský, Natalie C.J. Strynadka, Edward D. Sturrock, Dan Su, Xiao-Dong Su, Paz Suárez-Rendueles, Traian Sulea, Venkatesh Sundararajan, Ryoji Suno, Carolyn K. Suzuki, Fumiaki Suzuki, Hideyuki Suzuki, Nobuhiro Suzuki, Stephen Swenson, Rose L. Szabady, Pal Bela Szecsi, Lászlo Szilágyi, Muhamed-Kheir Taha, Eizo Takahashi, Kenji Takahashi, Toshiro Takai, Atsushi Takeda, Soichi Takeda, Jeremy J.R.H. Tame, Tomohiro Tamura, Fulong Tan, Keiji Tanaka, Carmen Tanase, Jordan Tang, Martha M. Tanizaki, Egbert Tannich, Guido Tans, Anthony L. Tarentino, Anchalee Tassanakajon, Hiroki Tatsumi, Norbert Tautz, Erin Bassford Taylor, Pedro Filipe Teixeira, Bhanu Prakash V.L. Telugu, Markus F. Templin, Shigeyuki Terada, Uchikoba Tetsuya, C. Thacker, Maulik Thaker, Heinz-Jürgen Thiel, Nicole Thielens, Gonzales Thierry, Karine Thivierge, Mark D. Thomas, Margot Thome, Mary K. Thorsness, Peter E. Thorsness, Natalie J. Tigue, Sokol V. Todi, Birgitta Tomkinson, Fiorella Tonello, Liang Tong, H.S. Toogood, Paolo Tortora, József Tözsèr, Luiz Rodolpho Travassos, James Travis, Dilza Trevisan-Silva, Francesca Trinchella, Neil N. Trivedi, Carol M. Troy, Harald Tschesche, Yu-Lun Tseng, Masafumi Tsujimoto, Anthony T. Tu, Kathleen E. Tumelty, Boris Turk, Dusan Turk, Vito Turk, Anthony J. Turner, Tetsuya Uchikoba, Takayuki Ueno, Alejandro P. Ugalde, Veli-Jukka Uitto, Sinisa Urban, Olivier Valdenaire, Adrian Valli, Jozef Van Beeumen, Bertus Van den Burg, Renier A.L. Van der Hoorn, Jan Maarten van Dijl, Peter Van Endert, Bram J. Van Raam, Harold E. Van Wart, Tom Vanden Berghe, Peter Vandenabeele, Margo Vanoni, Silvio Sanches Veiga, William H. Velander, Gloria Velasco, Josep Vendrell, I. István Venekei, Vaclav Vetvicka, F.-Nora Vögtle, Waldemar Vollmer, Kei Wada, Fred W. Wagner, Sun Nyunt Wai, Timothy Wai, Shane Wainwright, Kenneth W. Walker, Stephen J. Walker, Jean Wallach, Linda L. Walling, Peter N. Walsh, Hai-Yan Wang, Hengbin Wang, Jianwei Wang, Peng Wang, Ping Wang, Michael Wassenegger, Kunihiko Watanabe, Helen Webb, Joseph M. Weber, Niklas Weber, Daniel R. Webster, Shuo Wei, Rodney A. Welch, James A. Wells, Herbert Wenzel, Ingrid E. Wertz, Ulla W. Wewer, Alison R. Whyteside, Sherwin Wilk, Jean-Marc Wilkin, Claudia Wilmes, Jakob R. Winther, David S. Wishart, Alexander Wlodawer, J. Fred Woessner, Michael S. Wolfe, Wilson Wong, Roger Woodgate, Gerry Wright, Jiunn-Jong Wu, Qingyu Wu, Magdalena Wysocka, Chao Xu, Zhenghong Xu, Kinnosuke Yahori, Shoji Yamada, Nozomi Yamaguchi, Shinji Yamaguchi, Yoshio Yamakawa, Hiroki Yamamoto, Ikao Yana, Maozhou Yang, Na Yang, Chenjuan Yao, Tingting Yao, Noriko Yasuda, Toshimasa Yasuhara, Shigeki Yasumasu, Edward T.H. Yeh, Irene Yiallouros, Jiang Yin, Hiroo Yonezawa, Soon Ji Yoo, Tadashi Yoshimoto, Michael W. Young, Stephen G. Young, Nousheen Zaidi, Ludmila L. Zavalova, Peter Zavodszky, Aidong Zhang, Xianming Zhang, Yi-Zheng Zhang, Dominick Zheng, Guangming Zhong, Rong Zhong, Yuan Zhou, Zhaohui Sunny Zhou, Michael Zick, Paola Zigrino, and Andrei A. Zimin

Published
2013

18. Micromanaging aging with miRNAs. New messages from the nuclear envelope

Author

Yaiza Español, Alejandro P. Ugalde, and Carlos López-Otín

Subjects
Senescence, Longevity, Helminth genetics, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Progeria, microRNA, medicine, Animals, Humans, Caenorhabditis elegans, 030304 developmental biology, Genetics, Regulation of gene expression, 0303 health sciences, Membrane Proteins, Metalloendopeptidases, Cell Biology, biology.organism_classification, medicine.disease, Phenotype, 3. Good health, Disease Models, Animal, MicroRNAs, 030220 oncology & carcinogenesis, Nuclear lamina, RNA, Helminth, DNA Damage
Abstract

Over the last years, the discovery of microRNAs (miRNAs) has revolutionized the classic concepts of gene expression regulation and has introduced a new group of molecules that may contribute to the complex changes observed during aging. Although several Caenorhabditis elegans miRNAs have been proved to influence the nematode life span, the current knowledge about miRNA-mediated regulation of mammalian aging is still limited. Recently, we have analyzed the functional relevance of miRNAs in accelerate aging by using Zmpste24-/- mice, a murine model that phenocopies Hutchinson-Gilford progeria syndrome. These studies have revealed that the nuclear abnormalities present in these mice affect the expression levels of several miRNAs, including a marked upregulation of miR-1 and miR-29. Furthermore, we have found that the altered expression of these miRNAs may contribute to the progeroid phenotype of mutant mice by modulating the levels of key components of the somatroph axis and DNA damage response pathways. Here, we discuss these recent discoveries and summarize the present evidences regarding the involvement of aging-associated miRNAs or geromiRs in senescence and longevity regulation.

Published
2011

19. Cell autonomous and systemic factors in progeria development

Author

Carlos López-Otín, Fernando G. Osorio, Guillermo Mariño, Alejandro P. Ugalde, José M.P. Freije, and Xose S. Puente

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Biology, medicine.disease_cause, Biochemistry, Progeroid syndromes, LMNA, 03 medical and health sciences, Progeria, 0302 clinical medicine, medicine, Animals, Humans, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, integumentary system, Membrane Proteins, nutritional and metabolic diseases, medicine.disease, Somatotrophs, 3. Good health, Cell biology, Mandibuloacral dysplasia, MicroRNAs, Nuclear lamina, Tumor Suppressor Protein p53, Restrictive dermopathy, 030217 neurology & neurosurgery, Lamin, DNA Damage
Abstract

Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson–Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor–Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging.

Published
2011

20. Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

Author

Antonio Fueyo, José M.P. Freije, Álvaro F. Fernández, Carlos López-Otín, Guillermo Mariño, Alejandro P. Ugalde, and Fernando G. Osorio

Subjects
Premature aging, medicine.medical_specialty, endocrine system, Somatotropic cell, medicine.medical_treatment, Longevity, Biology, Progeroid syndromes, Insulin-like growth factor, Mice, Internal medicine, medicine, Animals, Insulin-Like Growth Factor I, Phenocopy, Mice, Knockout, Progeria, Multidisciplinary, Base Sequence, Growth factor, Gene Expression Profiling, Membrane Proteins, Metalloendopeptidases, Aging, Premature, Biological Sciences, medicine.disease, Somatotrophs, Disease Models, Animal, MicroRNAs, Endocrinology, Gene Expression Regulation, Liver, Growth Hormone, Lamin
Abstract

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson–Gilford progeria syndrome. In this work, we report that progeroid Zmpste24 -/ − mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24 -/ − mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.

Published
2010

21. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53

Author

Alejandro P, Ugalde, Andrew J, Ramsay, Jorge, de la Rosa, Ignacio, Varela, Guillermo, Mariño, Juan, Cadiñanos, Jun, Lu, José Mp, Freije, and Carlos, López-Otín

Subjects
Mice, Knockout, Aging, Molecular Sequence Data, Membrane Proteins, Metalloendopeptidases, Sequence Analysis, DNA, Fibroblasts, Article, Protein Phosphatase 2C, Disease Models, Animal, Mice, MicroRNAs, Gene Expression Regulation, Phosphoprotein Phosphatases, Animals, Tumor Suppressor Protein p53, Cells, Cultured, DNA Damage
Abstract

Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson-Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24(-/-) progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53(-/-) murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage.

Published
2010

22. Metalloproteases and the degradome

Author

Alejandro P, Ugalde, Gonzalo R, Ordóñez, Pedro M, Quirós, Xose S, Puente, and Carlos, López-Otín

Subjects
Amino Acid Motifs, Biocatalysis, Metalloproteases, Animals, Humans, Disease, Protein Processing, Post-Translational
Abstract

Metalloproteases comprise a heterogeneous group of proteolytic enzymes whose main characteristic is the utilization of a metal ion to polarize a water molecule and perform hydrolytic reactions. These enzymes represent the most densely populated catalytic class of proteases in many organisms and play essential roles in multiple biological processes. In this chapter, we will first present a general description of the complexity of metalloproteases in the context of the degradome, which is defined as the complete set of protease genes encoded by the genome of a certain organism. We will also discuss the functional relevance of these enzymes in a large variety of biological and pathological conditions. Finally, we will analyze in more detail three families of metalloproteases: ADAMs (a disintegrin and metalloproteinase), ADAMTSs (ADAMs with thrombospondin domains), and MMPs (matrix metalloproteinases) which have a growing relevance in a number of human pathologies including cancer, arthritis, neurodegenerative disorders, and cardiovascular diseases.

Published
2010

23. Metalloproteases and the Degradome

Author

Xose S. Puente, Alejandro P. Ugalde, Carlos López-Otín, Pedro M. Quirós, and Gonzalo R. Ordóñez

Subjects
Metalloproteinase, Thrombospondin, Proteases, biology, Disintegrin, biology.protein, Proteolytic enzymes, Context (language use), Computational biology, Matrix metalloproteinase, Genome
Abstract

Metalloproteases comprise a heterogeneous group of proteolytic enzymes whose main characteristic is the utilization of a metal ion to polarize a water molecule and perform hydrolytic reactions. These enzymes represent the most densely populated catalytic class of proteases in many organisms and play essential roles in multiple biological processes. In this chapter, we will first present a general description of the complexity of metalloproteases in the context of the degradome, which is defined as the complete set of protease genes encoded by the genome of a certain organism. We will also discuss the functional relevance of these enzymes in a large variety of biological and pathological conditions. Finally, we will analyze in more detail three families of metalloproteases: ADAMs (a disintegrin and metalloproteinase), ADAMTSs (ADAMs with thrombospondin domains), and MMPs (matrix metalloproteinases) which have a growing relevance in a number of human pathologies including cancer, arthritis, neurodegenerative disorders, and cardiovascular diseases.

Published
2010

24. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging

Author

María F. Suárez, Ignacio Varela, Juan Cobo, Juan Cadiñanos, José M.P. Freije, Félix de Carlos, Claire Navarro, Pierre Cau, Alejandro P. Ugalde, Nicolas Lévy, Carlos López-Otín, Fernando G. Osorio, Nicolas Foray, Sandrine Pereira, Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo-Instituto Universitario de Oncología, Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Cirugía y Especialidades Médico-Quirúrgicas, Universidad de Oviedo-Instituto Asturiano de Odontología, Collaboration, Universidad de Oviedo [Oviedo]-Instituto Universitario de Oncología, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Synchrotron Radiation Facility (ESRF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Oviedo [Oviedo]-Instituto Asturiano de Odontología, and Serduc, Raphael

Subjects
Farnesyltransferase, Zoledronic Acid, MESH: Mice, Knockout, Progeroid syndromes, Mice, 0302 clinical medicine, Geranylgeranylation, MESH: Animals, MESH: Aging, Premature, Enzyme Inhibitors, Pravastatin, Genetics, Mice, Knockout, 0303 health sciences, Progeria, Bone Density Conservation Agents, Diphosphonates, integumentary system, Imidazoles, MESH: Pravastatin, Aging, Premature, General Medicine, Progerin, Immunohistochemistry, MESH: Models, Animal, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Models, Animal, Drug Therapy, Combination, Lipodystrophy, MESH: Imidazoles, Premature aging, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Diphosphonates, Biology, General Biochemistry, Genetics and Molecular Biology, MESH: Bone Density Conservation Agents, 03 medical and health sciences, Prenylation, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Farnesyltranstransferase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Farnesyltranstransferase, MESH: Hydroxymethylglutaryl-CoA Reductase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Prenylation, nutritional and metabolic diseases, MESH: Immunohistochemistry, medicine.disease, MESH: Drug Therapy, Combination, Cancer research, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors
Abstract

International audience; Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.

Published
2008

25. Premature aging in mice activates a systemic metabolic response involving autophagy induction

Author

Guillermo Mariño, Alejandro P. Ugalde, Carlos López-Otín, José M.P. Freije, Ingrid van der Pluijm, Pedro M. Quirós, Ignacio Varela, Juan Cadiñanos, Natalia Salvador-Montoliu, and Molecular Genetics

Subjects
Premature aging, medicine.medical_specialty, Receptors, Retinoic Acid, Cellular homeostasis, Mice, Transgenic, AMP-Activated Protein Kinases, Protein Serine-Threonine Kinases, Biology, Mice, Progeria, AMP-Activated Protein Kinase Kinases, Internal medicine, Autophagy, Genetics, medicine, Animals, Humans, Molecular Biology, Genetics (clinical), PI3K/AKT/mTOR pathway, Werner syndrome, Receptors, Thyroid Hormone, Membrane Proteins, Metalloendopeptidases, Aging, Premature, General Medicine, Nuclear Receptor Subfamily 1, Group F, Member 3, Lipid Metabolism, medicine.disease, Hormones, Disease Models, Animal, Metabolic pathway, Glucose, Endocrinology, Ageing, Microtubule-Associated Proteins, Protein Kinases, Signal Transduction
Abstract

Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster. In this work, we describe the unexpected finding that Zmpste24-null mice, which show accelerated aging and are a reliable model of human Hutchinson-Gilford progeria, exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. We also show that this autophagic increase is associated with a series of changes in lipid and glucose metabolic pathways, which resemble those occurring in diverse situations reported to prolong lifespan. These Zmpste24(-/-) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition. On the basis of these results, we propose that nuclear abnormalities causing premature aging in Zmpste24(-/-) mice trigger a metabolic response involving the activation of autophagy. However, the chronic activation of this catabolic pathway may turn an originally intended pro-survival strategy into a pro-aging mechanism and could contribute to the systemic degeneration and weakening observed in these progeroid mice.

Published
2008

26. Identification of human aminopeptidase O, a novel metalloprotease with structural similarity to aminopeptidase B and leukotriene A4 hydrolase

Author

Araceli Díaz-Perales, Víctor Quesada, Luis M. Sánchez, Antonio Fueyo, Alejandro P. Ugalde, Carlos López-Otín, and María F. Suárez

Subjects
Protein Conformation, Angiotensin III, Molecular Sequence Data, Biology, Biochemistry, Aminopeptidase, Aminopeptidases, law.invention, Leukotriene-A4 hydrolase, Aminopeptidase B, law, Complementary DNA, Animals, Humans, Tissue Distribution, Northern blot, Amino Acid Sequence, Molecular Biology, Armadillo Domain Proteins, Epoxide Hydrolases, Metalloproteinase, Base Sequence, Brain, Cell Biology, Molecular biology, Recombinant Proteins, Protein Structure, Tertiary, Recombinant DNA, Trans-Activators, Sequence Alignment
Abstract

We have cloned and characterized a human brain cDNA encoding a new metalloprotease that has been called aminopeptidase O (AP-O). AP-O exhibits a series of structural features characteristic of aminopeptidases, including a conserved catalytic domain with a zinc-binding site (HEXXHX18E) that allows its classification in the M1 family of metallopeptidases or gluzincins. The structural complexity of AP-O is further increased by the presence of an additional C-terminal domain 170 residues long, which is predicted to have an ARM repeat fold originally identified in the Drosophila segment polarity gene product Armadillo. This ARM repeat domain is also present in aminopeptidase B, aminopeptidase B-like, and leukotriene A4 hydrolase and defines a novel subfamily of aminopeptidases that we have called ARM aminopeptidases. Northern blot analysis revealed that AP-O is mainly expressed in the pancreas, placenta, liver, testis, and heart. Human AP-O was produced in Escherichia coli, and the purified recombinant protein hydrolyzed synthetic substrates used for assaying aminopeptidase activity. This activity was abolished by general inhibitors of metalloproteases and specific inhibitors of aminopeptidases. Recombinant AP-O also cleaved angiotensin III to generate angiotensin IV, a bioactive peptide of the renin-angiotensin pathway with multiple actions on diverse tissues, including brain, testis, and heart. On the basis of these results we suggest that AP-O could play a role in the proteolytic processing of bioactive peptides in those tissues where it is expressed.

Published
2005

27. Identification and characterization of human archaemetzincin-1 and -2, two novel members of a family of metalloproteases widely distributed in archaea

Author

Jesus Alvarez, Víctor Quesada, F. Xavier Gomis-Rüth, Juan R. Peinado, Alejandro P. Ugalde, Carlos López-Otín, Araceli Díaz-Perales, and María F. Suárez

Subjects
Male, Nematoda, medicine.medical_treatment, ved/biology.organism_classification_rank.species, Amino Acid Motifs, Biochemistry, Genome, Mass Spectrometry, Genome, Archaeal, Catalytic Domain, Testis, Tissue Distribution, Trypsin, Phylogeny, chemistry.chemical_classification, Genetics, Hydrolysis, Proteolytic enzymes, Gene Expression Regulation, Developmental, Hydrogen-Ion Concentration, Recombinant Proteins, Liver, Horizontal gene transfer, Viruses, Protein Binding, Proteases, DNA, Complementary, Cells, Molecular Sequence Data, Biology, Catalysis, Evolution, Molecular, medicine, Escherichia coli, Humans, Amino Acid Sequence, Model organism, Molecular Biology, Gene, Vertebrata, Protease, Tissue, Base Sequence, Sequence Homology, Amino Acid, ved/biology, Myocardium, Computational Biology, Polypeptides, Cell Biology, Sequence Analysis, DNA, Blotting, Northern, Archaea, Protein Structure, Tertiary, Enzyme, chemistry, Genes, Metalloproteases, Peptides
Abstract

Systematic analysis of degradomes, the complete protease repertoires of organisms, has demonstrated the large and growing complexity of proteolytic systems operating in all cells and tissues. We report here the identification of two new human metalloproteases that have been called archaemetzincin-1 (AMZ1) and archaemetzincin-2 (AMZ2) to emphasize their close relationship to putative proteases predicted by bioinformatic analysis of archaeal genomes. Both human proteins contain a catalytic domain with a core motif (HEXXHXXGX 3CX4CXMX17CXXC) that includes an archetypal zinc-binding site, the methionine residue characteristic of metzincins, and four conserved cysteine residues that are not present at the equivalent positions of other human metalloproteases. Analysis of genome sequence databases revealed that AMZs are widely distributed in Archaea and vertebrates and contribute to the defining of a new metalloprotease family that has been called archaemetzincin. However, AMZ-like sequences are absent in a number of model organisms from bacteria to nematodes. Phylogenetic analysis showed that these enzymes have undergone a complex evolutionary process involving a series of lateral gene transfer, gene loss, and genetic duplication events that have shaped this novel family of metalloproteases. Northern blot analysis showed that AMZ1 and AMZ2 exhibit distinct expression patterns in human tissues. AMZ1 is mainly detected in liver and heart whereas AMZ2 is predominantly expressed in testis and heart, although both are also detectable at lower levels in other tissues. Both human enzymes were produced in Escherichia coli, and the purified recombinant proteins hydrolyzed synthetic substrates and bioactive peptides, demonstrating that they are functional proteases. Finally, these activities were abolished by inhibitors of metalloproteases, providing further evidence that AMZs belong to this catalytic class of proteolytic enzymes. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc., This work was supported by grants from Ministerio de Ciencia y Tecnología-Spain, Fundación La Caixa, the European Union (FP5 and FP6-Cancer Degradome), and the Daiichi Fine Chemical Company, Limited (Toyama, Japan)

Published
2005

28. Cell autonomous and systemic factors in progeria development.

Author

Fernando G. Osorio, Alejandro P. Ugalde, Guillermo Mariño, Xose S. Puente, José M.P. Freije, and Carlos López‑Otín

Subjects
*PROGERIA, *AGING, *GENETIC mutation, *GENETICS, *CELLULAR control mechanisms, *LAMINA epithelialis
Abstract

Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson–Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor–Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging. [ABSTRACT FROM AUTHOR]

Published
2011
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29. Rejuvenating somatotropic signaling: a therapeutical opportunity for premature aging?

Author

Guillermo Mariño, Alejandro P. Ugalde, and Carlos López-Otín

Subjects
Premature aging, Aging, medicine.medical_specialty, endocrine system, Somatotropic cell, Genotype, medicine.medical_treatment, media_common.quotation_subject, Longevity, Biology, Progeroid syndromes, insulin-like growth factor, 03 medical and health sciences, Insulin-like growth factor, Mice, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Rejuvenation, cancer, Insulin-Like Growth Factor I, 030304 developmental biology, media_common, Phenocopy, Mice, Knockout, 0303 health sciences, Progeria, Membrane Proteins, Metalloendopeptidases, progeria, Aging, Premature, Cell Biology, medicine.disease, Recombinant Proteins, 3. Good health, Endocrinology, Phenotype, Growth Hormone, Research Perspective, Signal transduction, 030217 neurology & neurosurgery, Signal Transduction
Abstract

We have recently reported that progeroid Zmpste24-/- mice, which exhibit multiple defects that phenocopy Hutchinson-Gilford progeria syndrome, show a profound dysregulation of somatotropic axis, mainly characterized by the occurrence of very high circulating levels of growth hormone (GH) and a drastic reduction in insulin-like growth factor-1 (IGF-1). We have also shown that restoration of the proper GH/IGF-1 balance in Zmpste24-/- mice by treatment with recombinant IGF-1 delays the onset of many progeroid features in these animals and significantly extends their lifespan. Here, we summarize these observations and discuss the importance of GH/IGF-1 balance in longevity as well as its modulation as a putative therapeutic strategy for the treatment of human progeroid syndromes.

30. Biodiversity responses to land-use change in the equatorial Andes

Author

Blanca Ríos-Touma, Paulina Rosero, Andrés Morabowen, Juan M. Guayasamin, Chelsea Carson, Santiago Villamarín-Cortez, Alejandro Solano-Ugalde, Ibon Tobes, and Francisco Cuesta

Subjects
Diversity metrics, Rarity, NDMs, Montane forests. agroforestry, Ecology, QH540-549.5
Abstract

Land-use change is a primary driver of biodiversity loss. Tropical ecosystems face rapid conversion rates due to the encroachment of agricultural lands and supply needs for goods and services from an increasing population and changing market demands. Measuring the effect of land conversion on species diversity is challenging due to incomplete and uneven knowledge of different taxonomical groups. Here, we contrast different metrics for measuring biodiversity loss across three land-use typologies: secondary forest, agroforestry, and monoculture for five taxonomic groups: birds, frogs, fish, dung beetles, and macroinvertebrates in the Andean piedmont forests of the western equatorial Andes. Albeit our limited and uneven sample in space and time, we found that rarity, Non-Metric Multidimensional Scaling, and Multinomial Classification Model (i.e., classifications of habitat specialists and generalists) constitute a more sensitive set of indicators to assess land-use change impacts on tropical mountain biodiversity compared to classical metrics. Likewise, our results showed that land-use intensification influenced community assemblages in the five taxonomic groups. These non-classical biodiversity metrics can provide better insight into the effect of land conversion on these highly biodiverse ecosystems composed of many rare species.

Published
2023
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31. The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function.

Author

Xurde M Caravia, Víctor Fanjul, Eduardo Oliver, David Roiz-Valle, Alba Morán-Álvarez, Gabriela Desdín-Micó, María Mittelbrunn, Roberto Cabo, José A Vega, Francisco Rodríguez, Antonio Fueyo, Mónica Gómez, Manuel Lobo-González, Héctor Bueno, Gloria Velasco, José M P Freije, Vicente Andrés, Borja Ibáñez, Alejandro P Ugalde, and Carlos López-Otín

Subjects
Biology (General), QH301-705.5
Abstract

Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely. We also found evidence that the absence of miR-29 triggers the up-regulation of its target, the master metabolic regulator PGC1α, which in turn generates profound alterations in mitochondrial biogenesis, leading to a pathological accumulation of small mitochondria in mutant animals that contribute to cardiac disease. Notably, we demonstrate that systemic hypertension and HFpEF caused by miR-29 deficiency can be rescued by PGC1α haploinsufficiency, which reduces cardiac mitochondrial accumulation and extends longevity of miR-29-mutant mice. In addition, PGC1α is overexpressed in hearts from patients with HF. Collectively, our findings demonstrate the in vivo role of miR-29 in cardiovascular homeostasis and unveil a novel miR-29/PGC1α regulatory circuitry of functional relevance for cell metabolism under normal and pathological conditions.

Published
2018
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32. Rare birds in Ecuador: Second annual report of the Committee for Ecuadorian Records in Ornithology (CERO)

Author

Jonas Nilsson, Juan F. Freile, Roger Ahlman, Dušan Milan Brinkhuizen, Paul J. Greenfield, and Alejandro Solano-Ugalde

Subjects
Distribución, estado, aves, Ecuador, Engineering (General). Civil engineering (General), TA1-2040, Science (General), Q1-390
Abstract

We summarize bird species records submitted to the Committee for Ecuadorian Records in Ornithology (CERO) from July 2013 to March 2014. CERO compiles Ecuador’s official country checklist and updates it annually. We present four new country records (Amazonetta brasiliensis, Porzana albicollis, Haematopus ater, Chroicocephalus Philadelphia), one new country record that antedates earlier records (Vireo flavifrons), first voucher documentation for four species (Larus californicus, Pangara guttata, Conirostrum bicolor, Cardellina pusilla), and 26 significant range extensions or records of rare and poorly known species (Oceanodroma leucorhoa, Oceanodroma hornbyi, Sula leucogaster, Phalacrocorax bougainvillii, Butorides virescens, Ardea herodias, Egretta rufescens, Egretta caerulea, Eudocimus albus, Eudocimus ruber, Anas clypeata, Anas cyanoptera, Aythya afflnis, Gallinago delicata, Limosa fedoa, Larus delawarensis, Hydroprogne caspia, Glaucidium griseiceps, Chloroceryle aenea, Platyrinchus saturatus, Myiarchus crinitus, Tyrannus niveigularis, Knipolegus poecilurus, Doliomis remseni, Setophaga castanea, Lonchura malacca). Three records are from the Galapagos Islands (Oceanodroma leucorhoa, Butorides virescens, Egretta caerulea), while all others were obtained in mainland Ecuador. Six species are eliminated from the Ecuadorian list (Geotrygon violácea, Topaza pella, Attila bolivianos, Pachyramphus rufus, Pachyramphus validus, Lonchura atricapilla). Two additional records were postponed for further expert revision (Thalassarche cauta) or for additional evidence (Neomorphus pucheranit) and three submitted records were rejected (Patagioenas oenops, Hydropsalis maculicaudus, Colaptes rupicola). This information updates our knowledge of the distribution and status of poorly known species in Ecuador, as well as the national bird checklist that currently reaches 1673 species (1608 confirmed with voucher documentation, 65 hypothetical).

Published
2014
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33. Erratum: Rare birds in Ecuador: first annual report of the Committee of Ecuadorian Records in Ornithology (CERO). Published in Avances en Ciencias e Ingenierías, 2013, Vol. 5, No. 2, Pags. B24-B41

Author

Juan F. Freile, Roger Ahlman, Dušan Milan Brinkhuizen, Paul J. Greenfield, Alejandro Solano-Ugalde, Lelis Navarrete, and Robert Sterling Ridgely

Subjects
Distribución, estatus, aves, Ecuador, Engineering (General). Civil engineering (General), TA1-2040, Science (General), Q1-390
Abstract

Pag. B24. Abstract, line 5: first voucher documentation for 10 species.Pag. B26. Figure 1 caption. Photo b) Ring-necked Duck Aythya collaris at Micacocha (D. M. Brinkhuizen); photo c) A. collaris at La Segua (R. Ahlman).Pag. B26. Cinnamon Teal Anas cyanoptera was reported on 1 June 2003, not 1 January 2003.Pag. B28. Figure 3 caption. h) Grey-hooded Gull, not Grey-headed Gull; i) Large-billed Tern Phaetusa simplex (R. Ahlman); j) Caspian Tern Hydroprogne caspia (R. Ahlman).Pag. B29. Figure 4 caption. e) and f) Great Crested Flycatcher Myiarchus crinitus; g) Swainson’s Flycatcher M. swainsoni. For photo f), the correct photograph is:Pag. B30. Table 1 corresponds to Table 2 as cited in text.Pag. B31. Table 2 corresponds to Table 1 as cited in text.Pag. B33. Wilson’s Snipe Gallinago delicata, line 3: (Figure 2i); line 13: (Figure 2h).Pag. B34. Pearly-breasted Cuckoo heading: 28 March 2008, not 38 March 2008.Pag. B36. White-bellied Pygmy-Tyrant, not Pygmytyrant.Pag. B36. Swainson’s Flycatcher Myiarchus swainsoni, line 2: (Figure 4g).Pag. B37. Great Crested Flycatcher Myiarchus crinitus, line 4: (Figures 4e, 4f).Pag. B39. Rejected records, line 2: (Table 2), not (Table 1).

Published
2014
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34. Rare birds in Ecuador: first annual report of the Committee of Ecuadorian Records in Ornithology (CERO)

Author

Juan F. Freile, Roger Ahlman, Dušan Milan Brinkhuizen, Paul J. Greenfield, Alejandro Solano-Ugalde, Lelis Navarrete, and Robert Sterling Ridgely

Subjects
Distribución, estatus, aves, Ecuador, Engineering (General). Civil engineering (General), TA1-2040, Science (General), Q1-390
Abstract

We summarise records of bird species submitted to the Committee of Ecuadorian Records in Ornithology (CERO) by the Ecuadorian and international ornithological community. CERO compiles the official country checklist and updates it annually. We present nine new country records (Anas acuta, Aythya collaris, Egretta rufescens, Coccycua pumila, Sublegatus modestus, Myiarchus panamensis, Vireo philadelphicus, Atlapetes albinucha, Icterus chrysater), four country records presented elsewhere and herein validated (Galbula cyanescens, Myiornis albiventris, Tumbezia salvini, Anthus cervinus), first voucher documentation for eight 10 species (Anas clypeata, Podiceps major, Sula leucogaster, Eudocimus ruber, Phimosus infuscatus, Gallinago delicata, Fluvicola pica, Machetornis rixosa, Progne subis, Progne elegans), additional records of two undocumented species in Ecuador (Calidris alpina, Leucippus taczanowskii), 34 significant range extensions or records of rare and poorly known species (Sarkidiornis melanotos, Anas bahamensis, A. cyanoptera, Netta erythrophthalma, Aythya affinis, Oceanites oceanicus, Oceanodroma hornbyi, Tigrisoma lineatum, Ardea herodias, Plegadis falcinellus, Limnodromus scolopaceus, Limosa fedoa, Chroicocephalus cirrocephalus, Phaetusa simplex, Hydroprogne caspia, Chlidonias niger, Coccyzus euleri, Heliodoxa gularis, Hylocharis humboldtii, Terenura spodioptila, Syndactyla rufosupercilliata, Contopus cooperi, Conopias trivirgatus, Myiarchus swainsoni cf. swainsoni, Myiarchus crinitus, Pyroderus scutatus, Vireo flavifrons, Catharus minimus, Sporophila lineola, Coryphospingus cucullatus, Chlorothraupis frenata, Passerina caerulea, Vermivora chrysoptera, Protonotaria citrea), and two new subspecies for the country (Eurypyga helias meridionalis and Petrochelidon pyrrhonota melanogaster). Three records are from the Galapagos Islands of Ecuador, while all others were obtained in the continental area of Ecuador. This information updates our knowledge of the distribution and status of poorly known species in Ecuador, as well as the national bird checklist that currently reaches 1657 species (1587 confirmed and documented, 70 hypothetical).

Published
2013
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